The document summarizes research on gibberellins, a class of plant hormones. It outlines the presentation topics, which include the history and discovery of gibberellins, their biosynthesis, the structure and reactivity of gibberellic acid, conversions between gibberellins, and approaches to total and partial synthesis. It then provides highlights on the history of gibberellin research from the initial discovery of the "bakanae" disease in rice to the isolation and structural elucidation of gibberellic acid. Biosynthesis occurs in three stages, and the structures and rearrangements of gibberellic acid under basic and acidic conditions are shown. Methods for oxidizing different carbons on the gibberellin

1. Highlights from the Synthesis of Gibberellins:
a 30 Year Odyssey
O OH
H
OC
HO H
CH3 CO2H
A Friday Afternoon Seminar
6 February 2004
Jonathan R. Scheerer
01-gibberellin-GA3-title.cdx 2/5/04 5:10 PM

2. Highlights from the Synthesis of Gibberellins:
O OH
H
OC
HO H
CO2H
CH3
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

3. A Brief History of Gibberellin Research:
O OH
H
OC
HO H
CO2H
CH3
1828 - first reports of "bakanae" disease in rice plants (foolish seedling; stupid rice crop)
1898 - first research paper, links disease to fungal infection
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

4. C20 and C19 Gibberellins: Structure and Nomenclature
11 12
20
1 CH3
HC 13
2 9
10 8 14
A 17 HO2C
5 16
3 4 6 HO2C
15 D
H H
HO2C CH3 7 CO2H
19 18 GA12
C20-Gibberellin Skeleton ent-gibberell-16-ene-7,19-dioic acid
11 12
1 O
H 13
2 9
8 14
OC 19 B 17
R
5 16
3 6 O
15
H O
H
CH3 7 CO2H R = CO2H
18 GA9
C19-Gibberellin Skeleton ent-norgibberell-16-ene-7,19-dioic acid 19,10-lactone
05-gibberellin-structureB.cdx 2/5/04 5:13 PM

5. Gibberellic Acid (GA3)
11 12
OH
1 O OH H
H 13
2 9
8 14 H3C
OC19 17
5 16 R
6
3 15 O
HO H OH
7 CO2H
GA3 O H
R = CO2H
CH3
18
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: O O OH
H H
OC OC
HO H HO H
Me CO2H Me CO2H
GA4 GA1
07-gibberellin-GA3.cdx 2/5/04 8:55 PM

6. A Brief History of Gibberellins:
O OH
H
OC
HO H
CH3 CO2H
Representative Biological Functions 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

7. Gibberellin Biosynthesis: Three Stages
H3C
HO Me H 3C H H
Stage A Stage B
HO2C
OH
H
H HO2C CH3 CHO
mevalonic acid (MVA) H3C CH3
GA12-aldehyde
ent-kaur-16-ene
Stage C
O
H
OC H3C
H
H
CH3 CO2H
H
HO2C CH3 CO2H
C19-gibberellins
and C20-gibberellins
10-gibberellin-biosynthesis1cdx 2/5/04 12:29 PM

8. Gibberellin Biosynthesis: Stage A
H 3C
*
H H 3C H
HO CH3
HO2C
Stage A * OPP
* OH
mevalonic acid (MVA)
H * H ent-CCP
H3C CH3 H3C CH3 ent-copalyl
*
ent-kaur-16-ene pyrophosphate
OPP
IPP
OPP Isopentenyl GGPP
pyrophosphate geranyl-geranyl
pyrophosphate
OPP
IPP IPP
OPP
OPP
DMAPP GPP FPP
Dimethylallyl
pyrophosphate
11-gibberellin-biosynthesis2 2/5/04 12:30 PM

9. Gibberellin Biosynthesis: ent-CCP to ent-kaurene
H Ha
H3C H H3C H
OPP
H H
H5R
H3C CH3 H3C CH3
H5S
ent-CCP ent-kaur-16-ene
ent-copalyl pyrophosphate
Ha Ha H
H H H
H4 H5R H5R
Ha H OPP H4
5S H5S H4
H5S
H5R
12-biosynthesis3.cdx 2/5/04 10:11 PM

