ABSTRACT OF DISSERTATION Pushpa Suresh Jayasekara ...

ABSTRACT OF DISSERTATION
Pushpa Suresh Jayasekara Mudiyanselage
The Graduate School
University of Kentucky
2010

PROGRESS TOWARDS THE SYNTHESIS OF TYPE B POLYCYCLIC
POLYPRENYLATED ACYLPHLOROGLUCINOL 7-epi-CLUSIANONE
________________________________
ABSTRACT OF DISSERTATION
________________________________
A dissertation submitted in partial fulfillment
of the requirements for the degree of
Doctor of Philosophy in the College of Arts and Sciences
at the University of Kentucky
By
Pushpa Suresh Jayasekara Mudiyanselage
Lexington, KY
Director: Dr. R.B. Grossman, Professor of Chemistry
Lexington, KY
2010
Copyright © Pushpa Suresh Jayasekara Mudiyanselage 2010

ABSTRACT OF DISSERTATION
PROGRESS TOWARDS THE SYNTHESIS OF TYPE B POLYCYCLIC
POLYPRENYLATED ACYLPHLOROGLUCINOL 7-epi-CLUSIANONE
Plants of the family Guttiferae produce polycyclic polyprenylated acylphloroglucinols
(PPAPs), which have interesting biological activities including anticancer and
antibacterial properties. The main structural features of PPAPs comprise of
bicyclo[3.3.1]nonane-2,4,9-triketone with one acyl group together with prenyl, geranyl,
or other C 10 H 17 groups. 7-epi-Clusianone, a type B PPAP with C-7 endo stereochemistry,
is being approached by establishing the cis relationship with C(4) allyl group and C(2)
methyl ester in the early stage of the synthesis. Then C(2) methyl ester is converted to
alkyne aldehyde and syn reduction followed by intramolecular aldol reaction to give
bicyclo[3.3.1]nonane structure with C(7) endo stereo chemistry.
Pushpa Suresh Jayasekara Mudiyanselage
February 5, 2010

PROGRESS TOWARDS THE SYNTHESIS OF TYPE B POLYCYCLIC
POLYPRENYLATED ACYLPHLOROGLUCINOL 7-epi-CLUSIANONE
By
Pushpa Suresh Jayasekara Mudiyanselage
Robert B. Grossman, Ph.D
Director of Dissertation
Mark S. Meier, Ph.D
Director of Graduate Studies
February 5, 2010

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DISSERTATION
Pushpa Suresh Jayasekara Mudiyanselage
The Graduate School
University of Kentucky
2010

PROGRESS TOWARDS THE SYNTHESIS OF TYPE B POLYCYCLIC
POLYPRENYLATED ACYLPHLOROGLUCINOL 7-epi-CLUSIANONE
___________________________
DISSERTATION
___________________________
A dissertation submitted in partial fulfillment
of the requirements for the degree of
Doctor of Philosophy in the College of Arts and Sciences
at the University of Kentucky
By
Pushpa Suresh Jayasekara Mudiyanselage
Lexington, KY
Director: Dr. R.B. Grossman, Professor of Chemistry
Lexington, KY
2010
Copyright © Pushpa Suresh Jayasekara Mudiyanselage 2010

To my dearest parents with all my love

ACKNOWLEDGMENTS
Pursuing a Ph.D has been the most painful and enjoyable experience so far in my
life. I accomplished this task with bitterness, frustration, self-confidence, facing hardships
while receiving encouragement and absolute true kindness from many people.
First and foremost, I must wholeheartedly thank my advisor, Professor Dr. Robert
B. Grossman, for accepting me as his Ph.D student without any hesitation. He showed me
the path towards my goal to become a research scientist with his vast knowledge and
dedication to science. I feel most thankful for his willingness to help and for listening to
my ideas on projects, regardless of their merit. Dr. Grossman has helped me
tremendously not only professionally but personally as well. He always understood my
situation and guided me with patience.
I also give my sincerest appreciation to the other members of my committee, Dr.
Mark Watson, Dr. Folami Ladipo and Dr. Joe Chappell. Many thanks for their support,
criticisms, and especially for their sense of humor. My special gratitude goes to Dr. Mark
Watson for his time, effort, and endless discussions that we had during my graduate
career. My graduate career became all the more endurable by having Dr. Watson in my
committee. I would like to thank to Dr. Chris Schardl for serving as my external
examiner. I want to thank Mr. John Layton for his enormous support for taking NMR
data, Dr. Sean Parkin for X-ray crystallography data and Mr. Art Sebesta for technical
support. In addition, my humble thanks go to Department of Chemistry for giving me the
opportunity to carry out my graduate studies at UK.
I am fortunate to have the opportunity to work with group of talented chemists in
Dr. Grossman‘s lab. I have enjoyed every moment that we have worked together in our
lab in CP 137. My sincere thanks goes to all the former and current lab mates including
Dr. Roxana Ciocina, Dr. Razi Husseni, Raghu Ram Chamala, Ronghua Lu, Sujit Pawar,
Nick and Avery for their friendships and their collective encouragements to finish this
dissertation.
iii

I would not have come this far without my parents, especially my mother. Since
childhood, she is the one who gave me the strength and motivated me every day. I love
both of you so much and thank you for all your endless love, kindness, for all the
sacrifices you have made and for giving me the good human qualities that both of you
have.
I want give gratitude from bottom of my heart to most important part of my life
my wife Shashi. We have lived several years in two states visiting only once a month and
during this hard time, she handled all the pressure very carefully while motivating me.
Thank you so much Shashi for all your support.
Finally, I want to thank my grandparents, my sister and Ushan, Shashi‘s parents
and her sister Ruvini for their enormous support, love and kindness. I am so grateful to
have a family, who understood and tolerated my absence for their needs during my
graduate career. I want to thank my aunties (Punchi and Nenda), Uncle (kalu mama), my
cousins Rohini akka, Rohitha aiya, Pali aiya, Gamini aiya and their families, Anushka
nagi and Kanishka for all their moral support and encouragements given over the years. I
owe them a lot. Finally yet importantly, I would like to thank my friends Indika, Malika
and their families, Sri Lankan community in Lexington including Dr. Bandula and Leela
Jayasekara
iv

TABLE OF CONTENTS
ACKNOWLEDGMENTS ................................................................................................. iii
LIST OF TABLES ............................................................................................................. vi
LIST OF FIGURES .......................................................................................................... vii
LIST OF SCHEMAS ....................................................................................................... viii
Chapter 1. Introduction to PPAPs................................................................................. 1
1.1 Introduction ............................................................................................................ 1
1.2 Introduction to PPAPs............................................................................................ 2
1.3 Phloroglucinols and monocyclic polyprenylated acylphloroglucinols (MPAPs)
….4
1.3.1. Biosynthesis of the hop α-acids and β-acids ...................................................... 5
1.4. Survey of polycyclic polyprenylated acylphloroglucinols (PPAPs) ...................... 6
1.5. History of PPAPs ................................................................................................... 7
1.5.1. Reassignment of certain PPAPs‘ relative stereochemistry ............................... 10
1.6. Biosynthesis of PPAPs ......................................................................................... 12
1.7. Biological activity of PPAPs ............................................................................... 15
1.7.1. Type A PPAPs .................................................................................................. 34
1.7.1.1. Hyperforin and its close analogues ................................................................ 34
1.7.1.2. Nemorosone ................................................................................................... 37
1.7.1.3. Garsubellin A ................................................................................................. 38
1.7.2. Type B PPAPs .................................................................................................. 58
1.7.2.1. Garcinol and its derivatives ........................................................................... 58
1.7.2.2. Clusianone and 7-epi-clusianone ................................................................... 58
1.7.2.3. Guttiferones A-E, Xanthochymol and their analogues .................................. 60
1.7.2.4. Lalibinones A-E and their analogues ............................................................. 62
1.7.3. Type C PPAPs .................................................................................................. 65
Chapter 2. Synthetic efforts toward PPAPs ...................................................................... 66
2.1. Introduction .......................................................................................................... 66
2.2. Shibasaki‘s approach to garsubellin A ................................................................. 66
2.3. Danishefsky‘s iodocyclization approach to PPAPs ............................................. 78
2.3.1. Iodonium induced carbocyclization approach to garsubellin A ....................... 78
2.3.1 Iodonium-induced carbocyclization approach to total synthesis of nemorosone
and clusianone ................................................................................................................... 83
2.4. Simpkins and Marazano & Delpech Effenberger cyclization (double acylation)
approach to total synthesis of clusianone.......................................................................... 88
iii

2.4.1 Progress towards the synthesis of nemorosone .................................................. 91
2.4.2. Formal synthesis of garsubellin A .................................................................... 95
2.5. Porco‘s total synthesis of clusianone ................................................................. 101
2.5.1. Retrosynthetic analysis of clusianone ............................................................. 102
2.6. Other approaches towards PPAPs ...................................................................... 105
2.6.1. Nicolaou‘s Se-mediated electrophilic cyclization approach ........................... 105
2.6.2. Nicolaou‘s Michael addition–aldol reaction approach ................................... 107
2.6.3. Kraus‘s Mn-mediated oxidative free radical cyclication approach ................ 108
2.6.3. Kraus‘s addition elimination-addition approach ............................................. 110
2.6.4. Mehta‘s Pd-mediated oxidative cyclization .................................................... 111
2.6.5. Mehta‘s intramolecular enol lactonization, retro-aldol and re-aldol cyclization
......................................................................................................................................... 112
2.6.6. Young‘s intramolecular allene-nitrile oxide [3 + 2] cycloaddtion ................. 113
2.6.7. Grossman‘s alkynylation–aldol approach ....................................................... 114
2.6.8. Nakada‘s Lewis acid promoted regioselective ring-opening reaction of the
cyclopropane approach ................................................................................................... 116
2.6.9. Takagi‘s acid catalyzed cyclization approach towards adamantane core of
plukenetione type PPAPs ................................................................................................ 117
Chapter 3. Our synthesis towards 7-epi-clusianone ...................................................... 119
3.1. Initial retrosynthetic analysis ............................................................................. 120
3.2 Forward synthesis ............................................................................................... 121
3.2.1 Synthesis of 2,4-diallyl-3-methyl-2-cyclohexenone ........................................ 121
3.2.2 Allylation, methylation and acidification ........................................................ 122
3.2.3 Alternate pathway towards 2,4-diallyl-3-methyl-2-cyclohexeone. ................. 122
3.2.3.1 Allylation ...................................................................................................... 122
3.2.3.2 Michael addition, cyclization and decarboxylation ...................................... 123
3.2.4 Conjugate addition, trapping enolate with TMS group followed by desilylation
......................................................................................................................................... 124
3.2.5. Carbonylation and allylation ........................................................................... 125
3.2.6. Reduction and oxidation ................................................................................. 126
3.2.7 Still–Gennari reaction, reduction and oxidation .............................................. 127
3.2.8 Aldol reaction .................................................................................................. 128
3.2.8.1 Aldol reaction under acidic conditions ......................................................... 128
3.2.8.2 Aldol reaction under basic conditions .......................................................... 130
3.3 The role of 1,2-allylic strain................................................................................ 131
3.4 Redesigning the synthesis ................................................................................... 133
3.4.1 New retrosynthetic analysis ............................................................................. 133
3.4.2 Forward synthesis ............................................................................................ 134
3.4.2.1 Isobutyl protection, allylation, methylation and acidification ...................... 134
3.4.2.2 Conjugate addition and carbonylation .......................................................... 135
3.4.2.3 Allylation and Claisen rearrangement .......................................................... 135
3.4.2.3.1 Structure and stereochemistry determination of 354a ............................... 138
iv

3.4.2.3.2 Proposed model for the stereochemical products for the Claisen
rearrangement ................................................................................................................. 138
3.4.2.4 Methyl enol ether protection, reduction and oxidation ................................. 139
3.4.2.5 Alkynylation ................................................................................................. 139
3.4.2.6 O-Allylation and carbonylation .................................................................... 140
3.4.2.7 Reduction, Claisen rearrangement and oxidation ......................................... 140
3.4.2.8 Syn reduction of alkynal and intramolecular aldol reaction ......................... 141
3.4.2.8.1 Complex with Co 2 (CO) 8 and hydrosilylation ............................................ 141
3.4.2.8.2 Hydrostannylation ...................................................................................... 143
3.4.2.8.3 Addition of thiophenol to keto alkynal 39 ................................................. 144
3.4.2.8.4 Structure and stereochemistry determination of 365 ................................. 145
3.4.2.8.5 Intramolecular aldol and oxidation reactions ............................................. 145
3.4.3 Attempts to form the 2,4,9-triketone system ................................................... 146
3.4.3.1. Curtius rearrangement approach .................................................................. 146
3.4.3.1.1. Synthetic plan 1 ........................................................................................ 146
3.4.3.1.2. 1,2-addition of Bu 3 SnCH 2 OMOM and allylic oxidation ......................... 147
3.4.3.1.3. 1,2-addition of MeLi and allylic oxidation ............................................... 148
3.4.3.1.4. Synthetic plan 2 ........................................................................................ 149
3.4.3.1.5. Me 2 CuLi addition to bicyclo enone 364 ................................................... 149
3.6. Experimental Section ......................................................................................... 151
Chapter 4. Conclusion ..................................................................................................... 178
Appendix ......................................................................................................................... 180
References ....................................................................................................................... 202
Vita .................................................................................................................................. 211
v

LIST OF TABLES
Table 1.1: Type A PPAPs ……………………………………………………………15
Table 1.2: Type B PPAPs ……………………………………………………………38
Table 1.3: Type C PPAPs ……………………………………………………………58
Table 3.1: Acid and solvent used for aldol reaction …………………………………..123
Table 3.2: Bases and solvent used for aldol reaction …………………………………..124
Table 3.3: Reagents and conditions of Me2CuLi addition …………………………..144
vi

LIST OF FIGURES
Figure 1.1: Xanthone, morellin, phloroglucinol, maclurin ................................................ 2
Figure 1.2: Hyperforin (1)................................................................................................... 3
Figure 1.3: Xanthochymol and cycloxanthochymol ......................................................... 3
Figure 1.4: Hops-derived α- and β-acids ........................................................................... 5
Figure 1.5: Type A, B and C PPAPs ................................................................................... 7
Figure 1.6: Rao‘s first proposed structure of xanthochymol (135) and corrected structure
of xanthochymol (96) .......................................................................................................... 9
Figure 1.7: Structure of clusianone ..................................................................................... 9
Figure 1.8: Garcinielliptones L and M .............................................................................. 10
Figure 1.9: Lavandulyl and ω- isolavandulyl groups ....................................................... 11
Figure 1.10 Products of oxidation of hyperforin .............................................................. 36
Figure 1.11 O-protected analogs of hyperforin................................................................. 37
Figure 1.12 Nemorosone derivatives ................................................................................ 38
Figure 1.13: Structure of clusianone, 7-epi-clusianone and propolone A ........................ 59
Figure 2.1: Chiral tetraamine 173 ..................................................................................... 75
Figure 3.1: Structure and stereochemistry determination of 322a using NOE ............... 126
Figure 3.2: Steriochemistry determination of 354a using NOE ..................................... 137
Figure 3.3: X-ray data structure of 364 .......................................................................... 143
Figure 3.4: Structure and stereochemistry determination of 365 .................................... 145
Figure 3.2: X-ray structure of 1,2-adduct 368 ................................................................ 151
vii

LIST OF SCHEMAS
Scheme 1.1 Proposed biosynthesis pathway of α-acids and β-acids .................................. 6
Scheme 1.2: Biosynthesis of MPAPs ............................................................................... 12
Scheme 1.3: Proposed biosynthesis mechanism for type A and B PPAPs ....................... 13
Scheme 1.4: Proposed biosynthesis mechanism for type C PPAP .................................. 14
Scheme 2.1: Shibasaki‘s retrosynthesis of 8-deprenyl-garsubellin A ............................. 67
Scheme 2.2: Shibasaki‘s approach to 8-deprenyl-garsubellin A, part 1 ........................... 68
Scheme 2.2a: Addition-elimination reaction on the carbonate 154 .................................. 69
Scheme 2.3: Shibasaki‘s approach to 8-deprenyl-garsubellin A, part 3 ........................... 70
Scheme 2.4: 1,2-allylic strain of the reactive conformation in 151b ................................ 71
Scheme 2.5: Shibasaki‘s retrosynthesis of garsubellin A ................................................. 72
Scheme 2.6: Shibasaki‘s forward synthesis of garsubellin A, part 1 ................................ 73
Scheme 2.7: Shibasaki‘s forward synthesis of garsubellin A, part 2 ................................ 74
Scheme 2.8: Ring-closing metathesis on 174 ................................................................... 75
Scheme 2.9: Shibasaki‘s intramolecular aldol approach towards garsubellin A .............. 76
Scheme 2.10: Shibasaki‘s intramolecular aldol approach towards garsubellin A, part 1 . 77
Scheme 2.11: Danishefsky‘s retrosynthetic analysis of garsubellin A ............................. 78
Scheme 2.12: Danishefsky‘s synthesis towards garsubellin A, part 1 .............................. 79
Scheme 2.13: Danishefsky‘s synthesis towards garsubellin A, part 2 .............................. 80
Scheme 2.13a: TMSI assisted strained cyclopropane ring opening ................................. 81
Scheme 2.14: Danishefsky‘s synthesis towards garsubellin A, part 3 .............................. 82
Scheme 2.15: Danishefsky‘s retrosynthetic analysis of nemorosone and clusianone ..... 83
Scheme 2.16: Danishefsky‘s synthesis towards nemorosone and clusianone, part 1 ....... 84
Scheme 2.17: Danishefsky‘s synthesis towards nemorosone and clusianone, part 2 ....... 85
Scheme 2.18: Danishefsky‘s synthesis towards nemorosone and clusianone, part 3 ....... 86
Scheme 2.19: Danishefsky‘s synthesis towards nemorosone and clusianone, part 4 ....... 87
Scheme 2.20: Stoltz‘s Effenberger cyclization approach ................................................. 88
Scheme 2.21: Simpkins‘ retrosynthetic analysis of clusianone ........................................ 89
Scheme 2.22: Simpkins‘ synthesis towards clusianone, part 1 ......................................... 89
viii

Scheme 2.23: Simpkins‘ synthesis towards clusianone, part 2 ......................................... 90
Scheme 2.24: Simpkins‘ synthesis towards clusianone, part 3 ......................................... 91
Scheme 2.25: Simpkins‘ synthesis towards nemorosone, part 1 ...................................... 92
Scheme 2.27: Simpkins‘ synthesis towards nemorosone, part 2 ...................................... 94
Scheme 2.28: Simpkins‘ formal synthesis of garsubellin A, part 1 .................................. 95
Scheme 2.29: Simpkins‘ formal synthesis of garsubellin A, part 2 .................................. 96
Scheme 2.30: Marazano‘s retrosynthetic analysis of clusianone ...................................... 97
Scheme 2.31: Marazano‘s synthesis of clusianone, part 1 ................................................ 97
Scheme 2.32. Marazano‘s synthesis of clusianone, part 2 ................................................ 98
Scheme 2.33: Marazano‘s synthesis of clusianone, part 3 ................................................ 98
Scheme 2.34: Marazano‘s synthesis of clusianone, part 4 ................................................ 99
Scheme 2.35: Proposed mechanism for the formation of 250 ........................................ 100
Scheme 2.36: Marazano‘s synthesis of clusianone, part 5 .............................................. 101
Scheme 2.37: Porco‘s retrosynthetic analysis of clusianone .......................................... 102
Scheme 2.38: Porco‘s synthesis of clusianone, part 1 .................................................... 103
Scheme 2.39: Porco‘s synthesis of clusianone, part 2 .................................................... 104
Scheme 2.40: Nicolaou‘s model compound of garsubellin A ........................................ 105
Scheme 2.41: Nicolaou‘s Se-mediated electrophilic cyclization approach, part 1 ......... 106
Scheme 2.42: Nicolaou‘s Se-mediated electrophilic cyclization approach, part 2 ......... 106
Scheme 2.43: Hyperforin and perforatumone ................................................................ 107
Scheme 2.44: Nicolaou‘s Michael addition-aldol reaction approach ............................. 108
Scheme 2.45: Kraus‘s Mn-mediated oxidative free radical cyclication approach .......... 109
Scheme 2.46: Proposed mechanism for the Mn mediated cyclization ........................... 109
Scheme 2.47: Kraus‘s addition elimination-addition approach, part 1 ........................... 110
Scheme 2.48: Kraus‘s addition elimination-addition approach, part 2 ........................... 111
Scheme 2.49: Mehta‘s Pd-mediated oxidative cyclization ............................................. 112
Scheme 2.50: Mehta‘s intramolecular enol lactonization ............................................... 113
Scheme 2.51: Young‘s intramolecular allene-nitrile oxide [3 + 2] cycloaddtion ........... 114
Scheme 2.52: Grossman‘s alkynylation–aldol approach ................................................ 115
Scheme 2.53: Nakada‘s Lewis acid promoted regioselective ring-opening ................... 116
Scheme 2.54: Takagi‘s acid catalyzed cyclization approach towards adamantane core 117
Scheme 3.1: Our initial retrosynthetic analysis .............................................................. 120
ix

Scheme 3.2: Synthesis of 2,4-diallyl-3-methyl-2-cyclohexenone .................................. 121
Scheme 3.3: Allylation, methylation and acidification ................................................... 122
Scheme 3.4: Alternate pathway towards 2,4-diallyl-3-methyl-2-cyclohexeone ............. 122
Scheme 3.5: Michael addition, cyclization and decarboxylation ................................... 123
Scheme 3.6: Methylation of cyclohexenone intermediate 336 using MeLi/CeCl 3 ......... 124
Scheme 3.7: Conjugate addition, trapping enole with TMS group followed by
desilylation ...................................................................................................................... 124
Scheme 3.8: Carbonylation and allylation ...................................................................... 125
Scheme 3.9: Reduction and oxidation of 322a ............................................................... 126
Scheme 3.10: Still–Gennari reaction, reduction and oxidation ...................................... 127
Scheme 3.11: Aldol reaction ........................................................................................... 128
Scheme 3.12: Aldol reaction under acidic conditions .................................................... 128
Scheme 3.13: Proposed mechanism for cis-trans isomerization ..................................... 129
Scheme 3.14: Aldol reaction under basic conditions ...................................................... 130
Scheme 3.15: The role of 1,2-allylic strain ..................................................................... 131
Scheme 3.16: 1,2-allylic strain of 321 ............................................................................ 132
Scheme 3.17: Second retrosynthetic analysis ................................................................. 133
Scheme 3.18: Isobutyl protection, allylation, methylation and acidification ................. 134
Scheme 3.19: Conjugate addition and carbonylation ..................................................... 135
Scheme 3.20: Failed Pd-catalyzed allylation reaction .................................................... 135
Scheme 3.21: O-allylation .............................................................................................. 136
Scheme 3.22: Claisen rearrangement .............................................................................. 136
Scheme 3.23: Proposed model for the stereochemical products for the Claisen
rearrangement ................................................................................................................. 138
Scheme 3.24: Methyl enol ether protection, reduction and oxidation ............................ 139
Scheme 3.25: Alkynylation ............................................................................................. 139
Scheme 3.26: O-Allylation and carbonylation ................................................................ 140
Scheme 3.27: Reduction, Claisen rearrangement and oxidation .................................... 140
Scheme 3.28: Complex with Co 2 (CO) 8 and hydrosilylation .......................................... 141
Scheme 3.29: Intramolecular aldol product .................................................................... 142
Scheme 3.30: Hydrogenation .......................................................................................... 144
Scheme 3.31: Addition of thiophenol to keto alkynal 39 ............................................... 144
x

Scheme 3.32: Intramolecular aldol and oxidation reactions ........................................... 145
Scheme 3.33: Attempts to form the 2,4,9-triketone system ............................................ 146
Scheme 3.34: Curtius rearrangement approach, plan 1 .................................................. 147
Scheme 3.35: 1,2-addition of Bu 3 SnCH 2 OMOM and allylic oxidation ........................ 147
Scheme 3.37: 1,2 addition of MeLi and allylic oxidation............................................... 148
Scheme 3.38: Curtius rearrangement approach, plan 2 .................................................. 149
Scheme 3.39: Me 2 CuLi addition to bicyclo enone 364 .................................................. 149
xi

Chapter 1.
Introduction to PPAPs
1.1 Introduction
Natural products, especially those derived from plants, have been used for
medicinal purposes since ancient times. Clay tablets of the Babylonian, Assyrian, and
Sumerian eras dated 2600 - 4000 BC are thought to be the earliest recordings of plant
usage as herbal remedies. 1 Egyptians also had many paintings of medicinal plants on
their tomb walls dated around 2200 – 2700 BC. 1 The Ebers papyrus, which dates from
around 1550 BC, is the most famous medical document of ancient Egypt. 1 It was
discovered by professor George Ebers in a tomb at Thebes in 1872 and contains more
than 800 medicinal recipes using medicinal plants. 1 Traditional Chinese medicine,
thought to be more than 5000 years old, is based on natural laws that govern good health
and longevity, namely yin and yang, and their medicinal practice is comprised mainly of
the use of medicinal plants. 1 Ancient medicine practiced in India, Ayurveda, meaning ―
the science of life‖, is also based on using medicinal plants. 1 Concoctions of different
parts of medicinal plants were made depending on the bodily humors. 1
This centuries-old usage of natural products certainly continues into the
present, as half of prescription drugs in the market today contain plant-derived
ingredients. The use of natural products as a source of drugs in the modern
pharmaceutical era began with the use of foxglove extract. 2 William Withering used
foxglove extract to treat heart patients, and he published this application in 1785. Digoxin
was discovered due to this treatment; GlaxoSmithKline markets this drug as Lanoxin, and
it is used to treat arrhythmia and congestive heart failure. 3 In 1806, Freidrich Serturner
extracted morphine from poppies, which led to the usage of controlled morphine doses
for pain and also led to a greater understanding of morphine receptors and the pathways
that are associated with them. 3 Arthur Eichengrün and Felix Hoffmann at Bayer
Company created aspirin in 1897. 2,3 Aspirin was the first synthetic drug synthesized from
a natural product, salicylic acid, extracted from the willow bark. 3,4 Then in 1928
1

Alexander Fleming discovered Penicillin from penicillium mold, and this discovery
changed modern medicine and the treatment and understanding of infectious disease. 3,4
1.2 Introduction to PPAPs
Another plant used for medicinal purposes is St. John‘s wort (Hypericum
perforatum), which is a yellow flowering plant that has been used since ancient times for
treatment of depression and anxiety. 5 Hypericum perforatum belongs to the plant family
Guttiferae, and the widespread interest in its antidepressant activity has increased
investigation of metabolites from this family. 6 Many of these metabolites are biologically
active compounds which contain an acylphloroglucinol moiety. 6 Guttiferae consists
mainly of tropical plants of 40 genera and about 1200 species, most of which are woody. 7
The Guttiferae family produces numerous xanthones, 8 including complex xanthones such
as morellin, 9,10 3,8-linked biflavonoids such as morellflavone (fukugetin), 11 lactones,
phenolic acids, benzophenones (phloroglucinols) and polyprenylated benzophenones
(Figure 1.1). 7,12 The word ―xanthone‖ is derived from Greek and means yellow and
designates the chemical compound dibenzo-[g]-pyrone. 8 Biogenetically, all of the
―isoprenylated benzophenone" derivatives may be derived from acylphloroglucinols such
as maclurin, which is regarded as a precursor for many xanthones in higher plants (Figure
1.1). 13,14
C H O
O
O
O
O
O H
O H
O
O H
O
O H
O
H O
O H
H O
O H
O H
x a n t h o n e
m o r e l l i n
p h l o r o g l u c i n o l s
m a c l u r i n
Figure 1.1: Xanthone, morellin, phloroglucinol, maclurin
2

Common to plants belonging to the family Guttiferae is their property of wound healing,
which has been connected to the established antimicrobial activities of the
phloroglucinols. 6
In 1971, Gurevich and coworkers isolated hyperforin (1) from Hypericum
perforatum L. (St. John‘s wort), and it showed antimicrobial activity against grampositive
bacteria. 15 In 1975, Bystrov and coworkers determined the structure of
hyperforin, which belongs to the class of polycyclic polyprenylated acylphloroglucinols,
not the xanthone structure described above (Figure 1.2). 16
H O
O
O
O
O
O
O H
O
i - P r
i - P r
1
Figure 1.2: Hyperforin (1)
In 1973, Rama Rao and coworkers isolated two interesting isoprenylated benzophenones,
xanthochymol (96) and cycloxanthochymol (107), from C. xanthochymus (Figure1.3). 17
The bioactivity of these molecules was not recorded at that time. 17
O H
O H
H O
O
O
O
O H
O
O
O
O
O H
9 6 1 0 7
Figure 1.3: Xanthochymol and cycloxanthochymol
3

1.3 Phloroglucinols and monocyclic polyprenylated acylphloroglucinols (MPAPs)
Phloroglucinols are 1,3,5-benzenetriols, and MPAPs are derivatives of
these phloroglucinols which contain an acyl group and two or three 3-methyl-2-butenyl
(prenyl) side chains as substituents in the aromatic nucleus. 18 MPAPs are reported to
show antimicrobial, antifungal and antifeedant activity. 19,20 For example, Humulus
lupulus (Cannabinaceae), commonly known as hops, is used in folk medicine as an
antibacterial agent (in the form of wound powders and salves), a tranquilizer (sleep
inducer), a diuretic, and to alleviate the symptoms of menopause. 21 The cones of the hop
plant, Humulus lupulus L. (Cannabaceae), are also an important raw material for the beer
brewing industry. After brewing, the essential oil and the bitter acids from the cones
contribute to the specific aroma and taste of the final product, beer. 21 These compounds
are monocyclic prenylated derivatives of phloroglucinols (MPAPs) and consist of -
acids, mainly humulone, cohumulone and adhumulone, and -acids, mainly lupulone,
colupulone and adlupulone (Figure 1.4). 22 The α-acids are converted during the brewing
process into iso-α-acids, compounds responsible for the flavor and the bitter taste of
beer. 23 However, the β-acids do not add any taste during the brewing process. 6 Although
β-acids are not important to the brewing industry, they show radical scavenging activity,
inhibition of lipid peroxidation, and antimicrobial activity. 6
4

O H
O
O H
O
R
R
H O
H O
O
H O
O
α-acids
β-acids
R α-acids β-acids
i-Pr cohumulone colupulone
i-Bu humulone lupulone
s-Bu adhumulone adlupulone
Figure 1.4: Hops-derived α- and β-acids
1.3.1. Biosynthesis of the hop α-acids and β-acids
Three types of reactions take place in this biosynthesis: the formation of
aromatic intermediates, the introduction of several prenyl side chains into the aromatic
ring, and the oxidation of a carbon atom from the phenolic nucleus (applies to -acids)
(Scheme 1.1). 21 The first reaction is similar to the initial step in the biosynthesis of
flavonoids; the successive condensations of three molecules of malonyl-CoA to
isobutyryl-CoA or isovaleryl-CoA lead to the formation of phloroglucinol
intermediates. 21 It‘s believed that PPAPs are biosynthetically made through these
acylphloroglucinol (MPAPs) intermediates. 6
5

R 1
O
S C o A
O H O
O O
O O
3 H O S C o A
R 1
S C o A
O
O
O H O
R 1
R 2
R 1
H O
O H
H O
O
R 2 R 2
R 1 = P h , i - P r
R 2 = p r e n y l o r g e r a n y l
Scheme 1.1 Proposed biosynthesis pathway of α-acids and β-acids
1.4. Survey of polycyclic polyprenylated acylphloroglucinols (PPAPs)
Polycyclic polyprenylated acylphloroglucinols (PPAPs) consists of a
bicyclo[3.3.1]nonane-2,4,9-trione skeleton with one acyl group and several prenyl and
geranyl groups. 6 These PPAPs can further cyclize to give adamantanes,
homoadamantanes, or dihydrofurano- or pyrano- fused structures. 6 Some of these
products have been shown to possess antioxidative, antiviral and antibiotic properties. 6
The PPAPs can be divided into three classes: type A, B and C. Type A PPAPs
have a C(1) acyl group and an adjacent C(8) quaternary center; type B PPAPs have a
C(3) acyl group, and type C PPAPs have a C(1) acyl group and a distant C(6) quaternary
center (Figure 1.5). 24
6

H O
R 1
R 1
O R 3
O H O O
O O
O
R 3 R 1 R 1
R 1 R 2
R 1 R 2
H O O
O O
R 1
R 3 t y p e A t y p e B
R 1
R 1
t y p e C
o r
O R 3
H O O
O
R 1 R 4
R 5
R 1 = M e , C 5 H 9 o r C 1 0 H 1 7
R 2 = H o r p r e n y l
R 3 = i - P r , i - B u , s - B u , P h
3 - ( O H ) C 6 H 4 , o r 3 , 4 - ( O H ) C 6 H 3
R 4 = M e , R 5 = O H o r R 4 - R 5 = C H 2 C H R 6
R 6 = H , C M e = C H 2 , o r C M e 2 O H
Figure 1.5: Type A, B and C PPAPs
Lists of type A, B, and C PPAPs reported and isolated to date is presented in Tables 1-3,
respectively. All the presented PPAPs have been isolated from the Guttiferae plant
family. The majority of these compounds are type A and B; garcinelliptones K (144), L
(146) and M (145) are reported to have type C structures. 25
1.5. History of PPAPs
In 1937, the indian scientist Sanjive Rao isolated a yellow crystalline
levorotatory phenol from Garcinia morella and named it morellin. 9 Rao determined the
composition of morellin to be C 30 H 34 O 6 and found that it contained four hydroxyl groups.
However, due to insufficient data, Rao et. al could not assign any structure to morellin. 9
In 1962 Kartha et al found morellin to be one of the few natural products containing a
bicyclo[2.2.2]octane ring system, making morellin a phloroglucinol. 10 By 1961 there
7

were 18 naturally occurring xanthones found from various families including guttiferae
and most of them were phloroglucinols. 8
Hyperforin was the first isolated PPAP 15 , and it is now classified as type
A. 26 In 1975 Bystrov and coworkers were able to detemine hyperforin‘s structure and its
absolute stereochemistry. 16
The first two type B PPAPs were isolated in 1973 by Rama Rao and
coworkers from fruits of G.xanthochymus, and they were named xanthochymol and
isoxanthochymol. The structure given at the time for xanthochymol was monocyclic. 17
Due to the low resolution of NMR and many overlapping peaks, this structure was
incorrectly assigned. 17 In addition, the chemical shifts were very different from the
literature values today. In 1974 David L. Dreyer isolated a compound from fruits of the
autograph tree (Clusia rosea) and named it as xanthochymol. 27 He used the following
findings as evidence to compare with Rao‘s xanthochymol structure: (a) three aromatic
protons, (b) three vinyl protons, (c) a C=CH, group, and (d) an uncertain number of vinyl
C-methyls. 27
In 1976 John F. Blount and Thomas H. Williams revised the structure of
xanthochymol and corrected the structure using NMR and X-ray crystallography. 28 In
there methodology, they used CDCl 3 as a solvent and TMS for the reference peak. Blount
et al clearly assigned the proton peaks and found that xanthochymol has gem-dimethyl
groups in the bicyclo[3.3.1]nonane (main skeleton) where previously they were assigned
in the bicyclo[3.3.0]octane ring (Figure 1.6). Overall, they were able to detemine the
correct structure with absolute configuration. 28
8

