Highlights from the Synthesis of Gibberellins:

Highlights from the Synthesis of Gibberellins:
a 30 Year Odyssey
HO
A Friday Afternoon Seminar
6 February 2004
01-gibberellin-GA3-title.cdx 2/5/04 5:10 PM
OC
CH 3
O OH
H
H
CO 2H
Jonathan R. Scheerer

Highlights from the Synthesis of Gibberellins:
HO
OC
CH 3
O OH
H
H
CO 2H
Outline of Presentation:
I. Introduction to Gibberellins: History, Ubiquity, and Biology
II. Biosynthesis
III. Gibberellic Acid: Structure and Reactivity
IV. Conversion of Gibberellic Acid into other Gibberellins
V. Total Synthesis
VI. Partial Synthesis / Stragedy
Relvant Reviews:
Mander, Chem. Rev. 1992, 573-612.
Mander, Nat. Prod. Rep. 2003, 49-69.
MacMillan, Nat. Prod. Rep. 1996, 229.
Crozier, A. Ed. The Biochemistry and Physiology of Gibberellins. Praeger: New York, 1983. (vol 1 and 2)
02-gibberellin-outline.cdx 2/5/04 5:11 PM

HO
OC
CH 3
O
H
A Brief History of Gibberellin Research:
H
CO 2H
1898 - first research paper, links disease to fungal infection
OH
1828 - first reports of "bakanae" disease in rice plants (foolish seedling; stupid rice crop)
1912 - Kurosawa found that filtrates from infected dried rice seedlings also causes disease
Concludes that bakanae is caused by discrete chemical
1935 - First use of term "gibberellin" in scientific literature
1938 - Crystalline compound (mix of three gibberellins) isolated from fungal filtrate
1945 - Research expands to U.S. and U.K.
1955 - compound isolated. termed "gibberellic acid"
1958 - correct structure proposed (stereochemical ambiguities remain)
1961 - structure verified by X-ray
1978 - First total synthesis (Corey)
03-bakanae.cdx 2/5/04 5:19 PM

2
HO2C 19
C 20 and C 19 Gibberellins: Structure and Nomenclature
1
A
3 4
2
3
20
CH3 10
H
CH3 18
OC
19
CH3 18
O
H
5
9
6
H C
8 14
7 CO2H B
11
H
7 CO2H 12
15
D
13
16
C 20-Gibberellin Skeleton
1
5
9
6
11
8
12
14
15
13
16
C 19-Gibberellin Skeleton
05-gibberellin-structureB.cdx 2/5/04 5:13 PM
17
17
GA 12
HO2C HO2C ent-gibberell-16-ene-7,19-dioic acid
GA 9
O
R
H
O
H
R = CO 2H
ent-norgibberell-16-ene-7,19-dioic acid 19,10-lactone

HO
2
3
11 12
1 O
OC
19 5
H
9
6
H
8 14
15
OH
13
16
17
CH3 18
7 CO2H Gibberellic Acid (GA 3)
H 3C
Fermented from Gibberellia fujikuroi (a fungus) on ton scale
Bioactive at low concentrations ((sub-nanomolar common for applications)
Widely investigated and applied for commercial uses
Retail prices: $10 / g
Current yields: 15-30 g / L culture
Also bio-available in decent quantity:
07-gibberellin-GA3.cdx 2/5/04 8:55 PM
GA 3
HO
OH
O
OC
R
O
H
H
Me
GA 4
O
H
H
CO 2H
OH
R = CO2H HO
OC
O
H
Me
H
CO 2H
GA 1
OH

HO
OC
CH 3
O OH
H
H
CO 2H
Representative Biological Functions of Gibberellins:
A Brief History of Gibberellins:
– Stimulate stem elongation by stimulating cell division elongation
– Breaks seed dormancy in plants which require winter freezing
– Stimulates flowering/budding in response to lengthening days
– Can induce seedless fruit development (parthenocarpic)
– Can delay senescence (ripening) in leaves and fruit
– Induces maleness (sex expression) in dioecious flowers
– Other growth effects on fruit and budding
08-gibberellin-functions.cdx 2/5/04 5:15 PM

HO 2C
HO Me
OH
mevalonic acid (MVA)
10-gibberellin-biosynthesis1cdx 2/5/04 12:29 PM
Gibberellin Biosynthesis: Three Stages
H3C H
Stage A Stage B
OC
O
H
CH 3
H
H3C CH3 ent-kaur-16-ene
H
CO 2H
C 19-gibberellins
and C 20-gibberellins
HO 2C
H 3C
H
CH 3
H
CO 2H
HO 2C
Stage C
H 3C
H
CH 3
H
CHO
GA 12-aldehyde