10. Gibberellin Biosynthesis: Stage B
H3C H CH3 CH3
H H
Stage B
H H H O
H3C CH3 HO2C CH3 CHO HO2C Hb
Hd
ent-kaur-16-ene GA12-aldehyde
see next slide
biosynthetic progenitor
H3C H H3C H
of all gibberellins
same biosynthesis for
OH
fungal or higher order plants H
HS H Hd
CH3 ent-kaur-16-en-19-ol HO2C CH3 Ha Hb
HR
OH
H3C H H3C H
Hc
H H Hd
HS CH3 HO2C CH3 Ha Hb
O
ent-kaur-16-en-19-al
13-biosynthesis4.cdx 2/5/04 10:35 PM

11. Gibberellin Biosynthesis: Ring Contraction
H3C H CH3
H
Stage B
H H
H3C CH3 HO2C CH3 CHO
ent-kaur-16-ene GA12-aldehyde
OH H
O
H OHC
HO2C H HO2C HO2C
H H
H H
O 1,2-radical
Enz Fe 4+ shift
OH
Enz Fe3+
H
O
HO
HO2C
radical trapping
H
H
14-biosynthesis5.cdx 2/5/04 12:37 PM

12. Gibberellin Biosynthesis: Stage C
CH3 CH3 CH3 OH CH3 R
H H and/or H H
H HO H R H
H
CHO HO2C CH3 CO2H HO2C CH3 CHO HO2C CH3 CO2H
HO2C CH3
early or late oxidations of C3, C13 R = H, OH
GA12-aldehyde
OH
HO
O R O R R
H H H
CO CO
R R R H
-very complex H H
-parallel pathways CO2H CO2H HO2C CH3 CO2H
Me Me
-organism dependent
(fungal or higher order plants)
-converge to common GA O
R
O R OH R H
H H
GAn OC
R H
R R H
H CO2H
CO2H HO2C CH3
CO2H HO2C CH3
Me
many complex, as yet incompletely oxidative decarboxlyation
defined, oxidative processes
15-biosynthesis6.cdx 2/5/04 12:40 PM

13. Rearrangements of Gibberellic Acid in Basic Media
O OH
OH HO H
H
0.01 N NaOH
OC
HO HO H
H
CO2H
CH3 CO2H HO2C CH3
GA3
OH
H O OH
via H
Gibberellic Acid
O
CO
H HO
CO2H H
–OOC CH3 CH3 CO2H
transformation can be
isolable effected by palladium
O OH O OH
H Base H
OC OC
HO H HO H
CH3 CO2H O OH CO2H
–O H CH3
retrograde favored equatorial
aldol / aldol O H C3 configuration
H3C CO2H
16-GA3rearrangements.cdx 2/5/04 11:41 AM

14. Rearrangements on Gibberellic Acid in Acidic Media
O OH OH
H
OC H+
HO H HO H
CH3 CO2H CO2H
(or H2NNH2) HO2C CH3
GA3
Gibberellic Acid Gibberellenic Acid
H H H OH
CH3 OH
H+
O CH3
H+ H2NNH2
CO2H 1,2 shift CO2H CH3 CO2H
CH3 CH3
Thermodynamically
more stable C9 epimer H OH
OH
R
"...gibberellic acid has enjoyed CH3 CO2H
H
a significant notoriety for instability and
rearrangement. This view appears to be
exagerated." L.Mander
17-GA3rearrangements-acid.cdx 2/5/04 11:38 AM

15. C11 oxidation: Bishydroboration
HO
O O H
BH3•SMe2 H
OC OC
AcO
H2O2, NaOAc
H AcO H OH
H
Me CO2Me CO2Me
Me
OH
H 2B H HB H H
OH
BH3
H H
HO
O
H
OC
HO H
Me CO2Me
e.g. GA35
18-GA-C11oxidation.cdx 2/5/04 11:34 AM

