A second route to the key tricyclic intermediate A for the synthesis of gibberellic acid was also

developed (Ref. 8):

OMEM
HO

O O

(EtO)2P
Me MgBr
OBn
O OBn
o
KOH, EtOH / H2O, 5 C O o
CuI, Et2O, -50 C
Me

O 1. OsO4 , NaIO4 , Py
o
OBn t-BuOH / H2O, 0 C MgBr
O
Me
o
2. NaOH, EtOH CuI, THF, -50 C
OBn

OH
1. HO
1. H2 , Pd/C, Na2CO3 , THF
HC(OEt)3 OMs (until complete removal
o O
O TsOH, 59 C of sulfur contaminant)

O
OBn
2. Sia2BH, THF, 2. H2 , Pd/C, THF
NaOH, H2O2 OBn 3. PCC, NaOAc, CH2Cl2
3. MsCl, Et 3N
CH2Cl2

H
O OMs
O o
t-BuOK MeLi, Et2O, 0 C
O O H
t-BuOH / PhH
O O

10.8

209
 OH
H HO H
O o
(EtO)3CH O O3 , MeOH, -78 C;

O o O o o
H TsOH, 57 C H Me2S, -78 C ® 0 C
Me Me
OH

CO3H
o
Na2CO3 , 54 C
ClCH2CH2Cl
H H
O2N NO2
O NaOH O
H
Me o Me
O EtOH, 0 C O Me Me
O HO OH
CHO O
OH
t -Bu S t -Bu

1. DMSO, (Cl3CCO)2O
o o
H H CH2Cl2, -60 C ® -50 C;
o o
O O
NaOH O Et3N, -50 C ® 23 C

o
O O Me MeOH, 0 C O OH 2. MEMCl, ( i-Pr)2NEt
CH2Cl2 , ∆
OH OH

H H 1. NaH, HCO2Et, DME

1. Ph3P=CH2
o o
O
HMPA / THF, ∆ EtOH(trace), 0 C ® 25 C
O
O OMEM 2. HOAc, H2O 2. t-BuOK, MeI, THF/HMPA
OMEM
O
B

OMe OEt
H
H H

NaH, HCO2Et NaH, THF;

O O

OMEM EtOH(trace) OMEM Red-Al, PhCH3

o o o
DME, 30 C HO -20 C ® 0 C

10.8

210
 OEt OEt

H H
Red-Al, Dabco aq. (CO2H)2
O HO
o o
OMEM PhCH3 , -20 C OMEM pH 3, 0 C

HO HO

OHC
H H
Ph3P=CH2

OMEM o OMEM
THF, 0 C
HO HO

The synthesis of the tricyclic intermediate A was further improved by the development of a
short and stereocontrolled synthesis of compound B (Ref. 9):

O
OMEM

MeCO CO2Me
1. n-BuLi, Et2O;
Br
Br + o
Br BF3 . Et2O, CH2Cl2 , -78 C
Br

2. DBU, Et2O 1 : 2 mixture (equilibrated)

H
MeO2C
CO2Me TMSOTf
Br

Me O
+ COMe Et3N, CH2Cl2
H Br

endolexo-Ac selectivity > 30 : 1

removed by SGC

10.8

211
 H
CO2Me O CO2Me
Br NaCl, aq. DMSO, ∆

o
OTMS PhCH3 , 160 C OTMS
Br

H 1. 9-BBN, THF; H
H2O2 , NaOH (n-Bu)2CuLi
O
O 2. PDC, mol. sieves o
O hexane / Et2O, -78 C
Br CH2Cl2 Br