O H
O H
O
O
O
O H
H O
O
O
O
O H
O
147 96
Figure 1.6: Rao’s first proposed structure of xanthochymol (135) and corrected
structure of xanthochymol (96)
The type B PPAP clusianone (112) was first isolated from the bark extraction of
Clusia congestiflora, and the structure was determined using X-ray crystallography in
1976 (Figure 1.7). 29
O
H O
O
O
1 1 2
Figure 1.7: Structure of clusianone
Nemorosone (5) and hydroxynemorosone (6) were first isolated by de Oliveira
who assigned them to be type C PPAP. 30 In 2001, Cuesta-Rubio isolated nemorosone
from floral resins of Clusia rosea and showed that nemorosone in fact had the type A
9

structure, where the positions of the bridgehead substituents were swapped from their
originally assigned positions. 26
The first type C PPAP was reported by the Lin group in 2004, and they have
isolated garcinielliptones M (145) and L (146) from the seeds of Garcinia subelliptica
(Figure 1.8). 25
H O
O
O
O
O
H O
O
O
O
O
i - P r
i - P r
1 4 6 1 4 5
Figure 1.8: Garcinielliptones L and M
1.5.1. Reassignment of certain PPAPs’ relative stereochemistry
To assign the correct structure of PPAPs, it is very important to know the
correct stereochemistry. Due to their complex structure and overlapping NMR chemical
shifts, this is a difficult task. In fact, the structure of garcinielliptone I (40) has been
assigned the same structure as hyperibone B (33) in previous literature. Later, NMR
spectral data and optical rotation data showed that garcinielliptone I (40) is the other
enantiomer of hyperibone A (39). 31,32
In 2000, Grossman and Jacobs explained that the orientation of the C(7)
substituent in the PPAPs (endo or exo) can be easily determined from the 1 H and 13 C
NMR spectral data. 33 The stereochemistry at C(7) was identified by examining the
chemical shift difference of the two H(6) or H(8) atoms and the chemical shift of C(7). 33
The C(7) stereochemistry is endo when the difference in the chemical shifts of the two
H(6) atoms is 0.3-1.2 ppm and the chemical shift of C(7) is 41-44 ppm, and it is exo
when the difference in the chemical shifts of the two H(8) atoms is 0.0-0.2 ppm and the
10

chemical shift of C(7) is 45-49 ppm. 33 In 2002, Matsuhisa et al reported isolation of new
type A PPAPs with exo C(7) substituents, hyperibones A (39), B (33), C (41), D (17), E
(20), F (21), G (15), H (109), and I (110) form aerial parts of Hypericum scabrum. 31 But
using the above data, Grossman and Ciochina proposed that hyperibones C (41), E (20),
F (21), H (109), and I (110) have an endo C(7) substituent, contrary to the originally
proposed exo orientation. 24 Also, they noticed, using NMR and optical rotation data, that
garcinielliptone I (40) is in fact enantiomeric to hyperibone A (39) and not identical to
hyperibone B (33), as originally proposed. 31,34
So far only the absolute configurations of hyperforin (1), 24 xanthochymol (96), 14
and isoxanthochymol (106) 14 have been determined experimentally. Some PPAPs
(hyperibone G (15) and propolone D (16) 31 , 35 hyperibone A (39) and garcinielliptone I
(40), 31,34-36 guttiferone E (91) and garcinol (92), 12,37-41 isoxanthochymol (106) and
isogarcinol (105) 12,39,40,42-44 ) have been isolated in both enantiomeric forms. When we
draw the structures of PPAPs, we choose to draw the C(9) ketone pointing toward the
reader, although it may not be the absolute configuration of any particular structure. We
include each PPAP‘s specific rotation in the tables because the specific rotation of a
compound can reveal its absolute configuration.
In the Tables, the lavandulyl and -isolavandulyl groups are defined as below.
(R)- lavandulyl
ω- isolavandulyl
Figure 1.9: Lavandulyl and ω- isolavandulyl groups
11

1.6. Biosynthesis of PPAPs
It is believed that PPAPs are biosynthetically derived from MPAPs. 6,13,14 The -
acid is an example of MPAP, and labeling experiments of these bitter acids has provided
evidence of their biosynthesis pathway. 45 The acylphloroglucinol moiety is
biosynthetically made via a polyketide pathway with association of one acyl-CoA group
and three malonyl-CoA groups (Scheme 2). 46,47 Enzyme-assisted combination of an acyl-
CoA group and three malonyl-CoA groups give the tetraketide product intermediate, and
it is cyclized via Claisen condensation into an acylphloroglucinol. 48-50 Further
electrophilic substituted reactions on acylphloroglucinol moiety and dimethylallyl
diphosphate (DMAPP) or geranyl diphosphate (GPP) result in prenylated or geranylated
product of acylphloroglucinol (Figure 1.21). 50
R 1
O
S C o A
O H O
O O
O O
3 H O S C o A
R 1
S C o A
O
O
O H O
R 1
R 2
R 1
H O
O H
H O
O
R 2 R 2
R 1 = P h , i - P r
R 2 = p r e n y l o r g e r a n y l
Scheme 1.2: Biosynthesis of MPAPs
Cuesta-Rubio proposed a mechanism for the cyclization of MPAPs to type A and
type B PPAPs via a common intermediate (Figure 1.22). 26 One prenyl group of the
geminal prenyl groups of the MPAP attacks prenyl pyrophosphate to result in a stable
tertiary carbocationic intermediate. Attack of the C(1) enol moiety on the carbocation
12

would give a type A PPAP, and the attack of the C(5) enol would result in a type B
PPAP. The stereochemistry of the C(7) prenyl group of PPAPs is established during the
initial stage when prenyl pyrophosphate attacks the MPAP. A single diastereomer of the
carbocationic intermediate leads to a type A PPAP with a C(7) exo prenyl group or to a
type B PPAP with a C(7) endo prenyl group. A majority of type A PPAPs have C(7) exo
prenyl groups, whereas most type B PPAPs have C(7) endo prenyl groups. 24 Adam and
coworkers proposed a similar mechanism for the biosynthesis of hyperforin. 46 Type C
PPAPs may be made biosynthetically from MPAPs having a quaternary center attached
to the acyl group instead of a prenyl group. This will lead to a tertiary carbocationic
intermediate with reaction of prenyl or geranyl pyrophosphate. Then, the attack of C(1)
from the carbocationic intermediate would result in a type C PPAP (Figure 1.23).
O H
O
O H
O
H O
R
O
5
H O
1 R
O
O P P
C ( 1 ) a t t a c k
C ( 5 ) a t t a c k
O
O
R
O H
O R
H O
O
O
O
t y p e A
e x o 7 - p r e n y l
t y p e B
e n d o 7 - p r e n y l
Scheme 1.3: Proposed biosynthesis mechanism for type A and B PPAPs
13

O H
O H
O
5 1
H O
O
H O
O
H O
O
R O
R O R O
O P P
t y p e C
Scheme 1.4: Proposed biosynthesis mechanism for type C PPAP
14

Table 1.1: Type A PPAPs
The following table of type A PPAPs was taken from a review article written by Dr.
Ciochina and Prof. Grossman. 24 Seven newly isolated natural products were added to the
table: prolifenone A (11), prolifenone B (12), sundaicumone A (25), sundaicumone B
(26), sampsonione N (36), sampsonione O (37) and sampsonione Q (73).
No. R groups Name Source a [α] D
b
H O
R 3
R 4
O
O
O
R 1
R 2
1
R 1 = isopropyl;
R 2 , R 3 , R 4 = prenyl
Hyperforin c,15,16,51 H. perforatum +41 (e, 5)
2
R 1 = s-Butyl;
R 2 , R 3 , R 4 = prenyl
Adhyperforin 52,d H. perforatum NR
3
R 1 = isopropyl;
R 2 , R 3 = prenyl; R 4 = H
Hyperevolutin A 53
H. revolutum Vahl
+84.4
(m,0.5)
4
R 1 = s-Butyl;
R 2 , R 3 = prenyl; R 4 = H
Hyperevolutin A d,53 H. revolutum Vahl NR
5
R 1 = Ph; R 2 = H;
R 3 , R 4 = prenyl
Cuban propolis, C.
rosea, C.
Nemorosone 7,26,30,54 grandiflora, C.
insignis, C.
+113 (0.1);
OMe: +150
(m, 0.8)
and +49
nemorososa
(1.4)
15

Table 1.1 (continued).
6
R 1 = 3-hydroxyphenyl;
R 2 = H;
R 3 , R 4 = prenyl
Hydroxynemorosone
7,d
C. nemorososa
OMe: +143
(m, 0.7)
7
R 1 = Ph; R 2 = H;
R 3 = lavandulyl;
R 4 = prenyl
Chamone I e,54 C. grandiflora NR
8
R 1 = isopropyl; R 2 = H;
R 3 = CH 2 CH 2 CMe 2 OH;
R 4 = prenyl
Garcinielliptone A 34 G. subelliptica –33 (0.6)
9
R 1 = sec-butyl;
R 2 = CH 2 CH 2 CMe 2 OH
Garcinielliptone D 34 G. subelliptica –22 (0.1)
10
R 1 = s-butyl; R 2 = H;
R 3 = prenyl;
R 4 = (E)-CH=CHCMe 2 OH
Garcinielliptone F 34 G. subelliptica –23 (0.09)
16

Table 1.1 (continued).
11
R 1 = 2-butyl; R 2 = geranyl;
R 3 = H; R 4 = prenyl
Prolifenone A 55 H. prolificum L.
+0.87
(0.57)
12
R 1 = isopropyl;
R 2 = geranyl; R 3 = H;
R 4 = prenyl
Prolifenone B 55 H. prolificum L.
+13.3
(0.57)
H O
R 2
O
O
O
R 1
X
OAc:
13
R 1 = Ph; X= H
R 2 = prenyl
Plukenetione D/E f,56
C. plukenetii
+34.5
(0.03) and
–37.6 (0.1)
14
R 1 = Ph; X = OAc
R 2 = prenyl
Insignone g,56
C. inignis
OMe:
+92.7 (1.6)
17

Table 1.1 (continued).
H O
O
R 3
O
O
O
R 1
R 2
15
R 1 = Ph;
R 2 , R 3 = prenyl
Hyperibone G 31 H. scabrum –29.3 (0.9)
16
R 1 = Ph;
R 2 , R 3 = prenyl
(enantiomer)
Propolone D 35 Cuban propolis +48.5 (0.7)
17
R 1 = Ph; R 2 = prenyl;
R 3 =
CH 2 CH(OH)CMe=CH 2
Hyperibone D e,31 H. scabrum –61.9 (0.7)
18
R 1 = isopropyl;
R 2 , R 3 = prenyl
Garsubellin A 32,57 G. subelliptica –21 (e, 1.1)
19
R 1 = sec-butyl;
R 2 , R 3 = prenyl
Garsubellin B e,57 G. subelliptica –36 (e, 0.6)
18

Table 1.1 (continued).
H O
O
R 1
O
O
O
R 2
P h
R 3
20
R 1 =
CH 2 CH(OH)CMe=CH 2 ;
R 2 = H;
R 3 = (E)-CH=CHCMe 2 OH
Hyperibone E e,f,31 H. scabrum –56.0 (0.2)
21
R 1 = prenyl; R 2 = H;
R 3 = (E)-CH=CHCMe 2 OH
Hyperibone F f,31 H. scabrum –31.0 (0.2)
22 R 1 , R 2 , R 3 = prenyl Sampsonione K e,58 H. sampsonii –5.6 (1.1)
23
R 1 , R 3 = prenyl;
R 2 = H
Sampsonione L 58 H. sampsonii +55 (0.06)
O H
H O O O
O
24 O
24 G. subelliptica –40 (0.2)
i - P r
19

Table 1.1 (continued).
H O
O
O
C O 2 H
O
O
25 25 C. sundaicum +52 (0.2)
H O
O H
C O 2 H
H O O
O
O
O
26 26 C. sundaicum +48 (0.1)
X
O
O
O
O
i - P r
27 X = OH Furohyperforin 60 H. perforatum
28 X = OOH
33-Deoxy-33-
hydroperoxyfurohyperforin
H. perforatum +75 (1.2)
61
20

Table 1.1 (continued).
29 No name 62 C. obdeltifolia +30.9 (0.3)
O H
O O
O O
30 Propolone C 35 Cuban propolis +35.7 (0.2)
P h
H O
O
O
R 2
O
O
R 1
31
R 1 = isopropyl;
R 2 = prenyl
Garsubellin D 57 G. subelliptica –12 (e, 0.4)
32 R 1 = s-butyl; R 2 = prenyl Garsubellin E 57 G. subelliptica –7 (e, 0.4)
33 R 1 = Ph; R 2 = prenyl Hyperibone B 31,35 H. scabrum
–20.8
(0.5);
–42.2 (0.1)
34
R 1 = 3,4-dihydroxyphenyl;
R 2 = (R)-lavandulyl
Garcinielliptone FB 63 G. subelliptica –66 (0.2)
21

Table 1.1 (continued).
H O
O O
O
35 O Sampsonione M 58 H. sampsonii +55 (0.04)
P h
22

Table 1.1 (continued).
H O
O O
O O
36 Sampsonione N 64 H. sampsonii
P h
+22.0
(0.09)
O H
O O
O
37 O Sampsonione O 64 H. sampsonii
P h
+87.9
(0.073)
H O
O
O
O
O
R
38 R = isopropyl Garsubellin C 32,57 G. subelliptica +39 (e,0.4)
39 R = Ph Hyperibone A 31,35 H. scabrum
+57 (0.2);
+63.7 (0.4)
40 R = Ph (enantiomer) Garcinielliptone I g,34 G. subelliptica -37.7(1.1)
23

Table 1.1 (continued).
41
O
O
O
O
O
P h
Hyperibone C 31 H. scabrum -27.3 (0.3)
O H
O O
O O
42 Chamone II e,54 C. grandiflora NR
P h
O H
O O
O O
43 Propolone B e,35 Cuban propolis +38.2 (0.6)
P h
H O O H
O O H
44
O
O
O
O
P h
15,16-Dihydro-16-
hydroperoxyplukenetione
F 65
C. havetiodes var.
stenocarpa
+24.7 (0.3)
24

Table 1.1 (continued).
O O
O O
R 3 R 1
R 2
45
R 1 = i-Pr; R 2 = H;
R 3 = CH 3
Papuaforin B 66 H. papuanum NR
46
R 1 = Ph; R 2 = H;
R 3 = prenyl
Scrobiculatone B 67 C. scrobiculata +44.7 (0.2)
47
R 1 = Ph; R 2 = H;
R 3 = prenyl
Plukenetione F h,56
C. plukenetii
-53.6
(0.03)
48 R 1 = Ph; R 2 , R 3 = prenyl
Hypersampsone F f,68
H. sampsonii +30 (0.2)
O
R 3
O
O
O
R 2
R 1
49
R 1 = Ph; R 2 = H;
R 3 = prenyl
Plukenetione G h56 C. plukenetii NR
25

Table 1.1 (continued).
O
R 2
O
O
O
R 1
R 3
50 R 1 = i-Pr; R 2 , R 3 = prenyl
Pyrano[7,28-b]-
hyperforin 69 H. perforatum +83.5 (0.3)
26

Table 1.1 (continued).
51
R 1 = Ph; R 2 = H;
R 3 = prenyl
Scrobiculatone A 66,67
C. scrobiculata
+44.6
(0.2)
52
R 1 = i-Pr;
R 2 = H; R 3 = CH 3
Papuaforin A 66 H. papuanum +13(0.1,m)
53
R 1 = s-Bu;
R 2 = H; R 3 = CH 3
Papuaforin C e66 H. papuanum +23 (.1,m)
54
R 1 = s-Bu;
R 2 = prenyl; R 3 = CH 3
Papuaforin D e66 H. papuanum +64(0.1,m)
55
R 1 = i-Pr;
R 2 = prenyl; R 3 = CH 3
Papuaforin E 66 H. papuanum +41(0.1,m)
O
O
O
O
R
56 R = Ph Propolone A 41 Cuban propolis +40 (0.1)
57 R = i-Pr Garcinielliptone B 34 G. subelliptica -23 (0.1)
27

Table 1.1 (continued).
O
R
O
O H
O
O
i - P r
58 R = prenyl
8-Hydroxy-
H. perforatum +34 (1.0)
hemiacetal 61
hyperforin-8,1-
59 R = CH 3 Hyperibone J 70 H. scabrum +16.9 (0.3)
60 O
O
Oxepahyperforin 61 H. perforatum -73.7 (0.8)
i - P r
H O O O
R
O
O
H
O
i - P r
O H
61 R = prenyl Garcinielliptin oxide 2 G. subelliptica +1 (0.3)
62 R = CH 2 CH 2 CMe 2 OH Garcinielliptone E 34 G. subelliptica -51 (0.2)
28

Table 1.1 (continued).
O H
H O O H
O O
O O
63
H O
i - P r
Garcinielliptone H 34 G. subelliptica -14.3 (0.1)
O O
H O
64 H O O Garcinielliptone G 34 G. subelliptica -53 (0.1)
O
i - P r
65
O
O
O
O
i - P r
Garcinielliptone J 34 G. subelliptica -166 (0.2)
P h
O
O
O
R 2
R 1 O
66
R 1 = prenyl;
R 2 = CH=CMe 2
Plukenetione A 71 C. plukenetii +1 (0.8)
29

Table 1.1 (continued).
67
R 1 = prenyl;
dimethyloxiranyl
R 2 = (S)-2,2-
28,29-Epoxyplukenetione
A 65
C. havetiodes var.
stenocarpa
-4.4 (1.0)
68
R 1 = geranyl;
R 2 = (S)-2,2-
dimethyloxiranyl
Sampsonione J 58 H. sampsonii +1.48 (0.2)
H
P h
O
O O O O H
69 No name 62 C. obdeltifolia +10.0 (0.4)
H O H
P h
O
70 Sampsonione I 58 H. sampsonii
O O O
+16.88
(0.1)
H
P h
O
O
O
R O H
O
71 R = geranyl Sampsonione A 72 H. sampsonii -49 (0.4)
72 R = prenyl Sampsonione B 72 H. sampsonii NR
30

Table 1.1 (continued).
O
P h
O
O O
R
O
73 R = prenyl Sampsonione Q 64 H. sampsonii
-9.64
(0.401)
P h
O
O
O
O
H O
R O O H
74 R = prenyl
Plukenetione C 56,65 C. plukenetii +65.9 (0.1)
75
CH=CHCMe 2 OOH
R = (E)-
33-hydroperoxyisoplukenetione
C 65
C. havetiodes var.
stenocarpa
-3.9 (0.2)
H
R 1
O
R 3
O
O
R 2 O
76
R 1 = Ph; R 2 = prenyl;
R 3 = CMe 2 OH
Plukenetione B 56
C. plukenetii
+17.2
(0.03)
77
R 1 = Ph; R 2 = geranyl;
R 3 = i-Pr
Hypersampsone D 68 H. sampsonii -35 (0.2)
31

Table 1.1 (continued).
R 1 = i-Pr; R 2 = geranyl;
78
R 3 = CMe=CH 2 Hypersampsone A 68 H. sampsonii +21 (0.3)
79
R 1 = Ph; R 2 = geranyl;
R 3 = CMe 2 OH
Sampsonione C 58 H. sampsonii +13 (0.2)
80
R 1 = Ph; R 2 = geranyl;
R 3 = isopropenyl
Sampsonione D 58 H. sampsonii +12 (0.2)
81
R 1 = Ph; R 2 = geranyl;
R 3 = O (ketone)
Sampsonione E 58
H. sampsonii
+57.6
(0.03)
82
R 1 = Ph; R 2 = geranyl;
R 3 = H
Sampsonione H 58 H. sampsonii +5.2 (0.07)
H
P h
O
O
O
R O
O H
83 R = geranyl Sampsonione F 58 H. sampsonii +14.5 (1.1)
84 R = prenyl Sampsonione G 58 H. sampsonii
+10.0
(0.01)
32

Table 1.1 (continued).
H
R 1
O
O
O
O
R
85
R 1 , R 2 = i-Pr
Hypersampsone B 68 H. sampsonii +12 (0.3)
86 R 1 = i-Pr; R 2 = H Hypersampsone C 68 H. sampsonii +14.3 (0.2)
87 R 1 = Ph; R 2 = i-Pr Hypersampsone E 68 H. sampsonii +39 (0.2)
a C. = Clusia, G. = Garcinia, H. = Hypericum.
b OMe or OAc indicates the specific rotation was measured for that derivative. The
values in parentheses are the concentration and the solvent (e = EtOH, m = MeOH, no
indication = CHCl 3 ). NR = not reported.
c The absolute configuration is known to be as shown.
d The first scientists to isolate nemorosone (5) and hydroxynemorosone (6) had the acyl
group on C(5) and the prenyl group on C(1) switched from what is shown; 7,73 later on, the
structure of nemorosone was revised to 5, as shown in the table, 26 but the structure of 6
was not revisited, so we are correcting its structure in this paper.
e Not all the stereocenters‘ configurations have been assigned.
f The stereochemistry of the C(7) substituent has been reassigned on the basis of the NMR
spectra; 33 see the text.
33

1.7. Biological activity of PPAPs
Many of the PPAPs have shown important biological activity including
anticancer, anti-HIV and antiviral properties.
1.7.1. Type A PPAPs
1.7.1.1. Hyperforin and its close analogues
St John's wort (Hypericum perforatum extracts) was used by the ancient Greeks
as a remedy for many skin injuries, burns, neuralgia and depression. 74,75 Evidence from
several clinical trials confirms that St. John‘s wort is an effective antidepressant for mild
to moderate depression versus placebo and standard antidepressants. 76 Experts attribute
this activity to the presence of hyperforin. 6,24,46,77 The relatively low rate of side effects
and good tolerability results in high acceptance by patients. 78
St. John‘s wort extract also has an approximately equally broad inhibitory effect
on the neuronal uptake not only of serotonin, noradrenaline, and dopamine but also of
broad inhibitory profile γ-aminobutyric acid (GABA), L-glutamate, and other
antidepressants that are either specific to one system or show overlapping inhibitory
effects. 79 Hyperforin (1) and its structural analogue adhyperforin (2), both derived from
St. John‘s wort, have been found to be inhibitors of reuptake of investigated
neurotransmitters. 79 However, hyperforin (1) does not act as a competitive inhibitor at the
transmitter binding sites of the transporter proteins but instead affects the sodium gradient
which then leads to an inhibition of uptake. 79
Hyperforin (1) is also a known antibacterial agent, 15 and it inhibits the growth of
all gram-positive bacteria at low concentrations (0.1 mg/mL). 74 Experiments indicate that
penicillin-resistant (PRSA) and methicillin-resistant Staphylococcus aureus (MRSA)
were susceptible to hyperforin. 74 However, hyperforin has not shown activity against
gram-negative bacteria or against Candida albicans. 74
34

Hyperforin (1) is a promising and novel anticancer agent. 50 By induction of
apoptosis in a dose-dependent manner with IC 50 values 3-20 M, hyperforin was able to
inhibit the growth of a wide range of human and rat tumor cell lines. 80,81 Also, it has
potential for reducing the invasion and metastasis growth of tumor cells, 82 and it inhibits
angiogenesis in vivo and several key steps of this process in vitro. 83
Hyperforin is a mixture of interconverting tautomers (enolized -dicarbonyl), and
pure hyperforin is unstable when exposed to light and oxygen. 52,84 This instability is a
serious problem for standardization and could also have dramatic effects on the
pharmacological activity of the extracts. 61 On the other hand, the dicyclohexylammonium
salt of this compound was found to be stable at room temperature and also in air. 85 A
majority of commercial St. John‘s wort extract contains 1-5% of 1. Extraction in aqueous
alcoholic medium has been used for this preparation. 86 Although the ammonium salt of 1
is stable, hyperforin (1) itself is susceptible to air oxidation. The oxidized products of
natural hyperforin are dependent on the nature of oxidizing agent, the solvent, and the
type of 1 used (ammonium salt or free acid form). 87 The hyperforin (1) can be converted
to hemiacetal 58, possibly through the C(3)-hydroxylated intermediate after treatment
with peroxidic reagents. The furan (136) and pyran (49) derivatives are the main products
when nonperoxidic reagents are used for oxidizing hyperforin (Figure 1.10). 24,87
35

H O
O
O
O
O
O
O
O
O H
i - P r
i - P r
5 8 1 3 6
O
O
O
O
i - P r
4 9
Figure 1.10 Products of oxidation of hyperforin
Hyperforin (1) is a potential antimalarial agent as its lithium salt showed modest
activity against Plasmodium falciparum with an IC 50 = 2 M. Plasmodium falciparum is
the most dangerous of the four Plasmodium species causing malaria in humans. 88 Verotta
et al. have synthesized different analogues of enolized -diketone moiety by O-acylation,
O-alkylation, -alkylation, or oxidative -functionalization of natural hyperforin. 88 The
homolog adhyperforin (2) (assayed as its dicyclohexylammonium salt) showed activity
(IC 50 = 1.4 M) against Plasmodium falciparum, which was similar to hyperforin. O-
Acylation of the enol moiety of hyperforin showed activity between the electron-poor and
more hydrolysis-sensitive nicotinate 137 (IC50 = 4.8 M) and the electron-rich and more
hydrolytically stable trimethoxybenzoate 138 (IC50 > 27 M); the reason for the higher
IC50 value for 138 might simply be related to its stability in the assay medium (Figure
1.11). 88 The enol ethers 139 show decreased activity (7.8 M), while the stable analogue
furohyperforin (27) showed a similar potency to the natural product (1.7 M), suggesting
a specific role for the oxygen-sensitive enolized -dicarbonyl. 88
36

O
O
N
O
O
O
O
O
i - P r
O
O
O
O
O
O
i - P r
1 3 7 1 3 8
O
O
O
O
i - P r
H O
O
O
O
O
i - P r
1 3 9 2 7
Figure 1.11 O-protected analogs of hyperforin
1.7.1.2. Nemorosone
Nemorosone (5), another type A PPAP, is found in the resins and latex of
plants of the Clusia (Clusiaceae) species. 54 This latex normally spreads throughout the
plant tissues and acts as a defensive agent against insect and microbial invasion when
tissues are damaged. 54 This latex resin is used by bees to build their hives and helps to
harden the cell walls of the hive. 54 In ancient times, people knew nemorosone to be
antiseptic. Propolis is now believed to be a reinforcing agent of the structure of the hive,
preventing diseases and parasites from entering the hive. 89
In 1996, de Oliveira and coworkers isolated 4 new PPAPs: clusianone
(109), 7-epi-clusianone (99), nemorosone (5), and hydroxynemorosone (6). 26 According
to their data, the structure of nemorosone suggested that it was a type C PPAP. 26 In 2001,
Cuesta-Rubio and coworkers found disputing evidence from their isolation of
nemorosone from Clusia rosea. With the help of NOE and saturation experiments, this
group proved that nemorosone is in fact a type A PPAP (5). 26
37

In vivo studies have shown that nemorosone (5) is a potential antileukemic
agent. 90 Nemorosone has been shown to be cytotoxic in both parental and chemoresistant
leukemia cell lines with IC50 values between 2.10 and 3.10 µg/mL. 90 This compound
also has shown cytotoxic activity against epitheloid carcinoma (HeLa), epidermoid
carcinoma (Hep-2), prostate cancer (PC-3) and central nervous system cancer (U251)
while O-methylated nemorosone exhibited less biological activity. 38
Bacterial activity studies of 5 and O-methylnemorosone (5a) have shown
that only 5 has antibacterial activity. 54 This suggests that the presence of the enol
functionality is essential to antibacterial activity. 38,54
The prenylation pattern also plays an important role for antibacterial
activity in these types of natural products. Nemorosone showed more bacterial activity
against Paenibacillus honeybee pathogen with respect to chamone II (42) (Figure
1.22). 38,54
O
O
O H
O
O
O
O M e
O
O
O
O
O
P h
P h
P h
5 5 a
4 2
Figure 1.12 Nemorosone derivatives
In addition to antimicrobial activity, nemorosone has shown antioxidant activity and
anticancer activity. 38 Nemorosone (5) has shown IC 50 (3.3-7.2 µM) values against four
cancer cell lines comparable to those of doxorubicin. 38 Also, 1 has shown activity (EC 50
= 0.8 µM) against HIV infected C8166 human T lymphoblastoid cells. 91
1.7.1.3. Garsubellin A
Garsubellin A (18) was isolated from the wood of Garcinia subelliptica
(Guttiferae), a tree which is grown for windbreaking in the Okinawa islands, Japan. 57
Researchers found that 18 could enhance choline acetyltransferase (chAT) activity by
38

154% at 10 M in comparison with the control culture containing 0.5% EtOH in a P10
rat septal neurons culture. 32 Choline acetyltransferase is a key enzyme for the synthesis of
the neurotransmitter acetylchlorine, and a deficiency of chAT is believed to contribute
diseases like Alzheimer‘s disease. 32
Table 1.2: Type B PPAPs
The following table of type B PPAPs was taken from a review article written by Dr.
Ciochina and Prof. Grossman. 24 Eight newly isolated natural products were added to the
table: sampsonione P (108) and oblongifolines A-G (101-102, 113-115, 117-118).
No. Structure Name Source a [] D b
R 3
H O
R 1
O
O
O
O H
R 2
88
R 1 , R 2 = prenyl, R 3 = OH Guttiferone A 12,92 S. globulifera,
G. livingstonei,
G. humilis
+34 (1.7)
39

Table 1.2 (continued).
89
R 1 = -lavandulyl
R 2 = prenyl; R 3 = OH
Guttiferone C c
S. globulifera
as mix
with 90
+92 (0.9)
90
R 1 = lavandulyl;
R 2 = prenyl, R 3 = OH
Guttiferone D c
as mix
with 89
+92 (0.9)
R 1 = (S)-lavandulyl;
Guttiferone E 12,38,41
Cuban propolis,
+101
91
R 2 = H; R 3 = OH
C. rosea
(0.5)
G. ovafolia
92
R 1 = (S)-lavandulyl;
R 2 = H; R 3 = OH
(enantiomer)
Garcinol
(camboginol) 39,40
G. cambogia,
G. indica
–138
(0.1)
93
R 1 = (R)-lavandulyl;
R 2 = H; R 3 = OH
Guttiferone F 93
Allanblackia
stuhlmannii
–293
(0.4)
40

Table 1.2 (continued).
+58
(0.1);
94 R 1 = prenyl;
R 2 = H; R 3 = OH
Aristophenone d,94,95
G. xanthochymus
OAc:
+53
(0.1),
+54 (0.1)
95
R 1 = geranyl;
R 2 = H; R 3 = OH
Guttiferone I e,96 G. griffithii –68 (1.2)
Cuban propolis,
G. xanthochymus,
96 R 1 = (S)--lavandulyl;
Xantho-
G. mannii,
+138
R 2 = H, R 3 = OH
chymol f,17,27,28,38,41,44,95,97
G. staudtii,
(0.1)
G. subelliptica,
Rheedia madrunno
41

Table 1.2 (continued).
97 R 1 = (S)-lavandulyl;
14-deoxygarcinol 98 M. coccinea 98 −42 (0.3)
R 2 = H; R 3 = H
O H
H O
R 1
O
O
O
O H
R 2
98 R 1 = (S)-lavandulyl;
7-epi-Garcinol M. coccinea 98
R 2 = H
O
O
O
R 2
O H
R 1
99
R 1 = CH 3 ; R 2 = Ph Hyperibone L 70 H. scabrum
+69.5
(0.2)
42

Table 1.2 (continued).
100
R 1 = CH 3 ; R 2 = i-Pr Hyperpapuanone 66 H. papuanum
+15 (0.1,
m)
101
R 1 = prenyl; R 2 = Ph 7-epi-Clusianone 73,99-101 C. sandinensis,
C. torresii
+62.3
(1.1)
O H
H O
R 1
O
O
O
O H
R 2
43

Table 1.2 (continued).
102 R 1 , R 2 = prenyl
Guttiferone G 92,102
G. humilis,
G. macrophylla
–25
(0.04)
103
R 1 = prenyl; R 2 = H Oblongifolin A 103 G. oblongifolia
+23
(0.35)
104 R 1 = geranyl; R 2 = H Oblongifolin D 103 G. oblongifolia +44.6
(0.21)
O H
O
O
O
O
O H
R
105 R = prenyl
Isogarcinol
(cambogin) g,39,40
G. indica,
G. cambogia
G. pedunculata
–224 (m,
0.1)
44

Table 1.2 (continued).
G. pyrifera
106 R = prenyl
(enantiomer)
Isoxanthochymol f,12,42-44
G. subelliptica
G. xanthochymus
+181 (e,
0.6)
G. ovafolia
as 2:3
107
R = CH 2 CH 2 CMe=CH 2 Cycloxanthochymol 43,44 G. pyrifera
G. subelliptica
mix with
72: +158
(m, 0.1)
45

Table 1.2 (continued).
O H
O
O
O
O
O H
R
108
R = prenyl 7-epi-isogarcinol 98 Moronobea
coccinea
–158
(1.0)
O
P h
O
O
O
O H
R
109
R = (E)-CH=CHCMe 2 OH Hyperibone H d,31 H. scabrum
+12.4
(0.4)
110
R = prenyl Hyperibone I d,31 H. scabrum
+13.3
(0.3)
46

Table 1.2 (continued).
O
P h
111
O
O
O
O H
Sampsonione P 64
H. sampsonii
+18.6
(0.022)
O
R 1
O
R 3
O
O H
R 2
112
R 1 = Ph;
R 2 , R 3 = prenyl
Clusianone 7,29,100
C. congestiflora,
C. spiritu-santesis,
C. torresii
+58.3
(0.7)
OMe:
+61 (1.4)
113
R 1 = isobutyl;
R 2 = CHPhCH 2 CO 2 H;
R 3 = prenyl
Laxifloranone 104
Marila laxiflora
+23.6
(m, 0.8)
47

Table 1.2 (continued).
114
R 1 = Ph; R 2 = prenyl;
R 3 = lavandulyl
Spiritone c67
C. spiritus-
sanctensis
NR
O H
H O
R 1
O
O
O
O H
R 2
115
R 1 = H; R 2 = geranyl Guttiferone B 12 S. globulifera –44 (0.5)
O
H O
O
R 2
O
R 1
O H
116
R 1 = OH, R 2 = prenyl Oblongifoline B 103 G. oblongifolia
+17.6
(0.21)
48

Table 1.2 (continued).
117
R 1 = OH, R 2 = geranyl Oblongifoline C 103 G. oblongifolia
+14.5
(0.21)
118
R = H; R 2 = geranyl Oblongifoline E 105 G. oblongifolia
+65.1
(0.4)
O H
O
H O
O
O H
O
119 Guttiferone H c,67 95 G. xanthochymus
+94
(0.006)
O H
O
O O
O
R 2 R 3 R 4
O H
120 R 2 = prenyl;
R 3 = geranyl; R 4 = H
Oblongifoline F 105
G. oblongifolia
−85.6
(0.41)
49