16. C12 oxidation of Gibberellin Skeleton
OH O OH
OH OAc OH OAc O OAc
H
OC Br Pb(OAc)4, I2 OC Br Zn, HOAc OC
H H H
Me CO2Me Me CO2Me Me CO2Me
Zn
Pb4+
Br OH Br O Br OH Br
O OH
H H
H H H
–1e– H H
OH OH OH
O O O OH
H H H
OC OC OC
H H H
Me CO2H Me CO2H Me CO2H
GA70 GA69 GA31
19-GA-C12oxidation.cdx 2/5/04 11:32 AM

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

18. C18 Hydroxylation of Gibberellin Skeleton
O H O H
H H
OC OC
O HO H
H
CO2Me CO2Me
Me
OH
NaOH
O H
HO2C H
RhCl(PPh3)3
O DABCO
H
H CO2Me
Me
9 : 1 at C4 O H
H
OC
O H
H AllylOH HO H 2 : 3 mixture of
OC DBU CO2Me 3α and 3β−OH
O
O H
CO2Me
O–
Thomson, Mander, JCS Perkin I, 2000, 2893.
21-GA-C18hydroxlation.cdx 2/5/04 11:25 AM

19. Conversion of C19 Gibberellins into C20 Variants
O OMOM OMOM
H H
Li/NH3 SOCl2;
OC
MOMO tBuOH CH2N2
H H
CH3 CO2Me CO2Me
HO2C CH3
OMOM
OMOM H
H
Li/NH3 Cu (powder)
H
tBuOH H PhH, 80˚C CO2Me
CO2Me CH3
O CH3
N2 O
OMOM CHO OMOM
H H
KH, DMF; O2
OC
OK OK OK
H H O
CO2Me CO2Me O
CH3 HO2C CH3 O O
C20 gibberellins: e.g. GA19
22-GA-C19toC20.cdx 2/5/04 11:23 AM Mander, Tet. Lett. 1985, 5725.

20. Radical Cascade: Attempted Deoxygenation at C3
O OAc
H
O
CO H OAc
Bu3SnH H
RO H O
Me CO2Me
O
H
Me CO2Me
O
SnR3
O OAc
H R3Sn-S O
S H OAc
equatorial (α) H
CO
C3 hydroxyl removed
PhO O without event O
H
CO2Me O
Me H
Me CO2Me
Bu3SnH O
R3Sn-S OPh
O
R3Sn-S
OAc H OAc
H H
O
O
O 5-exo O 5-exo
H H
Me CO2Me CO2Me
O Me
O
Barton, McCombie, JCS Perkin I, 1975, 1574.
Mander,TL, 1996, 4255.
23-GA-radicalcascade.cdx 2/5/04 11:15 AM *synthetic application: Sherburn,JACS, 2003, 12108.

21. Dismantling and Reconstituting the A-Ring
O OH OH
H H
OC
HO H H
Me CO2Me methyl gibberellate CO2Me Corey-Carney Acid
HO2C CH3
TsCl, pyr Zn
Br
O OH O OH
H NaBr, H
OC OC
HMPA
TsO H H 1) mCPBA
Me CO2Me CO2Me 2) NaOH
Me
76%
I OH
O HO H
OH
F3C O H
1) I2, NaHCO3
Zn OC 2) TFAA, pyr HO
O H
HO H CO2Me
90% 60% HO2C CH3
Me CO2Me
Danheiser, Strategies and Tactics in Organic Synthesis.
24-GA3-coreytotal1.cdx 2/5/04 12:45 PM Ed. Lindberg 1984, 22-65.