HO 2C
HO
*
CH 3
OH
mevalonic acid (MVA)
DMAPP
Dimethylallyl
pyrophosphate
OPP IPP
Isopentenyl
pyrophosphate
OPP
11-gibberellin-biosynthesis2 2/5/04 12:30 PM
Gibberellin Biosynthesis: Stage A
Stage A
H 3C
H
H3C CH3 IPP IPP
OPP
GPP
*
*
H
*
*
ent-kaur-16-ene
FPP
H 3C
H
H 3C CH 3
H
OPP
OPP
ent-CCP
ent-copalyl
pyrophosphate
OPP
GGPP
geranyl-geranyl
pyrophosphate

H 3C
H
H 3C CH 3
12-biosynthesis3.cdx 2/5/04 10:11 PM
H
Gibberellin Biosynthesis: ent-CCP to ent-kaurene
OPP
ent-CCP
ent-copalyl pyrophosphate
H a
H
H 5S
H 5R
H 4
OPP
H 3C
H
H 3C CH 3
H
ent-kaur-16-ene
H5R H5S H a
H
H 4
H 5R
H 5S
H
H5R H5S H a
H a
H
H 4
H

H S
H R
H 3C
H
H 3C CH 3
H 3C
OH
H
CH3 13-biosynthesis4.cdx 2/5/04 10:35 PM
H
ent-kaur-16-ene
H
H 3C
H
H
HS CH3 O
ent-kaur-16-en-19-al
Gibberellin Biosynthesis: Stage B
Stage B
ent-kaur-16-en-19-ol
HO 2C
CH 3 H
H
CH 3
CHO
GA 12-aldehyde
biosynthetic progenitor
of all gibberellins
same biosynthesis for
fungal or higher order plants
H 3C
H
HO 2C CH 3
H a
H
Hd Hb H c
HO 2C
H
H 3C
H
HO 2C CH 3
CH 3 H
H b
H a
H
H d
Hd Hb O
see next slide
OH

H
HO2C Enz
H 3C
H 3C CH 3
O
H
H
H
ent-kaur-16-ene
Fe 4+
OH
14-biosynthesis5.cdx 2/5/04 12:37 PM
H
Gibberellin Biosynthesis: Ring Contraction
Enz
HO 2C
Stage B
OH
Fe 3+
HO
HO2C H
H
O
O
H
H
H
H
1,2-radical
shift
HO 2C
CH 3 H
H
CH 3
HO 2C OHC
H
radical trapping
CHO
GA 12-aldehyde

HO 2C
CH 3 H
H
CH 3
CHO
GA 12-aldehyde
R
O
HO 2C
CO
OH
-very complex
H
-parallel pathways
Me
-organism dependent
(fungal or higher order plants)
-converge to common GA
GA n
R
OC
Me
CH 3 H
H
CH 3
H
CO 2H
CO 2H
many complex, as yet incompletely
defined, oxidative processes
15-biosynthesis6.cdx 2/5/04 12:40 PM
Gibberellin Biosynthesis: Stage C
O
H
H
CO 2H
R
R
and/or
HO
R
HO 2C
O
R
HO2C CO
Me
CH 3 H
H
CH 3
H
H
CH 3
CHO
early or late oxidations of C3, C13
H
OH H
CO 2H
CO 2H
R
R
OH
R
HO 2C
HO
R
HO2C R
HO2C CH 3 H
H
CH 3
R = H, OH
O
H
CH 3
H
CH 3
oxidative decarboxlyation
CO 2H
H
CO 2H
H
CO 2H
R
R
R

HO
GA 3
OC
CH 3
O OH
H
H
Gibberellic Acid
HO
OC
CH 3
H
retrograde
aldol / aldol
Rearrangements of Gibberellic Acid in Basic Media
CO 2H
CO 2H
via
O
O OH
H
16-GA3rearrangements.cdx 2/5/04 11:41 AM
O
–OOC
–O
H 3C
H
H
CH 3
Base
H
CO 2H
CO 2H
0.01 N NaOH
O OH
H
OH
HO
HO
OC
O
CH 3
H
CO
HO
HO
CH 3
H
HO 2C
CO 2H
H
CO 2H
isolable
H
CH 3
O OH
H
favored equatorial
C3 configuration
H
CO 2H
OH
OH
transformation can be
effected by palladium

