Natural Products with Halogen-Bearing Stereogenic Centers ...

MeO
H
N
Natural Products with Halogen-Bearing Stereogenic Centers:
Natural Origin and Synthesis
Dr. Jared T. Shaw
Evans Group Seminar
February 1, 2002
Occurrence of Halogenated Natural Products:
Gribble, G. W., Progress in the Chemistry of Organic Natural Products, 1996, 68, 1-498. 2288 references!
Gribble, G. W., Acc. Chem. Res., 1998, 31, 141-152.
Constituents of Laurencia:
Erickson, K. L., Marine Natural Products, 1983, 31-256.
Fluorinated Natural Products:
Harper, D. B., O'Hagan, D. O., Natural Product Reports, 1994, 11, 123-133.
Haloperoxidases:
Butler, A., Walker, J. V., Chem. Rev., 1993, 93, 1937-1944.
Butler, A., Coord. Chem. Rev., 1999, 187, 17-35.
Franssen, M. C. R., Catalysis Today, 1995, 22, 441-457.
Synthesis of Halogenated Natural Products:
Murai, A., Studies in Natural Products Chemistry, 1997, 19, 411-461.
Halogenated Natural Products Synthesized in the Evans Group
Completed:
Br
Me
H
OH
H
O
HO
MeO
N
Epibatidine
shaw 01/02 2/4/02 1:54 PM
Cl
HO
O
O
N
H
H
H
H
O
H
H
H
H
O
Me
O
Me
N Me
H O
O
HO
Cl
O
H
O
N H
H
N
N
H
O H
N
H
NH
O
O
O O
HO
Phorboxazole B
HO
OH
OH
O
OH
HO
Teicoplanin
O
O
HO
O
HO
Cl
HO
O
H
N
H
H
NH
HO
NH
O
Cl
O
H
N
OH
OH
NH 2
O
OH
N
H
O
O
H 2N
Cl
H
N
O
Vancomycin
O
O
Me
In Progress:
Me
MeO
Me
Me
O
H OH
O
OH
NH
Me
O
MeO
Me
O O Me
H
O
O
NH
NHMe
Callipeltoside A
H
Cl

Distribution of Halogenated Natural Products
2500
2000
1500
1000
500
0
16/103
F
Cl
812/2051 630/1782
Br
"Chiral" = Contains A Halogen-Bearing Stereocenter
Outline
8/70
I
Total
"Chiral"
I. Fluorinated natural products
II. Chlorinated/brominated natural products
A. biogenesis
B. Methods of stereoselective chlorination and bromination
1. SN2 Displacement: "X - "
2. Electrophilic halogenation: "X + "
3. Polycyclization
4. Acyclic stereocontrol employing haloalkenes
5. The Kharasch reaction
C. Syntheses
1. Oppositiol, prepinnaterpene, laurencial, dactylyne
2. Comparative syntheses of laurencin and related structures
3. Comparative syntheses of kumausyne and kumausallene
4. Syntheses aplysiapyranoids and thyrsiferol/venusatriol by electrophilic monocyclization
5. Selected polycyclzations leading to natural products
6. Diels-Alder spproaches to plocamium natural products and virantmycin
7. Callipeltoside sidechain
8. Halomon
9. Outlyers: Hapalindole G & Axinellamines
shaw 03/04 2/4/02 1:56 PM

HO
F
O
N
N
O O
Me Me
The Fluorinated Natural Products
•Most fluorinated natural products are derived from fluoroacetyl Co-A
F
H 2NSO 2
F
O
O
SCoA
SCoA
n
n=4, 6, 7, 8
NHBz
shaw 05/06 2/4/02 1:57 PM
N
F
N
MsCl;
KOt-Bu
58%
O
N
N
HO OH
Nucleocidin
OH
OH
F
O
O
OH
Me
HO2C OH
HO2C CO2H F
(2R, 3R)-2-fluorocitric acid
F
H 2NSO 2
The Fluorinated Natural Products:
Moffatt's Synthesis of Nucleocidin
NH 2
N
N
N
O N
O O
Me Me
N
TFA/
H 2O
77%
NHBz
N
BzCl/Pyr
97%
H 2NSO 2
F
N
O N
O O
Me Me
N
O N
O O
Me Me
NH 2
N
N
N
O
NBz 2
N
F
H
F
O
OH
N
N
HO OH
F
Nucleocidin
AgF/I 2
77%
(Bu 3Sn) 2O;
H 2NSO 2Cl
87%
NH 2
O
NH 2
N
O
OH
N
OH
4-fluorothreonine
I
F
Gribble, 1996
N
O N
NBz 2
N
N
O O
Me Me
diastereoselection 65:35
HO
F
1) LiN 3/DMF; 93%
2) hv; H + /H 2O;
NaBH 4; 26%
N
O N
O O
Me Me
NH 2
Moffatt, J. G., et al, J. Am. Chem.Soc., 1976, 98, 3346-3357.
N
N

The Biogenic Origin of Halogenated Natural Products
• Chlorine is incorporated by nucleophilic displacement as Cl - or through the reactions of alkenes with
chloroperoxidases (CPO's), ie as "Cl + "
• Bromine is almost exlusively incorproated as "Br + " by bromoperoxidases (BrPO's)
• Iodoperoxidases have been identified, but not studied in as much detail as CPO and BrPO
As a result, most halogen-bearing stereogenic centers occur as halohydrins or polycyclics!
"Br + "
Me
Me
R
R'
"X + "
Nu
R
+
X
R'
Nu = H 2O, X - , ROH, C=C
Examples of Halogen Biosynthesis
HO Cl
Me Me
Br +
epoxidation
Cl
Laurencenyne Prerogioloxepane
- attack
HO Cl
O
Br H H Cl
Rogioloxepane C
shaw 07/08 2/4/02 1:58 PM
Me
Me
Me
Geranyllinalool
H
OH
O
H
O
Br H H Cl
Rogioloxepane B
Isolated from Laurencia microcladia
Br
Me
R
Me
Nu
X
R'
Me
O
Br H H Cl
Rogioloxepane A
Me
Me
3-Bromobarekoxide
isolated from Laurencia luzonensis
O
Pietra, F., et al, Helv. Chim. Acta, 1992, 75, 310-322
Jefford, C. W. Chem. Commun., 2000, 1155-1156