Table 1.2 (continued).
O H
O
O O
O
R 2 R 3 R 4
O H
121 R 2 = prenyl; R 3 = H; R 4 =
geranyl
Oblongifoline G 105
G. oblongifolia
+5.9
(0.41)
O H
O
O
O
O H
O
122 Coccinone A 98 M. coccinea
H
+ 28
(1.0)
50

Table 1.2 (continued).
O H
123
O
O
O
O
O H
Coccinone B 98 M. coccinea −55 (0.3)
O H
124
Coccinone C 98 M. coccinea −60 (0.2)
51

Table 1.2 (continued).
O H
125
O
O
O
O
O H
O H
O H
−76
126 Coccinone D 98 M. coccinea
(0.4)
127
Coccinone E 98
M. coccinea
−70
(0.3)
52

Table 1.2 (continued).
O H
128
H O
O
O
O
O H
Coccinone F 98 M. coccinea −32 (0.7)
H O
O
O
O
O H
O H
129 Coccinone G 98 M. coccinea −16 (1.0)
53

Table 1.2 (continued).
O H
130
H O
O
O
O
O H
Coccinone H 98 M. coccinea +2 (1.0)
131
O
O
O
i - P r
O H
C H 3
Enaimeone A 66
H. papuanum
+27.8
(0.1, m)
O H
O R
O
O
O H
C H 3
O H
54

Table 1.2 (continued).
132
R = i-Pr Enaimeone B 66 H. papuanum
+29.4
(0.1, m)
133
R = s-Bu Enaimeone C c,66 H. papuanum
+32.9
(0.1, m)
O
H 3 C
O
O
R 1
H
O H
R 2
134
R 1 = i-Pr;
R 2 = CMe=CH 2
Ialibinone A 106 H. papuanum –22 (0.1)
135
R 1 = s-Bu;
R 2 = CMe=CH 2
Ialibinone C c,106 H. papuanum –26 (0.1)
136
R 1 = i-Pr;
R 2 = CMe 2 OH
1´-Hydroxy-
ialibinone A 66
H. papuanum
+3.7
(0.1, m)
55

Table 1.2 (continued).
O
R 1
O
O
O H
H 3 C
R 2
137
R 1 = i-Pr;
H
R 2 = CMe=CH 2
Ialibinone B 106 H. papuanum –91 (0.1)
138
R 1 = s-Bu;
R 2 = CMe=CH 2
Ialibinone D c,106 H. papuanum –72 (0.1)
139
R 1 = i-Pr;
R 2 = CMe 2 OH
1´-Hydroxy-
ialibinone B 66
H. papuanum
–35.7
(0.1, m)
140
R 1 = s-Bu;
R 2 = CMe 2 OH
1´-Hydroxy-
ialibinone D c,66
H. papuanum
–30.3
(0.1, m)
141
O
O
O
H 3 C
i - P r
O H
Ialibinone E 106 H. papuanum –33 (0.1)
H
56

Table 1.2 (continued).
O H
142
H O
O
O
O H
Gambogenone c,95
G. xanthochymus
-5
(0.003),
(m)
O O
143 Hyperibone K 70 H. scabrum
O O
P h
+22.3
(0.3)
a C. = Clusia, G. = Garcinia, H. = Hypericum, S. = Symphonia.
b OMe or OAc indicates the specific rotation was measured for that derivative. The
values in parentheses are the concentration and the solvent (e = EtOH, m = MeOH, no
indication = CHCl 3 ).
c Not all the stereocenters‘ configurations have been assigned.
d The stereochemistry of the C(7) substituent has been reassigned on the basis of the
NMR spectra; see the text. 33
e Two different compounds reported almost simultaneously have both been named
guttiferone I. 96,102
f The absolute configuration is known and is opposite to what is shown.
g The absolute configuration is known to be as shown.
57

1.7.2. Type B PPAPs
1.7.2.1. Garcinol and its derivatives
Garcinol (92) and isogarcinol (105), also known as camboginol and
isocamboginol, were isolated from the hexane extract of the fruit rind of Garcinia
indica. 14,24,39,40 In traditional Indian cooking, the dried rind of G. indica (‗Kokum‘) is
used as a garnish for curry. 107 Garcinol (92) has shown many bioactivities including
antioxidative activity, chelating activity, free radical scavenging activity, antiglycation,
antiinflammatory activity and antitumor activity. 108-110 Garcinol (92) has the ability to
scavenge 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical three times more effectively
than DL-α-tocophenol, and the hydroxy radical more effectively than DL-α-tocophenol, and
methyl radical, and superoxide anion. 107,110 Very common diseases caused by hydroxy
radicals include stress-induced gastric ulcers and nonsteroidal antiinflammatory druginduced
gastric, 111 so garcinol may be very useful for curing these disease. 111
Helicobacter pylori is another important pathogen/carcinogen which is responsible for
various gastrointestinal disorders including chronic gastritis, gastric inflammatory
diseases, peptic ulcer disease and gastric cancer. Garcinol (92) might be a solution for
these illnesses because it has shown excellent inhibition against Helicobacter pylori. 107,110
The antiinflammatory activity of garcinol is dose-dependent. Recently, a group of
scientists found that garcinol showed activity against the TPA-induced ear inflammation
of CD-1 mice. 108 Garcinol exhibits strong antibacterial activity against methicillinresistant
S. aureus (MRSA) (MIC = 6-25 µg/mL) while standard vancomycin only has
MIC = 6 µg/mL. 43
1.7.2.2. Clusianone and 7-epi-clusianone
Clusianone (112) was first isolated from the hexane extract of bark and
broken twigs of Clusia congestiflora (Guttiferae) which was collected near Fresno,
Columbia in 1974. 29 The structure was identified by X-ray diffraction. 29 From this X-ray
data, it was clear that the prenyl group at C-7 was in an exo orientation. However, no
NMR data was reported for this compound at that time. 29 In 1991, delle Monache and
58

coworkers isolated 112 from Clusia sandiensis, and for the first time NMR data was
reported. Unfortunately, due to the complexity of the data and the unavailability of an
authentic sample of clusianone, no mention was made of the C(7) stereochemistry. 99 In
1996, de Oliveira and coworkers isolated 112 from Clusia spiritus-santensis and reported
the NMR data and X-ray crystal structure. 7 The NMR data reported was different from
delle Monache‘s NMR data. In 1998, Santos and coworkers isolated 7-epi-clusianone
(99) from Rheedia gardneriana and reported its NMR and X-ray crystal structure,
showing C(7) endo stereochemistry. 101,112
The anti-HIV activity and toxicity of clusianone and 7-epi-clusianone
(101) was tested in C8166 human T lymphoblastoid cells infected with HIV-1 MN . 91 7-epi-
Clusianone (101) showed potent anti-HIV activity with an in vitro EC 50 value of 2 µM. 91
On the other hand, clusianone (112) showed activity at very low concentration, (EC 50 =
0.02 µM) but also showed increased cytotoxity. 91 In this experiment, propolone A (56)
showed the most promising activity with an EC 50 value of 0.32 µM. After comparison of
the anti-HIV activities of the above prenylated benzophenones, it is clear that the ketoenolic
equilibrium is not essential to the antiviral activity. Also 112 (EC 50 = 0.02 µM and
TC 50 = 0.1 µM) and 101 (EC 50 = 2 µM and TC 50 = 20 µM) showed very distinct EC 50 and
TC 50 values. This difference may be due to the stereochemistry (exo and endo) at C-7
(Figure 1.13). 91
O
O
H O
O
O
H O
O
O
O
O
O
O
7 7
1 1 2 1 0 1 5 6
Figure 1.13: Structure of clusianone, 7-epi-clusianone and propolone A
59

Streptococcus mutans is an important microbial agent that utilizes sucrose
to form both acids and glucans which cause dental cariogenicity. 113 7-epi-Clusianone
(101) has been found to inhibit the development and acidity of S. mutans biofilm in vitro
by inhibition of glucan synthesis, disruption of acid production, and acid tolerance. 113
7-epi-Clusianone (101) is also inhibits the anaphylactic contraction of
isolated guinea-pig ileum and prevents allergen-evoked histamine release with similar
effects to the standard antiallergic agent azelastine. 1 The IC 50 value of 101 in this system
is 2.3 µM and the IC 50 for standard azelastine is 3.33 µM. 114
The flagellate protozoan Trypanosoma cruzi affects 18 million people in
Latin America and is responsible for 45,000 deaths every year by inducing Chagas
disease. 73 7-epi-Clusianone (101) has shown activity against T. cruzi present in murine
blood (IC 50 = 260 µg/mL, 518 µM) in vitro, 29 times higher than the control drug
Gentian Violet (LC 50 = 7 µg /mL, 18 µM). 73 7-epi-Clusianone has also shown strong
toxicity (LC 50 = 25 ppm, 49.7 µM) in the brine shrimp lethality (Artemia salina Leach)
assay, and it may be a potential anticancer agent. 73 7-epi-Clusianone has shown an
endothelium-dependent vasodilator effect at low concentrations in the rat aortic rings. 115
1.7.2.3. Guttiferones A-E, Xanthochymol and their analogues
Xanthochymol (96), guttiferone E (91) and guttiferone H (119) were isolated from
the edible tropical fruit Garcinia xanthochymus. 116 These compounds were tested for
inhibition activity of three human colon cancer cell lines HCT116, HT29, and SW480
and found to induce loss of the mitochondrial membrane potential and G1 arrest at their
IC50 concentrations and induced caspase activation at IC 50 * 2 concentrations. 116 All
three compounds and all three cell lines have shown an increase in gene expression of
XBP1, ATF4 and DDIT3/CHOP genes. These genes are components of the endoplasmic
reticulum stress response. The DDIT4/REDD1 genes can be up regulated by inhibition of
the mTOR survival pathway. Xanthochymol (96), guttiferone E (91), and guttiferone H
(119) have a high chance to inhibit human clone cancer cells growth at least in part, by
60

activating the endoplasmic reticulum stress response and inhibiting the mTOR cell
survival pathway. 116 It is believed that these results may contribute to the anticancer
activity of these novel compounds. 116
Also, xanthochymol (96) and cycloxanthochymol (107) were isolated from
Garcinia indica and tested for activity against the human cancer cell line clone (COLO-
320-DM), breast (MCF-7) and liver (WRL-68) in the MTT assay. 117,118 It was found that
pure xanthochymol and cycloxanthochymol showed activity against the cell lines but that
the activity was even higher when they were in a mixture. 117 Testing mixtures of
xanthochymol (96) and cycloxanthochymol (107) for cytotoxicity in MTT assay at (1:1),
(1:2) and (2:1) showed that the (1:2) mixture showed maximum cytotoxic activity
against the cell lines. 117
Pure xanthochymol showed strong antibacterial activity against methicillinresistant
S. aureus with MIC range from 3.13-12.5 µg/mL. Similarly, its activity against
MRSA is nearly equal to that of antibiotic vancomycin (6.25 µg/mL). 119 Also it was
found that the C(1) hydroxyl group plays a role in this activity against the MRSA. 119
Xanthochymol (96) shows inhibitory activity against the DNA topoisomerases I
and II. 119 For topoisomerase I IC 50 = 30 µg/mL, standard camptothecin was 0.87 µg/mL,
while for topoisomerase II IC 50 = 40 µg/mL, standard control etoposide was IC 50 = 70
µg/mL. 119 It was also found that absence of hydroxyl group caused diminution of above
activity. 119
Inseparable mixtures of 91 and 96 were extracted from Garcinia and Clusia
species. 12 The crude extract of G. pyrifera containing 40% of 96 and 91 mixture showed
strong inhibitory activity against tubulin depolymerization (IC 50 = 20 µM), suggesting it
may be a possible inhibitor for cell replication. For the same experiment, paclitaxel
(Taxol) showed IC 50 = 0.5 µM. 44 This inhibition activity of microtubule depolymerization
vanished after etherifying the enol by methylation, or cyclization and the same result was
observed after protection or oxidation of the hydroxyl groups. 44 . However, the activity
remained if one of the hydroxyl groups was protected. 44 Also, reduction of double bonds
led to a total loss of activity. 44
61

Guttiferone A (88), B (115), C (89), and D (90) were isolated from Calophyllum
lanigerum (Guttiferae), although guttiferone C (89) and D (90) were obtained as an
inseparable mixture 12 . All these compounds showed inhibition activity against the
cytopathic effect of in vitro HIV infection in human lymphoblastoid CEM-SS cells with
EC 50 values of 1-10 µg/mL. However, there was no indication of a decrease in viral
replication. 12
The HIV-inhibitory activity of guttiferone F (93) in extracts of Allanblackia
stuhlmannii was tested. Compound 93 showed cytoprotection activity against HIV in
vitro (EC 50 = 23 µg/mL) and cytotoxicity ( IC 50 = 82 µg/mL) toward the host cells. 93
Guttiferone E (91), xanthochymol (96), aristophenone A (94), isoxanthochymol
(106), and cycloxanthochymol (107) showed cytotoxic activity against the SW-480 colon
cancer cells (IC 50 = 7.-33.33 µM) and antioxidant activity in the DPPH free radical assay
(IC 50 = 35-125 µM). 95
Guttiferone G (100) was extracted from Garcinia cochinchinensis, a tree growing
in Vietnam, and showed inhibitory activity against the human sirtuins SIRT1 (IC 50 = 9
µM), which regulates HIV transcription, and SIRT2 (IC 50 = 22 µM), which is a tubulin
deacetylase. 120
Guttiferone I (95) exhibits inhibition of binding activity of the -liver X receptor
(LXRα) (IC 50 = 3.43 µM) but is less effective against the β-receptor (LXRβ) ( IC 50 ≥ 15
µM). 74 LXR agonists are therapeutical agents for the control of plasma cholesterol
levels, increasing reverse cholesterol transport. 74
1.7.2.4. Lalibinones A-E and their analogues
Five new tricyclic phloroglucinol derivatives (lalibinones A-E 134, 137, 135, 138
and 141) were found from the petroleum ether extract of the aerial parts of Hypericum
papuanum. 121 The Hypericum papuanum is a tree that grows in all mountainous regions
of New Guinea, and its leaves are used in folk medicine for the treatment of sores and
wound healing. 121 Lalibinones C (135) and D (138) showed stronger antibacterial activity
against B. cereus, S. epidermidis than lalibinones A (135) and B (138) but showed almost
62

identical activity against M. luteus. 106 Lalibinones E (141) did not show any antibacterial
activity in this experiment. 106
Also from Hypericum papuanum, scientists isolated more active compounds such
as hyperpapuanone, 1´-hydroxyialibinones A (136), B (139), and D (140), and
enaimeones A–C (131–133). 122 1´-Hydroxyialibinones A (136), B (139), and D (140)
exhibit similar or slightly lower antibacterial activity compared with lalibinones A (134),
B (137) and D (135). Also, hyperpapuanones showed moderately potent antibacterial
activity against all B. cereus, S. epidermidis and M. luteus. Enaimeones A–C (131–133)
showed antibacterial activity as effective as of lalibinones A-C (134, 137, 135), but
showed weaker cytotoxicity against the KB cells. 122
63

Table 1.3: Type C PPAPs
No. Structure Name Source a [] D b
HO
O
R
O
O
O
144 R = Ph Garcinielliptone K 25 G. subelliptica
+27
(0.3)
145 R = isopropyl Garcinielliptone M 25 G. subelliptica
+73
(0.2)
HO
O
146 O O
i-Pr
O
Garcinielliptone L 25
G. subelliptica
–41
(0.3)
a G. = Garcinia.
b The values in parentheses are the concentrations (solvent is CHCl 3 ).
64

1.7.3. Type C PPAPs
Garcinielliptones L (146) and M (145) were isolated from the seeds of G.
subelliptica and two have shown potent inhibitory effects on the release of β-
glucuronidase and histamine (garcinielliptones L, IC 50 = 22.9 and >30 µg/mL;
garcinielliptones M, IC 50 = 13.6 and 19 µg/mL). The inhibitory values explain that 146
and 135 have potential to be an antiinflammatory agent. 25
Garcinielliptones FB was
isolated from the same plant and has shown moderate activity against liver (IC 50 = 6.8
µg/mL), breast (IC 50 = 6.3 µg/mL) and colon (IC 50 = 11.2 µg/mL) cancer cell lines. 123
Copyright © Pushpa Suresh Jayasekara Mudiyanselage 2010

Chapter 2. Synthetic efforts toward PPAPs
2.1. Introduction
Because of PPAPs‘ intriguing biological activity, they are very promising targets
for organic synthesis. Because of their challenging structure and widespread human
consumption, only three PPAPs, (±)-garsubellin A (18), (±)-nemorosone (5), and (±)-
clusianone (112) have been made synthetically so far. Although PPAPs have been known
for decades, it was not until 1999 that the first synthetic effort was made by Prof.
Nicolaou. 124 A decade after the first synthetic effort there has been only three PPAPs
synthesized in a total of seven publications from five research groups. 63,125-130
So far, all the approaches towards the construction of the
bicyclo[3.3.1]nonanetrione core structure have depended on the ´-annulation of a
three-carbon bridge onto a cyclohexanone derivative. 24
2.2. Shibasaki’s approach to garsubellin A
Shibasaki‘s first reported synthetic effort in this area was a synthesis of 8-
deprenyl-garsubellin A (18). He carried out a synthesis in which all the stereocenters
matched their natural configurations (Scheme 2.1). 131
66

H 3 C C H 3
H O
H 3 C
H 3 C
5
18
H O
7
O
3
C H 3
C H 3
O
C H 3
O
C H 3
H 3 C C H 3
g a r s u b e l l i n A ( 1 8 )
H O
H O
1 9
1 8
O
O H
1 8
O
3
O
3
5 1
1 4 0
5 1
O O
O
O
i - P r
i - P r
S t i l l e
c o u p l i n g
1 , 3 s h i f t
H O
H O
1 8
O
O H
1 8
I
O
3
5
1
141
O
5
O
O O
1
i - P r
O
W a c k e r o x i d a t i v e
c y c l i z a t i o n
i - P r
M i c h a e l a d d i t i o n a n d
l a c t o n i z a t i o n
1 4 2 1 4 3
O
1 8
O
5
O O
1 4 4
1
i - P r
+
O
O
C l
1 4 5
N O 2
Scheme 2.1: Shibasaki’s retrosynthesis of 8-deprenyl-garsubellin A
Shibasaki‘s retrosynthetic analysis of 140 began with replacing the C(3) prenyl
group with iodine creating the alkenyl iodide 141. The C(4)-O bond was then
disconnected to give the enone 142, which might have cyclized via an intramolecular
Wacker-type reaction to form the tetrahydrofuran moiety in 141. The C(1)-C(2) bond of
67

enone 142 was then disconnected, planning to introduce it via a 1,3-shift of unsaturated
lactone 143. The C(2)-O and C(4)-C(5) bonds of 143 were then disconnected to give
intermediates 144 and 145 (Scheme 2.1).
E t O 2 C
O
O
O
1 . C u I , M e M g B r
2 . ( C H 3 ) 2 C H C H O
146 55 % 147
O O T B S
H
i - P r
O O H
H
i - P r
O O T B S
O O T B S
H
H 1 . C u C N / M e L i ( 1 / 3 )
i - P r
1 . D I B A L - H , 88 % N C
i - P r
H + ; 55 % 2 s t e p s
2 . T M S C N , E t
O T M S
3 N ( c a t )
2 . M e M g B r , 83 %
148 149
3 . ( C l 3 C O ) 2 C O , p y r
C H 2 C l 2 , 98 %
1 5 0
1 . K O - t B u , - 78 o C
2 . L i C l O 4 , - 78 o C
3 . O
O N O 2
C l 145
4 . D M A P , 12 - c r o w n - 4
70 %
1 . B F 3 O E t 2
2 . D e s s - M a r t i n p e r i o d i n a n e O
80 % - 2 s t e p s
A r O
O
1 8
O
O
O
1 5 2
O
i - P r
1 . T B S O T f , 2 , 6 - l u t i d i n e
5 9 %
2 . K H M D S
3 . B r C H 2 C O O E t , H M P A
8 5 %
O
1 5 1
O
O O
H
1 8
O
O
O
i - P r
O
i - P r
1 5 3 a ( a : b = 2 5 : 1 )
Scheme 2.2: Shibasaki’s approach to 8-deprenyl-garsubellin A, part 1
Shibasaki‘s synthesis started with the conjugate addition of methylmagnesium
bromide to the -unsaturated ketone 146, which was followed by the kinetic trap of the
magnesium enolate with isobutyraldehyde to give 147 as a single stereoisomer (Scheme
2.2). The alcohol was then protected with a silyl group; the ketone was alkylated with
ethyl bromoacetate to give 148. The keto ester 148 was then reduced to the keto aldehyde
with DIBAL-H; cyanosilylation of this aldehyde produced 149 as a mixture of
68

diastereomers (1.3:1). Addition of a higher-order cuprate reagent to the cyano group of
149 provided the methyl ketone, which was further subjected to selective methylation and
protection to give acetonide 150. Deprotection of the TBS group with BF 3 .OEt 2 and
oxidation of the secondary alcohol with Dess–Martin periodinane yielded the diketone
151 as a diastereomeric mixture (1.3:14). After deprotonation of 151, the resulting
enolate was treated with chloroacrylate 145. Instead of the expected bicyclo compound
142 via addition-elimination and Dieckmann condensation, the authors isolated the
addition-elimination product 152 together with lactone 153. The authors also found that
152 could be converted into 153 in the presence of p-nitrophenol and base. Initially
Shibasaki and coworkers received poor yields for the above conversion; however,
eventually they were able to optimize the reaction conditions to allow 151 to be directly
converted to 153 in good yields. Unfortunately, these optimized conditions gave the
isomer 153a, which contained the unnatural relative configuration, as the major product
in a 25:1 ratio.
O
O
O
O
O O
O O
i - P r
i - P r
154 O O
155 ( a , b = 1 : 1 . 2 )
O
1 8
Scheme 2.2a: Addition-elimination reaction on the carbonate 154
Shibasaki and coworkers soon discovered that the carbonate 154 gave a much less
diastereoselective addition-elimination reaction than the acetonide compound 150 did in
their initial attempt. From this pathway Shibaski‘s group finally acquired the major
isomer 155b, which contained the natural relative configuration (Scheme 2.2a). 132
69

3
4
2
O
O
O
i - P r 1 . C u C N / E t 2 N P h 2 S i L i
1
T E S O
2 . m - C P B A , K F , D M F
3 . A l 2 O 3 , t o l u e n e
O O 155 b 3 . T E S O T f , 2 , 6 - l u t i d i n e O O
156
4 . D e s s - M a r t i n p e r i o d i n a n e
( 33 % 3 s t e p s )
( 54 % 4 s t e p s )
O
O
T E S O
O
O O
O
D B U , C H 2 C l 2
1 . 0 . 1 M L i O H , T H F
i - P r
i - P r
O
( 92 %)
O
2 . N a 2 P d C l 4 , T B H P
O
O
A c O H - H 2 O ,
O 157 O 158
( 54 % 2 s t e p s )
O
O
O
i - P r
1 . M e 2 A l S E t , C H 2 C l 2
2 . E t 3 S i H , P d / C , C H 2 C l 2
O H
O
O
O
1 . I 2 , C A N , C H 3 C N O
100 %
O
i - P r
O H
2 . P d C l 2 ( d p p f )
D M F
159 B u 3 S n
160
( 50 % 2 - s t e p s )
O
i - P r
Scheme 2.3: Shibasaki’s approach to 8-deprenyl-garsubellin A, part 3
The removal of the C(3)-C(4) unsaturated double bond of compound 155b was
important for the formation of the C(1)-C(2) bond. The Et 2 NPh 2 Si group was introduced
via conjugate addition of an aminosilylcuprate to form a C(4)-silyl product, which was
immediately followed by Tamao-Fleming oxidation with m-CPBA to afford a -hydroxy
lactone. The -hydroxy lactone was then protected with a triethylsilane group to give 156
in 33% yield over 3 steps (Scheme 2.3). The lactone 156 was then treated with Me 2 AlSEt
to give the thioester; Fukuyama reduction of the thioester gave an aldehyde, which was
successfully converted to the bicyclo[3.3.1] core structure 157 with Al 2 O 3 via an
intramolecular aldol reaction. Compound 157 was then treated with Dess−Martin
periodinane to give the ketone in 157, and -elimination by DBU gave the enone 158.
Deprotection of the carbonate of 158 with LiOH was followed by Wacker oxidation to
afford the -alkoxy enone 159. Finally, iodination followed by Stille coupling with
tributylprenyltin completed the synthesis of 160. The same reaction pathway was applied
70

to the acetonide 153a with unnatural (C18 epi) configuration to afford the C(18) epimer
of 160.
O
X
C H O
O O
X
6
O H
O
i - P r
O
i - P r
O
O O
O
O
161 162
O
O
O
O
X
6
C H O
O
O
O
H O
X
C H O
1 5 1 a 1 5 1 b
X
O
C H O
H O
X
C H O
O
O
O
O
O
1 5 1 c
O
151 d
Scheme 2.4: 1,2-allylic strain of the reactive conformation in 151b
Shibasaki was unable to induce an intramolecular aldol reaction to form the B ring in a
different approach to garsubellin A; this failure could be due to the 1,2-allylic strain of
the reactive conformation in 151b for the cyclization (Scheme 2.4).
71

H O
H O
O
18
5
O H
H O
O
O
3
1
( ± ) 1 8
S t i l l e
O O c o u p l i n g
H O
i - P r
O
O
R C M
1 8
O
5
O
I
3
O
1
O O
1 6 3
O
i - P r
i - P r O
i - P r
O
O
164 165
M O M O
W a c k e r o x i d a t i v e
c y c l i z a t i o n
C l a i s e n
r e a r r a n g e m e n t
O
O
O
M O M O
O
O
1 6 6
a l d o l
c o n d e s a t i o n
i - P r
M O M O
O
O
O T I P S
i - P r
167 168
Scheme 2.5: Shibasaki’s retrosynthesis of garsubellin A
In 2005, Shibasaki and coworkers completed the racemic total synthesis of
garsubellin A using a different approach from their early synthetic strategy (Scheme
2.5). 126 Shibasaki‘s retrosynthetic analysis of (±)-18 began with replacement of the C(3)
prenyl group with iodine to give alkenyl iodide 163. The C(4)-O bond was then
disconnected to give the enone 164, which might have cyclized via an intramolecular
Wacker type reaction to form the tetrahydrofuran moiety in 163. The C(2)-O and C(3)-
C(4) bonds of 164 were then disconnected to give intermediate 165. The C(1)-C2) bond
of 165 was disconnected to give intermediate 166, which could be prepared from 167 via
aldol condensation and O-allylation. The C(1)-C(2) and C(5)-C(6) bonds of 167 were
then disconnected to give the known intermediate 168.
72

O 1 . M e M g B r , C u I ; O H
i - P r C H O ( 61 %)
O T I P S 1 . P h S i H
5
3 , C o ( a c a c ) 2 , O 2 , ( 73 %)
2 . M O M C l ( 96 %)
2 . T I P S O T f ,
i - P r
2 , 6 - l u t i d i n e ( 92 %)
3 . K H M D S , p r e n y l b r o m i d e ( 98 %)
168
169
1 . A D - m i x , C H
O 3 S O 2 N H 2
H O T I P S 1 . L D A , T M E D A ; O H O T I P S 2 . t r i p h o s g e n e , p y r .
C H 3 C H O ( 94 %)
( 30 % 2 s t e p s )
i - P r
i - P r 3 . H . F p y r i d i n e
2 . M a r t i n s u l f u r a n e
4 . P D C , C e l i t e
M O M O
( 98 %)
170 M O M O 171
( 70 % 2 s t e p s )
O H O
O 1 . N a H M D S , e t h y l e n e c a r b o n a t e ,
O a l l y l i o d i d e ( 82 %)
O
O
O
i - P r
5 O 1 i - P r
O
2 . N a O A c , 200 ° C ( 96 %)
O
M O M O
172
M O M O
165
Scheme 2.6: Shibasaki’s forward synthesis of garsubellin A, part 1
The enone 168 was prepared from the commercially available ethyl enol ether of
1,3-cyclohexanedione 169 via prenylation followed by methylation and acidic hydrolysis
of the vinyl ether (Scheme 2.6). Copper-catalyzed conjugate addition of MeMgBr to the
enone 168, in situ trapping of the magnesium enolate with isobutyraldehyde and
protection of the resulting OH group with a TIPS group gave ketone 169. The
Mukaiyama hydration of the prenyl group followed by MOM group protection and
prenylation on the less hindered -position gave ketone 170. Selective deprotonation of
C(5) of ketone 170 was followed by an aldol reaction with acetaldehyde; this highyielding
reaction took place without competing retro-aldol reaction, even in this sterically
hindered environment. Dehydration with Martin sulfurane then gave -vinyl ketone 171.
The prenyl group was then converted to a diol with zero diastereoselectivity using
Sharpless dihydroxylation with AD-mix- diol protection as a carbonate and removal of
the TIPS group followed by oxidation gave -diketone 172. O-Allylation with allyl
iodide followed by Claisen rearrangement on the face opposite to the C(7) prenyl group
then gave the quaternized diketone 165 with very high diastereoselectivity.
73

O
O
O
M O M O
O
5 1
1 6 5
O 1 . H o v e y d a - G r u b b s c a t .,
( 92 %)
O
i - P r
2 . ( P h S e ) 2 , P h I O 2 , p y r O .
3 . C S A , ( 70 % 2 s t e p s )
O
O O
1 . L i O H
2 . N a 2 P d C l 4 , T B H P
O
i - P r ( 71 % 2 s t e p s )
H O
3 . I 2 , C . A N
166
4 . p - T s O H . 2 H 2 O ,
H 3 C C H 3
( 80 % 2 s t e p s )
H O
O
I
O
O O
i - P r
163
.
P d C l 2 d p p f
t r i b u t y l p r e n y l t i n
( 2 0 % )
H O
H 3 C
H 3 C
H O
7
O
3
C H 3
C H 3
O
C H 3
O
C H 3
( ± ) - 1 8
H 3 C C H 3
Scheme 2.7: Shibasaki’s forward synthesis of garsubellin A, part 2
The crucial B ring was formed using ring closing-metathesis with the Hoveyda–Grubbs
catalyst (92% yield). The resulting diketone was oxidized in the allylic position with
(PhSe) 2 and PhIO 2 ; removal of the MOM protection group gave triketone 166 (Scheme
2.7). Then the carbonate protection was removed, and the alcohol and enone moieties
were condensed oxidatively in an intramolecular Wacker oxidation. Iodination at the -
position of the enone and acid catalyzed dehydration gave the tertiary alcohol 163.
Finally, Stille coupling of 163 with tributylprenyltin completed the total synthesis of
garsubellin A ((±)-18) in a total of 21 steps from 168.
The alkylation of the Li enolate of 2-cyclohexenone with prenyl bromide and a
catalytic amount (5%) of chiral tetraamine 173 (Figure 2.1) (unpublished compound from
Koga group) gave 6-prenyl-2-cyclohexenone with 95% enantiomeric excess in 65%
yield; however, they did not carry this compound forward in their synthesis.
74

N
N
H
173
M e
N
N M e 2
Figure 2.1: Chiral tetraamine 173
Shibasaki’s first total synthesis of garsubellin A was an important milestone, but
it had some drawbacks such as the dihydroxylation of 171 proceeding with no
diastereoselectivity. Also, the oxidation of the C(2)-C(4) enone of 166 to the -alkoxy
enone of 163 in the intramolecular Wacker oxidation relied on an internal OH group that
was in a position to attack the enone–Pd complex in an intramolecular fashion. Although
Shibasaki’s method may be very useful for synthesizing PPAPs containing a
tetrahydrofuran ring fused to the C(4)-C(5) bond, such as garsubellin A, his method is
much less applicable when synthesizing PPAPs (such as hyperforin) that lack this feature.
Furthermore, ring-closing metathesis cannot be used for the synthesis of hyperforin
unless the multiple prenyl groups in the molecule are protected (Scheme 2.8).
M e O
O
O
H o v e y d a - G r u b b s I I
M e O
O
O
M O M O
1 7 4
M O M O
1 7 5
Scheme 2.8: Ring-closing metathesis on 174
Contemplating these drawbacks and future developments towards PPAPs synthesis,
Shibasaki and coworkers, in 2007, published another synthetic strategy for constructing
the bicyclo[3.3.1]nonane 176 with double bridgehead quaternary centers. The authors
hoped to extend this new synthetic route towards the synthesis of garsubellin A and
hyperforin (Scheme 2.9).
75

9
O
4
O
1
O
i n t r a m o l e c u l a r
a l d o l r e a c t i o n
H O C
O
O
5
M O M O
1 7 6
M O M O
1 7 7
O
O
p r e n y l a t i o n
O
O T I P S
c o n j u g a t e
a d d i t i o n
O
M O M O
178 M O M O 179 168
Scheme 2.9: Shibasaki’s intramolecular aldol approach towards garsubellin A
Shibasaki and coworkers initially constructed the bicyclic system via an
intramolecular aldol type reaction in synthesis of 8-desprenylgarsubellin A (140).
However, Shibaski‘s group could not use an aldol reaction to construct the bicyclic ring
towards garsubellin A (18) due to the high congestion at the C(6) nucleophilic center
(Scheme 2.4). The group‘s redesigned synthetic strategy began with the disconnection of
C(4)-C(5) bond to get diketo aldehyde intermediate 177 (Scheme 2.9). They planed to
construct the bicyclo[3.3.1]nonane ring system via intramolecular aldol reaction from
intermediate 177. The diketo aldehyde 177 was going to be made from diketone 178.
Disconnecting the C(5)-C(9) bond of 178 gave intermediate 179, which was going to be
made from known cyclohexenone 168.
76

O
M O M O
O
M O M O
H O C
O
O T I P S
1 7 9
O
1 8 1
O
1 . K H M D S
P r e n y l b r o m i d e
T B A I ( 9 8 % )
2 . K H M D S
( 5 2 % )
1 . t o l u e n e
N , N - d i e t h y l a n i l i n e
1 8 0 o C ( 8 5 % )
1 . N a O E t , E t O H
M O M O
O
O M O M
O
O
O
O T I P S
1 8 0
O
1 8 2
O
1 . H F - p y r i d i n e
p y r i d i n e
2 . P D C
3 . N a H M D S
( 6 5 % 3 s t e p s )
1 . ( s i a ) 2 B H
H 2 O 2
a q . N a O H
2 . D e s s - M a r t i n
p e r i o d i n a n e
( 5 4 % 2 s t e p s )
M O M O
1 7 7
2 . D e s s - M a r t i n
p e r i o d i n a n e
( 87 % 2 s t e p s )
M O M O
1 7 6
Scheme 2.10: Shibasaki’s intramolecular aldol approach towards garsubellin A,
part 1
The alcohol-protected ketone 179 was converted to its potassium enolate with
KHMDS and prenylated from the -side (axial) at C(4); next, under basic conditions, this
product epimerized to the -prenylated compound 180 (Scheme 2.10). Removal of the
TIPS group followed by oxidation with PDC and O-allylation gave the allyl enol ether
181. After Claisen rearrangement took place in an axial direction, the -allylic -diketone
182 was formed in a good diastereomeric ratio (>33:1). Terminal olefin-selective
hydroboration, followed by oxidative workup, and further oxidation with Dess–Martin
periodinane gave keto aldehyde 177. The key intramolecular aldol reaction formed the
bicyclic alcohol, with NaOEt and ethanol, and the oxidation of the resulting compound
gave synthetic intermediate 176. With this new synthetic strategy, Shibasaki solved some
of the problems of his previous synthesis, specifically, by using intramolecular aldol and
77