CH 3
HO
GA 3
H
OC
CO 2H
Rearrangements on Gibberellic Acid in Acidic Media
CH 3
O OH
H
H
Gibberellic Acid
H
CO 2H
CH 3
O
1,2 shift
OH
17-GA3rearrangements-acid.cdx 2/5/04 11:38 AM
R
CH 3
H
H +
(or H 2NNH 2)
CO 2H
OH
CH 3
HO
HO 2C
CH 3
Thermodynamically
more stable C9 epimer
H
CH 3
H
CO 2H
Gibberellenic Acid
CO 2H
"...gibberellic acid has enjoyed
a significant notoriety for instability and
rearrangement. This view appears to be
exagerated." L.Mander
OH
OH
CH 3
H +
H
H +
CO 2H
H 2NNH 2
OH

AcO
OC
Me
O
H
CO 2Me
BH 3
18-GA-C11oxidation.cdx 2/5/04 11:34 AM
C11 oxidation: Bishydroboration
H 2B
BH 3•SMe 2
H 2O 2, NaOAc
H
AcO
HB
H
HO
OC
Me
O
H
H
OC
Me
HO
O
H
H
CO 2Me
HO
H
H
H
CO 2Me
e.g. GA 35
H
OH
OH
OH
H

OC
Me
O H
H
CO 2Me
Br OH
H
OC
H
Me
OH
Br
OAc
Br O
CO 2H
19-GA-C12oxidation.cdx 2/5/04 11:32 AM
O
H
H
C12 oxidation of Gibberellin Skeleton
Pb(OAc) 4, I 2
OH
H
H
Pb 4+
OC
Me
OC
Me
GA 70 GA69
O
H
O H
H
O
CO 2Me
Br OH
H
CO 2H
H
OH
Zn
–1e –
Br
OAc
Br
OC
Zn, HOAc
Me
O
H
H
O
H
CO 2H
GA 31
OH
OC
Me
OH
O
H
H
H
CO 2Me
OH
OH
OAc

MOMO
MOMO
MOMO
acyloin
rearrangement
OC
Me
OC
O
H
2 steps
Me
OC
Me
H
O
H
CO 2Me
CO 2Me
H
CO 2Me
NaOMe
20-GA-C14hydroxlation.cdx 2/5/04 11:29 AM
O
H
H
C14 Hydroxylation of Gibberellin Skeleton
OH
O
OAc
OTBS
OH
O
O
O
OH
OH
1) DMDO
2) TBAF
MOMO
HO H
O
OH
OC
Me
O
H
dipole
minimized?
OH
H
HO O
Ab initio: ∆5.7 kcal
MOMO
H
CO 2Me
OC
Me
OH
O
OH
O
H
NaOMe
H
OH
CO2Me OAc
Mander, Tetrahedron, 1998, 11637.
O

O
HO 2C
9 : 1 at C4
OC
Me
O
O
O
H
H
H
Me
O–
H
CO 2Me
NaOH
O
OC
21-GA-C18hydroxlation.cdx 2/5/04 11:25 AM
C18 Hydroxylation of Gibberellin Skeleton
H
CO 2Me
O
H
H
H
H
CO 2Me
H
AllylOH
DBU
HO
HO
OC
O
O
H
OH
OC
H
CO 2Me
O
H
H
H
RhCl(PPh 3) 3
DABCO
CO 2Me
H
2 : 3 mixture of
3α and 3β−OH
Thomson, Mander, JCS Perkin I, 2000, 2893.

MOMO
OC
CH 3
H
OC
CH 3
Li/NH 3
tBuOH
H
O OMOM
H
H
CO 2Me
CO 2Me
O
OMOM
22-GA-C19toC20.cdx 2/5/04 11:23 AM
Conversion of C 19 Gibberellins into C 20 Variants
CH 3
H
H
CO 2Me
KH, DMF; O 2
Li/NH 3
tBuOH
OMOM
HO 2C
HO 2C
CHO
H
CH 3
H
H
CH 3
H
CO 2Me
Cu (powder)
PhH, 80˚C
CO 2Me
C 20 gibberellins: e.g. GA 19
OMOM
N 2
OMOM
O
SOCl 2;
CH 2N 2
H
CH 3
H
CO 2Me
OK OK O O
OMOM
OK
O
Mander, Tet. Lett. 1985, 5725.
O

SnR 3
PhO
S
RO
O
R 3Sn-S
O
O
O
O
O
CO
Me
CO
Me
OPh
Me
H
H
H
H
CO 2Me
H
CO 2Me
Bu 3SnH
H
CO 2Me
23-GA-radicalcascade.cdx 2/5/04 11:15 AM
Radical Cascade: Attempted Deoxygenation at C3
OAc
OAc
OAc
Bu 3SnH
R 3Sn-S
O
O
O
O
O
O
equatorial (α)
C3 hydroxyl removed
without event
5-exo
O
O
H
H
Me
Me
H
H
CO 2Me
H
H
CO 2Me
OAc
R 3Sn-S
O
O
OAc
O
O
H
Me
H
5-exo
H
CO 2Me
OAc
Barton, McCombie, JCS Perkin I, 1975, 1574.
Mander,TL, 1996, 4255.
*synthetic application: Sherburn,JACS, 2003, 12108.