H H
MEMCl
O O
(i-Pr)2NEt, CH2Cl2
OH OMEM

References:
1. E. J. Corey, M. Narisada, T. Hiraoka, and R. A. Ellison, J. Am. Chem. Soc. 1970, 92, 396.
2. E. J. Corey, T. M. Brennan, and R. L. Carney, J. Am. Chem. Soc. 1971, 93, 7316.
3. E. J. Corey and Carney, R. L. J. Am. Chem. Soc. 1971, 93, 7318.
4. E. J. Corey and Danheiser, R. L. Tetrahedron Lett. 1973, 4477.
5. E. J. Corey, R. L. Danheiser, and S. Chandrasekaran, J. Org. Chem. 1976, 41, 260.
6. E. J. Corey, R. L. Danheiser, S. Chandrasekaran, P. Siret, G. E. Keck, and J.-L. Gras,
J. Am. Chem. Soc. 1978, 100, 8031.
7. E. J. Corey, R. L. Danheiser, S. Chandrasekaran, G. E. Keck, B. Gopalan, S. D. Larsen,
P. Siret, and J.-L. Gras, J. Am. Chem. Soc. 1978, 100, 8034.
8. E. J. Corey and J. G. Smith, J. Am. Chem. Soc. 1979, 101, 1038.
9. E. J. Corey and J. E. Munroe, J. Am. Chem. Soc. 1982, 104, 6129.

212
10.9
(±) - Antheridium - Inducing Factor ( AAn )
 Antheridic Acid

OH

HO
Me H
CO2Me
O

Retrosynthetic analysis of antheridic acid produced a totally different plan of synthesis from
that which had been employed for the structurally related target gibberellic acid. The synthesis of
antheridic acid, which included a number of novel steps, allowed definitive assignment of structure
and revised stereochemistry at C(3).

I
DMF 1. Na, t-BuOH
Br
+ Ni
Br
Ni
o
MeO MeO NH3 / THF, -78 C
CO2Me CO2Me 2. MeI

H H
1. TBDMSOTf, CH2Cl2
o
Zn(BH4)2 , Et2O 2,6-lutidine, -78 C

O o HO 2. Dibal-H, CH2Cl2
cyclohexene, -57 C
Me CO2Me Me CO2Me o
-78 C
diastereoselection 8 : 1

t -Bu
N
O
1 TsNHN=CHCOCl Cu
H H
PhNMe2 O N
o
CH2Cl2 , 0 C t -Bu
O
TBDMSO TBDMSO
2. Et3N PhCH3 , ∆
Me OH Me O CHN 2

H o
1. Br2 , 0 C
CCl4 / Et2O Et2AlCl
H H
TBDMSO 2. DBU, DMF TBDMSO o
Me CH2Cl2 , 0 C
Me o
50 C
O O O O

213
 10.9
O
MeCO3H LiNEt2 , THF

TBDMSO EtOAc TBDMSO

Me Me
O O O O

NO2
OH OH
1. KOH, H2O/EtOH
NO2 , PhH 2. K2S2O8 , RuCl3 ,

TBDMSO TBDMSO t-BuOH/H2O

Me Me 3. CH2N2 , Et2O
O O H O O
N

O O
OH CF 3COO

TFAA, Py, MeOH / H2O

TBDMSO o TBDMSO pH 7
Me CH2Cl2 , -23 C Me
CHO CO2Me
CF 3COO O OMe
H

O O
CF 3COO CF 3COO
1. NaClO2 , NaH2PO4
DBU H2O / t-BuOH
TBDMSO o TBDMSO 2. 2,6-lutidine
Me H THF, -22 C H
Me CF3CH2OH
CHO CO2Me CHO CO2Me

O O
o
1. TMSCl, LDA, -78 C
O 2. (i-Pr)2NEt, MeI NaBH4
O
TBDMSO
H
+ - O TBDMSO o
Me H2C=NMe2 I , Me H MeOH, -30 C
CO2Me CO2Me
O O
3. aq. K2CO3

214
10.9
OH OH

HF . Py, CH3CN O
O
3 5
TBDMSO HO
H Me H
Me
CO2Me CO2Me
O O

Compound A possesses the structure originally proposed for the methyl ester of AAn (see K.
Nakanishi, M. Endo, U. Naf, and L. F. Johnson, J. Am. Chem. Soc. 1971, 93, 5579). However, the
270-Mhz 1H NMR spectrum of synthetic A was different from that reported for AAn methyl ester with
respect to the protons at C(3) and C(5). Therefore, the 3α-alcohol, compound B, was synthesized as
shown below.