Claisen rearrangement instead of the ring-closing metathesis. However, Shibasaki did not
carry reactions further from 176.
2.3. Danishefsky’s iodocyclization approach to PPAPs
In 2005 Danishefsky and coworkers published a total synthesis of garsubellin A
(18), and later, in 2007, published the total syntheses of nemorosone and clusianone. His
novel approach for these syntheses was iodolactonization to build the core structure of
these target compounds. 129
2.3.1. Iodonium induced carbocyclization approach to garsubellin A
1 6
H O
22
5
H O
2 3
9
O
1
27
O
O
1 0
n u c l e o p h i l i c
a c y l a t i o n H O
H O
O
I
O
K e c k r a d i c a l
a l l y l a t i o n
1 8
1 8 3
H O
H O
H O
H
O
3
I
O
I
i o d o
O c a r b o c y c l i z a t i o n
H
H O
H
O
H O O
185
184
O
O
c o n j u g a t e
O T I P S
a d d i t i o n
d e a r o m a t i z a t i o n
e l i m i n a t i o n
H 3 C O O C H
21
3
6
H O
H 3 C O O C H 3
O H O
186 187
188
2 7
Scheme 2.11: Danishefsky’s retrosynthetic analysis of garsubellin A
78

Danishefsky‘s retrosynthetic analysis (Scheme 2.11) began with the disconnection of the
C(1)-C(10) bond to give 183. Intermediate 2 was going to synthesized from intermediate
184 via Keck radical allylation followed by iodination at C(1). The C(3)-C(27) bond was
then disconnected to give 185, and disconnection of the C(1)-C(9) bond of 185 gave
diketone 186. Disconnecting the C(22)-O bond gave nonocyclic intermediate 187, which
can be synthesized from protected phloroglucinol 188 via dearomatization.
O T I P S
1 . n - B u L i , E t 2 O , 0 C
O T I P S
H 3 C O O C H 3
1 8 8
2 . p r e n y l b r o m i d e
H 3 C O O C H 3
1 8 9
K 2 O s O 4 . H 2 O
K 2 C O 3 , K 3 F e ( C N ) 6
C H 3 S O 2 N H 2 , t - B u O H
H 2 O , r . t
O T I P S
H 3 C O O C H 3
H O
H O
190
1 . p - T s O H 2 H 2 O
2 , 2 - d i m e t h o x y p r o p a n e ,
a c e t o n e , r t
2 . T B A F , T H F
( 7 0 % f r o m 1 8 8 )
O H
O
P d ( O A c ) 2 , P P h 3
H 3 C O O C H 3
H 3 C O O C H 3
O
T i ( i - P r O ) 4 , a l l y l m e t h y l a c r b o n a t e O
C 6 H 6 , 80 C ( 62 %)
O
O
191
192
Scheme 2.12: Danishefsky’s synthesis towards garsubellin A, part 1
Danishefsky‘s synthesis started with prenylation 133 at the ortho position of the
protected phloroglucinol 7. Os-catalyzed dihydroxylation on the newly installed prenyl
group 134 followed by acetonide formation and TBAF desilylation produce 191 in 70%
79

overall yield (Scheme 2.12). The resulting product 191 was used to make 192 with
Pd(OAc) 2 , PPh 3 , Ti(i-PrO) 4 and allyl methyl carbonate either by C-allylation or by O-
allylation followed by rapid Claisen and Cope-like rearrangement. 135-137
O
H 3 C O O C H 3
O
H 2 O , d i o x a n e
O
( 71 %)
1 9 2
H C l O 4
H O
H
O
1 9 3
O
O
G r u b b s I I
C H 2 C l 2 , 4 0 C
( 6 8 % )
H O
H O
H O
H O
O
1 8 6
I
O
I
1 9 4
O
I 2 , K I , K H C O 3
T H F - H 2 O
( 8 5 % )
I
O
H O
H O
1 . i - P r M g C l , L i 2 C u C l 4
a l l y l b r o m i d e , T H F
78 C - 0 C ( 67 %)
H O
2 . T M S I , 1 N H C l , 0 C
C H 2 C l 2 ( 9 8 % )
I
O
1 8 5
H O
I
O
I
O
I 2 , C A N
C H 3 C N , 5 0 C
( 7 7 % )
H
O
1 8 4
Scheme 2.13: Danishefsky’s synthesis towards garsubellin A, part 2
80

H O
H O
I
O
I
1 9 4
I
O
i - P r M g C l , L i 2 C u C l 4
a l l y l b r o m i d e , T H F
7 8 C - 0 C , ( 6 7 % )
H O
H O
O
I
O
T M S I
( 9 8 % )
H O
H O
I
O
H
O
184
Scheme 2.13a: TMSI assisted strained cyclopropane ring opening
Treatment of acetonide 192 with perchloric acid in a water-dioxane mixture initially
deprotected it; following a Michael-type cyclization, intermediate 193 is formed in 71%
yield (Scheme 2.13). Conversion of intermediate 193 to 186 was carried out in 68% yield
using Grubbs olefin cross-metathesis. 138,139 The bicyclo[3.3.1] moiety of intermediate 185
was constructed using an iodocarbocyclization reaction, which proceeded in 85% yield;
under these reaction conditions, a second iodination took place at the bridgehead
carbon. 139,140 A third iodination at C(3) then produced 194 in 77% yield. Halogen-metal
exchange followed by allylation gave not only allylation at C(3), but also transannular
Wurtz cyclopropanation, giving a highly strained intermediate in 67% yield. However,
upon addition of TMSI, the strained cyclopropane ring was opened to give tricyclic 184
in 98% yield (Scheme 2.13a). 141,142
81

H O
H O
I
O
1 8 4
H
O
1 . A I B N , a l l y l t r i b u t y l t i n
C 6 H 6 , 80 C ( 82 %)
H O
2 . G r u b b s I I
( 82 %)
H O
O
H
O
195
i - P r M g C l ,
L D A , T M S C l ,
I 2 , 7 8 - 0 C
( 2 5 - 3 6 % )
T M S O
H
O
O
I
O
O
T H F , 7 8 C - 0 C
( 7 2 % )
1 8 3
T M S O
O
O H
1 . D M P
H O
O
O
H O
O
2 . E t 3 N ( H F ) 3
T H F , 8 8 %
H O
O
1 9 6
1 8
Scheme 2.14: Danishefsky’s synthesis towards garsubellin A, part 3
Keck radical allylation 143 of the secondary iodide of 184 followed by Grubbs
cross-metathesis of the resulting diallylated intermediate gave desisobutyrylgarsubellin
A, 195, in 73% yield (Scheme 2.14). Treatment of 195 with LDA and TMSCl followed
by addition of iodine resulted in the iodide 183 in variable yield. Halogen–metal
exchange of i-PrMgCl and intermediate 183 followed by addition of isobutyraldehyde
82

provided the aldol adduct 196 as a mixture of isomers. Dess–Martin oxidation followed
by removal of TMS with Et 3 N(HF) 3 resulted in garsubellin A in 88% yield.
2.3.1 Iodonium-induced carbocyclization approach to total synthesis of nemorosone
and clusianone
H 3 C C H 3
H 3 C C H 3
H 3 C C H 3
H O
H 3 C
H 3 C H O
O
C H 3
C H 3
O
C H 3
O
C H 3
H O
O
C H 3
C H 3
O
O
P h
H O
O
C H 3
C H 3
O
O
P h
H 3 C C H 3
g a r s u b e l l i n A ( 1 8 )
H 3 C C H 3
n e m o r o s o n e ( 5 )
H 3 C C H 3
c l u s i a n o n e ( 1 1 2 )
5 , 1 1 2
O
M e O
1 9 7
O
Scheme 2.15: Danishefsky’s retrosynthetic analysis of nemorosone and clusianone
Nemorosone (5) and clusianone (112) are structurally similar to garsubellin A;
taking advantage of this, Danishefsky and coworkers 129 were able to synthesize the
common intermediate 197, which leads to 5 and 112 with the help of the iodonium
induced carbocyclization method used in their previous total synthesis of garsubellin A
(18) (Scheme 2.15).
83

M e O
M e O
O M e
O H
M e O
O H P d ( O A c ) 2 ,
P P h 3 , T i ( O i P r ) 4 ,
198 M S ( 4 0 A ),
50 C
199
( 50 %)
O
L i I , 2 , 4 , 6 - c o l l i d i n e
2 0 0
O M e
1 4 0 C ( 8 2 % )
O
M e O
O M e
O
2 0 1
G r u b b s I I
C H 2 C l 2 , 4 0 C
( 7 9 % )
O
I 2 , K I , K H C O 3
T H F - H 2 O , R T
f o r 2 0 2 3 2 %
f o r 2 0 3 2 9 %
f o r 2 0 4 2 4 %
M e O
I
I
C H 3 I
O C H 3
O
O
I +
I
+
O M e O
M e O
O
202
203 204
Z n , T H F
H 2 O , 65 ( 87 %)
C 201
201
( 78 %)
I
O
Scheme 2.16: Danishefsky’s synthesis towards nemorosone and clusianone, part 1
Danishefsky and coworkers began their synthesis of intermediate 197 with -
allylpalladium chemistry, which introduces the two allyl groups to commercial 3,5-
dimethoxyphenol 198, obtaining the diallylic intermediate 199 in 50% yield (Scheme
2.16). The allyl groups of intermediate 199 were then converted to prenyl groups through
a twofold using Grubbs catalyst to give 200 in 79% yield. 138 Deprotection of one of the
methoxy groups with LiI and 2,4,6-collidine gave diketone 201 in 82% yield. Iodoniumassisted
carbocyclization gave a mixture of products containing only a 32% yield of
84

intermediate 202; 139,144 however, the other two by-products could be converted back to
intermediate 201 in high yields by the action of Zn in aqueous THF.
I
O
C H 3
C H 3
I
1 . i - P r M g C l , E t 2 O - T H F
7 8 o C ( 9 3 % )
I
O
C H 3
C H 3
M e O
2 0 2
O
2 . T M S I , C H 2 C l 2
0 o C ( 9 8 % )
M e O
2 0 5
O
2 0 5
a l l y l B u 3 S n
A I B N , B e n z e n e
8 0 o C ( 8 4 % )
M e O
O
C H 3
C H 3
O
197
Scheme 2.17: Danishefsky’s synthesis towards nemorosone and clusianone, part 2
As in the garsubellin synthesis, diiodide 202 was reduced to iodide 205, and Keck
radical allylation gave the intermediate 197, 143 which could be used for the synthesis of
either nemorosone or clusianone. (Scheme 2.17)
85

M e O
O
1 9 7
O
L D A , T M S C l
I 2 ( 5 1 % )
M e O
2 0 6
O
I
O
T M S
1 . i - P r M g C l , P h C H O
2 . D M P , C H 2 C l 2
3 . T B A F , T H F
R T
( 6 1 % 3 s t e p s )
M e O
O
O
O
P h
L D A ,
B r
2 -
t h i e n y l c y a n -
o c u p r a t e
( 88 %)
M e O
2 0 7 2 0 8
O
O
O P h
G r u b b s I I
( 9 1 % )
M e O
O
C H 3
C H 3
O
O
P h
L i I
2 , 4 , 6 - c o l l i d i n e
1 4 0 o C ( 3 1 % )
H O
O
O
O
P h
2 0 9
5
Scheme 2.18: Danishefsky’s synthesis towards nemorosone and clusianone, part 3
Intermediate 197 was treated with excess LDA in the presence of excess TMSCl,
and quenching with iodine gave iodide 206 in 51 % yield (Scheme 2.18). Halogen–metal
exchange of 206 followed by addition of benzaldehyde resulted in an aldol product.
Without further purification, the intermediate was subjected to Dess–Martin oxidation
followed by desilylation with TBAF produce 207 in 61% overall yield for the three steps.
Addition of LDA to 207 resulted in the formation of a metal–vinyl complex; this complex
was transformed into the corresponding higher order thienylcyanocuprate. 140 Allylation
occurred after addition of allyl bromide and resulted in bis-allyl intermediate 208 in 88%
86

yield. A twofold cross-metathesis 111 reaction converted 208 to diprenyl intermediate 209
in 91% yield; this reaction followed by demethylation gave nemorosone (5) in 31% yield.
M e O
O
O
1 9 7
1 . L D A , T H F
P h C H O
2 . D M P , C H 2 C l 2
( 5 7 % )
M e O
O
O
2 1 0
P h
H
O
L D A , T M S C l
I 2 ( 4 8 % )
O
I
A l l y l S n B u 3
O
G r u b b s I I
M e O
O
211
P h
O
E t 3 B , C 6 H 6
( 7 1 % )
M e O
O
O P h
212
( 9 4 % )
O
M e O
O
213
P h
O
1 0 % N a O H
1 , 4 - d i o x a n e
( 6 4 % )
H O
O
O
O P h
109
Scheme 2.19: Danishefsky’s synthesis towards nemorosone and clusianone, part 4
The synthesis of clusianone was concluded from intermediate 3 (Scheme 2.19).
Compound 197 was metallated at C(3) with LDA and treated with benzaldehyde,
and Dess–Martin oxidation gave triketone 210 in 57% yield. Compound 210 was then
converted into its C(1) iodo intermediate 211 via the silyl enol ether. The iodo group in
intermediate 211 was then replaced with an allyl group by allyltributylstannane and
triethylboron in the presence of air. 145 Diallyl intermediate 212 was then converted to
87

diprenyl intermediate 213 in 94% yield using a double cross-metathesis reaction. 138 The
conversion of the methoxy group to the enol, which was accomplished using aqueous
sodium hydroxide in 1,4-dioxane (64% yield) gave the target molecule clusianone.
2.4. Simpkins and Marazano & Delpech Effenberger cyclization (double acylation)
approach to total synthesis of clusianone
Both Simpkins on the one hand, and Marazano & Delpech on the other,
completed the total synthesis of clusianone by applying an Effenberger cyclization
approach to construct the bicyclo[3.3.1]nonanetrione core structure. This approach to
PPAPs was pioneered by Stoltz. 146
H 3 C C H 3
O T B S
C l
O
O
C l
K O H , B n E t 3 N C l
H 2 O , 1 0 - 2 3 o C
( 3 6 % )
H
H O
O
C H 3
C H 3
H
O
Scheme 2.20: Stoltz’s Effenberger cyclization approach
In 1984, Effenberger and coworkers published the reaction between
cyclohexanone methyl enol ether and malonyl dichloride to give the bicyclo[3.3.1]nonane
trione core structure. 147 In 2002, Stoltz and coworkers published a modified procedure
for the synthesis of the bicyclo[3.3.1]nonane core structure of garsubellin A by changing
the ratio of enol ether to malonyl dichloride and by changing methyl enol ether to a TBS
silyl enol ether to obtain cleaner products in modest yields (Scheme 2.20). 146
88

H O
1
O
5
L i t h i a t i o n a n d
p r e n y l a t i o n a t
b r i d g e h e a d
c a r b o n
Scheme 2.21: Simpkins’ retrosynthetic analysis of clusianone
O
E f f e n b e r g e r
c y c l i z a t i o n
H
O M e 215
O
H O
3
O
C l
O P h
H
C l
O O
109 214 216
In 2006 Simpkins and coworkers published a racemic total syntheis of clusianone.
Simpkins‘ retrosynthetic analysis began with the disconnection of the C(1) prenyl
substituent and C(3) benzoyl substituent of 109 to give diprenyl bicyclo[3.3.1]nonane
trione intermediate 214 (Scheme 2.21). The disconnection of the C(1)-C(2) and C(4)-
C(5) bonds gave methyl enol ether intermediate 215. Simpkins planned to install the
C(1)-C(2) and C(4)-C(5) bonds using the Effenberger cyclization.
O
L D A
P r e n y l b r o m i d e
O
1 . M e L i
O
M e M g B r
M e 3 S i C l , H M P A
O M e
217 218
O M e
2 . H C l
( 8 8 % 2 s t e p s )
2 1 9
C u B r S M e 2
8 8 %
O
O
t - B u O K , D M S O
O M e
O M e
M e 2 S O 4
( 8 7 % )
( 85 : 15 )
( 75 : 25 )
220 ( a : b ) 221 ( a : b )
Scheme 2.22: Simpkins’ synthesis towards clusianone, part 1
89

Simpkins and coworkers began their forward synthesis with prenylation of known
vinylogous ester 217, which gave diprenylated intermediate 218; 148 this step was
followed by methylation with MeLi and acidic hydrolysis to give 2,3,4-substituted
cyclohexenone 219 in 88% yield over two steps (Scheme 2.22). Copper-catalyzed
conjugate addition of MeMgBr to enone 219 resulted in an 85:15 ratio of ketone
diastereomers 220a and 220b in 88% yield. This mixture was then converted to
regioisomeric mixtures of the corresponding methyl enol ethers with the aid of tBuOK in
DMSO, giving 221a and 221b with 75:25 ratio in 87% yield. 149
O
O
O M e
+
O M e
C l C l
1 . E t 2 O ,- 20 o C
2 . K O H , B n E t 3 N C l
R T
2 2 1 a 2 2 1 b
H O
O
2 2 2
O
C H ( O M e ) 3 O
p - T s O H
M e O H , 50 o C M e O
( 24 % f r o m
O
9 a / 9 b ) 223
Scheme 2.23: Simpkins’ synthesis towards clusianone, part 2
The bicyclo[3.3.1]nonanetrione core structure 222 was achieved via Effenberger
cyclization with malonyl dichloride and 221. The compound 222 was obtained in 30%
yield after basic extraction, and 220a and 220b were also obtained in 55 % yield (Scheme
2.23). The methyl enol ether was found to be more effective in this system than the silyl
enol ether (OTBS). Diketone 222 was converted to its methyl enol ether under acidic
conditions with trimethyl orthoformate in 24 % yield over 2 steps.
90

M e O
O
2 2 3
O
L D A ( 2 e q ) , T H F
P r e n y l b r o m i d e ( 5 e q )
( 9 1 % )
M e O
O
2 2 4
O
L T M P ( 2 e q ) , T H F
P h C O C l ( 3 e q )
( 9 1 % )
M e O
L i O H , H 2 O
O
O
D i o x a n e
( 90 %)
M e O O
O
P h O
225 109
Scheme 2.24: Simpkins’ synthesis towards clusianone, part 3
To complete the synthesis, ketone 223 was prenylated at the bridgehead carbon to
give 224 in 91% yield (Scheme 2.24). Acylation at C(3) using LTMP and benzoyl
chloride then gave O-methylclusianone 225 in 91% yield, 150 and deprotection with LiOH
in dioxane offered the target compound in 90% yield for the last step.
In 2007, Simpkins and coworkers expanded the Effenberger cyclization to the
total synthesis of clusianone and a formal synthesis of garsubellin A by synthesizing a
late intermediate in Danishefsky‘s synthesis; 63,129 furthermore, they also advanced to a
later intermediate in the synthesis of nemorosone from the common
bicyclo[3.3.1]nonanetrione intermediate.
2.4.1 Progress towards the synthesis of nemorosone
Simpkins and coworkers followed the same strategy towards nemorosone that
they applied for the synthesis of clusianone (Scheme 2.25). 128
91

O
1 6 8
L D A , - 7 8 o C
p r e n y l b r o m i d e
( 7 7 % )
O
2 2 6
M e M g B r ( 1 . 5 e q )
C u I ( 1 0 % )
T H F , M e 2 S , 0 o C
( 8 8 % )
O
T B S C l , E t 3 N , N a I
C H 3 C N , r e f l u x
( 87 %)
227 228
O T B S 1 . m a l o n y l d i c h l o r i d e
E t 2 O , 2 0 o C , 2 4 h
2 . B n E t 3 N C l , K O H
H 2 O , r t , 6 h
O
O
O H
229
M e 2 S O 4 , K 2 C O 3
A c e t o n e , r e f l u x , 1 h
( 2 9 % )
M e O
O
2 3 0
O
+
O
O
2 3 1
O M e
Scheme 2.25: Simpkins’ synthesis towards nemorosone, part 1
The synthesis of nemorosone began with known enone 168 151 (Scheme 2.25), which was
converted to intermediate 226 after prenylation in 77% yield. Conjugate addition of
MeMgBr followed by protection of the ketone with a TBS group gave silyl enol ether
intermediate 228 in 88% and 87% yields respectively. The Effenberger cyclization was
observed under Stoltz‘s conditions to give the bicyclo[3.3.1]nonane trione intermediate
229, and, without purification, the enol was converted to two isomers of methyl enol
ether (230 and 231) using Me 2 SO 4 in the presence of a base in 29% yield.
92

O
1 . L T M P , - 7 8 o C
2 . L i ( 2 - T h ) C u C N , , 4 0 o C
O
M e O
2 3 0
O
3 . p r e n y l b r o m i d e
- 7 8 o C - - 4 0 o C
( 7 4 % )
M e O
O
2 3 2
2 3 2
1 . L D A , T M S C
7 8 o C - 0 o C
O
2 . I 2
( 6 0 % )
M e O
O
2 3 3
Scheme 2.26: Simpkins’ synthesis towards nemorosone, part 2
The next step was to install the iodine group at the bridgehead C(1) center.
Following Danishefsky‘s strategy, 129 halogen–metal exchange would be used incorporate
the acyl group (Scheme 2.26). The intermediate 232 was isolated in 74% yield after it
was prenylated at C(3) via a higher order cyanocuprate. When attempting the iodination
at the bridgehead carbon using LDA, TMSCl and iodine, the unexpected triene product
233 was isolated in 60% yield.
93

O
1 . L T M P , 7 8 o C
O
M e O
2 3 0
O
2 . T M S C l
( 7 8 % )
M e O
O
T M S
234
2 3 4
1 . L D A , T M S C l
- 7 8 o C - 0 o C
2 . I 2
( 40 %)
O
I
M e O O
T M S
235
Scheme 2.27: Simpkins’ synthesis towards nemorosone, part 2
As a result, the alkylation and acylation steps were reversed. Compound 230 was
protected at C(3) with LiTMP and TMSCl to give 243 in 78% yield. Then, bridgehead
iodide 235 was obtained after using Danishefsky‘s reaction conditions in 40% yield
(Scheme 2.27). The iodo intermediate 235 was an important intermediate towards the
synthesis of nemorosone; however, authors did not carry out further reactions with this
intermediate due to a lack of materials.
94

2.4.2. Formal synthesis of garsubellin A
O
L D A
P r e n y l b r o m i d e
( 7 1 % )
O
1 6 8 2 3 6
M e M g B r , C u I ( c a t )
T H F / D M S
( 7 0 % )
O
2 3 7
T B S C l , N a I
E t 3 N , M e C N
r e f l u x
( 9 5 % )
O T B S 1 . m a l o n y l d i c h o r i d e
E t 2 O
2 3 8
2 . B n N E t 3 C l , K O H
H 2 O
H O
m C P B A
O
O
H
H O
C H 2 C l 2
O ( 22 % f o r 2 s t e p s ) H O
230 239
H
O
Scheme 2.28: Simpkins’ formal synthesis of garsubellin A, part 1
Simpkins‘ formal synthesis of garsubellin A began with prenylation of the known enone
168 151 to given an -prenylated enone intermediate 236 in 71% yield (Scheme 2.28). The
Cu-catalyzed conjugate addition of MeMgBr to enone 236 followed by TBS protection
gave silyl enol ether intermediate 238 in 70% and 90% yields, respectively. The
Effenberger cyclization was carried out with malonyl dichloride and silyl enol ether 238,
which yielded bicyclo[3.3.1]nonanetrione 230. Next, tricyclic intermediate 239 was
obtained via an epoxidation–cyclization sequence with mCPBA in 22% yield over two
steps. The diastereomeric ratio for the epoxidation-cyclization was 2:1, and the major
product was found to have the desired stereochemistry. The synthesis was continued with
the desired isomer.
95

2 3 9
T M S C l , I m
D M A P , D M F
( 9 0 % )
T M S O
H O
O
H
O
2 4 0
2 4 0
1 . L T M P , T H F
L i ( 2 - T h ) C u C N
a l l y l b r o m i d e
( 5 0 % )
2 . E t 3 N - H F , T H F
( 9 3 % )
H O
H O
O
H
O
2 4 1
D a n i s h e f s k y ' s i n t e r m e d i a t e
t o w a r d s g a r s u b e l l i n A
Scheme 2.29: Simpkins’ formal synthesis of garsubellin A, part 2
The alcohol of tricyclic 239 was protected with a TMS group, and then allylation
of C(3) with LTMP, Li(2-Th)CuCN and allyl bromide; desilylation and conversion of the
allyl group to a prenyl group via Grubbs cross-metathesis gave Danishefsky‘s
intermediate 241 in his garsubellin A synthesis (Scheme 2.29). 63 The above synthetic
strategy broadened the applicability of the Effenberger cyclization and also has a widened
applicability to bridgehead metalation in the synthesis of PPAPs.
In 2007, Marazano and coworkers published a similar approach towards the
synthesis of clusianone. 125 The key step to the bicyclo[3.31]trione core structure involved
the Effenberger cyclization approach, 147 the main difference between Simpkins‘ and
Marazano‘s approach being that Simpkins used a methyl enol ether, whereas Marazano
used a silyl enol ether (Scheme 2.30).
96

O
E f f e n b e r g e r
c y c l i z a t i o n
H O
O
O
P h
112
C l
O S i M e 3
242
O O
C l
216
Scheme 2.30: Marazano’s retrosynthetic analysis of clusianone
O
i - P r I ( 3 e q )
O
L D A , T H F
O H
K 2 C O 3 ( 4 e q )
M e 2 C O , r e f l u x
243 ( 90 %)
244
2 4 5
O
O
O
M e L i , T H F
H C l
( 9 2 % 2 s t e p )
L D A , H M P T
p r e n y l b r o m i d e
O
p r e n y l b r o m i d e
O
M e C u
B f 3 . E t 2 O
( 85 %)
246
O
O
247 248
( 248 / 249 : 7 / 3 , 82 %)
2 4 9
Scheme 2.31: Marazano’s synthesis of clusianone, part 1
Marazano‘s synthesis started with the protection of the known prenylated -
diketone 243 with i-PrI in the presence of a base, which gave the enol ether intermediate
244 in 90% yield (Scheme 2.31). The second prenylated product 245 was obtained when
treated with LDA and prenyl bromide, and, without purification, it was transformed to
97

intermediate 246 after methylation and acidification in 92% yield for the over two steps.
The diastereomers 248 and 249 were isolated in 82% yield after conjugate addition of
MeCu to 246 followed by a third prenylation. 125
O
O
T M S O T f
O S i M e 3
2 4 8
2 4 9
C H 2 C l 2
( q u a n t i t a t i v e )
2 4 2
Scheme 2.32. Marazano’s synthesis of clusianone, part 2
The mixture of cyclohexanone intermediates 248 and 249 were converted to the silyl enol
ether intermediate 242 in quantitative yield (Scheme 2.32).
O S i M e 3
O
O
C l
C l
H O
O
2 4 2
1 . T M S O T f ( 0 . 2 e q )
C H 2 C l 2 , 10 o C , 1 h
t h e n 15 o C , 5 h
2 . D M A P
( 38 %)
O
2 5 0
Scheme 2.33: Marazano’s synthesis of clusianone, part 3
Treatment of 242 with malonyl dichloride (1 eq) in the presence of 0.2 eq TMSOTf at
−10 C gave the desired bicyclo[3.3.1]trione intermediate, in 35% yield. An unexpected
lavandulyl-substituted phloroglucinol derivative 250 was also obtained in 38% yield
(Scheme 2.33). However, after changing the Lewis acid TMSOTf to BF 3 ∙Et 2 O, the
98

desired bicyclic product 251 was obtained in 35% yield. A by-product, cyclic ether 252
was also isolated in 25% yield. The compound 252 is significant because it has a C(7)
endo prenyl group (Scheme 2.34).
O S i M e 3
2 4 2
C l
O
O
C l
1 . B F 3 . E t 2 O ( 0 . 2 e q )
C H 2 C l 2 , - 1 0 o C , 2 h
t h e n 2 0 o C , 5 h
2 . D M A P
H O
O
O
O O
O
251 ( 35 %)
252 ( 25 %)
Scheme 2.34: Marazano’s synthesis of clusianone, part 4
99

C l
T M S
O
H
O T M S
C l
H O
2 5 3
O
H O
2 5 4
O
- H C l
T M S O
O
O
H C l
T M S O
O
O
255 256
- T M S C l - T M S C l
2 5 2 2 5 0
Scheme 2.35: Proposed mechanism for the formation of 250
The proposed mechanism for the formation of 250 proceeds through the cationic
intermediate 254, itself formed by a fragmentation process (Scheme 2.35). This cationic
intermediate 254 can be recyclized to give the bicyclo[3.3.1]trione intermediate 255 or
the lavandulyl derivative 256. Desilylation then gives 252 and 250, respectively.
100

H O
O
2 5 1
O
P h C O C N
E t 3 N , T H F
( 6 5 % )
O
H O
P h O
O
1 0 9
Scheme 2.36: Marazano’s synthesis of clusianone, part 5
Marazano and Delpech completed the total synthesis of clusianone after acylation
with PhCOCN and Et 3 N in 65% yield (Scheme 2.36). 136
2.5. Porco’s total synthesis of clusianone
In 2007, Porco and coworkers published a short synthesis of clusianone via a
tandem alkylative dearomatization-annulation process to construct the
bicyclo[3.3.1]nonanetrione core. 130 Porco and coworkers carried out several model
studies using different Michael donors and Michael acceptors.
101

2.5.1. Retrosynthetic analysis of clusianone
1 0
1
O
9
5
1 , 2 a d d i t i o n
1
9
C H O
O
7
5
M i c h a e l a d d t i o n
e l i m i n a t i o n
H O
O
3
P h
O
H O
O
3
P h
257
O
H O
2 5 8
O H
O
P h
O H
C O 2 M e
O A c
2 5 9
p r e n y l a t i o n
O H O
P h
H O O H
a c y l p h l o r o g l u c i n o l
260
Scheme 2.37: Porco’s retrosynthetic analysis of clusianone
The retrosynthetic analysis of clusianone began with the disconnection of the C(9)-C(10)
bond to give the aldehyde 257 (Scheme 2.37). Next, the C(1)-C(9) and C(5)-C(7) bonds
of 257 were going to be installed via Michael addition–elimination reactions of
clusiaphenone B 258 with -acetoxy enal 259. The clusiaphenone B 258 intermediate
would be synthesized from commercially available acylphloroglucinol 260.
102

H O
O H O
O H O
P h B r
P h
O H a q . K O H , 0 o C H O O H
( 40 %)
260 258
C O 2 M e
O A c
2 6 1
L i H M D S , T H F
( 7 0 % )
c o n v e x
O
O
O H
a d d i t i o n
e l i m i n a t i o n
M e O 2 C
C O 2 M e
O
M e O
2 6 2
O
O
P h
H O O
P h O
263
s i n g l e d i a s t e r e o m e r
Scheme 2.38: Porco’s synthesis of clusianone, part 1
The polyisoprenylated benzophenone clusiaphenone B 258 was synthesized in
40% yield by C-prenylation of acylphloroglucinol 260 (Scheme 2.38). 137 The reaction of
clusiaphenone B intermediate 260 with -acetoxymethyl acrylate 261 in the presence of
LiHMDS at 0 C allowed for a diastereoselective dearomatization–annulation process in
which an additional Michael–elimination reaction occurred to afford the
bicyclo[3.3.1]nonanetrione intermediate 263 in 70% yield. NMR data and X-ray crystal
structure of the p-bromobenzoate of the enol ether derivative confirmed the backbone
structure of the bicyclo intermediate 263. The second acrylate molecule approached the
262 from the convex face; this resulted in an addition–elimination process, yielding a
single diastereomeric bicyclo intermediate 262. After screening several analogs of
clusiaphenone derivatives and acrylate derivatives, the authors discovered the sterically
hindered -acetoxymethyl acrylate derivatives do not undergo the second addition–
elimination process, and the reaction stopped after the reaction of the first acrylate
derivative with the clusiaphenone derivative.
103

C H O
O A c
H O
2 5 8
O H
O
P h
O H
2 5 9
1 . K H M D S , T H F , 6 5 o C
2 . T M S C H N 2 , i P r 2 N E t
C H 3 C N , M e O H
( 5 4 % )
1
M e O
C H O
O
3
5
O P h
264
O
M g B r
1 . T H F , 7 8 o C
2 . A c 2 O , i P r 2 N E t , D M A P
C H 2 C l 2 , 0 o C t o r t
( 7 4 % )
M e O
1
O
O
O A c
3
5
P h
O
1 . P d ( P P h 3 ) 4 , H C O 2 N H 4
t o l u e n e , 1 0 5 o C
( 9 0 % )
2 . G r u b b s C a t
2 - m e t h y l - 2 - b u t e n e
( 8 9 % )
M e O
2 6 5 2 6 6
1
O
O
3
5
P h
O
L i O H , d i o x a n e
, ( 7 7 % )
o r
L i C l , D M S O
, ( 8 9 % )
1
Scheme 2.39: Porco’s synthesis of clusianone, part 2
Treatment of clusiaphenone B 258 with KHMDS and -acetoxy enal 259 in THF
afforded the desired annulated product (Scheme 2.39). Without purification, the crude
compound was transformed to its methyl enol ether 264 in 54% yield. 137 The addition of
vinylmagnesium bromide to the aldehyde 264 followed by acetylation of the resultant
alcohol yielded the allylic ester 265 in 74% yield. The Pd-catalyzed formate reduction 142
of 265 afforded the C-7 allyl intermediate in 90% yield. Next, the C-7 allyl group was
converted to a prenyl group with the Grubbs cross-metathesis 138 reaction to give O-
methylclusianone 266 in 89% yield. The total synthesis of clusianone was completed
after demethylation of 266 with the help of LiOH in dioxane or LiCl in DMSO (77% and
89% yield, respectively).
104

2.6. Other approaches towards PPAPs
In addition to the above synthetic routes towards PPAPs, several groups have
contributed and are still contributing to the goal of finding more paths towards the
synthesis of not only garsubellin A, clusianone, or nemorosone but also more complex
PPAPs such as hyperforin and xanthochymol.
2.6.1. Nicolaou’s Se-mediated electrophilic cyclization approach
In 1999, Nicolaou and coworkers published the first synthetic effort toward
PPAPs in which they prepared a model compound of garsubellin A. 124,139 The group
initially developed the selenium-mediated cyclization to build the bicyclo[3.3.1]nonane
core structure and applied this method towards their synthesis of the model compound
267 (Scheme 2.40).
H 3 C C H 3
S O 2 P h
H O
H 3 C
H 3 C
H O
7
O
3
H 3 C C H 3
C H 3
C H 3
O
C H 3
O
C H 3
g a r s u b e l l i n A ( 1 8 )
7
H O
O
M e O 3
2 6 7
C H 3
C H 3
O
O
H
O
O
Scheme 2.40: Nicolaou’s model compound of garsubellin A
105