HO
OC
Me
Zn
O
H
90%
F 3C
H
CO 2Me
TsCl, pyr
TsO
O
HO
OC
Me
24-GA3-coreytotal1.cdx 2/5/04 12:45 PM
Dismantling and Reconstituting the A-Ring
O
OH
H
methyl gibberellate
HO2C CO2Me Corey-Carney Acid
O
H
I
OC
Me
H
CO 2Me
O
H
H
CO 2Me
OH
NaBr,
HMPA
OH
Br
OC
Me
O
H
1) I 2, NaHCO 3
2) TFAA, pyr
60%
H
CO 2Me
HO
HO
HO 2C
CH 3
OH
Zn
H
CH 3
H
H
CO 2Me
OH
1) mCPBA
2) NaOH
OH
76%
Danheiser, Strategies and Tactics in Organic Synthesis.
Ed. Lindberg 1984, 22-65.

THPO
O
OMe
o-allyl eugenol
K, TiCl 3
(50%)
H
Corey Synthesis of GA 3: Hydronaphthalene Approach
THPO
OH
OH
7 steps
H
BnO
CHO
"...quenching reactions involving
50g of potassium can provide moments
of great drama, as well as piquant stimulation
for the experimentalist."
25-GA3-coreytotal2.cdx 2/5/04 12:47 PM
O
1) Cl 3CCO) 2O,
NEt 3, DMSO
2) MEMCl, iPr 2NEt
60%
O
O
THPO
OMe
1) H 2, Rh/C
2) Li, NH 3
3) PDC
50% from [4+2] adduct
H
HO
THPO
O
H
BnO
OMEM
PhH, 80˚C
90%
OMOM
O
HO
H
BnO
Oxidation Products:
H
H
COR
OH
O
O
O
O
1) DHP, TsOH
2) NaBH 4
H
H
OMe
3) MOMCl, iPr 2NEt
4) LAH
5) MsCl, NEt 3 ; H 2O
R=H / OH
O
O
Corey, JACS, 1978, 8034.
OH
OH

Cl
THPO
O
O
Contraction of B-Ring; A-Ring Formation through Cycloaddition
H
H
O
OMEM
OMEM
26-GA3-coreytotal3.cdx 2/5/04 12:51 PM
1) OsO 4, NMMO
2) Pb(OAc) 4
nBuLi;
O
Cl Cl
72%
OHC
OHC
H
OMEM
89%
THPO
O
78%
HO
H
OMEM
1) Ph 3PCH 2
HMPA, 65˚
2) AcOH
57%
160˚C, PhH
H
H
OMEM
LiN(iPr)C6H11; O
Cl
H
MeI
55%
O
O
70%
Bn 2NH 2 + -TFA –
OHC
O
THPO
Me
H
O
H
H
OMEM
O
OMEM
Corey, JACS, 1978, 8034.

HO
HO
O
Me
I
OC
Me
H
O
O
H
H
H
CO 2Me
OMEM
OH
1) TFAA, pyr
2) Zn
3) PrSLi
27-GA3-coreytotal4.cdx 2/5/04 12:53 PM
Gibberellic Acid Endgame: Corey
1) ZnBr 2
2) KOH, Na 2RuO 4
HO
OC
Me
95%
1) mCPBA
2) NaOH
3) I 2, NaHCO 3
O
H
H
CO 2H
OH
HO 2C
HO 2C
GA 3
H
Me
H
Me
H
CO 2H
H
CO 2Me
OH
TsCl, NEt 3;
MeOH
OH
Corey-Carney Acid
Corey, JACS, 1978, 8034.

O
Alternative Route to Key Tricyclic Intermediate: The Hammer and Tongs Approach
O
Me
O
O
6 steps
H
H
48%
OBn
OMEM
O
OH Me
O
3 steps 7 steps
OBn
67% 60%
NaOH,
EtOH
1) EtOCHO, NaH
2) KOtBu, MeI
88%
28-GA3-coreytotalrevised1.cdx 2/5/04 12:54 PM
46% 4 steps
O
O
O
OMe
H
H
O
Me
O
OMEM
3 steps
O
O
1) EtOCHO, NaH
2) RedAl
3) H +
4) Ph 3PCH 2
39%
O
O
H
H
OH
OMs
O
KOtBu
93%
O
Corey, JACS, 1978, 8034.
OMEM