Examples of Halogen Biosynthesis
• The vast majority of the natural products herein discussed are isolated from the seaweeds (algae)
of the genus Laurencia and Plocamium.
• Sea hares of the species Aplysia that feed on the seaweed are also sources of the natural products
and can modify them
Laurencia seaweed
V-BrPO=
Vanadium
Bromoperoxidase
H-CPO=
Heme-
Chloroperoxidase
shaw 09/10 2/4/02 2:00 PM
Br
Me
Br
HO
Me
Me Me
Me
O
Me
OH
Me
Br
Cl
Aplysia sea hare
Br
Br
Me
Me Me
O
Me
Me
Br
Cl
O Me
+
Br
Cl
Me
Me
Me Me
O
Me
Br
Cl
Faulkner, D. J., et al, Comp. Biochem. Physiol., 1974, 49B, 37-41
Haloperoxidases Catalyze Selective Oxidations
AcO
Ph
n-Bu
S Me
V-BrPO/
H2O2 pH 6.5
25 °C
O -
S +
Me
S S +
Me
Ph Me
H-CPO/
H2O2 pH 5.5
25 °C
Ph
n-Bu
O
O -
Me
O
Me Me
OH
Me
H-CPO/
H2O2 pH 5.5
25 °C
AcO
OH
Me
Yield (%) ee (%)
6 0
99 89
67 96
78 96
52 95
Ph Me 20 90
Sulfoxidation: Allenmark, A., et al, J. Org. Chem., 1997, 62, 8455-8458
Epoxidation: Hager, L. P. & Jacobsen, E. N., et al, J. Am Chem. Soc., 1993, 115, 4415-4416
Propargylic Oxidation: Hager, L. P. & Hu, S., J. Am. Chem. Soc., 1999, 121, 872-873
Benzylic Oxidation: Zaks, A., et al, J. Am. Chem. Soc., 1995, 117, 10419-10424

Haloperoxidases Catalyze Unselective Bromohydrin Formation
OH
Me
OH
OH
Me
OH
Br
Br
(+/-) (+/-)
H-CPO, Br - , H2O2 H-LPO, Br
61% 39%
- , H2O2 V-BrPO, Br
- -
- N-Bromoacetamide 75% 25%
, H2O2 66% 34%
H-CPO=Heme-dependent chloroperoxidase from Caldariomyces Fumago (fungus)
H-LPO=Heme-dependent lactoperoxidase (haloperoxidase) from bovine milk
V-BrPO=Vanadium-dependent bromoperoxidase from Corallina Officinalis (marine algae)
"One of the most interesting, yet unsolved problems in the area of
marine biohalogenation, is the biogenesis of the chiral
halogenated marine natural products."
Butler, A. Chem. Rev., 1993, 93, 1937–1944.
"All haloperoxidases catalyze smooth, yet unselective
chlorination, bromination or iodination of relatively electron-rich
groups in organic compounds...However, there must be more
stereo- and/or regioselective halogenating enzymes in nature,
regarding the presence of halometabolites like 44 and 45."
Franssen, M. C. R., Catalysis Today, 1994, 22, 441-457
Me
Me
shaw 11/12 2/4/02 2:01 PM
Br
Br
Cl
Me
H
O
Br
C
OH
Coughlin, P., et al, Biotechnology Letters, 1993, 15, 907-912
Enzyme-Catalyzed Bromohydrin Formation
HO
Laurediol
O
H
Br
OH
OH
E-Prelauretin
Lactoperoxidase;
NaBr, H 2O 2, pH 5.5
0.05% Yield
(0.41% BORSM)
Lactoperoxidase;
NaBr, H2O2, pH 5.5
0.03% Yield
(0.19% BORSM)
Me
Me
Me
O
H
Me Me
H
Cl Cl
44 45
O
H
Br
O
H
Br
OH
E-Prelauretin
O
Laurallene
Murai, A., et al:
Tetrahedron Lett., 1995, 36, 737-740
Tetrahedron, 1997, 53, 8371
Cl
Br
H
Cl

HN
HN
R
Nucleophilic Displacement:
OR
R R'
O
R'
Br -
-or-
CBr4/PR3 LA/Br -
Methods of Halogenation
R
Br
R R'
Bromoetherification/ Oxymercuration-Bromination
Me
O
O
Me
Me
OH
Hg(OTF) 2
Me
CCl 3
CCl 3
OH
"Br + "
O
TfHg
Me Me
R 1
O
Br
Br
OH
O
R'
Me Me
LiBr; Br2
Br
O
Me Me
Methods of Halogenation
CCl 3
M = Cu, Fe, Ru, Mo
CuCl/BiPy
61%
CuCl/BiPy
98%
shaw 13/14 2/4/02 2:02 PM
R 1
O
HN
Cl Cl
HN
Cl
R 2
O
The Kharasch Reaction:
R 2
Cl
Cl
Cl
O
Cl
Cl
Cl
M n
Me
O
M n+1 Cl
Me
O
O
Me
O
O
Me
O
R
R
R'
R 1
R 1
CCl 3
Cycloaddition/Sigmatropic
Rearrangement:
Cl
O
O
Br
OH
Cl
Cl Cl
Cl
R 2
R
R' Br
R Cl
O
Polyene Cyclization
Br
R 2
Me
Me
R 2
R 3
Me
Hg(OTFA) 2, etc
or Br +
Me
Me
Me
O
CuCl/BiPy
74%
O
O
O
Me
O
Me
R
R
O
Cl
OMe
Cl
Cl
Weinreb, S. M., et al, Tetrahedron, 1988, 44, 4671-4678
Itoh, K., et al, J. Org. Chem, 1993, 58, 464-470
Speckamp, W. N., et al, Synlett, 1993, 739