S e P h
O
O
H 3 C
268
O
O A c O M e
C H 3
N - P S P
S n C l 4 , C H 2 C l 2
9 5 %
O
O
S e P h
O
O A c
C O 2 M e
O
O
C H 3
C H 3
C O 2 M e
2 7 0
2 6 9
Scheme 2.41: Nicolaou’s Se-mediated electrophilic cyclization approach, part 1
In the synthesis, allylic enol acetate intermediate 268 was treated with
N-(phenylseleno)phthalimide (N-PSP) and SnCl 4 at –78 C;
this enol intermediate
underwent selenium-induced cyclization via the proposed intermediate 269 to grant the
desired bicyclo product 270 (Scheme 2.41).
O
O
S e P h
C H 3
O C H 3
C O 2 M e
2 7 0
1 . L i A l H ( O t B u ) 3
T H F ( 9 5 % )
2 . L i H M D S
S O 2 P h
P h O 2 S
T H F ( 8 2 % )
3 . n B u 3 S n H
A I B N ( 9 3 % )
Scheme 2.42: Nicolaou’s Se-mediated electrophilic cyclization approach, part 2
O
O
S O 2 P h
7 C H 3
H O C H 3
C O 2 M e
2 7 1
2 6 7
Later, Nicolaou‘s group successfully applied Se-mediated electrocyclization to achieve
their target 267. The reduction of 270 with LiAl(O t Bu) 3 in THF, then treatment of the
resulted alcohol with LiHMDS and trans-bis(phenylsulfonyl)ethylene followed by
106

addition of nBu 3 SnH and AIBN gave intermediate 271 (Scheme 2.42). After a few
reactions from 271, Nicolaou‘s group was able to complete the model synthesis of 267.
2.6.2. Nicolaou’s Michael addition–aldol reaction approach
In 2005, Nicolaou and coworkers tried an alternative approach to construct the
bicyclo[3.3.1]nonane core of the model systems hyperforin and perforatumone (Scheme
2.43). 152 They used acrolein derivatives and cyclic -keto ester derivatives (272) in a
Michael addition–aldol reaction pathway to form the desired bicyclic core structure of
PPAPs (Scheme 2.44).
.
H 3 C C H 3
7
O
C H 3
O
O
O O
H O
3
C H 3
O
C H 3
O
O
H 3 C C H 3
h y p e r f o r i n ( 1 )
p e r f o r a t u m o n e
Scheme 2.43: Hyperforin and perforatumone
107

M e
O
M e
C H O
O
M e
M i c h a e l a d d i t i o n
a l d o l
M e
M e
O H
273
M e
272
O
O O
o x i d a t i o n
M e
M e
M e
275
M e
M e
O
O
f r a g m e n t a t i o n O O
O
O
M e
M e
M e
M e
M e
H O
.
O M e
274
276
Scheme 2.44: Nicolaou’s Michael addition-aldol reaction approach
The bicyclic enone intermediate 274 was observed after the Michael addition–
aldol reaction of methacrolein and -keto ester 272 followed by oxidation. This reaction
strategy could be an effective and short method to synthesize the bicyclic core of
hyperforin and other PPAPs. Next, dihydroxylation and fragmentation of intermediate
274 afforded intermediate 276 and, after this, transformation took place via intermediate
275.
2.6.3. Kraus’s Mn-mediated oxidative free radical cyclication approach
Kraus and coworkers utilized a Mn(III) acetate and Cu(II) acetate-based,
oxidative free-radical Snider protocol 153 to construct the bicyclic ring core 279 of PPAPs
(Scheme 2.45). 154,155
M e
O
M e
O
O H
M e
108

O 1 . M n ( O A c ) 3
O B r 1 . N a O H H O O
C O 2 M e C u ( O A c ) 3 H C O 2 M e
H C O 2 M e
2 . 3 . 5 e q N B S O
2 . 140 o C
O
( 55 % 2 s t e p s )
277 278 279
Scheme 2.45: Kraus’s Mn-mediated oxidative free radical cyclication approach
The reaction of keto ester 277 with Mn(OAc) 3 (2 eq) and Cu(OAc) 3 (1 eq)
predominantly gave bicyclo intermediate 280. Then, bromination of 280 with 3.5
equivalents of NBS resulted 278 in 55% yield. Substitution of the bromide 278 with O-
allyl followed by Claisen rearrangement gave expected 279. The yields for the last two
steps were not reported.
O C O 2 M e
2 7 9
M n ( O A c ) 3
C u ( O A c ) 3
H
2 8 0
O
C O 2 M e
( 3 ) M n O
-( M n ( I I ) O
C O 2 M e
C O 2 M e
2 8 1 2 8 2
Scheme 2.46: Proposed mechanism for the Mn mediated cyclization
A possible mechanism for the Mn mediated cyclization of 279 can be proposed as
follows (Scheme 2.46). The Mn(III) reacts with the carbonyl oxygen to form Mn(III)-
based enol ether intermediate 281, which undergoes an electron transfer with loss of
109

Mn(II) to afford a stable keto radical. Then, the radical reacts with the electrons of the
double bond to give a 6-endo cyclic radical product; Cu(III) is then added to oxidize this
resultant radical product. 153
2.6.3. Kraus’s addition elimination-addition approach
Kraus and coworkers have come up with an alternative pathway to create the
bicyclic core structure of PPAPs via a Michael addition–elimination reactions of cyclic -
ketoester 283 and -sulfonate acrolein (284) derivative 285 (Scheme 2.47). 156
M e
M e
O C O 2 M e
2 8 3
S O 2 P h
O A c
284
O A c
N a H
( 71 %)
O O C O C O 2 M e
t B u t B u O K
2 8 6
S O 2 P h
( 5 6 % )
M e
O O A c t
C O 2 M e B u O K
t
S O 2 P h B u C O C l
( 80 %)
285
S O 2 P h
H O
M e C O 2 M e
O
287
Scheme 2.47: Kraus’s addition elimination-addition approach, part 1
Michael addition-elimination of cyclic -keto ester 283 and gave 285 in 71%
yield and then, acetate 285 was converted to pivalate 286 in 80% yield. Reaction of 286
with t BuOK afforded 287 in 56% yield.
110

M e
O C O 2 M e
2 8 8
O
O M e
1 . t B u O K
H O
M e
2 . 1 5 e q u i v . t B u O H
6 e q u i v . N a , N H 3
( 8 5 % )
O H
T I P S O
1 . P C C , c e l i t e
C O 2 M e C H M e
2 C l 2 , 87 %
2 . T I P S O T f , K H
289
O
C O 2 M e
2 9 0
Scheme 2.48: Kraus’s addition elimination-addition approach, part 2
Recently, Kraus and coworkers applied Michael addition–elimination to construct
a bicyclic intermediate 290 (Scheme 2.48). 157 Reaction of keto ester 288 and methyl
acrylate followed by Birch reduction and cyclization gave diol 289 in 85% yield. Then,
the compound 289 was oxidized with PCC and the resulting diketone was silylated to
give 290.
2.6.4. Mehta’s Pd-mediated oxidative cyclization
In 2004, Mehta and coworkers published the first enantiospecific approach
towards PPAPs; they performed this feat by synthesizing the bicyclic framework 31 using
Kende cyclization. 158,159 The stereochemistry at C(7) was established by starting the
synthesis with -pinene.
111

O
L D A , T M S C l
- p i n e n e 2 9 1
O T M S
P d ( O A c ) 2
2 9 2
C H 3 C N - D C M
( 3 0 % t w o s t e p s )
O
2 9 3
Scheme 2.49: Mehta’s Pd-mediated oxidative cyclization
(−)--Pinene was converted to ketone 291 after several steps. Then the compound 291
was transformed to the TMS enol ether 292. Pd(OAc) 2 -mediated Kende cyclization gave
bicyclic intermediate 293 in 30% yield over 2 steps (Scheme 2.49). 158
2.6.5. Mehta’s intramolecular enol lactonization, retro-aldol and re-aldol cyclization
In recent years, Mehta and coworkers published another pathway to construct the
bicyclic 36 by using intramolecular enol-lactonization followed by a retro-aldol–aldol
strategy (Scheme 2.50). 160
112

O
2 9 4
1 . L D A
p r e n y l b r o m i d e
( 6 9 % )
2 . m e t h y l a c r y l a t e
t B u O K
( 7 4 % )
C O 2 M e
O
K O H , M e O H
6 0 o C ( 8 3 % )
2 9 5 2 9 6
O
O
D I B A L - H
C H 2 C l 2
( 6 2 % )
O
O H
1 . P C C , C H 2 C l 2
( 9 1 % )
2 . L D A
p r e n y l b r o m i d e
( 7 0 % )
O
2 9 8
O
2 9 7
Scheme 2.50: Mehta’s intramolecular enol lactonization
LDA mediated regioselective prenylation of 294 gave prenylated ketone in 69%
yield and the reaction of the resulting ketone with methyl acrylate gave keto ester 295 in
74% yield. Hydrolysis of ester 295 under basic conditions followed by lactonization gave
296 in 83% yield. Then, DIBAL-H assisted retro-aldol and aldol reactions of 296 gave
expected bicyclo alcohol 35 in 62% yield. Oxidation of 297 with PCC and LDApromoted
prenylation gave 298 (Scheme 2.50).
2.6.6. Young’s intramolecular allene-nitrile oxide [3 + 2] cycloaddtion
Young and coworkers published a unique synthetic route to construct the bicyclic
core structure of 303 using intramolecular allene-nitrile oxide [3 + 2] cycloaddition
(Scheme 2.51). 161
113

M e
M e
O T M S
2 9 9
M e O N O 2
M e O
300
M e
T i C l 4
( 44 %)
M e
M e
M e
O
3 0 1
N O 2
O M e
P h N C O
E t 3 N
( 4 0 % )
N
O
H
R a n e y N i , H 2 N O M e
2
M e
M e O M e O H , 100 % M e
M e
O O
M e
M e
M e
M e
302 303
Scheme 2.51: Young’s intramolecular allene-nitrile oxide [3 + 2] cycloaddtion
Lewis acid-catalyzed Mukaiyama aldol condensation of silyl enol ether 299 and
300 gave methoxy diastereomers 301 in 44% yield. Then, 301 was allowed to react with
phenyl isocyanate in refluxing benzene to give 302. Finally, reductive cleavage of 302
gave 303 in quantitative yield.
2.6.7. Grossman’s alkynylation–aldol approach
Grossman and Ciochina, in 2003, published another approach towards the
construction of the bicyclo[3.3.1]nonane ring core of PPAPs. 162 The main idea was to
prepare the bicyclo ring by an intramolecular aldol reaction of a cis enal. Grossman
explained that the cis enal creates better reaction moiety with an enol or enolate and
better undergoes intramolecular aldol reactions than a regular aldehyde. Grossman and
Ciochina attempted this new idea towards a synthesis of compound 39 (Scheme 2.52). 162
114

M e O 2 C
O
3 0 4
E t O
E t O
S n B u 3
1 . P d ( O A c ) 4
( 4 8 % )
2 . H C O 2 H
( 7 1 % )
M e O 2 C
C H O
O
3 0 5
1 . C o 2 ( C O ) 8
( 8 7 % )
2 . E t 3 S i H
T M S T M S
( 94 %)
E t 3 S i
O
M e O 2 C
O
1 . c a t . 6 N a q H C l
( 7 2 % )
2 . N M O / T P A P
( 8 7 % )
S i E t 3
O
O
C O 2 M e
3 0 6
3 0 7
Scheme 2.52: Grossman’s alkynylation–aldol approach
Reaction of the diketone 304 with Pb(OAc) 4 followed by addition of alkynyltributyltin
gave -alkynylated product in 48% yield. Then, acid-mediated deprotection of resulting
product gave alynal 305 in 71% yield. The alynal 305 was then reacted with Co 2 (CO) 8 to
give the Co 2 (CO) 6 complex in 87% yield, and syn hydrosilylation of the resulting
complex gave (E)--silyl eneal 306 in 94% yield with complete regio- and
stereoselectivity. Acid catalyzed cyclization of 306 gave two diastereomeric alcohols (1:1
dr) in 72% yield, and oxidation of these alcohols with NMO and TPAP gave -silyl
enone 307 in 87% yield.
115

2.6.8. Nakada’s Lewis acid promoted regioselective ring-opening reaction of the
cyclopropane approach
In 2006, Nadaka and coworkers published another approach towards the
construction of the bicyclic core structure of PPAPs. 163 The key reaction in this approach
was the Lewis acid mediated, region selective ring-opening of tricyclic[4.4.0.0]dec-2-ene
derivative 311 to grant the bicyclo[3.3.1]nonane core structure 312 (Scheme 2.53). 163,164
M e O
M e O
3 0 8
M e O
M e O
1 . N a C l O 2 , N a H 2 P O 4
O T B D P S 2 . C D I
( E t O 2 C C H 2 C O 2 ) 2 M g
C H O
O T B D P S
3 1 1
O
C O 2 E t
3 . T s N 3 , T E A
( 6 4 % 3 s t e p s )
Z n C l 2
( 7 0 % t w o s t e p s )
E t O 2 C
M e O O T B D P S
[ C u O T f ] 2 . C 6 H 6 ( 5 m o l %)
O
N 2
M e O L i g a n d 310 ( 15 m o l %)
C O 2 E t
309
O H
O
3 1 2
O M e
O T B D P S
O
N N
310
O
Scheme 2.53: Nakada’s Lewis acid promoted regioselective ring-opening
The aldehyde 308 was successfully synthesized from a commercially available
source. Then, aldehyde 308 was oxidized to its carboxylic acid, which was converted to a
-keto ester and thence to -diazo -keto ester 309 in 64% yield over three steps.
Compound 309 was allowed to react with CuOTf (5 mol%) and ligand 310 to give the
tricyclo[4.4.0.0]dec-2-ene 311. Without isolating the resulted tricyclic compound, a
Lewis acid-promoted ring-opening reaction was carried out to give bicyclic intermediate
312.
116

2.6.9. Takagi’s acid catalyzed cyclization approach towards adamantane core of
plukenetione type PPAPs
For the first time, Takagi and coworkers published an acid-catalyzed cyclization
approach towards the synthesis of the adamantane core 319 of the plukenetione type
PPAPs (Scheme 2.54). 165
C O 2 E t
O A c
H O
O
314
O 1 . L i B H 4
O E t
1 . L D A
O E t ( 100 %)
92 %
2 . M e L i ( 78 %)
E t O 2 C
H O
2 . K 2 C O 3 ( 3 e q u i v )
O E t
3 . P d ( O H ) 2 / C
T B A B ( 1 e q u i v )
t O
315 B u O O H
( 55 %)
316
313
C s 2 C O 3 , O 2
( 58 %)
O 1 . T M S C l
O
O E t i m i d a z o l e
O E t
C r O 3 , 3 , 5 - D M P
( 85 % t w o s t e p s )
H O
T M S O
2 . L T M P
O
O b e n z o y l c h l o r i d e
O
317 ( 88 %)
318
T f O H , C H 2 C l 2
O
O
( 5 9 % )
O
3 1 9
O
Scheme 2.54: Takagi’s acid catalyzed cyclization approach towards adamantane
core
LDA-mediated successive Michael reaction of enone 313 with acrylate 314 gave the -
alkylated product in 92% yield. Treatment of the resulted ketone with K 2 CO 3 and TBAB
gave annulation product 315 in 55% yield. The carbonyl group of 315 was reduced with
LiBH 4, and then, gem dimethyl groups were introduced with MeLi, and Pd-catalyzed
117

allylic oxidation gave keto enol intermediate 316. The secondary alcohol group was
oxidized, and the tertiary alcohol then protected with TMS group to prevent a hetero-
Michael reaction. A benzoyl group was attached to the -position of the enone using
LTMP and benzoyl chloride. Finally, acid-catalyzed cyclization gave 319 in 59% yield.
Copyright © Pushpa Suresh Jayasekara Mudiyanselage 2010
118

Chapter 3. Our synthesis towards 7-epi-clusianone
Many of the PPAPs have shown potentially useful bioactivity, such as anticancer,
antibiotic and anti-HIV activity. For example hyperforin, a type A PPAP widely known
for its anti-depression activity, is considered to be the main bioactive agent in Hypericum
perforatum L (St. John‘s wort). 16,61,72 The type B PPAPs xanthochymol 17 and garcinol 14
have shown antibiotic activity against methicillin-resistant S. aureus. 43 PPAPs are often
found in bitter-tasting fruits that have been popular in folk medicine, and most PPAPs
that have been tested for toxicity have shown low toxicity. 166 Apart from PPAPs‘
interesting bioactivities, their structures are enriched with acyl group, prenyl groups,
geranyl groups and many adjacent quaternary centers, and a bicyclo[3.3.1] chemical
moiety with specific stereochemistry, making them challenging to synthesis. 24
Though PPAPs are very promising targets for organic synthesis considering their
intriguing biological activity, challenging structure and wide spread human consumption,
only three PPAPs — (±)-garsubellin A, (±)-nemorosone and (±)-clusianone — have so
far been made synthetically. 63,125-130 PPAPs have been known for decades, but the first
synthetic effort was reported only in 1999 by Prof. Nicolaou. After a decade from the
first synthetic effort, only three PPAPs have been synthesized by a total of seven
publications from five research groups. All synthetic strategies have been focused on
PPAPs that have a prenyl group at C(7) with exo stereochemistry. However, a large
majority of type B and large minority of type A PPAPs have the C(7) prenyl group in the
more sterically congested endo orientation. Our goal is to develop a stereocontrolled
synthesis towards the C(7) endo type B PPAP, 7-epi-clusianone. To date, there are no
synthetic efforts found in the literature towards 7-epi-clusianone. Like many PPAPs, 7-
epi-clusianone has shown very interesting bioactivities such as anticancer and antibiotic
properties. 73,91,113-115
119

3.1. Initial retrosynthetic analysis
O
5
O
O
a c y l a t i o n ,
1 G r u b b s I I
7
O H
P h
O
O
i n t r a m o l e c u l a r
a l d o l O
O H
O
320 321 a
C H O
O
3 2 1 b
S t i l l - G e n n a r i
M e O
O
O
1 7 a l l y l a t i o n
M e O c a r b o x y l a t i o n
5
O
O
O
322 323 324
O
3 2 5
O
Scheme 3.1: Our initial retrosynthetic analysis
Our initial retrosynthetic analysis of 7-epi-clusianone (101) (Scheme 3.1) began with the
disconnection of the benzoyl group and replacement of the sensitive prenyl groups with
more robust allyl group to give bicyclo[3.3.1]nonanetrione intermediate 320. The C(2)-O
bond and C(4)-C(5) bonds were disconnected to give the cis enal intermediate 321. This
compound might cyclize by an intramolecular aldol reaction (IA) from 321a, but would
be expected to assume its thermodynamically more favorable conformer and
diastereomer 321b. We believed that the 321a-321b equilibrium could be shifted towards
321a during the IA reaction. We thought the cis enal of 321 could be made from the -
allyl--ketoester intermediate 322. The -ketoester intermediate 323 could be obtained
after disconnection of axial allylic group of intermediate 322. From a stereochemical
point of view, it would be crucial to establish the cis relationship between the C(1) ester
and C(7) allyl group of 322 to install the C(7) endo stereochemistry of our target.
Intermediate 323 could be synthesized from tetrasubstituted cyclohexanone 324, which
could be synthesized easily from commercially available 1,3-cyclohexanedione (325).
120

3.2 Forward synthesis
Our forward synthesis began from the commercially available, cheap 1,3-
cyclohexanedione.
3.2.1 Synthesis of 2,4-diallyl-3-methyl-2-cyclohexenone
O
K O H / C u
O
O H
O
O a l l y l b r o m i d e O 5 % p T s O H . 2 H 2 O O
( 47 %)
B e n z e n e , r e f l u x
325 326 ( 75 %)
327
Scheme 3.2: Synthesis of 2,4-diallyl-3-methyl-2-cyclohexenone
Allylation of 1,3-cyclohexanedione with KOH and allyl bromide gave -allyl-diketone
326 in 47% yield. 167 The original paper claimed 79% yield for this reaction after
crystallization. The role of Cu in the reaction is unclear, but yields are better in its
presence. Diketone 326 was converted to its vinylogous ester 327 with isobutyl alcohol,
and a catalytic amount of p-TsOH∙2H 2 O in benzene in 75% yield (Scheme 3.2). 151,168
121

3.2.2 Allylation, methylation and acidification
O
O
L D A
B r
O
O
M e L i
1 N H C l
( 8 9 % )
3 2 7 3 2 8 3 2 9
O
Scheme 3.3: Allylation, methylation and acidification
The allylation at the -position of intermediate 327 gave ´-diallylic
vinylogous ester 328. 169 Without purification, the crude oily compound was subjected to
methylation followed by acidification to give intermediate 2,4-diallyl-3-methyl-2-
cyclohexenone 329 in 89% yield (Scheme 3.3). 151
3.2.3 Alternate pathway towards 2,4-diallyl-3-methyl-2-cyclohexeone.
We also devised another route to 11 that began with methyl acetoacetate.
3.2.3.1 Allylation
O
O
3 3 0
O
O O
N a H / T H F
N a H / B u L i
O
B r
55 ° C
B r 0 ° C
( 73 - 81 %)
331
( 67 %)
O
3 3 2
O
O
Scheme 3.4: Alternate pathway towards 2,4-diallyl-3-methyl-2-cyclohexeone
Methyl -allylacetoacetate 331 was obtained from commercially available
methylacetoacetate, NaH and allyl bromide in 73–81% yield. 170 The intermediate 331
122

was transformed to -allylic intermediate 332 with the agency of NaH, BuLi and allyl
bromide in 67% yield (Scheme 3.4). 171
3.2.3.2 Michael addition, cyclization and decarboxylation
O
O
O
O
P P h 3 , C H 3 C N
O
( 74 %)
332 O
333
O
O
N a O M e
M e O H
O
H O +
O
334
O
O
O
3 5
L i I 2 H 2 O
D M S O
( f o r 2 s t e p s 8 7 % )
O
3 3 6
Scheme 3.5: Michael addition, cyclization and decarboxylation
The Michael addition of diallylic β-ketoester intermediate 332 to acrolein catalyzed
by triphenylphosphine in acetonitrile gave β-ketoester aldehyde intermediate 333 in 74%
yield. To close the ring, an aldol reaction was performed on intermediate 333 with
sodium methoxide in methanol to give the β-ketoester 334 and carboxylic acid 335
intermediates. The mixture of 334 and 335 was decarboxylated under Krapcho conditions
to afford α,β-unsaturated ketone 336 in 87% yield over 2 steps (Scheme 3.5). 172
123

O O H O
M e L i / C e C l 3
P C C
T H F , 0 o C , 2 h
S i l i c a g e l
( 85 %)
( 68 %)
336 337 329
Scheme 3.6: Methylation of cyclohexenone intermediate 336 using MeLi/CeCl 3
Methylation of cyclohexenone intermediate 336 using MeLi/CeCl 3 afforded
alcohol 337 in 85% yield, and PCC oxidation 173 gave cyclohexenone 329 in 68% yield
(Scheme 3.6). 174
3.2.4 Conjugate addition, trapping enolate with TMS group followed by desilylation
O
M e 2 C u L i
O T M S
T B A F
O
329 T M S C l
E t 3 N
D M P U
( 84 %)
338
T H F
( 80 %)
( d r = 3 : 1 )
3 2 4
Scheme 3.7: Conjugate addition, trapping enole with TMS group followed by
desilylation
Conjugate addition of Me 2 CuLi to 2,4-diallyl-3-methyl-2-cyclohexenone 329
followed by simultaneous trapping of the resulting enolate with TMSCl gave TMS enol
ether 338 in 84% yield. 175 Direct conjugate addition without trapping the enolate resulted
in low yields. The TMS group was then removed to get 2,4-diallyl-3,3-
dimethylcyclohexanone 324 in 3:1 diastereomeric ratio in 80% yield (Scheme 3.7). 68
124

3.2.5. Carbonylation and allylation
O
O
O
M e O O M e
M e O
N a H / c a t . K H
O
P d ( P h 3 ) 4
O A c
3 2 4
B e n z e n e , r e f l u x
3 2 3
E t 3 N
M e O H , 6 0 o C
O
M e O
O
+
M e O
O
O
( 4 6 % ) ( 3 2 % )
3 2 2 a 3 2 2 b
Scheme 3.8: Carbonylation and allylation
The 2,4-diallyl-3,3-dimethylcyclohexanone 324 was converted to -keto ester 323 with
dimethyl carbonate, cat. KH and NaH in benzene. 176 Mander‘s carboxylation with LDA
and MeO 2 CCN failed in this system. The catalytic amount of KH was not necessary for
the reaction to proceed, but it gave cleaner crude product. Without further purification,
Pd-catalyzed allylation of 323 with allyl acetate and triethylamine in methanol gave
diastereomeric allylic products 322a and 322b. The major diastereomer was 322a, an
axial allylic product, as confirmed using NMR studies (Scheme 3.8).
125

3.2.5.1. Structure and stereochemistry determination of 322a
H
O
H
H C H 3
O
2
H
4
H
H 3 C
H
H
H
6
O M e
H
H
Figure 3.1: Structure and stereochemistry determination of 322a using NOE
The 1 H NMR chemical shifts of 322a and 322b were assigned by COSY
experiments, and the stereochemistry of 322a was unambiguously determined by a
NOESY experiment. In particular, the C(6) and C(4) H atoms and the H atoms of the
C(2) allyl group all had strong NOE interactions, confirming that they were all axial.
3.2.6. Reduction and oxidation
M e O
O
O
L i A l H 4
E t 2 O
H O
O H
D e s s - M a r t i n
p e r i o d i n a n e
C H 2 C l 2
( 50 %)
3 2 2 a 3 3 9 3 4 0
H
O
O
Scheme 3.9: Reduction and oxidation of 322a
126

Keto ester 322a was reduced to its diol 339 with LAlH 4 in Et 2 O. 177 The crude product of
339 was oxidized to keto aldehyde 340 with Dess–Martin periodinane in CH 2 Cl 2 in 50%
yield (Scheme 3.9). 178
3.2.7 Still–Gennari reaction, reduction and oxidation
H
O
C F
C F 3
3
O
O
O
O O M e O M e
P
O
341
O O
1 . L i A l H 4
N a H M D S
2 . D e s s - M a r t i n
T H F
p e r i o d i n a n e
( 82 %)
( 45 %)
340 342
( 15 : 1 d r )
O
H
O
+
H
O
O
3 2 1
3 4 3
Scheme 3.10: Still–Gennari reaction, reduction and oxidation
The keto aldehyde 340 was converted to Z unsaturated ester 342 using highly
stereoselective modified Horner–Emmons olefination with bis(trifluoroethyl)phosphonoacetate
341 and NaHMDS in THF in 82% yield and 15.1 dr. 179 Without separation,
LiAlH 4 reduction followed by Dess–Martin periodinane oxidation gave the key
intermediate Z aldehyde 321 in 45% yield along with a small amount of 343 (Scheme
3.10). 177,178
127

3.2.8 Aldol reaction
O
H
O
?
O
O H
3 2 1
3 4 4
Scheme 3.11: Aldol reaction
We were anticipating the intramolecular aldol reaction of 321 to result in the
bicyclo[3.3.1]nonane core structure 344 (Scheme 3.11).
3.2.8.1 Aldol reaction under acidic conditions
O
H
O
H +
H
O
O
S o l v e n t
3 2 1
3 4 5
Scheme 3.12: Aldol reaction under acidic conditions
Unfortunately, all our attempts to carry out the aldol reaction in acidic medium
resulted in the isomerization of 321 to the E aldehyde 345 (Scheme 3.12) (Table 1).
128

Table 3.1: Acid and solvent used for aldol reaction
Acid
Solvent
6 M HCl THF
TFA CH 2 Cl 2
THF
Conc. H 2 SO 4
Triflic acid
THF
THF
We initially used HCl, TFA and conc. H 2 SO 4 for the reaction (Table 1). We
hypothesized that, the acids‘ conjugate bases were capable of assisting the conversion of
321 to 345 (Scheme 3.13).
H +
O
H
O
A -
H + A -
S o l v e n t
H
O
O
A
O H
H
O
H
O
A
H
O
Scheme 3.13: Proposed mechanism for cis-trans isomerization
129

Therefore, we exposed 321 to triflic acid, whose conjugate base (CF 3 SO 3 - ) was
nonnucloephilic, but the result was the same.
3.2.8.2 Aldol reaction under basic conditions
O
H
O
B a s e
O
O
H
3 2 1 3 4 6
Scheme 3.14: Aldol reaction under basic conditions
Table 3.2: Bases and solvent used for aldol reaction
Base
NaH
t-BuOK
NaH/KOH
LDA
KOH
Solvent
Benzene
THF
Benzene
THF
MeOH
130

Unfortunately, even in the various basic conditions (Table 2), we did not observe
any signs of an aldol reaction. The main isolated product was the bicyclic unsaturated
lactone 346 (Scheme 3.14), the product of a Tishchenko reaction.
After analyzing the above data, it became very clear that the Z aldehyde 321 was
strongly inhibited from enolizing under acidic or basic conditions, which was necessary
for a successful aldol product.
3.3 The role of 1,2-allylic strain
H C H 3
H C H 3
H
H H
C H 3
C H 3
H 3 C C H 3
H
H
H
H 3 C
C H 3
C H 3
H
3 4 7 a
3 4 7 b 3 4 7 c
Scheme 3.15: The role of 1,2-allylic strain
The 1,2-allylic strain (1,2-A strain) is defined as the steric interaction between the alkene
moiety and the methyl group in compound 347. This interaction plays an important role
in influencing the conformational equilibria of the alkenes. 180,181 For example, steric
interactions between the geminal dimethyl groups and the C(sp 2 ) methyl group
destabilize 347b compared to 347a and 347c (Scheme 3.15). 181
131

C H O
C H O
O
H O
3 2 1 b
3 2 1 c
O
H O
O
3 2 1 a
O
3 2 1 d
Scheme 3.16: 1,2-allylic strain of 321
We hypothesized that 1,2-A strain inhibited the enol and enolate formation in 321,
as necessary for the aldol reaction (Scheme 3.16). The conformation 321d, the most
important intermediate for intramolecular aldol product and the enolate form of 321a,
experiences severe 1,2-A strain. This factor may raise the energy of the 321d sufficiently
high that the aldol reaction cannot proceed at a reasonable rate
132

3.4 Redesigning the synthesis
The outcome of our initial route encouraged us to redesign the synthesis in a way to
minimize the 1,2-A strain of the enolate intermediate for the aldol reaction. Considering
these factors, we thought to disconnect the C(1)-C(2) bond of 2 instead of C(4)-C(5)
(Scheme 18) to get the intermediate (Z)-keto aldehyde 27 (27a and 27b) for the
intramolecular aldol reaction.
O
9
5
O
O
1
2
2 7
O H
P h
7
a c y l a t i o n ,
G r u b b s I I
O
H O
1
2
O
3 2 0
i n t r a m o l e c u l a r
a l d o l
O
2
1
O
O
O
C O 2 M e
348 a C H O 348 b
349
O
a l l y l a t i o n
O
O
C O 2 M e
350 351
Scheme 3.17: Second retrosynthetic analysis
3 2 5
O
3.4.1 New retrosynthetic analysis
The C(4)-O bond and C(1)-C(2) (instead of C(4)-C(5)) bonds of 320 were
disconnected to give cis enal intermediate 348. We thought that this compound might
cyclize by an intramolecular aldol reaction (IA) from 348a, but we expected it to assume
its thermodynamically more favorable conformer 348b. We believed that the 348a–348b
equilibrium could be shifted towards 348a during the IA reaction. The enolate of 348

would not be expected to have significant 1,2-allylic strain. We thought the cis enal of
348 could be made from -allyl -ketoester intermediate 349. The -ketoester
intermediate 350 could be obtained after disconnection of the axial allylic group of
intermediate 349. From a stereochemical point of view, it would be crucial to allylate 350
trans to the C(7) allyl group in order to install the C(7) endo stereochemistry of our
target. Intermediate 350 could be synthesized from disubstituted cyclohexenone 351,
which could be synthesized easily from commercially available 1,3-cyclohexanedione
(Scheme 3.17).
3.4.2 Forward synthesis
Our forward synthesis began with the synthesis of 4-allyl-3-methylcyclohexenone
from the commercially available, inexpensive starting material 1,3-cyclohexanedione.
3.4.2.1 Isobutyl protection, allylation, methylation and acidification
O
3 2 5
O
H 3 C
H 3 C
O H
5 % p T s O H . 2 H 2 O
B e n z e n e , r e f l u x
( 9 5 % )
O
1 . L D A
B r
O
2 . M e L i
3 . 1 N H C l
352
( 90 %)
H 3 C C H 3
O
3 5 1
Scheme 3.18: Isobutyl protection, allylation, methylation and acidification
The 1,3-cyclohexanedione was converted to its vinylogous ester 352 in 95%
yield. Ketone 352 was allylated with LDA and allyl bromide. 146 Without purification, the
crude oily material was subjected to methylation 151 followed by acidification to give 4-
allyl-3-methyl-2-cyclohexenone 351 in 90% yield over 3 steps (Scheme 3.18).
134

3.4.2.2 Conjugate addition and carbonylation
1 . M e 2 C u L i
E t 2 O , 0 o C
O
2 . C H 3 O C O C N O
H M P A
O O M e
351 ( 71 %)
350
Scheme 3.19: Conjugate addition and carbonylation
To the resulted enone 351, dimethylcuprate, HMPA, and methyl cyanoformate
were added, and -keto ester intermediate 350 was obtained in 71% yield (Scheme
3.19). 182 The reaction produced approximately equal amounts of O-acylation and C-
acylation without the co-solvent HMPA. A common replacement for HMPA is DMPU,
but the reaction gave lower yields with DMPU, and in higher scale we obtained
substantial amounts of recovered by-products.
3.4.2.3 Allylation and Claisen rearrangement
O A c
O
O
O M e
350
5 % P d ( P P h 3 ) 4
E t 3 N , M e o H
Scheme 3.20: Failed Pd-catalyzed allylation reaction
The introduction of an axial allyl group to the -position of 350 was important to
establish the C(7) endo stereochemistry of the target molecule. Unfortunately, the Pd-
135

catalyzed allylation reaction failed, possibly due to steric hindrance around the reaction
moiety (Scheme 3.20).
O
O
O M e
3 5 0
N a H
B r
T H F , r e f l u x
( 75 %)
O
O
O M e
353
Scheme 3.21: O-allylation
However, NaH and allyl bromide gave the O-allylated product 353 in 75% yield
(Scheme 21), 183 and heating the allyl enol ether intermediate 353 at 150 C in toluene in a
sealed tube gave two diastereomeric Claisen rearrangement products, 354a and 354b, in
3:1 d.r (Scheme 3.22). 126
O
O
O M e
3 5 3
T o l u e n e
1 5 0 o C
o v e r n i g h t
( 1 0 0 % )
( d r = 3 : 1 )
O
O
O M e
3 5 4 a
+
M e O
O
O
3 5 4 b
Scheme 3.22: Claisen rearrangement
After carefully analyzing COSY and NOESY spectra of the two isomers, we found that
the major product, 354a, had the desired trans relationship between the two allylic
groups. In particular, one of the C(2) allylic H atoms had strong NOE interactions with
136

the C(4) H and the C(3) methyl H atoms, which confirmed that C(2) allylic group was
axial.
C H 3
H
H
H
H
4
H 3 C
H
6
H
H
2
O
C O 2 M e
H
H
Figure 3.2: Steriochemistry determination of 354a using NOE
137