O
H
1) BuLi;
2) DBU
Br
OMEM
enantioselective variant
has appeared
Br Br
Br Br CHO
Cope Rearrangement for B/C Ring Junction
9 steps saved over original
synthesis
29-GA3-coreytotalrevised2.cdx 2/5/04 12:58 PM
1) nBu 2CuLi
2) MEMCl, iPr 2NEt
65%
R
O
H
O
N B
Ts
nBu
10% mol
99%ee
81%
R = 3-indole
MeO2C Me
+ C2 isomer
2: 1
1) BF3•OEt2 87%
2) TMSOTf, NEt3 53%
O
Br
H
Br O
CHO
Br
O
1) 9BBN;
NaOH, H 2O 2
2) PDC
5 steps
76%
Br
[3,3]
Br
CO 2Me
OTMS
160˚C
DMSO, H2O NaCl
71%
H
Br O
CO 2Me
OTMS
Corey, JACS, 1982, 6129.
Corey, JACS, 1994, 3611.

MeO
HO 2C
MeO
TFA
MeO
CO 2Me
35%
CO 2Me
OMe
30-GA3-mandertotal1.cdx 2/5/04 1:00 PM
MeO
Mander: Fluorene Approach
1) Li, NH 3
2)
CO 2Me
OCOCH 2Cl
O
O
N 2
OCOCH 2Cl
I
MeO
MeO
OMe
CO2H CO
88% 2Me
36%
1) HCN; NaOH
2) (ClCH 2CO) 2O
3) (ClCO) 2; CH 2N 2
64%
1) Na 2CO 3, MeOH
2) H + , (HOCH 2) 2
3) MOMCl, iPr 2NEt
4) tBu(chx)NLi; CO 2
5) H 2, Pd/C
68%
MeO
MeO
PPA
CO 2Me
CO 2Me
H
CO 2H
OMOM
O
O
O
Mander, JACS. 1980, 6626.

MeO
PhOCO
MeO
Mander: A-Ring Assembly through Birch Reduction/Alkylation
CO 2Me
OC
Br
Me
CO 2H
O
H
CO 2H
H
CO 2Et
H
CO 2Me
31-GA3-mandertotal2.cdx 2/5/04 1:03 PM
OMOM
O
O
O
O
OMOM
O
O
1) KOtBu, K, NH 3; MeI
2) CH 3CHN 2
66%
KHCO 3, KBr 3
86%
Na, NH 3; MeI
C7 ester controls alkylation
MeO
MeO
MeO 2C
MeO 2C
PhOCO
HO 2C
Me
Me
H
Me
CO 2Me
H
CO 2Et
H
CO 2Et
O
O
OMOM
O
O
OMOM
O
O
4 steps
Mander, JACS. 1980, 6626.
Baker, Chem. Com. 1972, 951.

PhOCO
OC
1) DBU
2) H 2O, H +
3) TMSCl
90%
O
Br
Me
PhOCO
H
CO 2Et
PhOCO
OC
Br
H
Me
31B-GA3-mandertotal3.cdx 2/6/04 10:12 AM
O
OMOM
O
O
OC
H
Me
H
O
CO 2Me
Mander: Gibberellic Acid
5 steps
H
CO 2Me
OTMS
O
OH
O
O
OC
O
H
Me
H
CO 2Me
NBS, hν
95%
1) Ph 3PCH 2,
ClCH 2CH 2OTMS
2) K 2CO 3, MeOH
3) nPrSLi, HMPA
75%
OH
O
O
O
PhHC
O
HO
1) OsO 4, NMMO
2) PhCHO, H +
OC
OC
Me
H
Me
O
H
O
H
H
CO 2Me
CO 2H
OH
OH
O
O
GA 3
Mander, JACS. 1980, 6626.

O
O
Me
89%
OC
Me
O
OMe
O
H
OCOCCl 3
O
H
N 2
CO 2Me
H
CO 2Me
OH
O
O
TFA
1) KH, Et 3NH-OAc
2) (sia) 2BH; NaOOH
3) PDC
OH
O
32-GA3-mandertotal4.cdx 2/5/04 1:09 PM
O
Mander: A-ring Aldol Approach (GA 1)
OCOCCl 3
O
O
99% O
49% O
80%
1) (H 2C=CHCH 2) 3Al
2) (EtCO) 2O, DMAP
78%
K 2CO 3,
MeOH
1:1 at C3
60%
HO
OC
O
Me
O
H
4 steps
H
CO 2Me
H
CO 2Me
N 2
OH
O
O
OH
O
O
HO
OH
O
1) (sia) 2BH;
NaOOH
2) PDC
3) LDA; Ph 2Se 2
4 steps
50%
OC
Me
O
H
hv,MeOH
CO 2Me
GA 1
H
CO 2Me
OH
O
O
OH
Mander, JACS. 1980, 6626.