O
H
O H
Br
PMBO
Me OH
EtO 2C
Me
O O
X
O O
shaw 15/16 2/4/02 2:03 PM
O
Br
MsO
Synthesis of Laurencia Natural Products:
T. Masamune's Prepinnaterpene & Oppositol
Me
BnO H
Me OH
Me
OBn
OBn
Bu 4NBr, 100 °C
55% (35% alkene)
OBn
OTBS
CO 2Et
Me
2 steps
92%
HO
MsO BnO
MeLi
100%
Br
Me
H
Me
CHO
Br
Me
OBn
Me
O
Bu 4NBr
100 °C
H
Br
OBn
PPTs
HO
Br
Me
H
Me
96%
Oppositol
BnO
63%
Me
Me
Br
Me
OBn
Br -
3 steps
95%
Br
Me
BnO
H
HO Me Me
Prepinnaterpene
Me
Me
Me
Br
10%
OBn
(+ 20% alkene)
Masamune, T., et al, Tetrahedron Lett, 1987, 28, 4303-4306
Synthesis of Prepinnaterpene & Oppositol:
Improved Core Syntheses
PdCl 2(BINAP)
Me
86%ee
X=I, OTf
Me
PMBO
5 steps
TBSO
EtO 2C
PMBO
H
O O
Oppositol
Me
EtO 2C
O O
Me
ds = "excellent"
O
H
Me
Br
KOt-Bu
PMBO
KO
OBn
O
H
Masamune
Intermediate
EtO
EtO 2C
O O
Me
O
Me
OBn
Shibasaki, M., et al, Tetrahedron Asymm, 1995, 28, 757-766
Kim, D., et al, Tetrahedron Lett, 1997, 38, 415-416
Br
Me
Br
KHMDS
Br
Br
O OPMB

Me
Me
O
Me
Me
Me
OsO 4
83%
Me
O
Synthesis of Laurencia Natural Products:
Iwata's Laurencial
OH
Me
Me
Me
diastereoselection 95:5
Me
HO
8 steps
Me
Br
Me
PivO
O
O
Me
shaw 17/18 2/4/02 2:05 PM
Me
Br
B
A
OH
O
Me
OH
MeMgI
81%
SOCl 2,
ZnCl 2
81%
87%
OH
MeO OMe
Me
Me
Me Me
Me
Me
Me
Me
O
Me
Me
O
O
Cl
Me
O
Me
Me
Me
O
O
Me
Me
Me
O O
O
Br
O
Br
Me
PPTs
O
O3, MeOH
pTSA
46%
A: diastereoselection >95:5
B: diastereoselection 70:30
Synthesis of Dactylyne
Murai's regioselective epoxy alcohol opening:
O
R OH
R
Br
OTBS
O
O
OBz
OMPM
OH
Ti(Oi-Pr) 4/
Et 2NH-HX
OR
Et 2AlCl/
Et 2NH-HX
Ti(Oi-Pr) 4/
Et2NH-HBr 78%
O
Me
OHC
1) MsCl
2) DBN
73%
Me
Me
Me
Me
Me
Me
Me
O
Cl
O
(+/-)-Laurencial
Br
Me
O
89%
O
Me
O
H
O
Me
OH
Me
Me
Iwata, C, et al, Tetrahedron, 1998, 54, 1396-1406
R OH
R
HO
X
X
HO
HO
see also Sharpless, K. B., et al, J. Org. Chem., 1985, 50, 15571560
Cl
Cl
HO
OMs
OH
Et 2AlCl
90-100%
E = Dactylyne
Z = Isodactylyne
PivO
OH
Br
Br
OTBS
OH
O
OBz
OMs
OMPM
OH
Murai, A, et al, Tetrahedron Lett, 1992, 33,
4349-4352

TMS
TBDPSO
TMS
Synthesis of Laurencia Natural Products
• Before the 1988 synthesis of Laurenyne by Overman, there was only one synthesis
of an oxocane-containing natural product known, ie T. Masumune's synthesis of Laurencin in
0.003% yield.
• In the last decade, however, many syntheses of medium-ring ether natural products from the
Laurencia series have appeared.
OH
shaw 19/20 2/4/02 2:07 PM
O
H
OAc
Br
Me
Laurencin
Principle Synthetic Challenges:
1) medium ring formation
2) diastereoselectivity across ring
3) regiochemical control of unsaturation
O
Cl
Laurenyne
Overman's Synthesis of Laurencia Natural Products:
Laurenyne
O
SAD
Cl
OTs
TMS
single diastereomer
SnCl 4
37%
OH
10 steps
Me
O
TBDPSO
TMS
Et 3NHCl/
Ti(Oi-Pr) 4
68%
O
O
Cl
OEt
Cl
OTs
Laurenyne
TMS OH TMS Cl
+
OH
Cl
HO
OH
regioselectivity 25:75
TsCl/Pyr
86%
OTBDPS
EtO
PPTs TMS Cl
98%
HO
20 Steps, 0.6% yield
Absolute Configuration
Reassigned
OTs
Overman, L. E., et al, J. Am. Chem. Soc., 1988, 110, 2248-2256

PivO
i-Pr 3Si
MeO
PhS
OMe
Me
O
OSEM
OH
Overman's Synthesis of Laurencia Natural Products:
Laurencin
O
H
n-BuLi;
(-)-Ipc2BOMe; OH
EtCHO
70% yield
92% ee OSEM
OAc
Me
13 Steps
O
H
OAc
PhS
SnCl4 57%
5g scale
PivO
OH
Me
1) Br2/DPPE 2) TBAF
40%
Me
O
1) TBSOTf
2) 9-BBN
3) Pd(PPh 3) 4
OMe
SPh
OAc
Br
Me
87% for
3 steps
OSEM
OAc
80%
O
H
OAc
Br
Me
SPh
SPh
Laurencin
OTBS
OSEM
O
OSEM
Me
1) TBAF 2)
OMe /DIPEA
Br
OPiv
MeO
Me
24 steps/2% yield
OPiv
Overman, L. E., et al, J. Am. Chem. Soc., 1995, 117, 5958-5966
Overman's Synthesis of Laurencia Natural Products:
Isolaurepinnacin
O
1) PhSO2Cl 2) Et2AlCl/ Et2NH2Br 94%
OSO2Ph OH
Br
MeLi
91%
Me Me Me
OTIPS
O
H
Br
H
Cl
(+)-Isolaurepinnacin
12 steps/15% Yield
shaw 21/22 2/4/02 2:08 PM
(R)-BINAl-H
5 steps/
49%
MeO
Me
OMe
OH
O
Br
OTIPS
O
H
Br
H
Cl
diastereoselection >95:5
SiMe 3 Et 2AlCl
SnBu 3
88%
MeO
Br
Cl
1) BCl3 OH 2) TBAF
Me
90%!
Me
5 steps
total
Overman, L. E., et al, J. Am. Chem. Soc., 1993, 115, 9305-9306
Br
Br
OH
OTIPS
O
SiMe 3
OMe
Cl
SiMe 3
AgOTf/
DIPEA
95%
OTIPS