O O

O 1. HF . Py, CH3CN O NaBH4

TBDMSO 2. PDC, CH2Cl2 O o

Me H Me H MeOH, -30 C
mol. sieves CO2Me
CO2Me O
O

OH OH

O LiOH, DME O

HO HO
H Me H
Me
CO2Me CO2H
O O

1
H NMR and infrared spectral data of (±)-B, (±)-B methyl ester, and (±)-B methyl ester 3-
benzoate were identical with those of AAn and the corresponding derivatives. Mass spectra of the
methyl esters of (±)-B and AAn were identical. Chromatographic mobility of (±)-B relative to
gibberellic acid (GA3) (as standard) was identical with that reported for AAn. Therefore, this synthesis
also proved that antheridium inducing factor, AAn, must be regarded as possessing stereostructure B
rather than A as originally supposed.

References:
1. E. J. Corey and A. G. Myers, J. Am. Chem. Soc. 1985, 107, 5574.
2. E. J. Corey, A. G. Myers, N. Takahashi, H. Yamane, and H. Schraudolf, Tetrahedron Lett.
1986, 27, 5083.

215
 10.10
(±) - Retigeranic Acid

Me
Me
H
H
Me
H
CO2H

The multistrategic retrosynthetic analysis of retigeranic acid, which led to the synthesis
outlined below, has been described in Section 6.6 of Part One.

Me

Me O N
H EtAlCl2
CHO
+ Me O
PhH, ∆ PhH

Me Me 1. Ph3P, DEAD, PhCO2H

o o
LAH, Et2O, -20 C Et2O, -25 C

O OH 2. KOH, MeOH/ H2O

Ph2
+ P
Me Rh (CH 2)4 - Me
BF 4
1. P o
Ph2 1. MgBr , Et2O, 0 C

OH H2 , 950 psi, THF O o

H 2. KHSO4 , 150 C, 40 torr
2. CrO3 , H2SO4 , acetone

Me CO2Me Me CHO Ph3P O

Me Me O
CO2Me
O
OHC H (A)
o PhCH3
H 150 C, 120 h H

216
10.10
o
1. LAH, Et2O, 0 C
Me O Me O
Me 2. o-O2NC6H4SeCN Me O
O
H
(n-Bu)3P, THF
CO2Me O O

3. MCPBA
H o H
CH2Cl2 , -78 C;
o o
Me2S, -78 C ® 25 C

Me
Me
COOH
1. 0.07 N H2SO4 , MeOH 1. (COCl)2 , PhH

2. 0.3 N NaOH 2. Et3N, PhH

H

Me
Me
. O
Me
Me
O

H
H H

SMe Me OH
Me Me
o Me
SMe , n-BuLi, THF, -78 C 1. CuOTf, Et3N, PhH
SMe
H SMe
2. NaIO4 , aq. dioxane
H 3. Al / Hg, THF /H2O

Me Me H
Me H Me
Me H
1. H2 , Pd / C, Py, THF
Me
H

O
2. NaOMe, MeOH O
H o H
-78 C; HOAc

217
 10.10
Me H 1. OsO4 , Py; NaHSO3
Me
1. TsNHNH2 , EtOH H 2. Pb(OAc)4 , CH2Cl2
Me
O 3. neutral Al2O3
2. BH , CHCl3 H mol. sieves, CH2Cl2
O
o
3. (n-Bu)4NOAc, 65 C

Me Me Me
Me
H NaClO2 , NaH2PO4 H
H H
H2O / t-BuOH
Me Me
H H
CHO CO2H

Preparation of the ylide A (Ref. 3):

O O
1. KOH, EtOH, ∆ Br O
HO OH
+ EtO OEt
2. COCl , Py O
Br
OH

+
- Ph3P O Ph3P O
Br O
1. BF3 . Et2O KN(TMS)2 , PhCH3 O
O O
2. Ph3P

References:
1. E. J. Corey, M. C. Desai, and T. A. Engler, J. Am. Chem. Soc. 1985, 107, 4339.
2. B. B. Snider, D. J. Rodini, and J. van Straten, J. Am. Chem. Soc. 1980, 102, 5872.
3. E. J. Corey and N. Raju, Tetrahedron Lett. 1983, 24, 5571.