Me
SEMO
MOMOH 2C
CN
CO 2Me
H
Me
O 3, MeOH
86%
H
CN
Yamada: Intermolecular [4+2] Ring A Construction
H
OMe
CH 2OMOM
SEMO
MOMOH 2C
2) NaOH
3) Ac 2O
57%
33-GA3-yamadatotal.cdx 2/5/04 2:48 PM
O
H
H
Me
Me
allene,
hν
69%
H
O
O
H
SEMO
MOMOH 2C
O
CO 2Me
CH 2OMOM
O
H
H
Me
OMe
H
1) K, NH 3
2) Swern
CH 2OMOM
1) AlCl 3
2) mCPBA
O
49%
Nakanishi, Chem. Com, 1969, 528.
3) MOMCl, iPr 2NEt
4) Ph 3PCH 2
53%
TMSO
SEMO
MOMOH 2C
OC
1) Na, NH 3
2) AcOH, H 2O
O
H
Me
3) K 2CO 3, MeOH
80%
O
SEMO
MOMOH 2C
H
H
Me
H
H
H
Me
CH 2OMOM
OMe
10 steps
CH 2OMOM
OMOM
OMe
Yamada, TL, 1989, 971.

SEMO
MOMOH 2C
91%
HO 2C
OC
H
H
Me
H
Me
O
H
Me
H
CH 2OMOM
8 steps
H
CO 2H
H
CO 2H
34-GA3-yamadatotal2.cdx 2/5/04 2:50 PM
Yamada: Synthesis of Gibberellic Acid
1) I 2, NaHCO 3
2) DBU
OMOM
OMOM
OMOM
1) MOMCl, iPr 2NEt
2) LDA
99%
HO
HO 2C
OC
O
H
Me
H
Me
H
CO 2H
H
CO 2MOM
OH
GA 3
6 steps (Corey et al)
MOM-protected
Corey-Carney Acid
OMOM
30% from tri-MOM-ether
Yamada, TL, 1989, 971.

CO 2Me
O
OMe
H
EtO2C MeO
52%
OC
O
H
MeO
H
H
O
then
LiN(chx)iPr;
MeI
Br
MgI
OMEM
OMEM
36-GA3-DeClerqtotal.cdx 2/5/04 4:29 PM
Synthesis of GA 5 via Furan [4+2]: DeClercq
Br
5 steps
81%
1) PPTS
2) NaClO 2
50%
46%
O Br
MeO 2C
O
CO 2Et
OC
Me
O
H
H
OH
H
CO 2H
O
kinetic
product
OH
OH
GA 5
Bu 2CuLi
65%
O
β-cyclodextrin
H 2O, 65˚C
96%
>95:5
MeO 2C
EtO 2C
O
O
CO 2Et
OH
3 steps
50%
H
OH
OH
PhH
80˚C
OH
OH
thermodynamic
product
DeClercq, Tet. Lett. 1986, 1731.

MeO 2C
Me
H
Me
Me
Me
(–)-methyl dehydroabietate
1) H 2, RuO 2
2) H 2CrO 4
3) Ph 3PCH 2
4) BH 3/H 2O 2
H
MeO2C Me
epimerization at C6
Me
H
MeO2C Me
CO 2Me
Me
OH
37-GA12-Tahara-total.cdx 2/5/04 3:00 PM
H
H
GA 12 Synthesis from Dehydroabiatate: Tahara
AlCl 3
39%
CO 2Me
1) H 2CrO 4
2) SOCl 2;
CH 2N 2
MeO 2C
Me
Me
H
Wenkert, JACS, 1958, 211.
OH 1) H2, Pd/C
2) AcCl, AlCl3 3) mCPBA;
NaOH
Me
H
MeO2C Me
H
Me
MeO 2C Me
H
CO 2Me
CrO 3, HOAc
N 2
O
CO 2Me
CuSO 4,
hν
1) CH 2N 2
2) H 2SO 4
Me
H
MeO2C Me O
H
MeO2C Me
O
Me
H
MeO2C Me
Me H
H
CO 2Me
GA 12
KOH
OH
CO2H O
Tahara, JCS Perkin I, 1972, 320.
Tahara, TL, 1976, 1515.
4 steps