TMS
MeO
Murai's Synthesis of Laurencia Natural Products:
Laurencin
OTBS Me
+ Me O
O
O Br
A B
regioselection
7:1
O
Me O
Si
Me
H
O
Si
OH
O
OH
Pt
O
O
H
OAc
OH
Me
Li°
77%
O
H
OAc
OH
thermodynamic
control, 12:1
1) CBr 4/Oct 3P; 87%
2) TBAF-HF/97%
Br
OTBS
PivO
Me
O
Laurencin
Me
O
O
Me
O
1) TBAF/95%
2) SO 3-Pyr/86%
Pb(OAc) 4
92%
O
27 steps from A & B
2.5% yield
PivO
Synthesis of Laurencia Natural Products:
Holmes & Clark's Laurencin
OTBDPS
OTBDPS
diastereoselection
3.5:1
shaw 23/24 2/4/02 2:12 PM
Me Me
Si
Si
O
Me Me
O
= "Pt(DVS) 2
O
OTBDPS
OTBDPS
HO
O
O
diastereoselection >95:5
KOH/H2O2 HO
65%
HO
O
OTBDPS
OH
O
1) pTSA
2) PivCl
85%
OH
O OH
Me
Me
O
Murai, A., et al, Tetrahedron Lett, 1992, 4345-4348
O
OTBDPS
O
74%
KHMDS
(2R,8αS)-CSO
Me
Me
N
O S
O
O
Br
Me
O
O
O
OTBDPS
O
O
H
O
OAC
Laurencin
OTBDPS
26 steps
0.4% yield
Holmes, A. B., et al, J. Am. Chem. Soc., 1993, 115, 10400-10401.

O
HO
O
1
O
OTBDPS
Synthesis of Laurencia Natural Products:
Holmes & Clark's Laurencin - Retraction!
KHMDS
(2R,8αS)-CSO
HO
HO
O
O
O
O
OTBDPS
OTBDPS
Br
Me
O
H
OAC
Laurencin
"The synthesis of lactone 1 as reported by J. S. Clark, Ph. D. Thesis, Cambridge University,
1988, is correct. The synthesis of (+)-laurencin in ref 1 is difficult to account for and must
probably be charged to the fallibility of the other junior author and the gullibility of the senior
author."
Holmes, A. B., et al, J. Am. Chem. Soc., 1996, 118, 6806.
OH
O
(R)-Malic Acid
OH
shaw 25/26 2/4/02 2:13 PM
Synthesis of Laurencia Natural Products:
Holmes & Clark's Laurencin - Retooled
HO
O
Br - PPh 3 +
OH
• Use of various oxidants in the enolate oxidations
failed to provide acceptable yields or selectivities
O
O
OTBDPS
• Route was abandoned and the correct diastereomer
of hydroxy-lactone was prepared from malic acid
• Stereochemical assignments were carefully monitored
en route to laurencin
O
H
Me
O
O
Me
HO
Various [O]
Bad
Reaction!
Br
Me
O
HO
OH
O
O
H
O
OAC
Laurencin
Me
O
Me
O
OTBDPS
Holmes, A. B., et al, J. Am. Chem. Soc., 1997, 119, 7483-7498

HO
Me
O
O
(+)-DET
+
Me
O
O OTBS
12
steps
Cl
Me
shaw 27/28 2/4/02 2:15 PM
Synthesis of Laurencia Natural Products:
Murai's Obtusenyne
Cl
1) n-BuLi
2) Lindlar's Cat.
OTBS
89%
O O
Cl
O OTBS
HO
Me
diastereoselection
2:1
EtMgBr
CuI
DMDO; DIBALH
71%
Cl
TfO
O OTBS
O
OH
Cl
Br
Me
Cl
OTBS
OTBS
KHMDS/
PhNTf 2
O
(+)-Obtusenyne
Synthesis of Laurencia Natural Products:
Suzuki's Rogioloxepane A
OBn
OTBS
BnO OH
H H
Me O
OMPM
+
Me
O
11steps
OMPM
OTBS
Br
H H
Cl
O
O O
Cl
O
O
Cl
OH
OTBS
Cl
OTBS
Murai, A., et al, J. Org. Chem., 1999, 64, 2616-2617
n-BuLi/
OBn
BF3•OEt2 Me
78% OTBS
(Bu 3Sn) 2O;
Zn(OTf) 2
75%
Me
(+)-Rogioloxepane
OBn
OH
O
OH
27 steps/5% yield
Absolute Configuration
Confirmed
OMPM
OTBS
OMPM
Suzuki, T., et al, Tetrahedron Lett., 2001, 42, 1543-1546

BnO
N O
BnO
Me
O
H
H
O O
diastereoselection >95:5
BnO
Me
BnO
Me
BnO
O
H
H
+
O
Bn
Synthesis of Laurencia Natural Products:
Crimmins' Laurencin
O
Bn
N
O
(Cy 3P) 2RuCl 2CHPh
94%
Bn
H
O
Bn
O
N
N
TESO OAc
Me
Me
O
O
O
7 steps
49%
TESO O
shaw 29/30 2/4/02 2:23 PM
H
O
I
O
O
O
NaHMDS/
Allyl-I
71%
NaHMDS/
Allyl-I
75%
Br
Me
BnO
Me
BnO
O
N
O
O
Bn
diastereoselection >95:5
H
O
Bn
O
O
H
OAc
Laurencin
N
O
O
PivCl/Et3N LiXp 76%
HO 2C
OBn
18 Steps/6% yield
Synthesis of Laurencia Natural Products:
Crimmins' Isolaurallene
O
OSO 2Ar
NaHMDS
75%
(Cy 3P) 2RuCl 2CHPh
OH
94%
LiCuBr2 67%
BnO
Me
BnO
TESO
Me
H
O
H
O
Bn
O
N
TESO
Me
O
O
H
H
OH
O
OBn
Me
BrCH 2CO 2H
NaH; 88%
Me
Crimmins, M. T., et al, Org. Lett., 1999, 1, 2029-2032
O
OAc
O
C
O
NaBH4; Swern
83%
4 steps
OH
65%
BnO
O
Me H
BnO
Me
H
O
CHO
OAc
PPTs/MeOH
CBr4/Oct3P 58%
Br
Br
Me
O
O
H
H
(-)-Isolaurallene
C
OBn
1) (4- d Icr) 2BCH 2CHCH 2
2) Ac 2O; 93%
OBn
Crimmins, M. T., et al, J. Am. Chem. Soc., 2001, 123, 1533-1534
Br