22. Corey Synthesis of GA3: Hydronaphthalene Approach
O O
H
7 steps PhH, 80˚C
OMe
OMe 90% OMe
O
O HO O
BnO HO
o-allyl eugenol
BnO
H H
1) H2, Rh/C 1) DHP, TsOH
K, TiCl3 2) Li, NH3 2) NaBH4
(50%) O O
3) PDC 3) MOMCl, iPr2NEt
OMOM 4) LAH
THPO CHO THPO 5) MsCl, NEt3 ; H2O
BnO
50% from [4+2] adduct Oxidation Products:
H H H
H
1) Cl3CCO)2O,
NEt3, DMSO OH
OH OH
OMEM O
2) MEMCl, iPr2NEt H H
OH O
THPO THPO O
60%
"...quenching reactions involving OH
O
50g of potassium can provide moments
of great drama, as well as piquant stimulation COR R=H / OH O
for the experimentalist."
25-GA3-coreytotal2.cdx 2/5/04 12:47 PM Corey, JACS, 1978, 8034.

23. Contraction of B-Ring; A-Ring Formation through Cycloaddition
H H
1) OsO4, NMMO OHC
2) Pb(OAc)4 Bn2NH2+-TFA–
OMEM OHC OMEM
O 89% O 78%
THPO THPO
1) Ph3PCH2 OHC H OMEM
OMEM H OMEM
H nBuLi; HMPA, 65˚
Cl O
O 2) AcOH
Cl Cl 57%
HO THPO
O
O 72%
OMEM OMEM
H H
160˚C, PhH LiN(iPr)C6H11;
H Me
O Cl MeI
H H
O O
O 70% O
55%
26-GA3-coreytotal3.cdx 2/5/04 12:51 PM Corey, JACS, 1978, 8034.

24. Gibberellic Acid Endgame: Corey
OMEM 1) ZnBr OH
H 2 H
2) KOH, Na2RuO4
Me
H H
95%
CO2H
O HO2C Me
O TsCl, NEt3;
MeOH
I
O OH 1) mCPBA OH
HO H H
2) NaOH
OC
HO H 3) I2, NaHCO3 H
CO2Me CO2Me
Me HO2C Me
Corey-Carney Acid
O OH
1) TFAA, pyr H
2) Zn
OC
3) PrSLi HO H
Me CO2H GA3
27-GA3-coreytotal4.cdx 2/5/04 12:53 PM Corey, JACS, 1978, 8034.

25. Alternative Route to Key Tricyclic Intermediate: The Hammer and Tongs Approach
O OMs
O O
3 steps 7 steps O
Me
OBn OBn
67% 60% O
KOtBu
93%
H H
O H
O NaOH, O
EtOH 3 steps
O O
O O
O
Me 46% 4 steps Me
OH O
O
6 steps 48%
OMe
H
H H
1) EtOCHO, NaH 1) EtOCHO, NaH
2) KOtBu, MeI 2) RedAl
O O
OMEM
OMEM OMEM 3) H+
88% 4) Ph3PCH2
OH
39%
28-GA3-coreytotalrevised1.cdx 2/5/04 12:54 PM Corey, JACS, 1978, 8034.

26. Cope Rearrangement for B/C Ring Junction
O CO2Me
Br
Br MeO2C
Br Me
1) BuLi;
+ C2 isomer OTMS
2) DBU 2: 1
1) BF3•OEt2 Br
87%
2) TMSOTf, NEt3 160˚C
9 steps saved over original [3,3] DMSO, H2O
53%
synthesis NaCl
71%
H H
H
1) nBu2CuLi 1) 9BBN;
2) MEMCl, iPr2NEt O NaOH, H2O2
O
O O
OMEM Br 2) PDC Br
65% 76%
enantioselective variant
has appeared R
O O
CHO CO2Me
N B nBu
H Ts
Br Br CHO
10% mol Br 5 steps OTMS
99%ee Br Br
81%
Corey, JACS, 1982, 6129.
R = 3-indole Corey, JACS, 1994, 3611.
29-GA3-coreytotalrevised2.cdx 2/5/04 12:58 PM