3.4.2.3.1 Structure and stereochemistry determination of 354a
3.4.2.3.2 Proposed model for the stereochemical products for the Claisen
rearrangement
O
O
O M e
3 5 3
O
M e O 2 C
T S 1
C O 2 M e
O
T S 2
O
O
M e O 2 C
C O 2 M e
T S 3
T S 4
O
O O M e
354 a
( d r = 3 : 1 )
M e O O
O
354 b
Scheme 3.23: Proposed model for the stereochemical products for the Claisen
rearrangement
The stereoselectivity can be explained as above (Scheme 3.23). The most stable
conformation of 353 is half-chair with the C(7) allyl group in the equatorial position. For
the Claisen rearrangement, 353 can go though the TS1, TS2, TS3 and TS4 transition
states to afford 354a or 354b (Scheme 24). In TS1, the Claisen rearrangement proceeds
on the top face to avoid the steric repulsion from C(6) axial methyl group, where TS2
experiences steric interactions between the C(6) methyl group and the incoming allyl
group. As a result, TS1 has lower energy, resulting in the diastereomer 354a
predominantly. TS3 and TS4 have higher energy transitions due to steric repulsion from
the C(4) allyl group.
138

3.4.2.4 Methyl enol ether protection, reduction and oxidation
O
O O M e
( M e O ) 3 C H
H 2 S O 4 , M e O H
M e O
O
24 h , R T
( 95 %)
O M e
3 5 4 a 3 5 5
1 . L i A l H 4 / E t h e r
2 . D M P / C H 2 C l 2
M e O
( 91 % f o r 2 s t e p s ) O
H
3 5 6
Scheme 3.24: Methyl enol ether protection, reduction and oxidation
The ketone of -keto ester intermediate 354a was protected with trimethyl
orthoformate and a catalytic amount of concentrated sulfuric acid in methanol to give the
enol ether intermediate 355 in 95% yield. 184 The aldehyde 356 was obtained in 91%
yield after LiAlH 4 reduction followed by Dess–Martin periodinane oxidation (Scheme
3.24). 177,178
Our original plan was to convert the aldehyde 346 to its cis enal with the Still–
Gennari reagent, which we used in the previous synthesis. 179 Unfortunately, the expected
reaction failed, possibly due to the steric crowdedness of the reaction center. As a result,
we decided to proceed with two sequential one-carbon homologations of the aldehyde.
3.4.2.5 Alkynylation
M e O
O
B u L i
T M S C H N 2
H 0 o C t o R T M e O
356 ( 66 %)
357
Scheme 3.25: Alkynylation
139

The aldehyde 356 was then converted to keto-protected terminal alkyne 357 with
lithiated TMSCHN 2 in 66% yield. Methyl enol ether protection was crucial for this
reaction. Other protecting groups such as a triethylsilyl group caused many equivalents
(10 eq) of the reagents to be required, and the yields were variable (Scheme 3.25). 184,185
3.4.2.6 O-Allylation and carbonylation
M e O
3 5 7
a l l y l O H , T s O H
B e n z e n e
( 9 6 % )
O
3 5 8
C O , P d C l 2
C u C l 2 , N a O A c O
M e O H ,
( 72 %)
M e O 2 C 359
Scheme 3.26: O-Allylation and carbonylation
The methyl enol ether 357 was transformed into its allyl enol ether 358 in 96%
yield by refluxing in allyl alcohol and a catalytic pTsOH∙2H 2 O in benzene. 186 Onecarbon
homologation of alkyne 358 was carried out using palladium-catalyzed
carbonylation in methanol to afford alkynoate 359 in 72% yield (Scheme 3.26). 187
3.4.2.7 Reduction, Claisen rearrangement and oxidation
1 . L i A l H 4 , E t 2 O
- 7 8 o C t o - 3 0 o C
( 9 4 % )
D M P / C H 2 C l 2
O
M e O 2 C
3 5 9
2 . P y r i d i n e ,
( 7 5 % )
O
H O H 2 C
3 6 0
( 7 8 % )
O
O H C
3 6 1
Scheme 3.27: Reduction, Claisen rearrangement and oxidation
140

After LiAlH 4 reduction of 359, Claisen rearrangement in pyridine heated in a
sealed tube gave the C-allylic ketone intermediate 360 in 75% yield. 186 Dess–Martin
oxidation then gave alkynal 361 in 78% yield (Scheme 3.27).
3.4.2.8 Syn reduction of alkynal and intramolecular aldol reaction
The syn reduction of the alkynal moiety of intermediate 39 was very crucial for
the intramolecular aldol reaction. The reduction had to be carried out in the presence of
several allyl groups in a sterically crowded environment. Palladium-catalyzed
hydrogenation reactions are very commonly used for syn reduction of alkynes, but they
gave multiple products in the present system, 188-190 including reduction of double
bonds. 190
3.4.2.8.1 Complex with Co 2 (CO) 8 and hydrosilylation
One method for syn reduction of complex systems like this was to heat the Co 2 (CO) 6
complex of the sterically hindered alkyne with Et 3 SiH. 162
O
O H C
1 . C o 2 ( C O ) 8
C H 2 C l 2 , R T
( 60 %)
O
H
2 . E t 3 S i H , ( C l C H 2 ) 2
T M S T M S E t 3 S i C H O
361 60 o C , 1 h
362
( 58 %)
Scheme 3.28: Complex with Co 2 (CO) 8 and hydrosilylation
141

In the present case, alkynal 361 reacted with Co 2 (CO) 8 to give the Co 2 (CO) 6
complex in 60% yield. The Co 2 (CO) 6 complex was treated with Et 3 SiH and
Me 3 SiC≡CSiMe 3 in (CH 2 Cl) 2 to give (E)-α-silyl enal 362 in 58% yield with complete
regio- and stereoselectivity (Scheme 3.28). However, the 1 H NMR spectrum of Co 2 (CO) 6
complex appeared very broad, the yields were not consistent, and the reaction was very
slow.
O
O
a q . H C l / T H F 1 . D M P / C H 2 C l 2
O
S i E t 3
H
O H
2 . T B A F / T H F
E t 3 S i C H O
( 25 % f o r 3 s t e p s )
362 363
3 6 4
O
Scheme 3.29: Intramolecular aldol product
Nevertheless, sufficient amounts of enal 362 were obtained to subject it to acidic
conditions to promote an intramolecular aldol (IA) reaction. The IA product,
bicyclo[3.3.1]-nonane intermediate 363, was obtained as two diastereomers (1:1).
Without purification, 363 was oxidized with Dess–Martin‘s periodinane, 178 and
desilylation with TBAF gave the bicyclo[3.3.1]nonane target 364 in 25% yield over 3
steps (Scheme 3.29). 191,192 An X-ray crystallographic study of 364 established its
structure unambiguously.
142

Figure 3.3: X-ray data structure of 364
The successful preparation of the 7-endo-allylbicyclo[3.3.1]nonane skeleton
shows the validity of our approach to synthesis 7-endo PPAPs and supports our
hypothesis on the failure of our initial route.
3.4.2.8.2 Hydrostannylation
Even though this is a viable route to 364, the observed poor yields for the last few
steps restricted the amount of material for further reactions towards the target molecule.
Examples of hydrogenation of alkynals, apart from the H 2 and transition metal catalyst
reactions, are very limited in the literature. But the Pd-catalyzed syn hydrostannylation of
alkynoates is a well known reaction. 193,194 Even though there was no precedent for the
hydrostannylation of alkynals, we decided to try to hydrostannylate our alkynal
intermediate 361.
143

O
O H C
3 6 1
10 %
P d ( P P h 3 ) 4 O
H
B u 3 S n H
( 84 %) H
C H O
348
Scheme 3.30: Hydrogenation
The result was very surprising. Instead of hydrostannylation, we observed a
highly stereoselective syn hydrogenation to give product 348 in 84% yield (dr = 90:10).
If we increased the reaction temperature, larger amounts of the other isomer (trans/anti)
were obtained. The mechanism of the above reaction is unclear at the moment (Scheme
3.30).
3.4.2.8.3 Addition of thiophenol to keto alkynal 39
S H
O
O H C
3 6 1
c a t . N a O E t
T H F
O S H
O H C
365
Scheme 3.31: Addition of thiophenol to keto alkynal 39
In another potential approach to a cis-enal, addition of thiophenol to ynal 361
gave enal 365 as a single diastereomer. Unfortunately, NOESY experiments showed that
the isomer that we obtained was the (Z)-enal, 365, which was not a suitable substrate for
the intramolecular aldol reaction (Scheme 3.31). In particular, the C(2) H atom of enal
had strong NOE interaction with H atoms of C(4) allylic, C(5) methyl and aromatic ring,
which confirmed that C(2) H atom and aldehyde H atom were trans to each other. We
further confirmed the stereochemistry by the chemical shift of C(2) H atom (6.61
ppm). 195,196
144

3.4.2.8.4 Structure and stereochemistry determination of 365
C H 3
H
H
O
S
O
6
C H 3
4
H
H
H
2
H
Figure 3.4: Structure and stereochemistry determination of 365
3.4.2.8.5 Intramolecular aldol and oxidation reactions
O
H
H C H O
348
1 . N a O E t
E t O H
2 . D e s s - M a r t i n
p e r i o d i n a n e
( 8 8 % )
O
3 6 4
O
Scheme 3.32: Intramolecular aldol and oxidation reactions
The intramolecular aldol reaction of hydrostannylation product 348 under acidic
conditions 162 yielded both the desired aldol product and the trans isomer of the
intermediate 348. However, under basic conditions, the intramolecular aldol product was
observed as a clean mixture of two diastereomeric products. 197 Without purification, the
alcohol was oxidized with Dess–Martin periodinane to grant the bicyclo[3.3.1]nonane
intermediate 364 in 78% yield for the last 2 steps (Scheme 3.32). 178 The syn reduction of
145

the alkyne alkynal 361 with Bu 3 SnH, intramolecular aldol reaction, and oxidation gave
higher yields than the previous pathway towards 364.
3.4.3 Attempts to form the 2,4,9-triketone system
O
?
O
O H
O
O
3 6 4 3 2 0
Scheme 3.33: Attempts to form the 2,4,9-triketone system
Our next goal was to install the hydroxyl group on the -position of the
intermediate 364 to afford the intermediate 320. Previous model studies of our group 190
and recently published results by Marazano and Delpech 198 had shown that many
common tools such as epoxidation across the -unsaturated double bond followed by
ring opening and oxidation failed to give the target product. In the dissertation of Dr.
Ciochina, apart from the epoxidation, she attempted several pathways towards the
formation of a 2,4,9-triketone intermediate, such as silylation, borylation, and other paths,
but none of these routes were successful (Scheme 3.33). 190 Therefore it was urgent and
necessary to develop new pathways towards the 2,4,9-triketone intermediate 320.
3.4.3.1. Curtius rearrangement approach
3.4.3.1.1. Synthetic plan 1
Our plan to prepare the 2,4,9-triketone intermediate is shown in Scheme 3.34. We
thought we would introduce the methyl group or a MOM-protected hydroxymethyl group
in a 1,2-addition to the C(2) ketone from the less hindered side. Then allylic oxidation
with rearrangement, deprotection and oxidation might gave the keto acid which might
146

undergo Curtius rearrangement to give the -amino enone. Acidic workup would then
give the target intermediate.
O
O
1 , 2 a d d i t i o n
O
R
O H
P C C
O
O
R
o x i d a t i o n
O
O
C u r t i u s
r e a r r a n g e m e n t
O
O
C O O H
O H
Scheme 3.34: Curtius rearrangement approach, plan 1
3.4.3.1.2. 1,2-addition of Bu 3 SnCH 2 OMOM and allylic oxidation
O
3 6 4
O
B u 3 S n
O M O M
366
B u L i
( 6 2 % )
O
3 6 7
O M O M
O H
P C C
S . M r e c o v e r e d
C r O 3 , H 2 S O 4 O
A c e t o n e
O
C r O 3 , 3 , 5 - d i m e t h y l p y r a z o l e
3 6 4
C H 2 C l 2
Scheme 3.35: 1,2-addition of Bu 3 SnCH 2 OMOM and allylic oxidation
The 1,2-addition product intermediate 367 was obtained in 62% yield after the
reaction of intermediate 364 with 366 and BuLi. 199 However, allylic oxidation of 367
with PCC gave only starting material, whereas Jones oxidation 200 and CrO 3 oxidation in
the presence of 3,5-dimethylpyrazole gave back diketone 364 (Scheme 3.35).
147

H +
O O O
H +
H
O O +
O
O
O
H
O
C r
O
O
O H
367
O H
O
H
O
H O
O O
C r
O H
O
O
3 6 4
O
Scheme 3.36: Proposed mechanism of oxidative cleavage
We hypothesized that CrO 3 was capable of assisting the conversion of 367 to
diketone 364 via the mechanism shown (Scheme 3.36).
3.4.3.1.3. 1,2-addition of MeLi and allylic oxidation
O
M e L i
O
O T H F
O H
364 ( 75 %)
368
P C C , s i l i c a
C H 2 C l 2
C r O 3 , H 2 S O 4
O
O
+ + S M
O
369 364
Scheme 3.37: 1,2 addition of MeLi and allylic oxidation
The diketone 364 was transformed to alcohol 368 via 1,2-addition of MeLi in
THF in 75% yield. 201 Unfortunately, allylic oxidation of 368 failed with PCC. We
observed only the 1,2-eliminated product 369 and starting diketone 364 (Scheme 3.37).
148

3.4.3.1.4. Synthetic plan 2
O
1 . M e 2 C u L i
O
o x i d a t i o n
O
2 . d e s a t u r a t i o n
O
3 6 4
O
C O 2 H
O
1 .
O
( P h O ) 2 P
N 3
O
( C u r t i u s r e a r r a n g e m e n t )
2 . a q . H C l
O
1 . G r u b b s I I
M e 2 C = C H M e
O
O H
2 . E t 3 N
320 O
P h C N
99
O
O H
O
P h
Scheme 3.38: Curtius rearrangement approach, plan 2
Since our previous reaction plan was unsuccessful, we devised another synthetic
plan to prepare the 2,4,9-triketone. We thought to introduce a methyl group by 1,4-
addition to the enone and reinstall the double bond to give -methylated enone. Then,
oxidation of the -methyl group to give a carboxylic acid might be followed by Curtius
rearrangement and acidic workup to achieve the target intermediate (Scheme 3.38)
3.4.3.1.5. Me 2 CuLi addition to bicyclo enone 364
O
O
O
O R
3 6 4
3 6 8 : R = H
3 7 0 : R = T M S
Scheme 3.39: Me 2 CuLi addition to bicyclo enone 364
149

Table 3.3: Reagents and conditions of Me 2 CuLi addition
Reagent/Solvent Temperature Product
Me 2 CuLi/Et 2 O
0 o C 368
(CuI/MeLi)
−15 o C 368
−40 o C 368
−78 o C 368
Me 2 CuLi/ TMSCl/ Et 2 O −78 o C 370
(CuI/MeLi)
Me 2 CuLi/ TMSCl/Et 2 O −78 o C- −40 o C 370
(CuCN/MeLi)
Me 2 CuLi/ Et 2 O
(CuBr.Me 2 S/MeLi)
−78 o C- −40 o C 368
Unfortunately, all attempts at 1,4-addition to 364 gave the unexpected 1,2-adduct
370. We hypothesized that C(4) was too hindered, and the boat conformation of 364
made C(4) even more hindered to methylate (Scheme 3.39) (Table 3).
150

Figure 3.2: X-ray structure of 1,2-adduct 368
3.6. Experimental Section
For all the compounds reported, the melting points were taken on an Electrothermal 910
and the IR data were collected on a Nicolet Magna-IR 560 spectrometer. The 400 MHz
1 H NMR and 100 MHz 13 C NMR data were collected on a Varian VXR-400S. The 50
MHz 13 C NMR data were collected on a Varian Gemini 200.
O
O
O
323
151

Methyl 3,5-diallyl-4,4-dimethyl-2-oxocyclohexanecarboxylate (323):
A mixture of NaH (0.50 g, 12.5 mmol), dimethyl carbonate (4.24 mL, 50.0 mmol) and
2,4-diallyl-3,3-dimethyl-cyclohexanone (1.03 g, 5.00 mmol) in dry benzene (24.0 mL)
was refluxed for 1 hour under N 2. Then, a catalytic amount of KH (10.0 mg) was added.
The resulting mixture was further refluxed overnight at 80-83 C. The cooled reaction
mixture was acidified with acetic acid (2.10 mL) and partitioned with a mixture of ether
and water. The organic layer was washed with water and brine and dried over MgSO 4 .
Evaporation of the solvent left a colorless oil which was used for the next reaction step
without further purification. 1 H NMR (400 MHz, CDCl 3 ): 12.2 (s, 1H), 5.54 (m, 2H),
5.10 (m, 4H), 3.3 (s, 3H), 2.79 (dd, J d = 14.10 Hz, J d = 6.53 Hz, 1H), 2.52 (m, 1H), 2.41
(dd, J d = 14.79 Hz J d = 10.32 Hz, 1H), 2.26 (m, 1H), 2.0-1.7 (m, 3H), 1.1 (m, 1H), 1.00
(s, 3H), 0.8 (s, 3H). 13 C NMR (400 MHz, CDCl 3 ): 195.1, 158.6, 124.1, 123.7, 120.1,
105.8, 103.5, 102.2, 42.7, 39.2, 29.6, 28.3, 24.4, 24.2, 20.4, 18.0, 14.6, 10.0, 9.5. Calcd
for C 16 H 24 O 3 .
O
O
O
322a
Methyl (1R * ,3S) 1,3,5-triallyl-4,4-dimethyl-2-oxocyclohexanecarboxylate (322a):
A solution of crude keto ester (1.52 g, 5.00 mmol), allyl acetate (0.60 mL, 5.50 mmol),
triethyl amine (0.50 mL, 5.50 mmol) and Pd(PPh 3 ) 4 (5 mol%, 0.28 g, 0.25 mmol) in 10
mL of methanol was refluxed under nitrogen atmosphere overnight. The solution was
evaporated to dryness under a vacuum, the residue was dissolved in ether and the solution
was filtered through a short silica column. Solvents were evaporated, and the resulting
152

yellow colored crude product was then chromatographed with 10% EtOAc and petroleum
ether. The major diastereomer 322a (0.69 g, 2.30 mmol, 46%) was isolated. 1 H NMR
(400 MHz, C 6 D 6 ): 5.83 (m, 2H), 5.48(m, 1H), 5.01 (m, 6H), 3.42 (s, 3H), 2.7 (dd, J d =
14.0 Hz J d = 7 Hz, 2H), 2.48 (dd, dd, J d = 7.3 Hz J d = 3.5 Hz, 1H), 2.29 (dd, dd, J d = 2.4
Hz J d = 9.7 Hz, 1H), 2.20 (t, J = 13.5 Hz, 1H), 2.16 (dddd, J d = 10.5 Hz J d = 4.1 Hz J d =
1.5 Hz J d = 1.8 Hz, 1H), 2.05 (dd, J d = 14.3 Hz J d = 3.3 Hz, 1H), 1.9 (dddd, J d = 14.0 Hz
J d = 7.7 Hz J d = 1.1 Hz J d = 1.1 Hz, 1H), 1.52 (m, 2H), 0.8 (s, 3H), 0.3 (s, 3H). Calcd for
C 19 H 28 O 3 .
2D NMR data for compound 322a
153

O
H
O
340
(1R * ,3R)-1,3,5-triallyl-4,4-dimethyl-2-oxocyclohexanecarboxaldehyde (340):
The keto ester 322a (0.14 g, 0.46 mmol) was dissolved in 10 mL of dry ether and cooled
to 0 C. Then lithium aluminum hydride (0.05 g, 1.40 mmol) was added and slowly
warmed to room temperature. The reaction mixture was stirred for 2.5 hours and again
cooled to 0 C, and then the reaction mixture was quenched with 0.05 mL of water, 0.05
mL of 15% NaOH and 0.15 mL of water. White precipitate was filtered and the filtrate
was collected in a round-bottom flask. The ether was evaporated and the crude product
used to carry out the next reaction.
The crude alcohol was dissolved in 3.8 mL of CH 2 Cl 2 at room temperature. In a
separate round-bottom flask, Dess–Martin periodinane (0.54 g, 1.3 mmol) was dissolved
154

in 1.5 mL of CH 2 Cl 2 and added slowly to the reaction mixture. This was then stirred 4 h
at room temperature and after the reaction was complete, 1.3 mL of 1M NaOH was added
and the organic component was extracted with ether. The ether layer was then washed
with water and brine and dried with anhydrous Na 2 SO 4 . The organic solvents were
evaporated and the remaining crude oil was chromatographed with 5% ethyl acetate and
petroleum ether to give 0.064 g (50%, 0.232 mmol) of 340. 1 H NMR (400 MHz, CDCl 3 ):
9.48 (s, 1H), 5.57 (m, 1H), 5.52 (m, 2H), 5.05 (m, 6H), 2.74 (m, 1H), 2.44 (m, 2H),
2.23 (m, 2H), 1.75 (m, 1H), 1.60 (m, 3H), 1.42 (m, 1H), 0.85 (s, 3H), 0.38 (s, 3H). Calcd
for C 18 H 26 O 2 .
O
O
O
342
Methyl (Z)-3- ((1R * ,3R)-1,3,5-triallyl-4,4-dimethyl-2-oxocyclohexyl)acrylate (342):
A solution of bis(2,2,2-trifluoroethyl) (methoxycarbonylmethyl)phosphonate (0.3 g, 1.0
mmol) in 20 mL of dry THF was cooled to –78 C under nitrogen and treated with
NaHMDS (0.5 mL, 2.0 M in THF, 1.0 mmol). The keto aldehyde 340 (0.27 g, 1.0 mmol)
was then added and the resulting mixture was stirred for 1 h at –78 C. TLC was taken
and the reaction was quenched with saturated NH 4 Cl. The products were extracted into
ether ( 3 mL). The ether layer was then washed with water and brine and dried with
anhydrous Na 2 SO 4 . The organic solvents were evaporated and the remaining crude oil
was chromatographed with 5% ethyl acetate and petroleum ether to give 0.27 g (0.82
mmol, 82%) of 342. 1 H NMR (400 MHz, CDCl 3 ): 6.60 (d, 13.07 Hz, 1H), 5.91 (d,
13.07 Hz, 1H), 5.70 (m, 2H), 5.41 (m, 1H), 4.02 (m, 6H), 3.68 (s, 3H), 2.95 (m, 2H), 2.61
(m, 1H), 2.58 (m, 2H), 2.41 (m, 2H), 2.10 (m, 1H), 1.95 (m, 1H), 2.64 (m, 1H), 1.14 (s,
3H), 0,63 (s, 3H). 13 C NMR (400 MHz, CDCl 3 ): 210.0, 166.7¸147.4, 138.6, 137.8,
155

133.1, 121.1, 118.4, 116.4, 115.3, 56.8, 54.2, 51.2, 43.8, 42.4, 40.7, 38.0, 34.7, 28.2, 27.2,
15.2. Calcd for C 21 H 30 O 3 .
O
O
H
321
(Z)-3-((1R * ,3R)-1,3,5-triallyl-4,4-dimethyl-2-oxocyclohexyl)acrylaldehyde (321):
The enester 342 (0.14 g, 1.00 mmol) was dissolved in 20 mL of dry ether and cooled to 0
C. Lithium aluminum hydride (0.11 g, 2.80 mmol) was added and slowly warmed to
room temperature. The reaction mixture was stirred for 4 hours and again cooled to 0 C,
and then the reaction mixture was quenched with 0.1 mL of water, 0.1 mL of 15% NaOH
and 0.3 mL of water. White precipitate was filtered and the filtrate was collected into a
round-bottom flask. The ether was evaporated and the crude products used to carry out
the next reaction.
The crude alcohol was dissolved in 8 mL of CH 2 Cl 2 at room temperature. In a
separate round-bottom flask, Dess–Martin periodinane (1.08 g, 2.60 mmol) was dissolved
in 3 mL of CH 2 Cl 2 and added slowly to the reaction mixture. This was then stirred 4h at
room temperature and after the reaction was completed, 2.6 mL of 1 M NaOH was added
and the organic component was extracted with ether. The ether layer was then washed
with water and brine and dried with anhydrous Na 2 SO 4 . The organic solvents were
evaporated and the remaining crude oil was chromatographed with 5% ethyl acetate and
petroleum ether to give 0.15 g (0.50 mmol, 50%) of 2. 1 H NMR (400 MHz, CDCl 3 ):
9.53 (d, 7.91 Hz, 1H), 6.52 (d, 12.73 Hz, 1H), 5.99 (dd, J d = 12.73 Hz, J d = 8.26 Hz,
1H), 5.71 (m, 2H), 5.43 (m, 1H), 5.0 ( m, 6H), 2.86 (dd, J d = 14.1, J d = 6.88 Hz, 1H), 2.58
(m, 3H), 2.41 (ddd, J d = 16.51 Hz, J d = 5.16 Hz, J d = 2.4 Hz, 1H), 2.31 (dd, J d = 14.1 Hz,
156

J d = 3.78 Hz, 1H), 2.23 (ddd, J d = 13.07 Hz, J d = 7.23 Hz, J d = 1.38 Hz, 1H), 1,94 (m,
1H), 1.58 (m, 2H), 1.1 (s, 3H). 13 C NMR (400 MHz, CDCl 3 ): 209.9, 192.0, 150.1,
138.0, 137.3, 131.64, 131.1, 120.0, 117.0, 115.9, 57.3, 55.3, 43.8, 43.6, 42.7, 41.8, 34.6,
28.0, 27.0, 15.4. Calcd for C 20 H 28 O 2 .
O
O
346
(2Z,4aR * ,6R,9S)-4a,6,8-Triallyl-7,7-dimethyl-4a,5,6,7,8,8a-hexahydro-2H-chromen-
2-one (346):
The enal 342 (0.03 g, 0.10 mmol) was dissolved in THF (0.50 mL) and t BuOK was added
slowly at the room temperature. Then the mixture was stirred for 3 h and TLC was taken.
The reaction was quenched with water and extracted with ether (5 mL). The ether layer
was then washed with water and brine and dried with anhydrous Na 2 SO 4 . The organic
solvents were evaporated and the remaining crude oil was chromatographed with 5%
ethyl acetate and petroleum ether. 1 H NMR (400 MHz, CDCl 3 ): 6.63 (d, 9.63 Hz, 1H),
6.0 (m, 1H), 5.9 (d, 9.28 Hz, 1H), 5.56 (m, 2H), 5.0 (m, 6H), 4.0 (d, 12.04 Hz, 1H), 2.44
(dd, 8.26 Hz, 1H), 2.30 (m, 1H), 2.20 (m, 4H), 1.65 ((ddd, J d = 10.04 Hz, J d = 5.16 Hz, J d
= 4.470Hz, 1H), 1.55 (m, 1H), 1.42 (m, 1H), 1.25 (s,3H), 0.66 (s, 3H). 13 C NMR (400
MHz,CDCl 3 ):
Calcd for C 20 H 28 O 2 .
157

O
O
O
350
Methyl 5-allyl-6,6-dimethyl-2-oxocyclohexanecarboxylate (350):
To a stirred suspension of copper(I) iodide (1.90 g, 10.0 mmol ) in dry diethyl ether (41.5
mL) at –5 C, MeLi (1.6 M in diethyl ether, 12.5 mL, 20.0 mmol) was added under
nitrogen atmosphere. The mixture was stirred at the same temperature (–5 C) for 1 h,
and 4-allyl-3-methylcyclohexenone (0.75 g, 5.0 mmol) in 3.6 mL of dry diethyl ether
was added very slowly. The reaction mixture was stirred for 1 h further at 0 C. HMPA (
6 mL, 36 mmol) was then added dropwise under vigorous stirring. The mixture was
cooled to –78 C, and methyl cyanoformate (2.4 mL, 24 mmol) and diethyl ether (6 mL)
were added slowly. The dry ice bath was removed, and the mixture was allowed to warm
to room temperature. After stirring 1 h at room temperature saturated aqueous NH 4 Cl/
NH 4 OH solution was added and the organic phase was extracted multiple times with
ether. The organic layers were combined, washed with brine and dried with anhydrous
NaSO 4 , and the solvent was evaporated. The resulting yellow crude product was then
chromatographed with 10% EtOAc and petroleum ether and 1.59 g (71%, 7.1 mmol) of a
mixture of diastereomers (350) was isolated. 1 H NMR (400 MHz, CDCl 3 ): 11.92 (s,
1H), 5.79 (m, 1H), 5.0 (m, 2H), 3.7 (s+m, 3H), 3.1 (s, 1H), 2.82 (m, 1H), 2.38 (m, 2H),
2.2 (m, 1H), 2.05 (m, 1H), 1.70 (m, 1H), 1.4 (m, 1H), 1.05 (s+s, 3H), 0.83 (s+s, 3H).
Calcd for C 13 H 20 O 3 .
158

O
O
O
353
Methyl 5-allyl-2-allyloxy-6,6-dimethyl-1-cyclohexenecarboxylate (353):
NaH (60% in oil, 0.53 g, 13.1 mmol) was washed with petroleum ether (10.0 mL, 3
times) in a 100 mL round-bottom flask and THF (26 mL) was added. The suspension was
cooled to 0 C, and methyl 3-allyl-2,2-dimethyl-6-oxocyclohexanecarboxylate (350)
(2.54 g, 11.4 mmol) in THF (26 mmol) was added dropwise over 5 min. The ice bath was
removed and the reaction mixture was allowed to warm to room temperature. The
reaction was stirred at room temperature for 1 h and allyl bromide (1.15 mL, 13.1 mmol)
dissolved in THF (1.40 mL) was added dropwise. After the addition, the reaction mixture
was stirred at 60 C for 36 h. TLC was taken, and the reaction mixture was then cooled in
an ice bath with water (10 mL) added dropwise. The organic components were extracted
with ether (20 mL, 3 times) and the organic layers were combined, washed with water
and brine, dried with anhydrous NaSO 4 and filtered. The filtrate was evaporated under
reduced pressure. The crude oil was chromatographed with 10% ethyl acetate and
petroleum ether to give 2.25 g (75%, 8.55 mmol) of 353. 1 H NMR (400 MHz, CDCl 3 ):
5.85 (m, 1H), 5.73 (m, 1H), 5.26 ( d, 17.12 Hz, 1H), 5.13 ( d, 10.79 Hz, 1H), 5.0 (m,
2H), 4.23 (s, 2H), 3.71 (s, 3H), 2.3 ( d, 13 Hz, 1H), 2.14 (m, 1H), 1.8 (m, 1H), 1.68 (dd,
J d = 23.08 Hz J d = 10.05 Hz, 1H), 1.4 (m, 1H), 1.28 (m,1H), 1.07 (s, 3H), 0.8 (s, 3H). 13 C
NMR (400 MHz, CDCl 3 ): 170.2, 152.2, 138.3, 121.6, 116.7, 116.2, 68.6, 51.5, 43.4,
36.1, 34.0, 27.3, 24.1, 22.6, 22.5. Calcd for C 16 H 24 O 3 .
159

O
O
O
354a
Methyl (4R*,6S)-1,3-diallyl-2,2-dimethyl-6-oxocyclohexanecarboxylate: (354a)
Methyl 5-allyl-2-(allyloxy)-6,6-dimethyl-1-cyclohexenecarboxylate (353) (2.18 g, 8.27
mmol) and dry toluene (26 mL) were heated at 150 C for 8 h in a sealed (pressure) tube.
TLC was taken, toluene was removed and crude oil was chromatographed with 10% ethyl
acetate and petroleum ether to give 2.18 g (100%, 8.27 mmol) of 354a in 3:1
diastereomeric ratio. 1 H NMR (400 MHz, CDCl 3 ): 5.70 (m, 1H), 5.60 (m, 1H), 5.01
(m, 4H), 3.70 (s, 3H), 2.72 (m, 1H), 2.55 (m, 2H), 2.37 (ddd, J d = 12.86 Hz, J d = 5.55 Hz,
J d = 1.76 Hz, 1H), 2.22 (m, 1H), 1.94 (m, 1H), 1.81 (m, 2H), 1.58 (m, 1H), 1.05 (s, 3H),
0.9 (s, 3H). 13 C NMR (400 MHz, CDCl 3 ): 207.6, 171.1, 137.6, 134.0, 117.5, 116.5,
68.7, 51.5, 42.6, 42.5, 38.0, 35.3, 33.8, 25.2, 24.6, 21.5 IR (neat): 3076, 2976, 2948,
1745, 1713, 1639, 1434, 1225 cm -1 . Calcd for C 16 H 24 O 3 .
160

2D NMR data for 354a
161

162

O
O
O
355
Methyl(4R*,6R)-1,5-diallyl-2-methoxy-6,6-dimethyl-2-cyclohexenecarboxylate (355):
Methyl 1,3-diallyl-2,2-dimethyl-6-oxocyclohexanecarboxylate (354a) (0.52 g, 2.00
mmol) and dry trimethyl orthoformate (10 mL) in methanol (2 mL) were added to a 100
mL round-bottom flask at room temperature. Then, a few drops of conc. H 2 SO 4 were
added and stirred at room temperature for 48 h. After completion of the reaction, the
solvents were completely removed. Saturated NaHCO 3 was added, and the organic
components were extracted with ether. The organic phase was washed with water and
brine and dried using anhydrous Na 2 SO 4 . The organic solvents were evaporated, and the
remaining crude oil was chromatographed with 5% ethyl acetate and petroleum ether to
give 0.52 g (1.90 mmol, 95%,) of 355. 1 H NMR (400 MHz, CDCl 3 ): 5.73 (m, 2H), 4.89
(m, 2H), 4.86 (d, 10.5 Hz, 1H), 4.47 (d, 4.84 Hz, 1H), 3.62 (s, 3H), 3.41 (s, 3H), 2.78 (m,
1H), 2.51 (dd, J d = 9.3 Hz, J d = 14.52, 1H), 2.26 (m, 1H), 2.12 (dt, J d = 16.9, J t = 5.58,
1H), 1.8-1.6 (m, 3H), 1.00 (s, 3H), 0.69 (s, 3H). 13 C NMR (400 MHz, CDCl3): 174.0,
154.4, 138.3, 137.1, 115.8, 115.0, 96.1, 59.6, 54.3, 51.4, 39.2, 38.8, 38.3, 34.3, 26.8, 22.5,
20.1. Calcd for C 17 H 26 O 3 .
163