O
PMBO CO 2Et
Br
Me
year
Overman 1995
Murai 1992
Holmes 1997
Boeckman 2001
Crimmins 1999
shaw 31/32 2/4/02 2:23 PM
O
OPMB
CO 2Et
O
H
Boeckman's Laurencin
1) CBS
Reduction
2) PhCOCl
82%
78%
8 steps
O
O
H
H
O
OPMB
Murai
Intermediate
O
PMBO CO2Et Me
O
PMBO
98% ee
9 steps
1) LiAlH 4
2) Dess-
Martin
Br
CO 2Et
Me
O
H
KHMDS
76%
MeO 2C
MeO 2C
PMBO
OAC
Laurencin
Synthesis of Laurencia Natural Products:
Summary
O
H
OAc
Laurencin
ds
across ring
>95:5
92:8
58:42
-
>99:1
Principle Synthetic Challenges:
1) Medium Ring Ether Formation
2) Alkene Regiochemistry
3) Diastereoselectivity
rs
of alkene #steps %yield
>95:5
88:12
>95:5
-
>95:5
24
>27 (30)
>28
22
18
2
2.5
1.2
4
6
Boeckman, R. K. Jr., et al, Unpublished Results
comments
good ds, general route
*first, but not best
good if claisen route panned out...
Good 8-membered ring synthesis
high yielding, general, but uses
oxazolidinone auxiliary at 3 stages of
the synthesis
*"first" post-masamune

O
Cl
"Br + "
Cl
OH
OH
TMSO
AcO
Synthesis of Laurencia Natural Products:
Kumausyne & Kumausallene
Me
H
H
O
H
Br
- HOAc
H
O
H
Br
Kumausyne Kumausallene
O
O
Br
Cl
(+/-)-trans-maneonene-B
Holmes, A. B., et al, Chem Comm, 1984, 1594-1595.
Me
Synthesis of Laurencia Natural Products:
Overman's Kumausyne
O
H
BnOCH2CHO RSO3H 69% O
H
H
O
H
OTBS
(EtO) 2P(O)CLiCl2 88%
TMSO
O
H H
OTBS
n-BuLi
88%
TMSO
shaw 33/34 2/4/02 2:24 PM
O
H H
OTBS
Me
Me
Me
O
OBn
H
O
H
Br
AcO
C
mCPBA
72%
O
O
H
O
OBn
+
O
O
H
O
H
H
14%
58%
O
H
OH
73%
diastereoselection >95:5
4 steps
Me
H
O
SiMe 3
BF 3•OEt 2
H
O
H
Br
(+/-)-Kumausyne
Me
O
Me
O
H
O
H
58%
Me
OBn
CHO
Overman, L. E., et al, J. Am. Chem. Soc., 1991, 113, 5378-5384

MeO
R
O
OTHP
OTHP
OH
O
OMe
TBDPSO
TBDPSO
TBDPSO
shaw 35/36 2/4/02 2:25 PM
Synthesis of Laurencia Natural Products:
Boukouvalas Kumausyne
5 steps
TMS
HO OH
HO
AcO
O
OTBDPS
5 steps
OTBDPS
H
O
H
Br
(+/-)-Kumausyne
PdCl2(0.1 equiv)
CuCl2(3 equiv)
CO, NaOAc, HOAc
93%
TMS
P + Ph3Br -
93%
91:9 E:Z
Me
O
HO
O
O
O
O
DIBAL-H
100%
Sugimura
Intermediate
OTBDPS
OTBDPS
Boukouvalas, J., et al, J. Org. Chem., 1998, 63, 916-917
Synthesis of Laurencia Natural Products:
Martín's Biomimetic synthesis of Kumausyne
12 steps
H
OH
O
H H
Br
+
1) TBCD
2) HCl/MeOH
92%
O
H H
Br
diastereoselection 50:50
Me
Me
Me
OH
Br Br
Br
O
TBCD
Br
11 steps
OTHP
OTHP
TBDPSO
TBDPSO
HO
H
OH
1) TBCD
2) HCl/MeOH
79%
O
H H
Br
diastereoselection 83:17
7 steps
H
O
H
Br
(+)-Deacetylkumausyne
Me
Me
Me
Martín, V. S., et al, J. Org. Chem., 1997, 62, 1570-1571

O
TMS
Br
H
O
H
O
H
kumausyne
intermediate
HO
C
OH
O
H
H
O
H
O
H
O
OBn
H
H
O
O
(+/-)-Kumausallene
BnO
Br
OH
Br
O
H
HO
Br
OH
Br
shaw 37/38 2/4/02 2:30 PM
H
O
Synthesis of Laurencia Natural Products:
Overman's Kumausallene
OTBS
H
1) LHMDS/PhSeCl
2) O3, Pyridine
70%
OTBS
H Br
Me
Me
Me
O
O
H
H
1) DCC/DMAP
2) Sb(SPh) 3
78%
1) Swern
2) TiCl4; 78%; TMS Ti(Oi-Pr) 4
Br
H
ds=84:16
C
H
O
O
H H
O
Br
H
HON
Me
OBn
C
S
NaOMe/
MeOH
83%
diastereoselection
>90:10
S
OSO 2Ar
H
O
H
O
H
HO 2C
+
H
O
H
O
H
H
MeO 2C
O
H
OTBS
Synthesis of Laurencia Natural Products:
Evans' Kumausallene
1) TBS-Cl/Im.
2) PBu3, CO2Me 97%
OBn
(TBCD)
86%
1) DIBAL-H
- + 2) BrPh3 P
3)TBAF
diastereoselection 94:6
BnO
O
BnO
TMS
diastereoselection 29:71
OBn
OTBS
CO 2Me
H
O
OTBS
H
O
H
O
H
OTBS
Me
LiBr 2Cu;
73%
H
Me
O
OH
Me
Overman, L. E., et al, J. Org. Chem., 1993, 58, 2468-2477
O
H
1) Jones [O]
2) Et3N, Bu3P, PhSeBr
57-74%
O 1) K-Selectride
2) PPTs
84%
Br
H
C
H
O
BnO COSePh
O
CO2Me BnO
O
H H
Br
(-)-Kumausallene
Et 3B, O 2,
(TMS) 3SiH
92%
O
O
CO 2Me
Evans, P. A., et al, Angew. Chem. Int. Ed., 1999, 38, 3175-3177
Me