218
10.11
7,20 - Diisocyanoadociane

Me NC

H
Me
CN

H H H
Me Me

7,20-Diisocyanoadociane, a novel marine-derived diterpenoid, was analyzed retrosynthetically

using the intramolecular Diels-Alder transform as T-goal concurrently with topological and
stereochemical guidance. The enantioselective synthesis outlined below allowed assignment of
absolute configuration.

o
1. 90 C O O
+
OH O O O 2. (COCl)2 , PhH O Cl

OH
1. PhSeTMS, HO
o
(n-Bu)3Sn O O
I2 , CH2Cl2 , 65 C

Pd(PPh3)4 , THF, ∆ O 2. MCPBA, CH2Cl2 , -20 C

o

o
3. Me2S, (i-Pr)2NH, 60 C

o
O LDA, THF, -78 C; O
O O H O O
Me
O CO2Me O

Me
H
CO2Me

threolerythro-diastereoselection 8 : 1
ca. 60% ee

219
 10.11

220
 O
o H O O
1. Red-Al, Et2O, -40 C 1. LAH, Et2O
O
2. TBDMSCl, Et3N 2. PDC, CH2Cl2
DMAP, CH2Cl2 Me mol. sieves
H
OTBDMS

H O O H O O
P(Ph)2Me o
PhCH3 , 150 C
O
o
Me THF, 0 C Me
H H

OTBDMS OTBDMS

O O 1. (n-Bu)4NF, THF O O
2. PDC, CH2Cl2 1. Dibal-H
o
mol. sieves H
PhCH3 , -20 C
H
EtO2C
(EtO)2P CO2Et H
2. NaH, BnBr
H H
H DMSO
TBDMSO Me O Me
n-BuLi, THF
o o
-78 C ® 25 C

O O
O O

H o
PhCH3 , 185 C H 1. H2 , Pd/C, EtOH
BnO
H BnO 2. PDC, CH2Cl2
H
H H
Me mol. sieves
Me

O O O O
1. LDA, THF
NH o
H 1. , TsOH, PhH, ∆ H -78 C; MeI
OHC O
o
H 2. NaOMe
H H 2. RuO4 , CCl4 , 0 C H THF/MeOH
Me 3. NaOMe, MeOH Me

10.11

221
 O
O O
1. MeLi, CeCl 3 , THF
o o
H HCl, H2O/acetone H -78 C ® 0 C
O O

H H H H 2. TFAA, Py, CH2Cl2

H H
Me Me Me Me

CF 3CO2 Me Me NC

Plus other three isomeric

H H diisocyanides, separable
Me TMSCN, TiCl4 Me
by chromatography.
CF 3O2C CN
H CH2Cl2 H H H
H H
Me Me Me Me

o
synthetic sample: [α]23D +23.0 (c 0.27, CHCl3), ca. 60% ee

o
natural product: [α]23D +47.8 (c 0.23, CHCl3)

References:
E. J. Corey and P. A. Magriotis, J. Am. Chem. Soc. 1987, 109, 287.

10.12

222
 Ginkgolide B Ginkgolide A

O O

HO HO
O O
O HO H O H
H O
O
t -Bu t -Bu
O Me O
Me
H H
HO O H HO O H

O O

The multistrategic retrosynthetic analysis of ginkgolide B, which led to the synthesis outlined
below, is presented in Section 6.7 of Part One. The synthetic route, an enantioselective version of
which was demonstrated , also led to ginkgolide A.

1. Total synthesis of (±)-ginkgolide B (Ref. 1):

OMe

1. (t-Bu)2CuCNLi2
O OMe o o
1. (MeO) 2CHCHO, PhH Et2O, -78 C ® -45 C
N
O
o 2. TMSCl, Et 3N
2. 6 N HCl, 0 C
o o
-45 C ® -10 C

OMe MeO
O
1. (CH2O)3 , TiCl4 LDA, DME
OMe o o o
CH2Cl2 , -78 C -78 C ® 0 C
TMSO t -Bu O t -Bu
o o o o
2. MeOH, 0 C ® 23 C Tf2NPh, 0 C ® 23 C

MeO MeO
O O O o
O 1. (Cy-Hex)2BH, THF, 0 C
O 2. HOAc; H2O2 , pH 10
Tf O t -Bu t -Bu
Pd(PPh3)4 , CuI O O 3. 1N HCl, pH 3
O
o 4. pH 11, 4 h; pH 3
n-PrNH2 , PhH, 16 C