O
O H
371
(4R*,6S)-1-Methoxy- 6-hydroxymethyl-4,4-diallyl-5,5-dimethylcyclohexene (371):
The ester (355) (3.50 g, 12.6 mmol) was dissolved in 126 mL of dry ether and the
mixture was cooled in an ice bath. Then LiAlH 4 (0.76 g, 20.1 mmol) was added very
slowly. After addition was completed, the ice bath was removed and the mixture was
stirred 4 h at room temperature. TLC was taken and the reaction mixture was again
cooled to 0 C. Then 0.75 mL of water and 0.75 mL of 10% NaOH were added. A few
minutes later another 2 mL of water was added. The reaction mixture was diluted with
ether and the solution was filtered. The filtrate was concentrated and the resulting
colorless oil was oxidized. 1 H NMR (400 MHz, CDCl 3 ): 5.83 (m, 1H), 5.77 (m, 1H),
4.95 (m, 4H), 4.72 (d, 3.35 Hz, 1H), 3.75 (dd, J d = 11.92, Hz, J d = 5.96 Hz, 1H), 3.64 (dd,
J d = 11.16, Hz, J d = 8.19 Hz, 1H), 3.42 (s, 3H), 2.50 (m, 1H), 2.24 (m, 3H), 2.11 (dt, J d =
16.74, Hz, J t = 5.22 Hz, 1H), 1.80 (m, 1H), 1,64 (m, 2H), 0.90 (s, 3H), 0.82 (s, 3H). 13 C
NMR (400 MHz, CDCl 3 ): 157.3, 138.6, 138.1, 115.5, 114.9, 95.7, 65.4, 54.0, 49.8,
39.1, 38.3, 38.2, 34.4, 27.1, 22.0, 17.9. Calcd for C 16 H 26 O 2 .
164

O
H
O
356
(1R * ,5R)-1,5-diallyl-2-methoxy-6,6-dimethyl-2-cyclohexenecarboxaldehyde (356):
The crude alcohol (371) was dissolved in 100 mL of CH 2 Cl 2 at room temperature. In a
separate round-bottom flask, Dess–Martin periodinane (7.50 g, 17.6 mmol) was dissolved
in 40 mL of CH 2 Cl 2 and added slowly to the reaction mixture. This was then stirred 4h at
room temperature. After the reaction was complete, 75 mL of 1M NaOH was added and
the organic components were extracted with ether. The ether layer was then washed with
water and brine and dried with anhydrous Na 2 SO 4 . The organic solvents were evaporated
and the remaining crude oil was chromatographed with 5% ethyl acetate and petroleum
ether to give 3.34 g (11.2 mmol, 89%) of 356. 1 H NMR (400 MHz, CDCl 3 ): 9.61 (s,
1H), 5.70 (m, 2H), 4.95 (m, 5H), 3.41 (s, 3H), 2.70 (dd, J d = 8.57 Hz, J d = 5.24 Hz, 1H),
2.21 (m, 3H), 1.7 (m, 3H), 0.93 (s, 3H), 0.87 (s, 3H). 13 C NMR (400 MHz, CDCl 3 ):
205.1, 154.1, 137.9, 136.6, 116.0, 114.8, 96.0, 60.6, 54.2, 40.0, 38.2, 35.4, 33.6, 27.3,
22.2, 18.3. IR (neat): 3074, 2974, 2925, 2834, 1724, 1672, 1639, 1212 cm -1 . Calcd for
C 16 H 24 O 2 .
165

O
357
(4R,6R * )-4,6-diallyl-6-ethynyl-5,5-dimethylcyclohex-1-en-1-yl methyl ether (357):
THF (27 mL) and hexane (3.5 mL) were added to a round-bottom flask and cooled to –78
C under nitrogen. Then trimethylsilyldiazomethane (2 M in ether, 3.60 mL, 7.20 mmol)
was added to the above mixture at –78 C, and after a few minutes BuLi (2.4 M in
hexane, 3.00 mL, 7.20 mmol) was added. The reaction mixture was stirred 10 to 15
minutes at the same temperature, and aldehyde 356 (5.96 mmol, 1.47 g) in 24 mL of THF
was added slowly. The reaction mixture was stirred for another 10 to 15 minutes at –78
C and warmed to 0 C. After warming to 0 C, the reaction mixture was stirred 1 h
before completely warming to room temperature. After completely warming to room
temperature the reaction was quenched with water and the organic components were
extracted with ether. The ether layer was then washed with brine and dried with
anhydrous Na 2 SO 4 . The organic solvents were evaporated and the remaining crude oil
was chromatographed with 5% ethyl acetate and petroleum ether to give 0.96 g (3.96
mmol, 67%) of 357. 1 H NMR (400 MHz, CDCl 3 ): 5.98 (m, 1H), 5.72 (m, 1H), 5.04-
4.90 (m, 4H), 4.55 (m, 1H), 3.4 (s, 3H), 2.56 (dd, J d = 13.4, Hz, J d = 5.95 Hz, 1H), 2.40
(dd, J d = 13.4, Hz, J d = 8.19 Hz, 1H), 2.31 (dd, J d = 6.33 Hz, J d = 2.31 Hz, 1H), 2.23 (s,
1H), 2.16 (dt, J d = 17.12 Hz, J t = 4.47 Hz, 1H), 1.78 (m, 2H), 1.63 (m, 1H), 1.08 (s, 3H),
1.00 (s, 3H). 13 C NMR (400 MHz, CDCl 3 ): 154.7, 138.1, 136.5, 115.8, 115.1, 93.3,
85.7, 71.9, 54.4, 43.0, 39.6, 37.1, 35.4, 27.3, 23.3, 23.2, 19.3. IR (neat): 3304, 3075,
2975, 2941, 2833, 2109, 1669, 1639, 1216 cm -1 . Calcd for C 17 H 24 O.
166

O
358
(4R * ,6R)-1-Allyloxy-4,6-diallyl-6-ethynyl-5,5-dimethylcyclohexene (358):
To a 25 mL round-bottom flask benzene (3.75 mL), allyl alcohol (0.70 mL) and p-
TsOH∙H 2 O (0.001 g, 0.005 mmol) were added and then refluxed for 1 h with a Dean-
Stark apparatus. The reaction mixture was then cooled to room temperature and methyl
enol ether 357 (0.06 g, 0.25 mmol) in 1.25 mL of benzene was added. The reaction
mixture was allowed to reflux for 2 h, and after the reaction was complete, the mixture
was cooled to room temperature. The solvent was removed completely, and saturated
NaHCO 3 was added. The organic layer was extracted with ether (25 mL) and washed
with water (10 mL) and brine (10 mL). The separated organic layer was dried with
anhydrous NaSO 4 and the solvent was removed to get the crude product. The crude oil
was chromatographed with 5% ethyl acetate and petroleum ether to give 0.065 g (96%,
0.24 mmol) of 358. 1 H NMR (400 MHz, CDCl 3 ): 6.03 (m, 1H), 5.9 (m, 1H), 5.72 (m,
1H), 5.33 (d, 17.49 Hz, 1H), 5.14 (d, 10.79 Hz, 1H), 4.95 (m, 4H), 4.54 (s, 1H), 4.22 (dd,
J d = 13.03 Hz, J d = 3.72 Hz, 1H), 4.04 (dd, J d = 13.03 Hz, J d = 3.35 Hz, 1H), 2.56 (dd, J d =
13.4, Hz, J d = 5.95 Hz, 1H), 2.40 (dd, J d = 13.4, Hz, J d = 8.19 Hz, 1H), 2.30 (m, 1H), 2.20
(s, 1H), 2,15 ((dt, J d = 17.5 Hz, J t = 3.72 Hz, 1H), 1.74 (m, 2H), 1.62 (dd, J d = 8.55 Hz, J d
= 16.75 Hz, 1H), 1.08 (s, 3H), 1.00 (s, 3H).
13 C NMR (400 MHz, CDCl 3 ) : 153.5,
138.2, 136.8, 133.8, 116.3, 115.8, 114.9, 94.5, 85.6, 72.0, 67.7, 50.0, 43.0, 39.6, 37.1,
35.4, 27.3, 23.3, 19.3. IR (neat): 3306, 3076, 2975, 2922, 2359, 1669, 1639, 1205 cm -1 .
Calcd for C 19 H 26 O.
167

O
O
O
359
Methyl3-[(1S * ,5R)-1,5-diallyl-2-allyloxy-6,6-dimethyl-2-cyclohexen-1-yl]-2-
propynoate (359):
PdCl 2 (3.54 mg, 0.02 mmol), CuCl 2 (144 mg, 0.85 mmol), and NaOAc (69.9 mg, 0.85
mmol) were placed in a 25 mL round-bottom flask and alkyne 358 (108 mg, 0.40 mmol)
in methanol (4.24 mL) were added. A rubber balloon filled with carbon monoxide was
attached to the flask, and mixture was allowed to stir at room temperature. The green
solution turned black after 2 h, and the reaction was stopped by adding 2 mL of water.
The organic layer was extracted with ether (10 mL) and then EtOAc (5 mL). The organic
fractions were combined and washed with brine and dried over anhydrous NaSO 4 . The
crude oil was chromatographed with 5% ethyl acetate and petroleum ether to give (0.28
mmol, 0.09 g, 72% yield) of 359. 1 H NMR (400 MHz, CDCl 3 ): 6.02-5.84 (m, 2H), 5.7
(m, 1H), 5.34 (dd, J d = 17.43 Hz, J d = 1.47 Hz, 1H), 5.53 (dd, J d = 10.58 Hz, J d = 1.47
Hz,1H), 5.02-5.46 (m, 4H), 4.54 (m, 1H), 4.20 (dd, J d = 13.22 Hz, J d = 4.47 Hz, 1H), 4.00
(dd, J d = 13.23 Hz, J d = 2.94 Hz, 1H), 3.70 (s, 3H), 2.58 (dd, J d = 13.81 Hz, J d = 6.17 Hz,
1H), 2.43 (dd, J d = 13.52 Hz, J d = 8.23 Hz, 1H), 2.29 (dd, J d = 9.70 Hz, J d = 5.88 Hz, 1H),
2.15 (dt, J d = 17.34 Hz, J t = 4.41 Hz, 1H), 1.74 (m, 2H), 1,62 (dd, J d = 8.23 Hz, J d = 17.34
Hz, 1H), 1.06 (s, 3H), 0.90 (s, H). 13 C NMR (400 MHz, CDCl 3 ): 152.3, 137.8, 135.8,
133.5, 116.2, 116.0, 115.6, 94.8, 91.2, 76.5, 67.5, 52.6, 42.4, 40.0, 37.1, 35.1, 27.2, 23.6,
19.5. IR (neat): 3409, 3076, 2975, 2949, 2840, 2231, 1715, 1672, 1640, 1434, 1244 cm -1 .
Calcd for C 21 H 28 O 3 .
168

O
O H
3-[(1S * ,5R)-1,5-diallyl-2-allyloxy-6,6-dimethylcyclohex-2-en-1-yl]-2-propyn-1-ol:
The alkyne ester (359) (1.30 g, 3.99 mmol) was dissolved in 40 mL of dry ether and the
mixture was cooled to –78 C in a dry ice/acetone bath. Then LiAlH 4 (0.242 g, 6.38
mmol) was added very slowly. After addition was completed, reaction mixture was
warmed to 30 C and stirred for 6 h. TLC was taken and 0.24 mL of water and 0.24 mL
of 10% NaOH were added. A few minutes later another 0.7 mL of water was added. The
reaction mixture was diluted with ether and the solution was filtered. Then the crude
eluted with 15% EtOAc in petroleum ether. Solvent was evaporated and pure alcohol was
obtained 1.12 g (94%, 3.73 mmol). 1 H NMR (400 MHz, CDCl 3 ): 5.99 (m, 1H), 5.9 (m,
1H), 5.7 (m, 1H), 5.32 (d, 17.2 Hz, 1H), 5.13 (d, 10.8 Hz, 1H), 5.52 (m, 4H), 4.52 (s,
1H), 4.28 (d, 5.20 Hz, 2H), 4.2 (d, 13.2 1H), 4.02 (d, 12.4 Hz, 1H), 2.5 (dd, J d = 14.00
Hz, J d = 6.00 Hz, 1H), 2.37 (dd, J d = 12.8 Hz, J d = 8.4 Hz, 1H), 2.3 (m, 1H), 2,14 (d, 17.2
Hz, 1H), 1.86 (m, 1H), 1.73 (m, 2H), 1.62 (dd, J d = 7.6 Hz, J d = 17.2 Hz, 1H), 1.01 (s,
3H), 0.99 (s, 3H). 13 C NMR ( 400 MHz, CDCl 3 ): 153.7, 138.2, 136.9, 133.9, 116.2,
115.8, 114.8, 94.6, 87.1, 82.3, 77.4, 67.6, 51.7, 43.0, 39.8, 37.1, 35.4, 27.4, 23.5, 19.5. IR
(neat): 3395, 3074, 2973, 2919, 1669, 1639, 1204 cm -1 . Calcd for C 20 H 28 O 2 .
169

O
O H
360
2,4,6-triallyl-2-(3-hydroxy-1-propyn-1-yl)-3,3-dimethylcyclohexanone (360):
O-allyl enol ether (1.12 g, 3.73 mmol) and dry pyridine (33 mL) were heated at 150 C
for 1.5 h in a sealed (pressure) tube. TLC was taken, pyridine was removed and crude
was isolated as a brown/red colored oil. The crude was purified using column
chromatography and the pure compound 360 (0.83 g, 2.79 mmol, 75%) was isolated. 1 H
NMR (400 MHz, CDCl 3 ): 5.70 (m, 3H), 5.05 (m, 6H), 4.33 (d, 5.55 Hz, 2H), 2.75 (m,
1H), 2.45 (m, 3H), 2.31 ( m, 1H), 2.04 (m, 1H), 1.92 (m, 2H), 1.75 (m, 1H), 1.66 (m,
2H), 1.18 (s, 3H), 0.80 (s, 3H). 13 C NMR (400
MHz, CDCl 3 ): 208.3, 137.6, 136.4, 133.1, 118.3, 116.7, 116.6, 85.7, 84.9, 62.0, 51.6,
45.9, 44.5, 40.4, 39.0, 35.3, 34.5, 34.1, 24.0, 19.1. IR (neat): 3434, 3075, 2973, 2937,
2834, 1715, 1640, 912 cm -1 . Calcd for C 20 H 26 O 2 .
170

O
O
H
361
3-((1S * , 3R)-1,3,5-triallyl-2,2-dimethyl-6-oxocyclohexyl)-2-propynal (361):
The alcohol 360 (825 mg, 2.77 mmol) was dissolved in 20 mL of CH 2 Cl 2 at room
temperature. In a separate round-bottom flask, Dess–Martin periodinane (1.53 g, 3.60
mmol) was dissolved in 7.7 mL of CH 2 Cl 2 and added slowly to the reaction mixture.
Then the mixture was stirred for 3 h at room temperature and after the reaction was
complete, 15 mL of 1M NaOH was added and the organic components were extracted
with ether. The ether layer was then washed with water and brine and dried with
anhydrous Na 2 SO 4 . The organic solvents were evaporated and the remaining crude oil
was chromatographed with 5% ethyl acetate and petroleum ether to give 0.68 g of 361
(2.29 mmol, 83%). 1 H NMR (400 MHz, CDCl 3 ): 9.21 (s, 1H), 5.63 (m, 3H), 5.0 (m,
6H), 2.80 (dd, J d = 12.81 Hz, J d = 8.24 Hz, 1H), 2.54-2.34 (m, 3H), 2.65 (d, 12.11 Hz,
1H), 2.4 (dd, J d = 16.30 Hz, J d = 4.35 Hz, 1H), 1.9 (m, 2H), 1.65 (m, 2H), 1,10 (s, 3H),
0,84 (s, 3H). 13 C (400 MHz, CDCl 3 ): 207.1, 177.0, 137.1, 121.8, 119.3, 117.0, 116.9,
96.9, 87.5, 62.8, 44.9, 44.7, 40.3, 38.2, 34.9, 34.3, 33.9, 24.0, 19.2. IR (neat): 3077, 2975,
2940, 2212, 1716, 1667, 1640 cm -1 . Calcd for C 20 H 26 O 2 .
171

O H C
O
S i E t 3
362
2-Triethylsilyl-3-(1,3,5-triallyl-2,2-dimethyl-6-oxocyclohexyl)acrylaldehyde (362):
Co 2 (CO) 8 (0.31 g, 0.91 mmol) was added to a solution of eynal 361 (0.24 g, 0.81 mmol)
in CH 2 Cl 2 (6.5 mL) at 0 °C. After about 7 h at room temperature, TLC was taken and the
solvent was evaporated. The residue was filtered through a short column of silica gel,
eluting with hexane (the brown eluant was discarded) and then with 30% EtOAc in
petroleum ether. The solvent was evaporated and resulted in the Co 2 (CO) 6 complex of
enal (0.28 g, 0.48 mmol, 87% yield) as a dark red oil.
The complex (0.28 g, 0.48 mmol,) was redissolved in dry (CHCl) 2 (3.25 mL), and
bis(trimethylsilyl)acetylene (0.22 g, 0.98 mmol) and triethylsilane ( 0.40 mL, 2.80 mmol)
were added. The mixture was stirred at 65 °C for 2 h (monitored by TLC). The solvent
was evaporated, and the residue was filtered through a short column of silica gel, eluting
with hexane (the brown eluant was discarded) and then with 10% EtOAc in petroleum
ether. The solvent was evaporated to provide enal 362 (0.11 g, 0.28 mmol, 58% yield) as
a colorless liquid.
172

H O
S i E t 3
O
Four drops of 6 M HCl were added to a solution of enal (0.20 g, 0.48 mmol) in THF (5
mL). After 4.5 h (monitored by TLC), water was added. The aqueous layer was extracted
with ether (2 30 mL), and the combined organic layers were washed with brine, dried
over MgSO 4 , and then evaporated. The remaining crude oil was chromatographed with
10% ethyl acetate and petroleum ether to give two diastereomers.
H O
S i E t 3
O
1 H NMR (400 MHz, CDCl 3 ): 5.85 (s+m, 2H), 5.55 (m,1H), 5.47 (m, 1H), 5.13-4.88
(m, 6H), 4.17 (d, 7.91 Hz, 1H), 2.74 (dd, J d =13.2 Hz, J d = 5.20 Hz, 1H), 2.38 (dd, J d =
8.0 Hz, J d = 7.20 Hz, 2H), 2.14 (d, 10.4 Hz, 1H), 1.88 (dd, J d = 13.2 Hz, J d = 8.80 Hz,
1H), 1.75 (dd, J d = 14.00 Hz, J d = 3.60 Hz, 1H), 1.6 ( t, 13.2 Hz, 1H), 1.1 (m, 1H), 0.92
(t, 8 Hz, 9H), 0.88 (s, 3H), 0.87 (s, 3H), 0.63 (m, 6H).
173

H O
S i E t 3
O
1 H NMR (400 MHz, CDCl 3 ): 6.0 (m, 1H), 5.66 (s, 1H), 5.58 (m, 1H), 5.38 (m, 1H),
5.15 (d, 16.99 Hz, 1H), 5.04 (d, 9.96 Hz, 1H), 4.98 (m, 4H), 4.15 (d, 5.57 Hz, 1H), 2.72
(dd, J d = 13.6 Hz, J d = 5.20 Hz, 1H), 2.44 (d, 8.4 Hz, 2H), 2,20 (d, 14.8, 1H), 2.13 (dd, J d
= 14.0 Hz, J d = 13.60 Hz, 1H), 1.92 (dd, J d = 13.2 Hz, J d = 8.80 Hz, 1H), 1.85 (d, 6.8 Hz,
1H), 1.68 (m, 1H), 1.31( m, 1H), 1.06 (m, 1H), 0.94(t, 7.6 Hz, 9H), 0,93 (s, 3H), 0,91 (s,
3H), 0.65 (m, 6H).
O
S i E t 3
O
372
3-triethylsilyl-1,5,7-triallyl-6,6-dimethylbicyclo[3.3.1]non-3-ene-2,9-dione (372)
The crude alcohol (without separating the diastereomers) (0.05 g, 0.13 mmol) was
dissolved in 2.00 mL of CH 2 Cl 2 in 25 mL round-bottom flask under nitrogen. The Dess–
Martin periodinane (0.08 g, 0.18 mmol) was dissolved in 0.5 mL of CH 2 Cl 2 and added to
the reaction mixture and stirred for 2 h at room temperature. The reaction was quenched
by adding 0.25 mL of 1 M NaOH and the product was extracted with ether. The organic
layer was washed with brine, dried with anhydrous NaSO 4 , and evaporated in the solvent.
The remaining crude oil was used to do the next reaction. 1 H NMR (400 MHz, CDCl 3 ):
6.85 (s, 1H), 5.8 (m, 1H), 5.48 (m, 1H), 5.36 (m, 1H), 5.10-4.84 (m, 6H), 2.88 (dd, J d =
174

13.39 Hz, J d = 4.10 Hz, 1H), 2.46 (dd, J d = 13.77 Hz, J d = 6.7 Hz, 1H), 2.39 (dd, J d =
13.77 Hz, J d = 7.82 Hz, 1H), 2.2 (d, 3.77 Hz, 1H), 2.0 (m, 3 H), 1.72 (m, 2H), 1.32 (m,
1H), 1.05 (s, 3H), 0.80 (s, 3H), 0.85 (t, 7.83 Hz, 9H), 0.64 (m, 6H). 13 C NMR (400 MHz,
CDCl 3 ): 209.7, 202.4, 162.9, 138.6, 137.2, 134.5, 134.3, 118.6, 118.4, 177.6, 65.3,
58.3, 45.4, 37.3, 35.3, 34.7, 37.7, 26.0, 20.47, 7.5, 2.9. IR (neat): 3435, 3056, 2956, 2876,
1724, 1664, 1639, 1585, 1418 cm -1 .
O H C
O
348
3-((1R * , 3R)-1,3,5-triallyl-2,2-dimethyl-6-oxocyclohexyl)acrylaldehyde (348):
Ynal 361 (90.0 mg, 0.30 mmol) and Pd(PPh 3 ) 4 (17.3 mg, 0.01 mmol, 5 mol%) were
dissolved in 0.3 mL of dry THF under nitrogen and cooled to 0 C. Bu 3 SnH (0.08 mL,
0.31 mmol) in 0.3 mL of THF was added dropwise via syringe and stirred at 0 C for 1 h.
After completion, the reaction THF was removed by a rotary evaporator and cold pentane
(10 mL) was added. The precipitated Pd was removed by filtering the solution through a
cilite column. Then, pentane was removed and the collected yellow colored crude oil
crude was chromatographed with 5% ethyl acetate and petroleum ether to give 0.07 g
(0.25 mmol, 84%) of 348. 1 H NMR (400 MHz, CDCl 3 ): 9.7 (d, 7.94 Hz, 1H), 6.49 (d,
13.51 Hz, 1H), 6.10 (dd, J d = 13.23, Hz, J d = 7.93 Hz, 1H), 3.03 (dd, J d = 15.28, Hz, J d =
7.5 Hz, 1H), 2.68 (m, 2H), 2.45 (m, 1H), 2.31 (dd, J d = 13.52, Hz, J d = 3.82 Hz, 1H), 2.11
(m, 2H), 1.95 (ddd, J d = 14.11, Hz, J d = 7.35 Hz, J d = 6.76 Hz, 1H), 1.68 (ddd, J d = 13.52,
Hz, J d = 9.40 Hz, J d = 4.12 Hz, 1H), 1.08 (s, 3H), 0.70 (s, 3H). 13 C NMR (400 MHz,
CDCl 3 ): 211.6, 193.2, 145.1, 137.4, 136.2, 132.4, 132.1, 119.7, 117.0, 116.9, 64.4,
45.6, 45.5, 40.8, 38.2, 35.2, 34.8, 34.3, 22.9, 18.9. IR (neat): 3076, 2975, 2938, 1705,
1673, 1640, 1440, 1370, 914 cm -1 . Calcd for C 20 H 28 O 2 .
175

H O
O
373
1,5,7-Triallyl-4-hydroxy-8,8-dimethylbicyclo[3.3.1]non-2-en-9-one (373):
Cis-enal (348) (0.96 g, 0.32 mmol) was dissolved in 3.2 mL of ethanol under nitrogen
atmosphere. Then, NaOEt (0.04 g, 0.64 mmol) was added slowly to the above reaction
mixture and stirred at room temperature for 2 h. The reaction mixture was quenched by
adding water, (1 mL) and the organic compounds were extracted in ether (10 mL) in
multiple extractions. Collected organic layers were pooled and solvent was removed.
Without purification the crude alcoholic compound was subjected to the next step.
O
O
364
(1R * ,5R,7R)-1,5,7-Triallyl-6,6-dimethylbicyclo[3.3.1]non-3-ene-2,9-dione (364):
The crude alcoholic compound was dissolved in 3.23 mL of CH 2 Cl 2 in 25 mL roundbottom
flask under nitrogen. The Dess–Martin periodinane (0.20 g, 0.48 mmol) was
dissolved in 1 mL of CH 2 Cl 2 , added to the reaction mixture, and stirred for 2 h at room
temperature. The reaction was quenched by adding 2 mL of 1 M NaOH and extracted in
ether. The organic layer was washed with brine, dried with anhydrous NaSO 4 , and
evaporated in the solvent, and the remaining crude oil was chromatographed with 5%
ethyl acetate and petroleum ether to give 0.08 g (0.28 mmol, 88% for 2 steps) of yellow
solid 364. 1 H NMR (400 MHz, CDCl 3 ): 6.8 (d, 10.25 Hz, 1H), 6.13 (d, 10.2 Hz, 1H),
176

5.82 (m, 1H), 5.44 (m, 2H), 5.0 (m, 6H), 2.91 (dd, J d = 14.0, Hz, J d = 5.2 Hz, 1H), 2.56
(m, 2H), 2.45 (m, 2H), 2.27 (m, H), 2.05 (m, 3H), 1.84 (ddd, J d = 16.0 Hz, J d = 10.4 Hz,
J d = 4.0 Hz, 1H), 1.4 (m, 1H), 1.01 (s, 3H), 0.99 (s, 3H). 13 C NMR (400 MHz, CDCl 3 ):
209.1, 199.5, 153.4, 137.4, 134.1, 134.1, 129.4, 118.8, 118.8, 117.1, 64.5, 57.2, 45.2,
38.0, 35.7, 34.7, 34.6, 29.9, 26.3, 21.1. IR (neat): 3076, 2976, 1727, 1678, 1639, 1614
cm 1 . Calcd for C 20 H 26 O 2 .
H O
O
368
(1R * ,5R * ,7R,4R)-1,5,7-Triallyl-4-hydroxy-4,8,8-trimethylbicyclo[3.3.1]non-2-en-9-
one (368):
The bicyclic enone 364 (0.03 g, 0.10 mmol) was dissolved in 1.5 mL of THF under
nitrogen. Then, the reaction mixture was cooled to 0 C and MeLi (0.11 mmol, 1.6 M in
Et 2 O, 0,06 mL) was added. TLC was taken after 3 h at 0 C, and the reaction was
quenched with water. The organic layer was extracted with ether, and the ether layer was
then washed with water, brine, and dried with anhydrous Na 2 SO 4 . The organic solvents
were evaporated, and the remaining crude oil was chromatographed with 5% ethyl
acetate and petroleum ether to give 0.023 g (0.07 mmol, 75%) of 368. 1 H NMR (400
MHz, CDCl 3 ): 5.92 (m, 1H), 5.6 (d, 9.99 Hz, 1H), 5.56 (m, 1H), 5.42 (d, 10.28 Hz,
1H), 5.35 (m, 1H), 5.12 (d, 17.05 Hz, 1H), 5.03 (d, 9.99 Hz, 1H), 4.93 (m, 4H), 2.69 (dd,
J d = 13.51, Hz, J d = 5.87 Hz, 1H), 2.50 (dd, J d = 13.51, Hz, J d = 5.58 Hz, 1H), 2.32 (dd, J d
= 13.52, Hz, J d = 9.4 Hz, 1H), 2.16 (m, 2H), 1.8 (m, 3H), 1.58 (m, 1H), 1.05 (s, 3H), 0.87
(s, 3H), 0.85 (s, 3H). 13 C NMR (400 MHz, CDCl 3 ): 214.5, 137.6, 135.2, 135.0, 134.9,
131.7, 118.7, 117.5, 116.7, 80.2, 58.2, 54.6, 44.7, 43.2, 35.1, 34.6, 34.0, 33.9, 25.2, 24.4,
18.3. Calcd for C 21 H 30 O 2
177

H O
O
O
O M e
367
4-[(Methoxymethoxy)methyl]-(1R * ,5R * ,7R,4R)-1,5,7-triallyl-4-hydroxy-8,8-
dimethylbicyclo[3.3.1]non-2-en-9-one (367):
(Methoxymethoxy)methyltributyltin (0.07 g, 0.20 mmol) was dissolved in 0.5 mL of
THF under nitrogen. Then, the reaction mixture was cooled to C and MeLi (0.20
mmol, 1.6 M in Et 2 O, 0.12 mL) was added and stirred for 20 minutes. Then, enone 364
(0.02 g, 0.10 mmol) was added and stirred for 4 h at the same temperature. TLC was
taken and the reaction was quenched with water. The organic layer was extracted with
ether, and the ether layer was then washed with water, brine, and dried with anhydrous
Na 2 SO 4 . The organic solvents were evaporated and the remaining crude oil was
chromatographed with 5% ethyl acetate and petroleum ether to give 0.02 g (0.06 mmol,
62%) of 2. 1 H NMR (400 MHz, CDCl 3 ): 5.88 (m, 1H), 5.67 (d, 10 Hz, 1H), 5.58 (m,
1H), 5.54 (d, 10 Hz, 1H), 5.40 (m, 1H), 5.10 (d, 16.8 Hz, 4.95 (m, 5H), 4.58 (d, 6.4 Hz,
1H), 4.53 (d, 6.4 Hz, 1H), 3.40 (d, 10.4 Hz, 1H), 3,31 (s, 3H), 3.24 (d, 10 Hz, 1H), 2.83
(s, 1H), 2.70 (dd, J d = 13.6 Hz, J d = 6 Hz, 1H), 2.53 (dd, J d = 13.2, Hz, J d = 6 Hz, 1H),
2.26 (m, 2H), 2.13 (dd, J d = 13.6, Hz, J d = 2.8 Hz, 1H), 1.83 (m, 2H), 1.6 (m, 1H), 1.05
(m, 1H), 0.88 (s, 3H), 0.87 (s, 3H). 13 C NMR (400 MHz, CDCl 3 ): 214.1, 137.5, 135.0,
134.8, 133.8, 132.3, 97.2, 80.6, 72.4, 56.8, 55.7, 54.7, 44.1, 35.2, 34.5, 34.2. Calcd for
C 23 H 34 O 4 .
Copyright © Pushpa Suresh Jayasekara Mudiyanselage 2010
178

Chapter 4. Conclusion
Plant Rheedia gardneriana produces an interesting type B PPAP, 7-epiclusianone,
and it has shown in vitro anti-HIV, anticancer and antibiotic activities. . 7-
epi-Clusianone, like a large majority of type B PPAPs and a large minority of type A
PPAPs, is a 7-endo PPAP. To this date, there are no synthetic efforts found in the
literature towards 7-endo PPAPs.
The goal of my research project was to develop a stereocontrolled synthesis of 7-
epi-clusianone. A successful synthesis of this molecule will give a synthetic route to 7-
endo-PPAPs and will enable to contribute to the current synthetic tools by developing
new methodologies and procedures.
During our first approach, we hypothesized that the 1,2-allylic strain inhibits the
enolization of the keto aldehyde to undergo intramolecular aldol reaction. After
redesigning the synthesis, we were able to construct the bicyclo[3.3.1]nonane core with
correct C(7) endo stereochemistry. Successful preparation of the 7-endoallylbicyclo[3.3.1]nonane
skeleton shows the validity of our approach in synthesising of
7-endo PPAPs and supports our hypothesis on the failure of our initial route. This
synthetic pathway also led us to find other unusual reaction patterns such as the
hydrogenation of an alkynal with Pd(PPh 3 ) 4 and Bu 3 SnH. This reaction has not been
reported in the literature, and further investigation of it is being carried out in our
laboratory.
Finally, in our lab, we were able to develop a catalytic classical resolution method to
synthesize enantiomerically pure 3,4-substituted 2-cyclohexenones. If a racemic synthesis
of 7-epi-clusianone can be completed, then with the help of enantiopure starting
meterials, we may be able to complete the first enantioselective total synthesis of 7-epiclusianone
as well.
Copyright © Pushpa Suresh Jayasekara Mudiyanselage 2010
179

Appendix
Table A.1: Crystal data and structure refinement for 364
Identification code 364
Empirical formula C 20 H 26 O 2
Formula weight 298.41
Temperature
90.0(2) K
Wavelength (Å) 1.54178
Crystal system, space group Monoclinic, P 21/c
Unit cell dimensions
a (Å) 9.1543(2)
α (°) 90
b (Å) 25.4610(7)
β (°) 109.647(1)
c (Å) 7.7090(2)
γ (°) 90
Volume (Å 3 ) 1692.19(7)
Z, Calculated density (Mg/m 3 ) 4, 1.171
Absorption coefficient (mm -1 ) 0.573
F(000) 648
Crystal size (nm) 0.35 x 0.15 x 0.06
Θ range for data collection (°) 3.47 to 69.44
Limiting indices
-10≤h≤10
-30≤k≤30
-9≤l≤7
Reflections collected / unique 22129 / 3088
180

Completeness to θ = 69.44 97.2 %
[R(int) = 0.0405]
Absorption correction
Semi-empirical from equivalents
Max. and min. transmission 0.966 and 0.793
Refinement method Full-matrix least-squares on F 2
Data / restraints / parameters 3088 / 0 / 202
Goodness-of-fit on F 2 1.161
Final R indices [I>2σ(I)] R1 = 0.0400, wR2 = 0.1048
R indices (all data) R1 = 0.0420, wR2 = 0.1065
Extinction coefficient 0.0037(6)
Largest diff. peak and hole 0.314 and -0.224 (e·Å–3
)
181