O
HO
HO
H
HO CO2Et EtO2C OH
H
MeO 2C
Cl
CCl 3
O
OH
OH
6 steps
Synthesis of Laurencia Natural Products:
Lee's Kumausyne & Kumausallene
Br
8 steps
H
EtO 2C
C
MeO
PhSe
H
O
O
H
H
O
H
O
H
O
O
H H
Br
Kumausallene
I
SePh
CO 2Et
CO 2Et
Me
Bu 3SnH, AIBN
86%
Bu 3SnH, AIBN
86%
13 steps
MeO
EtO 2C
EtO 2C
AcO
O
H
CO2Et O
H
diastereoselection >95:5
13 steps
H
O
H
Br
Kumausyne
O
H
H O
9 Steps
O
H
H O
CO 2Et
OH
Overman Intermediate
Me
Lee, E, et al, Tetrahedron Lett, 1997, 38, 7757-7758
Lee, E, et al, Tetrahedron Lett, 1998, 39, 317-318
Synthesis of Aplysia Natural Products:
Successful Application of Lee's Radical Methodology
H
O
O
H
H
(3Z)-Dactomelyne
shaw 39/40 2/4/02 2:31 PM
Diethyl Tartrate
O
Et
Br
7 steps;
45%
O
Ph
7 steps
55%
AIBN
Cl
Cy3SnH Cl
67% MeO2C TBDPSO
Cl
H
O
O
H
H
O
O
CO 2Me
O
H
Br
diastereoselection >95:5
MeO 2C
Cl
Ph
Et 3B
TMS 3SiH
98%
AIBN
Cy 3SnH
67%
Ph
O
O
HSiR 3
O
TBDPSO
Cl
Lee, E, et al, J. Am. Chem. Soc. , 1995, 117, 8017-8017
H
O
Ph
MeO2C O
H
O
diastereoselction 93:7
Cl
O
H
H
9 steps
40%
O
Br
Br CO 2Me

L-arabinose
TMS
HO
O
3
steps
O
TMS
81%
HO
Overman
Sugimura
Lee
Martín
Boukoulavas
shaw 41/42 2/4/02 2:33 PM
Me
O
Synthesis of Laurencia Natural Products:
Sugimura's Kumausyne
O
Me
O
OTBDPS
O
Me
PPh 3 + Br -
OTBDPS
CHO
O
Me
DIBAL-H
100%
5 steps
11%
+ SiMe 2Ph BF 3•OEt 2
O
O
AcO
O
OTBDPS
H
O
H
Br
Kumausyne
7 steps
30%
Me
Me
Me
O
O
Me
HO
O
O
O
Me
Me
12%
O O
Sugimura, H., et al, Tetrahedron Lett, 1995, 38, 5789-5792
Synthesis of Laurencia Natural Products:
Summary of Kumausyne and Kumausallene
AcO
Br
C
H O
Me
H
H
O
H
Br
H
O
H
Br
Kumausyne Kumausallene
1991
1995
1997
1997
1998
13/5.4
16/1.3
17/2.5
21/13
13/6.2
Overman
Lee
Evans
1993
1998
1998
+
Me
O
O
SiMe 2Ph
Me Me
73%
diastereoselection >95:5
year #steps/%yield year #steps/%yield
17/2
29/0.4
14/6
Me

Br
Me
Me
Cl
Me
O
regioselection 33:66
Me
Synthesis of Aplysia Natural Products:
Jung's Aplysiapyranoid D
N SH
Me +
Cl
OTBS
Br
+
Cl
O
Me Me
Br
Cl
4 steps
Me
O
Me
Me
Me
OTBS
TBAF
43% (two steps)
Me
O
Me
Me
OH
Me Me
TBCD
Cl
Me
1) Swern
2) Cr2Cl2/CHCl3 77%
OH
Me
Me
OH
Br
SAE
90%
>95%ee
Cl
OTBS
Me
TBSCl
Me
O
Me
Me
83%
O
Me Me
Cl
Aplysiapyranoid D
Synthesis of Aplysia Natural Products:
Jung's Aplysiapyranoids A & C
OH
Cl
OH
Me Me
Me
Me
Me
shaw 43/44 2/4/02 2:34 PM
5 steps
OH
NH 4Br/DMSO
Ti(OiPr) 4
Br
94%
4 steps
Br
Me
OH
Me
Me
Cl
OH
Me
OH
Me
Me
Cl
OH
NH 4Cl/DMSO
Ti(OiPr) 4
84%
Cl
Me
Me
Me
OH
OH
Jung, M. E., et al, J. Org. Chem., 1992, 56, 1347-1348
1) Swern
2) CrCl2/CHCl3 22%
TBCD
41%
Br
Br
TBCD
40%
Me
Me
Me
OH
Me
Me
O
Me
Cl
Aplysiapyranoid A
Br
Cl
Me
Jung, M. E., et al, Tetrahedron Lett., 1993, 34, 923-926
Jung, M. E., et al, J. Org. Chem., 1998, 63, 2982-2987
Br
Cl
Me
O
Me
Cl
Aplysiapyranoid C