MeO 2C
Me
H
Me
H
(±)- from synthesis of
steviol Tet ,1966, 879.
Me
O
Me
H
H
O
MeO 2C
H
O
O
Cross, Hanson, JCS, 1963, 2944.
1) NaBH 4
2) TsCl, pyr
38-GA12-Mori-total.cdx 2/5/04 3:03 PM
4 steps
Me
O
GA 12 Formal Synthesis: Mori
Me
H
Me
1) Br 2, HOAc
2) LiCl, DMF
3) Ph 3PCH 2
Me
H
H
O
H
H
MeO 2C
H
OTs
O
O
Me
H
Me
1) Ph 3PCHOAr
2) H 3O +
3) Ph3PCH2 10-30%
H
O
H
O
1) KOH, tBuOH
2) H 2CrO 4
MeO 2C
Me
H
Me
1) NaH
2) H 3O +
3) H 2CrO 4
10%
H
H
HO2C Me
H
MeO 2C
O
CO 2H
Me
H
Me
H
Me H
H
1) NBS, H 2O
2) DHP, H +
H
O
GA 12
H
OTHP
Br
Mori, Tet, 1976, 1497.

H
Me
Me
O
O
10 steps
37%
Me
H
H
O
Me
H
MeO2C Me
H
H
O
1) Bu 3SnH,
AIBN
2) SiO 2
H
H
Me
Me
O
H
H
HO2C Me
Me H
H
CO 2H
H
Me H
OAc
2) TBAF
Me
OAc
OTES
3:1 at C7
OTES
72% (4 steps)
2) Ac2O Cross, Hanson, JCS, 1963, 2944.
39-GA12-Ihara-formal.cdx 2/5/04 3:04 PM
GA 12 Formal Synthesis: Ihara
1) 200˚C
O
GA 12
SnR 3
Me
1) s-BuLi
O
H
Me
Me H
Me
O
O
A : B
93% (1:18 mix)
O
H
AcO
H
OTES
Me
O
H
5 steps
88%
Ihara, JACS, 2001, 1856.

O
O
H
O
O
Three Routes to Bicycle:
O
O
O
O OEt MeO2C OEt
OH
40-GA3-Stork-CDring.cdx 2/5/04 3:05 PM
O
Stork D-ring Approach: Reductive Cyclization
1) H 3O +
2) NaBH 4
3) (HOCH 2) 2 H +
4) PDC
O
O
O
Br NC
O
O
O
O
O
O
O
H
O
O
O
H
O
MeO 2C
O
O
CN
1) K, NH 3,
(NH 4) 2SO 4
2) HOAc, H 2O
O
H
O
O
O
O
O
O
O
H
H
OH
O
O
Stork, JACS, 1979, 7107.
Stork, JACS, 1965, 1148.

MeO
TBSO
6 steps
52%
TBSO
CO 2Me
OC
O
H
OH
H
OH
I
O 2N
O O
O
CO 2Me
N-tBu
= L
NiBr
2 2
41-anteridiogens3-Corey.cdx 2/5/04 3:31 PM
Total Synthesis of Antheridic Acid: Corey
H
TBSO
TBSO
H
EtAlCl2 51% overall
O O
53%
O O
80%
O 2N
7 steps
76%
TBSO
H
1) TMSCl, LDA
TBSO
2) Eschemoser's
salt, MeI, iPr2NEt 60%
OC
OH
H
N 2
O O
O
H
O
1) Cu(II)L 2
2) Br 2; DBU
CO 2Me
1) MeCO 3H
2) LiNEt 2
H
57%
4 steps
90%
TBSO
HO
OC
O
H
H
H
O O
OH
CO 2H
antheridic acid
original structure proposed as 3β−OH
Corey, Myers, JACS, 1985, 5574.
H

AcO
HO2C Proposed Biomimmetic Synthesis of Antheridic Acid Investigated
H
CO 2Me
A or B
AcO
MeO2C A) Im 2CO, H 2O 2 intramolecular delivery
B) mCPBA (k rel < 10 -2 ) intermolecular
42-anteridiogens2.cdx 2/5/04 3:33 PM
C9,10-epoxygibberellin
H
O
CO 2Me
Epoxide initiated
1,2 bond migration
Desired Bond Migration
could not beEffected
HO
AcO
MeO2C OC
O
H
OH
H
OH
CO 2H
antheridic acid
original structure
proposed as
3β−OH
CO 2H
H
Mander, JACS, 1987, 6839.
H

HO
MOMO
MOMO
OC
O I
O
CO
CO
O
H
H
KH
H
CO 2H
43-anteridiogens.cdx 2/5/04 3:35 PM
H
CO 2Me
CO 2Me
Conversion of GA 7 into Antheridic Acid
H
GA 7
H
H
O
O
4 steps
HO
OC
antheridic acid
original structure
proposed as
3β−OH
MOMO
MOMO
OC
OC
O
H
O
H
O
H
OH
CO 2H
CO 2Me
CO 2Me
H
O
H
1) DBU
2) H2, Rh
O
3) Ph3PCH2 H
1) LiN(chx)iPr;
Et 3NHCl
2) SeO 2, tBuOOH
3) Me 2BBr
4) LiOH
Mander, JACS, 1987, 6839.