Table A.2: Atomic coordinates ( x 10 4 ) and equivalent isotropic
displacement parameters (A 2 x 10 3 ) for 364
U(eq) is defined as one third of the trace of the
orthogonalized
U ij tensor.
________________________________________________________________
x y z U(eq)
________________________________________________________________
C(1) 6896(2) 3519(1) 5929(2) 18(1)
C(2) 6900(2) 2958(1) 6596(2) 19(1)
C(3) 5764(2) 2608(1) 5932(2) 20(1)
C(4) 4307(2) 2747(1) 4482(2) 18(1)
C(5) 4061(2) 3337(1) 4093(2) 18(1)
C(6) 3733(2) 3573(1) 5808(2) 19(1)
C(7) 4736(2) 4053(1) 6605(2) 20(1)
C(8) 6517(2) 3933(1) 7299(2) 20(1)
C(9) 5600(2) 3564(1) 4082(2) 17(1)
O(10) 5765(1) 3762(1) 2734(1) 21(1)
C(11) 8501(2) 3615(1) 5723(2) 21(1)
C(12) 8947(2) 3209(1) 4574(2) 23(1)
C(13) 10141(2) 2887(1) 5193(2) 29(1)
C(14) 4194(2) 4309(1) 8106(2) 25(1)
C(15) 2571(2) 4523(1) 7371(2) 29(1)
C(16) 2217(2) 5024(1) 7220(2) 35(1)
C(17) 2727(2) 3433(1) 2276(2) 21(1)
C(18) 2304(2) 4002(1) 1880(2) 22(1)
C(19) 1006(2) 4213(1) 1935(2) 27(1)
O(20) 3340(1) 2421(1) 3696(2) 24(1)
C(21) 7364(2) 4455(1) 7315(2) 26(1)
C(22) 7079(2) 3705(1) 9252(2) 24(1)
________________________________________________________________
182

Table A.3: Bond lengths [Å] and angles [°] for 364
_____________________________________________________________
C(1)-C(2) 1.519(2)
C(1)-C(9) 1.5201(19)
C(1)-C(11) 1.5494(19)
C(1)-C(8) 1.6101(19)
C(2)-C(3) 1.333(2)
C(2)-H(2) 0.9500
C(3)-C(4) 1.467(2)
C(3)-H(3) 0.9500
C(4)-O(20) 1.2176(18)
C(4)-C(5) 1.534(2)
C(5)-C(9) 1.5250(19)
C(5)-C(17) 1.537(2)
C(5)-C(6) 1.5694(19)
C(6)-C(7) 1.529(2)
C(6)-H(6A) 0.9900
C(6)-H(6B) 0.9900
C(7)-C(14) 1.5474(19)
C(7)-C(8) 1.566(2)
C(7)-H(7) 1.0000
C(8)-C(22) 1.532(2)
C(8)-C(21) 1.537(2)
C(9)-O(10) 1.2099(17)
C(11)-C(12) 1.504(2)
C(11)-H(11A) 0.9900
C(11)-H(11B) 0.9900
C(12)-C(13) 1.322(2)
C(12)-H(12) 0.9500
C(13)-H(13A) 0.9500
C(13)-H(13B) 0.9500
C(14)-C(15) 1.504(2)
C(14)-H(14A) 0.9900
C(14)-H(14B) 0.9900
C(15)-C(16) 1.312(2)
C(15)-H(15) 0.9500
C(16)-H(16A) 0.9500
C(16)-H(16B) 0.9500
C(17)-C(18) 1.503(2)
C(17)-H(17A) 0.9900
C(17)-H(17B) 0.9900
C(18)-C(19) 1.318(2)
C(18)-H(18) 0.9500
C(19)-H(19A) 0.9500
C(19)-H(19B) 0.9500
C(21)-H(21A) 0.9800
C(21)-H(21B) 0.9800
C(21)-H(21C) 0.9800
C(22)-H(22A) 0.9800
C(22)-H(22B) 0.9800
C(22)-H(22C) 0.9800
183

C(2)-C(1)-C(9) 107.45(11)
C(2)-C(1)-C(11) 106.80(12)
C(9)-C(1)-C(11) 111.15(11)
C(2)-C(1)-C(8) 111.72(11)
C(9)-C(1)-C(8) 107.02(11)
C(11)-C(1)-C(8) 112.62(11)
C(3)-C(2)-C(1) 125.87(13)
C(3)-C(2)-H(2) 117.1
C(1)-C(2)-H(2) 117.1
C(2)-C(3)-C(4) 121.52(13)
C(2)-C(3)-H(3) 119.2
C(4)-C(3)-H(3) 119.2
O(20)-C(4)-C(3) 122.50(13)
O(20)-C(4)-C(5) 122.47(13)
C(3)-C(4)-C(5) 114.97(12)
C(9)-C(5)-C(4) 107.23(11)
C(9)-C(5)-C(17) 112.81(12)
C(4)-C(5)-C(17) 110.68(12)
C(9)-C(5)-C(6) 107.40(11)
C(4)-C(5)-C(6) 105.43(11)
C(17)-C(5)-C(6) 112.87(11)
C(7)-C(6)-C(5) 112.64(11)
C(7)-C(6)-H(6A) 109.1
C(5)-C(6)-H(6A) 109.1
C(7)-C(6)-H(6B) 109.1
C(5)-C(6)-H(6B) 109.1
H(6A)-C(6)-H(6B) 107.8
C(6)-C(7)-C(14) 109.75(12)
C(6)-C(7)-C(8) 113.40(12)
C(14)-C(7)-C(8) 112.67(12)
C(6)-C(7)-H(7) 106.9
C(14)-C(7)-H(7) 106.9
C(8)-C(7)-H(7) 106.9
C(22)-C(8)-C(21) 108.52(12)
C(22)-C(8)-C(7) 112.12(12)
C(21)-C(8)-C(7) 107.41(12)
C(22)-C(8)-C(1) 108.75(12)
C(21)-C(8)-C(1) 110.60(11)
C(7)-C(8)-C(1) 109.44(11)
O(10)-C(9)-C(1) 123.50(13)
O(10)-C(9)-C(5) 123.03(13)
C(1)-C(9)-C(5) 113.47(11)
C(12)-C(11)-C(1) 113.97(12)
C(12)-C(11)-H(11A) 108.8
C(1)-C(11)-H(11A) 108.8
C(12)-C(11)-H(11B) 108.8
C(1)-C(11)-H(11B) 108.8
H(11A)-C(11)-H(11B) 107.7
C(13)-C(12)-C(11) 124.72(15)
C(13)-C(12)-H(12) 117.6
C(11)-C(12)-H(12) 117.6
C(12)-C(13)-H(13A) 120.0
C(12)-C(13)-H(13B) 120.0
H(13A)-C(13)-H(13B) 120.0
C(15)-C(14)-C(7) 113.29(13)
184

C(15)-C(14)-H(14A) 108.9
C(7)-C(14)-H(14A) 108.9
C(15)-C(14)-H(14B) 108.9
C(7)-C(14)-H(14B) 108.9
H(14A)-C(14)-H(14B) 107.7
C(16)-C(15)-C(14) 124.71(17)
C(16)-C(15)-H(15) 117.6
C(14)-C(15)-H(15) 117.6
C(15)-C(16)-H(16A) 120.0
C(15)-C(16)-H(16B) 120.0
H(16A)-C(16)-H(16B) 120.0
C(18)-C(17)-C(5) 114.15(12)
C(18)-C(17)-H(17A) 108.7
C(5)-C(17)-H(17A) 108.7
C(18)-C(17)-H(17B) 108.7
C(5)-C(17)-H(17B) 108.7
H(17A)-C(17)-H(17B) 107.6
C(19)-C(18)-C(17) 124.14(14)
C(19)-C(18)-H(18) 117.9
C(17)-C(18)-H(18) 117.9
C(18)-C(19)-H(19A) 120.0
C(18)-C(19)-H(19B) 120.0
H(19A)-C(19)-H(19B) 120.0
C(8)-C(21)-H(21A) 109.5
C(8)-C(21)-H(21B) 109.5
H(21A)-C(21)-H(21B) 109.5
C(8)-C(21)-H(21C) 109.5
H(21A)-C(21)-H(21C) 109.5
H(21B)-C(21)-H(21C) 109.5
C(8)-C(22)-H(22A) 109.5
C(8)-C(22)-H(22B) 109.5
H(22A)-C(22)-H(22B) 109.5
C(8)-C(22)-H(22C) 109.5
H(22A)-C(22)-H(22C) 109.5
H(22B)-C(22)-H(22C) 109.5
_____________________________________________________________
185

Table A.4: Anisotropic displacement parameters (A 2 x 10 3 ) for 364. The
anisotropic displacement factor exponent takes the form:
-2 Π 2 [ h 2 a* 2 U11 + ... + 2 h k a* b* U12 ]
_______________________________________________________________________
U12
U11 U22 U33 U23 U13
_______________________________________________________________________
C(1) 18(1) 22(1) 16(1) -1(1) 7(1) -
2(1)
C(2) 20(1) 24(1) 15(1) 2(1) 8(1)
3(1)
C(3) 22(1) 20(1) 19(1) 2(1) 10(1)
2(1)
C(4) 19(1) 22(1) 18(1) -2(1) 11(1) -
1(1)
C(5) 18(1) 21(1) 16(1) -1(1) 7(1) -
1(1)
C(6) 19(1) 22(1) 18(1) 1(1) 10(1)
1(1)
C(7) 25(1) 21(1) 16(1) 0(1) 9(1)
0(1)
C(8) 24(1) 22(1) 16(1) -2(1) 9(1) -
3(1)
C(9) 19(1) 17(1) 16(1) -2(1) 8(1)
1(1)
O(10) 22(1) 27(1) 17(1) 2(1) 10(1)
0(1)
C(11) 17(1) 28(1) 19(1) 0(1) 6(1) -
4(1)
C(12) 17(1) 32(1) 21(1) -1(1) 8(1) -
4(1)
C(13) 22(1) 36(1) 32(1) 1(1) 12(1) -
1(1)
C(14) 32(1) 25(1) 20(1) -2(1) 13(1)
1(1)
C(15) 35(1) 32(1) 25(1) -4(1) 17(1)
2(1)
C(16) 44(1) 36(1) 29(1) -1(1) 18(1)
7(1)
C(17) 18(1) 26(1) 18(1) -2(1) 6(1)
0(1)
C(18) 22(1) 27(1) 18(1) 1(1) 6(1) -
1(1)
C(19) 23(1) 26(1) 30(1) -1(1) 7(1)
1(1)
O(20) 23(1) 24(1) 26(1) -4(1) 9(1) -
4(1)
C(21) 31(1) 26(1) 25(1) -6(1) 13(1) -
7(1)
186

C(22) 26(1) 30(1) 16(1) -1(1) 6(1) -
1(1)
_______________________________________________________________________
187

Table A.5: Hydrogen coordinates ( x 10 4 ) and isotropic
displacement parameters (Å 2 x 10 3 ) for 364.
_______________________________________________________________________
x y z U(eq)
_______________________________________________________________________
H(2) 7791 2846 7575 23
H(3) 5902 2261 6410 24
H(6A) 2625 3673 5442 22
H(6B) 3930 3299 6773 22
H(7) 4538 4314 5583 24
H(11A) 8495 3965 5160 26
H(11B) 9300 3621 6965 26
H(12) 8325 3183 3312 27
H(13A) 10788 2902 6448 35
H(13B) 10351 2640 4384 35
H(14A) 4250 4044 9067 30
H(14B) 4914 4598 8693 30
H(15) 1742 4278 6988 35
H(16A) 3015 5281 7589 42
H(16B) 1162 5131 6741 42
H(17A) 3023 3287 1251 25
H(17B) 1800 3239 2312 25
H(18) 3016 4222 1571 27
H(19A) 270 4003 2240 33
H(19B) 808 4576 1671 33
H(21A) 8487 4399 7844 40
H(21B) 7042 4713 8059 40
H(21C) 7104 4586 6052 40
H(22A) 7002 3974 10126 37
H(22B) 8161 3593 9569 37
H(22C) 6434 3403 9309 37
_______________________________________________________________________
188

Table A.6: Torsion angles [°] for 364.
________________________________________________________________
C(9)-C(1)-C(2)-C(3) -14.83(19)
C(11)-C(1)-C(2)-C(3) -134.17(15)
C(8)-C(1)-C(2)-C(3) 102.27(16)
C(1)-C(2)-C(3)-C(4) -3.0(2)
C(2)-C(3)-C(4)-O(20) 170.50(14)
C(2)-C(3)-C(4)-C(5) -12.15(19)
O(20)-C(4)-C(5)-C(9) -139.78(13)
C(3)-C(4)-C(5)-C(9) 42.87(15)
O(20)-C(4)-C(5)-C(17) -16.35(18)
C(3)-C(4)-C(5)-C(17) 166.29(12)
O(20)-C(4)-C(5)-C(6) 106.00(15)
C(3)-C(4)-C(5)-C(6) -71.36(14)
C(9)-C(5)-C(6)-C(7) 16.03(16)
C(4)-C(5)-C(6)-C(7) 130.13(12)
C(17)-C(5)-C(6)-C(7) -108.93(14)
C(5)-C(6)-C(7)-C(14) 172.13(12)
C(5)-C(6)-C(7)-C(8) -60.89(15)
C(6)-C(7)-C(8)-C(22) -83.30(15)
C(14)-C(7)-C(8)-C(22) 42.14(16)
C(6)-C(7)-C(8)-C(21) 157.58(12)
C(14)-C(7)-C(8)-C(21) -76.99(14)
C(6)-C(7)-C(8)-C(1) 37.46(15)
C(14)-C(7)-C(8)-C(1) 162.90(11)
C(2)-C(1)-C(8)-C(22) 28.91(16)
C(9)-C(1)-C(8)-C(22) 146.27(12)
C(11)-C(1)-C(8)-C(22) -91.29(14)
C(2)-C(1)-C(8)-C(21) 147.98(13)
C(9)-C(1)-C(8)-C(21) -94.67(14)
C(11)-C(1)-C(8)-C(21) 27.78(17)
C(2)-C(1)-C(8)-C(7) -93.88(14)
C(9)-C(1)-C(8)-C(7) 23.48(14)
C(11)-C(1)-C(8)-C(7) 145.92(12)
C(2)-C(1)-C(9)-O(10) -131.95(14)
C(11)-C(1)-C(9)-O(10) -15.43(19)
C(8)-C(1)-C(9)-O(10) 107.93(15)
C(2)-C(1)-C(9)-C(5) 48.46(15)
C(11)-C(1)-C(9)-C(5) 164.97(11)
C(8)-C(1)-C(9)-C(5) -71.67(14)
C(4)-C(5)-C(9)-O(10) 116.96(14)
C(17)-C(5)-C(9)-O(10) -5.15(19)
C(6)-C(5)-C(9)-O(10) -130.15(14)
C(4)-C(5)-C(9)-C(1) -63.45(14)
C(17)-C(5)-C(9)-C(1) 174.45(11)
C(6)-C(5)-C(9)-C(1) 49.45(15)
C(2)-C(1)-C(11)-C(12) 52.34(16)
C(9)-C(1)-C(11)-C(12) -64.57(16)
C(8)-C(1)-C(11)-C(12) 175.34(12)
C(1)-C(11)-C(12)-C(13) -116.16(17)
C(6)-C(7)-C(14)-C(15) -63.99(16)
C(8)-C(7)-C(14)-C(15) 168.62(13)
189

C(7)-C(14)-C(15)-C(16) -109.33(18)
C(9)-C(5)-C(17)-C(18) -65.55(16)
C(4)-C(5)-C(17)-C(18) 174.31(12)
C(6)-C(5)-C(17)-C(18) 56.42(16)
C(5)-C(17)-C(18)-C(19) -109.68(17)
________________________________________________________________
190

Table A.8: Crystal data and structure refinement for 368.
Identification code 368
Empirical formula C 21 H 30 O 2
Formula weight 314.45
Temperature
90.0(2) K
Wavelength (Å) 1.54178
Crystal system, space group Triclinic, P -1
Unit cell dimensions
a (Å) 6.3410(1)
α (°) 82.198(1)
b (Å) 8.9482(2)
β (°) 84.205(1)
c (Å) 17.1320(3)
γ (°) 70.411(1)
Volume 905.74(3) A 3
Z, Calculated density (Mg/m 3 ) 2, 1.153
Absorption coefficient (mm -1 ) 0.555
F(000) 344
Crystal size (nm)
0.22 x 0.05 x 0.04 mm
θ range for data collection (°) 2.61 to 67.97
Limiting indices
-6≤h≤7
-10≤k≤10
-20≤l≤20
Reflections collected / unique 12602 / 3239
[R(int) = 0.0378]
Completeness to θ = 67.97 97.9 %
Absorption correction
Semi-empirical from equivalents
191

Max. and min. transmission 0.9781 and 0.8876
Refinement method Full-matrix least-squares on F 2
Data / restraints / parameters 3239 / 0 / 213
Goodness-of-fit on F 2 1.090
Final R indices [I>2σ(I)] R1 = 0.0398, wR2 = 0.1002
R indices (all data) R1 = 0.0412, wR2 = 0.1014
Extinction coefficient 0.0042(12)
Largest diff. peak and hole 0.300 and -0.186 (e·Å–3
)
192

Table A.9: Atomic coordinates ( x 10 4 ) and equivalent
isotropic
displacement parameters (A 2 x 10 3 ) for 368.
U(eq) is defined as one third of the trace of the
orthogonalized
U ij tensor.
_______________________________________________________________________
x y z U(eq)
_______________________________________________________________________
C(1) 950(2) 2860(1) 3184(1) 18(1)
C(2) -833(2) 2360(2) 3718(1) 19(1)
C(3) -1091(2) 938(2) 3782(1) 20(1)
C(4) 284(2) -395(2) 3305(1) 19(1)
C(5) 1403(2) 346(1) 2560(1) 18(1)
C(6) -463(2) 1489(1) 2032(1) 18(1)
C(7) -7(2) 3051(2) 1739(1) 20(1)
C(8) -48(2) 4047(1) 2426(1) 20(1)
C(9) 2558(2) 1352(1) 2880(1) 18(1)
O(10) 4579(1) 984(1) 2901(1) 23(1)
C(11) 2159(2) 3583(2) 3691(1) 22(1)
C(12) 2776(2) 2637(2) 4476(1) 25(1)
C(13) 2647(2) 3268(2) 5138(1) 33(1)
C(14) -1585(2) 3999(2) 1086(1) 25(1)
C(15) -1038(3) 3224(2) 337(1) 34(1)
C(16) -2447(4) 2821(2) -37(1) 53(1)
C(17) 3084(2) -972(2) 2108(1) 22(1)
C(18) 4045(2) -417(2) 1330(1) 25(1)
C(19) 6199(2) -672(2) 1148(1) 30(1)
C(20) 1986(2) -1653(2) 3823(1) 26(1)
O(21) -1082(1) -1213(1) 3057(1) 21(1)
C(22) 1418(2) 5096(2) 2133(1) 26(1)
C(23) -2411(2) 5128(2) 2640(1) 25(1)
_______________________________________________________________________
193

Table A.10: Bond lengths [Å] and angles [°] for 368
_____________________________________________________________
C(1)-C(9) 1.5148(17)
C(1)-C(2) 1.5273(16)
C(1)-C(11) 1.5422(17)
C(1)-C(8) 1.5991(17)
C(2)-C(3) 1.3258(18)
C(2)-H(2) 0.9500
C(3)-C(4) 1.5075(17)
C(3)-H(3) 0.9500
C(4)-O(21) 1.4317(15)
C(4)-C(20) 1.5252(18)
C(4)-C(5) 1.5736(16)
C(5)-C(9) 1.5179(17)
C(5)-C(17) 1.5380(17)
C(5)-C(6) 1.5553(16)
C(6)-C(7) 1.5299(16)
C(6)-H(6A) 0.9900
C(6)-H(6B) 0.9900
C(7)-C(14) 1.5398(17)
C(7)-C(8) 1.5626(17)
C(7)-H(7) 1.0000
C(8)-C(23) 1.5262(17)
C(8)-C(22) 1.5360(17)
C(9)-O(10) 1.2152(15)
C(11)-C(12) 1.5015(19)
C(11)-H(11A) 0.9900
C(11)-H(11B) 0.9900
C(12)-C(13) 1.318(2)
C(12)-H(12) 0.9500
C(13)-H(13A) 0.9500
C(13)-H(13B) 0.9500
C(14)-C(15) 1.496(2)
C(14)-H(14A) 0.9900
C(14)-H(14B) 0.9900
C(15)-C(16) 1.316(2)
C(15)-H(15) 0.9500
C(16)-H(16A) 0.9500
C(16)-H(16B) 0.9500
C(17)-C(18) 1.5011(18)
C(17)-H(17A) 0.9900
C(17)-H(17B) 0.9900
C(18)-C(19) 1.319(2)
C(18)-H(18) 0.9500
C(19)-H(19A) 0.9500
C(19)-H(19B) 0.9500
C(20)-H(20A) 0.9800
C(20)-H(20B) 0.9800
C(20)-H(20C) 0.9800
O(21)-H(21) 0.8400
C(22)-H(22A) 0.9800
C(22)-H(22B) 0.9800
194

C(22)-H(22C) 0.9800
C(23)-H(23A) 0.9800
C(23)-H(23B) 0.9800
C(23)-H(23C) 0.9800
C(9)-C(1)-C(2) 106.28(10)
C(9)-C(1)-C(11) 110.71(10)
C(2)-C(1)-C(11) 107.86(10)
C(9)-C(1)-C(8) 106.53(9)
C(2)-C(1)-C(8) 112.99(10)
C(11)-C(1)-C(8) 112.31(10)
C(3)-C(2)-C(1) 125.28(11)
C(3)-C(2)-H(2) 117.4
C(1)-C(2)-H(2) 117.4
C(2)-C(3)-C(4) 124.29(11)
C(2)-C(3)-H(3) 117.9
C(4)-C(3)-H(3) 117.9
O(21)-C(4)-C(3) 111.24(9)
O(21)-C(4)-C(20) 105.19(10)
C(3)-C(4)-C(20) 109.54(10)
O(21)-C(4)-C(5) 109.54(10)
C(3)-C(4)-C(5) 108.26(10)
C(20)-C(4)-C(5) 113.08(10)
C(9)-C(5)-C(17) 111.45(10)
C(9)-C(5)-C(6) 107.60(10)
C(17)-C(5)-C(6) 112.14(10)
C(9)-C(5)-C(4) 105.33(9)
C(17)-C(5)-C(4) 110.88(10)
C(6)-C(5)-C(4) 109.16(9)
C(7)-C(6)-C(5) 111.68(10)
C(7)-C(6)-H(6A) 109.3
C(5)-C(6)-H(6A) 109.3
C(7)-C(6)-H(6B) 109.3
C(5)-C(6)-H(6B) 109.3
H(6A)-C(6)-H(6B) 107.9
C(6)-C(7)-C(14) 110.32(10)
C(6)-C(7)-C(8) 112.63(10)
C(14)-C(7)-C(8) 113.44(10)
C(6)-C(7)-H(7) 106.7
C(14)-C(7)-H(7) 106.7
C(8)-C(7)-H(7) 106.7
C(23)-C(8)-C(22) 108.58(10)
C(23)-C(8)-C(7) 112.13(10)
C(22)-C(8)-C(7) 106.78(10)
C(23)-C(8)-C(1) 109.51(10)
C(22)-C(8)-C(1) 110.55(10)
C(7)-C(8)-C(1) 109.26(9)
O(10)-C(9)-C(1) 122.59(11)
O(10)-C(9)-C(5) 123.69(11)
C(1)-C(9)-C(5) 113.72(10)
C(12)-C(11)-C(1) 114.07(11)
C(12)-C(11)-H(11A) 108.7
C(1)-C(11)-H(11A) 108.7
C(12)-C(11)-H(11B) 108.7
C(1)-C(11)-H(11B) 108.7
195

H(11A)-C(11)-H(11B) 107.6
C(13)-C(12)-C(11) 124.47(14)
C(13)-C(12)-H(12) 117.8
C(11)-C(12)-H(12) 117.8
C(12)-C(13)-H(13A) 120.0
C(12)-C(13)-H(13B) 120.0
H(13A)-C(13)-H(13B) 120.0
C(15)-C(14)-C(7) 112.47(12)
C(15)-C(14)-H(14A) 109.1
C(7)-C(14)-H(14A) 109.1
C(15)-C(14)-H(14B) 109.1
C(7)-C(14)-H(14B) 109.1
H(14A)-C(14)-H(14B) 107.8
C(16)-C(15)-C(14) 125.55(17)
C(16)-C(15)-H(15) 117.2
C(14)-C(15)-H(15) 117.2
C(15)-C(16)-H(16A) 120.0
C(15)-C(16)-H(16B) 120.0
H(16A)-C(16)-H(16B) 120.0
C(18)-C(17)-C(5) 115.76(10)
C(18)-C(17)-H(17A) 108.3
C(5)-C(17)-H(17A) 108.3
C(18)-C(17)-H(17B) 108.3
C(5)-C(17)-H(17B) 108.3
H(17A)-C(17)-H(17B) 107.4
C(19)-C(18)-C(17) 124.83(13)
C(19)-C(18)-H(18) 117.6
C(17)-C(18)-H(18) 117.6
C(18)-C(19)-H(19A) 120.0
C(18)-C(19)-H(19B) 120.0
H(19A)-C(19)-H(19B) 120.0
C(4)-C(20)-H(20A) 109.5
C(4)-C(20)-H(20B) 109.5
H(20A)-C(20)-H(20B) 109.5
C(4)-C(20)-H(20C) 109.5
H(20A)-C(20)-H(20C) 109.5
H(20B)-C(20)-H(20C) 109.5
C(4)-O(21)-H(21) 109.5
C(8)-C(22)-H(22A) 109.5
C(8)-C(22)-H(22B) 109.5
H(22A)-C(22)-H(22B) 109.5
C(8)-C(22)-H(22C) 109.5
H(22A)-C(22)-H(22C) 109.5
H(22B)-C(22)-H(22C) 109.5
C(8)-C(23)-H(23A) 109.5
C(8)-C(23)-H(23B) 109.5
H(23A)-C(23)-H(23B) 109.5
C(8)-C(23)-H(23C) 109.5
H(23A)-C(23)-H(23C) 109.5
H(23B)-C(23)-H(23C) 109.5
_____________________________________________________________
196

Table A.11: Anisotropic displacement parameters (A 2 x 10 3 ) for 368.
The anisotropic displacement factor exponent takes the form:
-2 pi 2 [ h 2 a* 2 U11 + ... + 2 h k a* b* U12 ]
_______________________________________________________________________
U12
U11 U22 U33 U23 U13
_______________________________________________________________________
C(1) 14(1) 19(1) 24(1) -4(1) 2(1) -8(1)
C(2) 13(1) 23(1) 22(1) -5(1) 1(1) -7(1)
C(3) 13(1) 25(1) 22(1) -1(1) 1(1) -8(1)
C(4) 14(1) 19(1) 26(1) -1(1) 1(1) -8(1)
C(5) 14(1) 18(1) 24(1) -2(1) 1(1) -7(1)
C(6) 16(1) 19(1) 22(1) -4(1) 1(1) -8(1)
C(7) 17(1) 20(1) 23(1) -2(1) 1(1) -9(1)
C(8) 18(1) 17(1) 25(1) -3(1) 1(1) -7(1)
C(9) 15(1) 20(1) 20(1) -1(1) 2(1) -8(1)
O(10) 13(1) 28(1) 30(1) -6(1) 1(1) -8(1)
C(11) 18(1) 26(1) 26(1) -8(1) 3(1) -12(1)
C(12) 17(1) 32(1) 30(1) -6(1) 0(1) -11(1)
C(13) 26(1) 44(1) 31(1) -8(1) -3(1) -10(1)
C(14) 28(1) 23(1) 27(1) 3(1) -4(1) -12(1)
C(15) 52(1) 32(1) 24(1) 5(1) -4(1) -23(1)
C(16) 90(2) 55(1) 32(1) 5(1) -15(1) -49(1)
C(17) 18(1) 19(1) 29(1) -6(1) 3(1) -7(1)
C(18) 28(1) 21(1) 27(1) -9(1) 4(1) -9(1)
C(19) 31(1) 31(1) 31(1) -8(1) 8(1) -15(1)
C(20) 20(1) 26(1) 31(1) 1(1) -1(1) -9(1)
O(21) 15(1) 19(1) 32(1) -2(1) -1(1) -9(1)
C(22) 29(1) 24(1) 29(1) -3(1) 2(1) -16(1)
C(23) 21(1) 21(1) 31(1) -4(1) 2(1) -5(1)
_______________________________________________________________________
197

Table A.12: Hydrogen coordinates ( x 10 4 ) and isotropic
displacement parameters (Å 2 x 10 3 ) for 368.
________________________________________________________________
x y z U(eq)
________________________________________________________________
H(2) -1838 3131 4029 23
H(3) -2215 746 4153 24
H(6A) -553 955 1572 22
H(6B) -1927 1727 2337 22
H(7) 1551 2753 1488 23
H(11A) 3541 3671 3393 27
H(11B) 1177 4675 3780 27
H(12) 3294 1506 4497 31
H(13A) 2135 4394 5139 40
H(13B) 3066 2596 5615 40
H(14A) -3150 4099 1274 31
H(14B) -1478 5087 978 31
H(15) 452 3003 112 41
H(16A) -3954 3020 167 63
H(16B) -1957 2332 -512 63
H(17A) 4338 -1563 2448 26
H(17B) 2330 -1732 2014 26
H(18) 3025 159 939 30
H(19A) 7269 -1244 1524 36
H(19B) 6681 -283 642 36
H(20A) 1218 -1961 4312 39
H(20B) 3119 -1215 3949 39
H(20C) 2715 -2593 3539 39
H(21) -2345 -555 2950 32
H(22A) 927 5691 1624 38
H(22B) 2987 4419 2072 38
H(22C) 1275 5846 2518 38
H(23A) -2383 5654 3103 38
H(23B) -3413 4488 2760 38
H(23C) -2953 5938 2195 38
________________________________________________________________
198

Table A.13: Torsion angles [°]for 368.
________________________________________________________________
C(9)-C(1)-C(2)-C(3) -10.23(17)
C(11)-C(1)-C(2)-C(3) -128.99(13)
C(8)-C(1)-C(2)-C(3) 106.25(14)
C(1)-C(2)-C(3)-C(4) -3.0(2)
C(2)-C(3)-C(4)-O(21) -139.34(12)
C(2)-C(3)-C(4)-C(20) 104.78(14)
C(2)-C(3)-C(4)-C(5) -18.94(16)
O(21)-C(4)-C(5)-C(9) 173.01(9)
C(3)-C(4)-C(5)-C(9) 51.55(12)
C(20)-C(4)-C(5)-C(9) -70.02(13)
O(21)-C(4)-C(5)-C(17) -66.31(12)
C(3)-C(4)-C(5)-C(17) 172.23(10)
C(20)-C(4)-C(5)-C(17) 50.66(14)
O(21)-C(4)-C(5)-C(6) 57.72(12)
C(3)-C(4)-C(5)-C(6) -63.74(12)
C(20)-C(4)-C(5)-C(6) 174.69(10)
C(9)-C(5)-C(6)-C(7) 22.04(13)
C(17)-C(5)-C(6)-C(7) -100.86(12)
C(4)-C(5)-C(6)-C(7) 135.86(10)
C(5)-C(6)-C(7)-C(14) 168.13(10)
C(5)-C(6)-C(7)-C(8) -63.99(13)
C(6)-C(7)-C(8)-C(23) -86.53(12)
C(14)-C(7)-C(8)-C(23) 39.69(14)
C(6)-C(7)-C(8)-C(22) 154.66(10)
C(14)-C(7)-C(8)-C(22) -79.12(13)
C(6)-C(7)-C(8)-C(1) 35.06(13)
C(14)-C(7)-C(8)-C(1) 161.29(10)
C(9)-C(1)-C(8)-C(23) 150.38(10)
C(2)-C(1)-C(8)-C(23) 34.05(14)
C(11)-C(1)-C(8)-C(23) -88.25(12)
C(9)-C(1)-C(8)-C(22) -90.03(11)
C(2)-C(1)-C(8)-C(22) 153.64(10)
C(11)-C(1)-C(8)-C(22) 31.35(13)
C(9)-C(1)-C(8)-C(7) 27.21(12)
C(2)-C(1)-C(8)-C(7) -89.11(12)
C(11)-C(1)-C(8)-C(7) 148.59(10)
C(2)-C(1)-C(9)-O(10) -130.99(12)
C(11)-C(1)-C(9)-O(10) -14.12(16)
C(8)-C(1)-C(9)-O(10) 108.27(13)
C(2)-C(1)-C(9)-C(5) 48.20(13)
C(11)-C(1)-C(9)-C(5) 165.07(10)
C(8)-C(1)-C(9)-C(5) -72.54(12)
C(17)-C(5)-C(9)-O(10) -12.53(16)
C(6)-C(5)-C(9)-O(10) -135.85(12)
C(4)-C(5)-C(9)-O(10) 107.79(13)
C(17)-C(5)-C(9)-C(1) 168.29(10)
C(6)-C(5)-C(9)-C(1) 44.96(13)
C(4)-C(5)-C(9)-C(1) -71.39(12)
C(9)-C(1)-C(11)-C(12) -70.97(13)
C(2)-C(1)-C(11)-C(12) 44.92(14)
199

C(8)-C(1)-C(11)-C(12) 170.08(10)
C(1)-C(11)-C(12)-C(13) -141.21(13)
C(6)-C(7)-C(14)-C(15) -69.78(14)
C(8)-C(7)-C(14)-C(15) 162.78(11)
C(7)-C(14)-C(15)-C(16) 124.75(16)
C(9)-C(5)-C(17)-C(18) -70.46(14)
C(6)-C(5)-C(17)-C(18) 50.25(14)
C(4)-C(5)-C(17)-C(18) 172.55(10)
C(5)-C(17)-C(18)-C(19) 121.07(14)
________________________________________________________________
200

Table A.14. Hydrogen bonds for 368 [[Å] and [°]].
_______________________________________________________________________
D-H...A d(D-H) d(H...A) d(D...A)

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Vita
The author was born in Colombo, Sri Lanka May 3 rd 1974. He received a Bachelor of
Science degree in chemistry in 2001 from University of Colombo, Sri Lanka. He worked
as undergraduate and post undergraduate research assistant with Professor E.D. de Silva
at the University of Colombo and investigated the antibiotic and antifungal activity of
compounds present in Barringtonia ceylanica and Drosera indica. During his
undergraduate studies, he was the recipient of Mahapola National Scholarship, Sri Lanka.
He joined the Graduate Program at the Chemistry Department, University of Kentucky in
the Fall of 2003, and joined the research group of Dr. Robert B. Grossman in the Spring
of 2004. During his tenure at the University of Kentucky she was the recipient of the
100% PLUS award for outstanding achievement in Chemistry (2007) and the RTCF
Research Fellow (2009).
Nawarathne P. H. K. I. N., Jayasekara M. P. S., de Silva E. D. , Perera P. ,
Wijendra W. A. S.; ― Investigation of Antifungal Activity of Drosera indica,‖
Chemistry in Sri Lanka, 2005, 22(2), 18-19.
Jayasekara M. P. S, Ronghua Lu, Grossman R. B.; Catalytic Classical resolution
of γ-substituted cyclohexenones – manuscript in preparation
Jayasekara M. P. S, Grossman R. B.; Intramolecular aldol approach to 7-endo
Polycyclic Polyprenylated Acylphloroglucinols - Total synthesis towards 7-epiclusioanone-
manuscript in preparation
211