Me
Me
Br
Me
Me
Br
E,E-
Farnesol
Geraniol
O
O
Me
Me
7 steps
22%
shaw 45/46 2/4/02 2:36 PM
Synthesis of Laurencia Natural Products:
Thyrsiferol & Venusatriol
O
Me
O
H
Me OH Me
OH
O
H
Me
OH
Me
Me
Me
O
Me
Me
O
H
O
Me OH Me
OH
O
H
Me
OH
Me
(+)-Thysiferol Br
(+)-Venusatriol
Me
Me
"Br + "
Me
Me
O
H 2O
Me
O
O
H +
Me
Me
O
O
Me
Me Me
Synthesis of Laurencia Natural Products:
Corey's Venusatriol
Me
HO
O
Me
O
CN
TBCD
Zn°/HOAc
Br
Me
O
CN
O
R
+ Me
Me
O
Me
O
H
61%
Br
+
epimer 5%
26%
DIBAL-H
54%
Me
O CHO
Me
Me
Me
O
O
H
Br A
Me
BnO
OH
H
OH
PCC
Me 43%
Me
Me
BnO
O
OH
1) Swern
H
Me
OH
Me
Br
Me H
Me
O
H
Me
O O
t-BuLi; CeCl3; A
85%
O
Me
O
H
Me OH Me
O
H
OH
(+)-Venusatriol
H
Me
OH
Me
2) MeMgBr
3) TsOH/H2O 84%
Me
Me
O
Me
O
Me
O
H
HO H
H
Me
H
O
O
H
Me
Me
O
diastereoselection >95:5 Br
diastereoselection >95:5
Corey, E. J., et al, Tetrahedron Lett., 1988, 26, 3171-3174

Me
Me
Synthesis of Laurencia Natural Products:
Shirahama and Forsyth Improve the Bromocyclization
R OH "Br +"
Me
+ Br
Me
O
Me
R
H
Me
OR
+ Br
Me
Me
R
O
Me
H
+ Br
Me
Me Me
O H
Me
Me
O
Me
R
Me
Me
O
Me
R
Me
Br O
Me
R
Shirahama
Br Br
Me
R = H 80% 0% 20%
R = 0% 10% 90%
R =
R =
Me
Me
Forsyth
OBz
OBz
NC OH
shaw 47/48 2/4/02 2:37 PM
47% 32% 21%
12% 36% 52%
• Bulky R favors correct diastereomer, but also favors THF formation
Me
Me
CN
Shirahama, H., et al, J. Org. Chem., 1990, 55, 5088-5107
Forsyth, C. J., et al, J. Am. Chem. Soc, 2000, 122, 9099-9108
Synthesis of Laurencia Natural Products:
Forsyth's Oxymercuration as an alternative
Hg(TFA) 2
KBr
X
X
Hg
Me
O
H
Me
OR
X Me
X
X Hg
Me
X
Hg
O
Me
H
CN
Me Me
Me Me
Me O CN
Me O CN
BrHg BrHg
100%
(79% isolated)
Me Me
Me O R
Br
Br 2, Pyridine
300 nm
79%
Me
BrHg
Me
0% 0%
Me
Me
R
Me
Me Me
O H
O
CN
Me
CN
NC OH
Me
Cannot Be Prepared
Enantioselectively or
Resolved!

Me
Me
Me
Me
Synthesis of Aplysia Natural Products:
Hoye's Polycyclization
Me
OH
Me HO Me
Homogeraniol
2 steps
Me
Br
Me H
Me
Me
O
Me
O
Me
H
Br
Me H
Me
(+/-)-Aplysistatin
shaw 49/50 2/4/02 2:39 PM
H
O
CO 2Et
Me SPh CO2Me
OBn
SPh
AgBF 4/Br 2
Br
Me
1) Hg(TFA) 2
2) KBr
3) Br2, LiBr, pyr, O2 44%
Me
O
H
Me
O
+
Br
Me

Me
Me
NPS =
Me
Me
Me
Me
HO
HO
Synthesis of Aplysia Natural Products:
White's Aplysistatin
O
O
1) NPS*/Et 3N
2) NaBH 4
79%
Me
shaw 51/52 2/4/02 2:41 PM
R
O
SPh O
O
O
N
SPh
Hg(TFA) 2
KBr
Br 2, LIBr, O 2, pyr
Br
Me H
Me
Br
Me H
Me
Me
O
Me
O
Br
Me H
Me
Me
O
H
O
(+/-)-Aplysistatin
O
O
Me
O
Br
Me H
Me
13% 28%
H
26%
O
O
SPh
mCPBA/∆
68%
Corey's Use of Mercuriocyclization:
Aphidicolin & Stemodinone
CO2Me Me
OPO(OEt) 2
t-Bu
Hg(OTFA) 2;
NaCl
60%
R=H or R=OTBS
O
O
HO
HO
+
+
O
Br
Me H
Me
Me
O
H
7%
O
O
O
O
SPh
White, J. D., J. Am. Chem. Soc., 1982, 104, 3923-3928
ClHg
H
Me
R
CO2Me Me
O
CO2Me CO2Me Me Me
O
O
H
Me
Me H
(+/-)-Aphidicolin
O
H
Me
O
H
Me
Me
Me H
HO Me
H
(+/-)-Stemodinone
Corey, E. J. et al, J. Am. Chem. Soc., 1980, 102, 1742-1744
Corey, E. J. et al, J. Am. Chem. Soc., 1980, 102, 7612-7613

Me
Me
Me
Me
Me
Br
Me H
Me
Synthesis of Laurencia Natural Products:
Nishizawa's Isoaplysin-20
Me
OAc
(E, E)-Farnesyl Acetate
Me
OH
Me
H H
1.8%
(+/-)-Isoaplysin-20
Hg(TFA) 2/PhNMe 2
KBr; LiBr, Br 2, O 2
OH
NaOH/H 2O
Nishizawa, M., et al, J. Am. Chem. Soc., 1984, 106, 4290-4291
O
PhSe
O
Me
Br
Me H
Me
Me
Br
Me H
Me
Me
OH
Me
H H
16%
Me
OH
Me
H H
1.8%
OAc
OAc
Synthesis of Plocamium Natural Products:
The Diels-Alder approach
Me CHO
Tol/170 °C
53%
Me
CHO
Li
Cl Cl
diastereoselection 77:23
+ CHClBr -
+
30%
Me
Cl
Cl
Zn/HOAc
89%
Me
shaw 53/54 2/4/02 2:43 PM
Cl
Cl
"10%"
HO
CH 2Br 2
Zn°/TiCl 4
64%
Me
PhSe
Cl
+ Z isomer
Me
Cl
NBS
Cl
Zn/HOAc
"100%"
Cl
NaOCl
75%
PhSe
Cl
Me
+
H
Me
Me Me
Me
Me
chair/chair/chair
Me
Br
Me H
Me
H H
Cl
Me
Me
Br
OH
Cl
PhSeCl
68%
Cl
Br
O
Me
Me
Cl
Cl
Me
Cl
H
O
Me
H H
Me
17%
Me
H
O
Me
chair/boat/chair
Me
Me
Me
Cl
Cl PHICl
Br
Br
2
+
23%
19% Cl 33% Cl
Cl
Cl
Williard, P. G., et al, J. Org. Chem., 1985, 50, 3738-3749.
Cl
Me
O
OAc
Me
O