27. Mander: Fluorene Approach
MeO MeO
1) Li, NH3 PPA
HO2C OMe 2) MeO OMe
CO2H
I CO2Me
MeO 88% 36%
CO2Me
OCOCH2Cl
O
1) HCN; NaOH O
2) (ClCH2CO)2O
MeO N2 3) (ClCO)2; CH2N2 MeO
CO2Me CO2Me
64%
TFA 35%
OCOCH2Cl
1) Na2CO3, MeOH
OMOM
2) H+, (HOCH2)2 H O
O
MeO 3) MOMCl, iPr2NEt MeO O
CO2Me 4) tBu(chx)NLi; CO2 CO2Me CO2H
5) H2, Pd/C
68%
30-GA3-mandertotal1.cdx 2/5/04 1:00 PM Mander, JACS. 1980, 6626.

28. Mander: A-Ring Assembly through Birch Reduction/Alkylation
OMOM OMOM
H H
O 1) KOtBu, K, NH3; MeI O
2) CH3CHN2
MeO O O
MeO
CO2Me CO2H 66% MeO2C Me CO2Et
4 steps
O OMOM OMOM
H H O
O
KHCO3, KBr3
OC
O 86% PhOCO O
PhOCO
Br CO2Et HO2C Me CO2Et
Me
H O H O
Na, NH3; MeI
MeO O MeO O
CO2Me MeO2C Me CO2Me
CO2H
C7 ester controls alkylation
Mander, JACS. 1980, 6626.
31-GA3-mandertotal2.cdx 2/5/04 1:03 PM Baker, Chem. Com. 1972, 951.

29. Mander: Gibberellic Acid
O OMOM O OH
H H 1) OsO4, NMMO
O O
5 steps 2) PhCHO, H+
OC OC
PhOCO O O
Br CO2Et H
Me Me CO2Me
O OH
O OH H
1) DBU Br H O O
O
2) H2O, H+ OC NBS, hν
PhHC OC
O O
PhOCO O H
H CO2Me
3) TMSCl CO2Me Me
Me 95%
90%
O OTMS 1) Ph3PCH2, O OH
H H
ClCH2CH2OTMS
OC O OC
PhOCO H
2) K2CO3, MeOH HO H
Me CO2Me 3) nPrSLi, HMPA CO2H GA3
Me
75%
31B-GA3-mandertotal3.cdx 2/6/04 10:12 AM Mander, JACS. 1980, 6626.

30. Mander: A-ring Aldol Approach (GA1)
OCOCCl3
O OCOCCl3 OH
4 steps O
TFA hv,MeOH
O
N2
O
OMe 99% O 49% N2 O 80%
O OH OH OH
H O H
O 1) (H2C=CHCH2)3Al O 1) (sia)2BH; O
O 2) (EtCO)2O, DMAP NaOOH
O O O
CO2Me 78% 2) PDC
Me CO2Me 3) LDA; Ph2Se2 CO2Me
1) KH, Et3NH-OAc 50%
89% 2) (sia)2BH; NaOOH
3) PDC
O OH O OH O OH
H O
K2CO3, H H
MeOH O
OC 4 steps
OC OC
O O
1:1 at C3 HO O HO H
H H
Me CO2Me CO2Me CO2Me
Me Me
60%
GA1
32-GA3-mandertotal4.cdx 2/5/04 1:09 PM Mander, JACS. 1980, 6626.

31. Yamada: Intermolecular [4+2] Ring A Construction
OMe OMe
TMSO
O
1) AlCl3 OMe
2) mCPBA
H OC
CN
2) NaOH O
Me 49% H
CN 3) Ac2O Me
Me O
O
10 steps
CO2Me O Nakanishi, Chem. Com, 1969, 528.
57%
SEMO SEMO 1) Na, NH3 SEMO
H allene, H O H OMe
H O H 2) AcOH, H2O
hν
3) K2CO3, MeOH
69%
H H H
MOMOH2C Me CH2OMOM MOMOH2C Me CH2OMOM 80% MOMOH2C Me CH2OMOM
O3, MeOH SEMO SEMO
H 1) K, NH3 H OMOM
H O H
86% 2) Swern
CO2Me
H
3) MOMCl, iPr2NEt H
MOMOH2C Me CH2OMOM 4) Ph3PCH2 MOMOH2C Me CH2OMOM
53%
33-GA3-yamadatotal.cdx 2/5/04 2:48 PM Yamada, TL, 1989, 971.