AcO
75%
OC
O
H
antheridic acid
OMe
COCHN 2
CO 2Me
Cu(acac) 2
1) PhI(OAc) 2, I 2
2) Hg(OAc) 2 HOAc
Formal
synthesis
44-antheridiogens4-Mander.cdx 2/5/04 3:36 PM
O
H
Synthesis of Antheridiogens: Mander
HO 2C
71%
OC
OC
O
H
O
OMe
H
CO 2Me
O
1) PhI(OAc) 2, I 2
2) HSnBu 3
3) Zn, CH 2Br 2
TiCl 4
O
H
CO 2H
H
O
H
O
O
Me
18h, rt
added in situ
GA 103
75%
1) hν, MeOH
2) PDC
3) H 2, Pd
70%
O
O
BnO 2C
OH
O
OC
H
O
H
5 steps
31%
OC
CO 2H
O
H
N 2
H
O
OMe
HO
H
O
GA 104
H
Mander, JACS, 1997, 3828.

H
H
O
H
O
O
O
O
O
O
NaOMe
H
O
H
H
O
O
O
OH
Me
OH
OH
tBuMgCl
H
OH
SMe
14 steps
MeO2C O SMe
O
MeO2C O O
CO2Me House, JOC, 1973, 1398.
O
Zn,
HOAc
H
OH
H Br
CO2Me Ziegler, JOC, 1971, 3707. (model system)
MeO 2C
CO 2Me
45-cd-ring stragedy.cdx 2/5/04 3:43 PM
Aldol C/D Ring Strategies Not Discussed
Hg(II)O
H 2SO 4
HCl,
acetone
MeO 2C
Ireland, JOC, 1966, 2530. (toward kaurenes)
Takano, Ogasawara, Chem. Com., 1981, 635.
Takano, Ogasawara, Chem. Com., 1981, 637.
H
OH

H
MeO2C H
O
CO2Me 1) NaOMe
CO2Me2) HCl
O
CO 2H
CO 2H
46-cd-ring stragedy2.cdx 2/5/04 3:44 PM
Acylation C/D Ring Strategies Not Discussed
BF 3
AcOH
PPA
H
H
CO 2Me
H
O
O
O
O
O
Baker, Chem. Com., 1971, 180.
Lowenthal, JCS Perkin I, 1976, 944.
Jammaer, Tet., 1975, 2293.

O
H
H
MeO
O
O
O
OMs
OTs
CHO
SPh
DBU
O
H
N
H
O
MeS O
O
MeS O
47-cd-ring stragedy3.cdx 2/5/04 3:46 PM
Alkylation C/D Ring Strategies Not Discussed
TFAA
SnCl 4
H
O
TFAA
SPh
O
O
O
MeO
CHO
1) PhSCH 2Li
2) TsOH
6 steps
SMe
O
H
O
H
SMe
CO 2Me
O
O
SPh
O
GA 15
Nagata, JACS, 1972, 4654.
Trost, JOC, 1978, 1031.
Mander, Synthesis, 1981, 620.
Barco, Tet., 1989, 3935.

H
H
MeO
O
Me
Cl
H
OH
O
Me
OH
OMs
CO 2H
Ar
CN
H
PCl 5
H 3O +
Cl
O
HO 2C
O
CN
H O Zn, HOAc H
48-cd-ring stragedy4.cdx 2/5/04 3:57 PM
Rearrangement C/D Ring Strategies Not Discussed
H 2O, acetone,
2,6-Lutidine
H
poor conversion
Ar
H
BF 3•OEt 2
OH
Me
OH
OH
H
H
Cl
OH CN
Cross, MacMillan, JCS, 1958, 2520.
OH
O
OH
Ziegler, Tet., 1977, 373.
Monti, JOC, 1978, 4062.
Yamada, Synthesis, 1977, 581.
Mori, Tet., 1972, 3217.

49-cd-ring summary.cdx 2/5/04 3:58 PM
A Summary of General C/D Ring Strategies
H H
I) Reductive Ring Closure
II) Alkylation / Acylation
III) Aldol
IV) Carbenoid
OH
V) Rearrangement / Fragmentation
H
OH
O
"The problem of the synthesis
of gibberellic acid has provided the impetus for
the development of many
new synthetic methods . . . " Corey