Me
O
Me
Cl
Cl
O
Me
Si
Si
O
Me
O
O
Synthesis of Plocamium Natural Products:
Shea's T2IM Diels-Alder Approach
Me
Si
Me
Me
Br
PhICl 2
61%
OH
OH
3 steps
66%
O
O
Me
Br
O
CO 2t-Bu
shaw 55/56 2/4/02 2:45 PM
O
Cl
O
Cl
Cl
Tol/∆
74%
96%
DIBAL-H
85%
Me
Si
Me
Cl
Me
Me
Si
O
OH
Cl
O Br
Me
Me
one
pot!
Br
OH
MeMgBr/Mg°
Cl
O
Me
Br
1) TPAP/NMO
2) CrCl2/CHCl3 E/Z=94:6
89%; 58%
Me
Si
Me
Me
Si
Me
Cl
O
Mg
MgBr
NiCl 2(dppp)/ Cl
OMgBr
Synthesis of Callipeltoside Sidechain:
Chloroalkene Cyclopropanation
57%
Cl
Cl
O
diastereoselection >98:2
Et2Zn, TFA,
CH2I2 82%
O
CO 2t-Bu
DIBAL-H
90%
Cl
Cl
R
Me
Shea, K. J., et al, J. Org. Chem., 1997, 62, 8962-8963
Cl
61%
R=CH 2OH
OH
Br
Olivo, H., et al, Org. Lett., 2001, 2, 4055-4058
Evans, D. A., et al, Org. Lett., 2001, 3, 503-505
Patterson, I., et al, Angew. Chem. Int. Ed., 2001, 603-607
Cl
NOVOZYM-435
vinylpropionate

I
MeO 2C
MeO 2C
Synthesis of Virantmycin:
Corey's Ortho-Azaxylylene Intramolecular Diels-Alder
O LiCl
+
Me
Pd(OAc) 2 (2 mol%)
HOAc
85%
Me
CO2Et O
O
N
O
Me Me
Cl
Me
4 steps

HO
HO
Cl
Halomon: The Final Frontier
• The biggest challenge in HNP synthesis is the preparation of acyclic halogenated terpenes
• Only two syntheses of Halomon have been reported, and there is still much room for improvement
OH
Cl Me
Br
N +
Me Me
Cl -
Cl Cl
Viehe's Salt
Br
Halomon
75%
Me
Cl
1) TBSCl
2) Et 4N + Cl 2 -
59%
Cl
TBSO
Cl
Me
Br
Cl Me
Br
Bu 4NBrCl 2
HPLC
25%
OH
Cl
OH
Et 4N + Br 3 -
97%
MeC(OMe) 3
pTsOH/ 170 °C
55%
Cl
Me
Cl DBU
Cl
Me
86%
Br
Cl
Cl
Br
Neither Synthesis
Gives ANY
DIastereoselectivity
Cl
TBSO
OH
Me
Br
Br
O
Cl
OMe
MgBr
87%
Me
Cl
Me
Me
6 steps
73%
Cl
Br
Bu4NBrCl2 HPLC
27%
Cl
Myrcene
CHO
Mioskowski, C., et al, Angew. Chem. Int. Ed., 1998, 37, 2085-2086
Hirama, M., et al, Angew. Chem. Int. Ed., 2000, 39, 3430-3431
Outlyers
• Several recent diastereoselective syntheses of halogenated natural products
employ selective, but not terribly general, halogenation reactions.
Me
Me
Me
Me
O
O
O 75% Me
Me H
(-)-Carvone
O -
HO 2C
OTBS
NHCBz
PhtN NPht
O
O
O
HS
LiCl/
CSA
N +
EDC
Fukuyama, T., et al, J. Am. Chem. Soc., 1994, 116, 3125-3126
Carreira, E. M., et al, J. Am. Chem. Soc., 2000, 122, 8793-8794
shaw 59/60 2/4/02 2:49 PM
N
H
+ CO2 S
Cl
Me
OTBS
H
O
NHCBz
PhtN NPht
HN
RO
Cl
NH
O
O
N
NHR NHR
O
H HO
H
N
N
H
CCl 4
NH
Me
Me
H
Cl Me
H
NH
Me
NC
(-)-Hapalindole G
Cl
Axinellamines
OTBS
NHCBz
O
O
Me
PhtN NPht
diastereoselection >91:9

H 2N
N
H 2N
H
N
H
N
N
NH 2
R 1
N
N
O
OH
diastereoselection 81:19
R 2
H 2N
N
Outlyers II
H 2N
H
N
H
N
N
H
Cl +
H
NH 2
Bn OTIPS
OTIPS
O
Bn
N
N
NTs
O
Bn
O
N
N
O
H
NTs
O
H
OH
Bn Cl
OTBS
∆; 79%
NCS; 79%
Bn OTIPS
Bn OTIPS
O
N
N H
NTs
mCPBA
O
N
N OH H
NTs
Bn
Bn
H O
H O
shaw 61/62 2/4/02 2:51 PM
OTBS
R 1
N
N
Summary
O
R 2
H 2N
HN
HN
N
Cl
HN
H2N HO
RO
Cl
N
N
HN
H
N
H
N
H
NH 2
NH
NH
H
R 1
X
Palauamines/
Styloguanidines
OH
NHR
Axinellamines
NHR
Kinnel, R. G., et al, J. Am. Chem. Soc., 1993, 115, 3376-3377
Romo, D., et al, Org. Lett., 2001, 3, 1535-1538
Poitier, P., et al, Eur. J. Org. Chem., 2001, 237-243
• Many selective approaches to the construction of halogen-bearing stereocenters
have been developed
• Nucleophilic displacement of alcohols is an important and selective method for
the construction of a bromine-bearing center
• Mono- and polycyclizations provide the opportunity to use the introduction of bromine
to control the stereo- and regiochemistry of other stereogenic centers
• Few methods are truly general and most are developed in the context of one particular
natural product class
Y
O
R 2