32. Yamada: Synthesis of Gibberellic Acid
SEMO
OMOM O OH
H H H
OC
H HO H
MOMOH2C Me CH2OMOM CO2H GA3
Me
8 steps
OMOM
H
6 steps (Corey et al)
H
HO2C Me CO2H
MOM-protected
1) I2, NaHCO3 Corey-Carney Acid
91%
2) DBU
OMOM
O OMOM H
H
1) MOMCl, iPr2NEt
OC 2) LDA
H
H HO2C Me CO2MOM
Me CO2H 99%
30% from tri-MOM-ether
34-GA3-yamadatotal2.cdx 2/5/04 2:50 PM Yamada, TL, 1989, 971.

33. Synthesis of GA5 via Furan [4+2]: DeClercq
OMe O
OH
MgI O
Bu2CuLi O
O Br
then MeO2C MeO2C
Br
CO2Me 65%
Br 3 steps
46% 50%
OMEM OH
H H OH
O
β-cyclodextrin
O O
5 steps H2O, 65˚C
EtO2C
H OH
EtO2C 81% CO2Et OH 96%
MeO >95:5
kinetic PhH
LiN(chx)iPr; product 80˚C
52%
MeI
OH
O OMEM O OH H
H H
O
OC 1) PPTS OC
H H
2) NaClO2 CO2H CO2Et OH
Me GA5
MeO thermodynamic
50% product
36-GA3-DeClerqtotal.cdx 2/5/04 4:29 PM DeClercq, Tet. Lett. 1986, 1731.

34. GA12 Synthesis from Dehydroabiatate: Tahara
Me
Me Me
Me Me
AlCl3 CrO3, HOAc H KOH
H
39% O
H MeO2C Me O
MeO2C Me MeO2C Me
(–)-methyl dehydroabietate Wenkert, JACS, 1958, 211.
Me Me
1) H2, RuO2 Me
OH H2, Pd/C
1) 1) CH2N2
2) H2CrO4 2) AcCl, AlCl3 2) H2SO4
3) Ph3PCH2 OH
3)mCPBA; H
H CO2Me MeO2C Me CO2H
4) BH3/H2O2 CO2Me NaOH MeO2C Me
MeO2C Me
epimerization at C6
OH Me H
Me Me H
H H
1) H2CrO4 CuSO4,
2) SOCl2; O O
hν
H H H
H CH2N2 H N2 MeO2C Me CO2Me
MeO2C Me CO2Me MeO2C Me CO2Me 4 steps
GA12
Tahara, JCS Perkin I, 1972, 320.
37-GA12-Tahara-total.cdx 2/5/04 3:00 PM Tahara, TL, 1976, 1515.

35. GA12 Formal Synthesis: Mori
O O
Me Me H 1) Ph3PCHOAr Me H
1) NBS, H2O
4 steps 2) H3O+ 2) DHP, H+
H H H
O H O
H H 3) Ph3PCH2
MeO2C Me MeO2C Me MeO2C Me
10-30%
(±)- from synthesis of
steviol Tet ,1966, 879. H H
H 1) NaH Me H OTHP
1) Br2, HOAc Me O
2) LiCl, DMF 2) H3O+
Me H Br
H
3) Ph3PCH2 O 3) H2CrO4 O
H H H
MeO2C Me MeO2C Me
H O 10%
Me O
O Cross, Hanson, JCS, 1963, 2944. H
Me Me H
1) NaBH4 1) KOH, tBuOH H
2) TsCl, pyr 2) H2CrO4
H
H OTs H
Me HO2C Me CO2H GA12
O
O
38-GA12-Mori-total.cdx 2/5/04 3:03 PM Mori, Tet, 1976, 1497.

36. GA12 Formal Synthesis: Ihara
H
H 1) Bu3SnH, H H
Me AIBN H Me Me
Me Me
SnR3 Me Me
O 2) SiO2 Me O O
O O O
A:B O
O
93% (1:18 mix)
H H H
Me H H
1) 200˚C 1) s-BuLi 5 steps
H Me OTES
2) TBAF Me 88%
OAc OAc O
H
O OTES 2) Ac2O
3:1 at C7 72% (4 steps)
10 steps
37% H
Me H H
Me H AcO
H Me
H O H
HO2C Me CO2H
MeO2C Me OTES
Cross, Hanson, JCS, 1963, 2944. GA12
39-GA12-Ihara-formal.cdx 2/5/04 3:04 PM Ihara, JACS, 2001, 1856.

37. Stork D-ring Approach: Reductive Cyclization
H H H
O + O
1) H3O 1) K, NH3,
O 2) NaBH4 (NH4)2SO4 O
O O
O OH
O + 2) HOAc, H2O
3) (HOCH2)2 H
4) PDC
Three Routes to Bicycle:
H
O O
O O O O
O
O O O
H H
O O O
O O O
O O O
O Br NC CN O O
O
O O
O OEt MeO2C OEt MeO2C O
OH
Stork, JACS, 1979, 7107.
40-GA3-Stork-CDring.cdx 2/5/04 3:05 PM Stork, JACS, 1965, 1148.

38. Total Synthesis of Antheridic Acid: Corey
I
1) Cu(II)L2
7 steps 2) Br2; DBU
MeO
NiBr2
2 N2
CO2Me TBSO TBSO EtAlCl2
H
51% overall 53% 80%
O O O O
O2N
OH OH
O2N
H 1) MeCO3H
2) LiNEt2
H
TBSO H TBSO H TBSO H
76% 57%
O O O O O O
6 steps
O
52%
O O O
H H H
OC OC OC
1) TMSCl, LDA O 4 steps OH
TBSO H TBSO H HO H
CO2Me 2) Eschemoser's CO2Me CO2H
90%
salt, MeI, iPr2NEt
antheridic acid
60% original structure proposed as 3β−OH
N-tBu
=L
OH
41-anteridiogens3-Corey.cdx 2/5/04 3:31 PM Corey, Myers, JACS, 1985, 5574.

39. Proposed Biomimmetic Synthesis of Antheridic Acid Investigated
C9,10-epoxygibberellin
O OH
A or B
H
AcO H
Epoxide initiated
AcO H
CO2Me 1,2 bond migration AcO H
HO2C CO2Me MeO2C MeO2C CO2H
Desired Bond Migration
could not beEffected
A) Im2CO, H2O2 intramolecular delivery
-2
B) mCPBA (krel < 10 ) intermolecular
O
H
OC
OH
HO H
CO2H
antheridic acid
original structure
proposed as
3β−OH
42-anteridiogens2.cdx 2/5/04 3:33 PM Mander, JACS, 1987, 6839.

40. Conversion of GA7 into Antheridic Acid
O H
H O
OC H
OC
HO H OH
HO H
CO2H
CO2H
GA7 antheridic acid 1) LiN(chx)iPr;
original structure Et3NHCl
proposed as 2) SeO2, tBuOOH
3β−OH 3) Me2BBr
O
I
4) LiOH
O H O
O H
CO OC
MOMO H MOMO H
CO2Me CO2Me
1) DBU
KH
2) H2, Rh
O O ) Ph PCH
3 3 2
O O
H H
CO 4 steps OC
MOMO H MOMO H
CO2Me CO2Me
43-anteridiogens.cdx 2/5/04 3:35 PM Mander, JACS, 1987, 6839.