10.12

223
 MeO
O O

t -Bu 1. (COCl)2 , PhH t -Bu TrOOH, 1 N NaOH

2. (n-Bu)3N, PhCH3 , ∆ o
H acetone, -30 C
CO2H H
O

S
O S
OH

t -Bu HS SH t -Bu PDC, HOAc, CH2Cl2

o o
H O TiCl4 , CH2Cl2 , 0 C H O mol. sieves, 0 C
H H
O O

S MeO
S O
O o o 1. LiNEt2 , THF
1. HIO4 , -30 C ® 23 C OMe
o o
t -Bu MeOH/CH2Cl2/H2O (1%) t -Bu -25 C ® 0 C

2. CSA, MeOH 2. Ph
H O H H O H N
O O o
O PhO2S , 0 C
2 : 1 mixture

MeO H OMe
O
O
OMe
H
o
t -Bu CSA, CH2Cl2 hv, NBS, CCl4 , 10 C
t -Bu
O

HO O H O H
O
O

H OMe H OMe H OMe

O O O
Br
H H H
1. AgNO3 , CH3CN
O
t -Bu
+ O
t -Bu
+ O
t -Bu

Br Br 2. separation by SGC
O H O H Br O H

O O O

60% 30% 10%

10.12

224
 H OMe H OMe H OMe

O O O
O2NO
H H H
t -Bu
O + O
t -Bu
+ O
t -Bu

O2NO O
O H O H O H

O O 1. Zn, HOAc O
2. PDC, CH2Cl2

1. 20 eq. DBU, 20 eq. H2O, PhH/MeOH

2. PDC, CH2Cl2

o H +- o
PPTS, Py, PhCl, 135 C 1. TrOOH, BnMe 3N Oi-Pr, THF, -10 C
t -Bu
O
2. (MeO) 3P
O
O H

O O
O H O
EtCO2t-Bu, LDA H

O
t -Bu THF/HMPA t -Bu CSA, CH2Cl2
O
t -BuO2C
O o o
O H -78 C ® -30 C OH O H
Me
O O

O O
O HO H TBDMSO H
H O H
O O
TBDMSOTf 1. OsO4 , Py
t -Bu t -Bu
Me O O
Me
H 2,6-lutidine H 2. I2 , CaCO3
HO O H CH3CN HO O H MeOH
O O
B

O O

HO HO
O O
O RO H O HO H
H H
O BF3 . Et2O, CH2Cl2 O
t -Bu t -Bu
O Me O
Me
H H
HO O H HO O H

O O

R = TBDMS
10.12

225
 O
O
Preparation of the acetylenic OBO ester:
O

O O O O
1. NaOEt, EtOH 1. KOH, EtOH/H2O
EtO OEt EtO OEt HO2C
2. o o
Cl 2. 150 C ® 175 C
EtOH

O
O
1. (COCl)2 , PhH BF3 . Et2O
O O O
o
2. O O CH2Cl2, -20 C
OH

An efficient enantioselective route for the total synthesis of ginkgolide B has been established by
synthesizing the key intermediate A in an enantiomerically pure from (Ref. 2).

Ph
H Ph

OMe 1. 10 mol % O OMe

N B

OMe Me OMe
0.6 eq. BH3 . THF (t-BuCO)2O, Et3N
O HO
o H DMAP, CH2Cl2
THF, 10 C
2. HCl, MeOH
o
[α]23D +36.6 (c 2.5, MeOH)
93% ee

OMe OMe

OMe OMe 1. BH3 . THF, THF

t-BuMgCl, cat. CuCN o o
0 C ® 23 C; NaOH, H2O2
t -BuCOO t -Bu
H o 2. PDC, CH2Cl2
Et2O, -20 C o
mol. sieves, 0 C

10.12

226
 OMe OMe
1. (CH2O)3 , TiCl4
OMe OMe o
KH, THF; CH2Cl2 , -78 C
O t -Bu TBDMSO t -Bu
o o o
TBDMSCl, 0 C 2. MeOH, 0 C ® 23 C

2 : 1 mixture

MeO MeO

O O

O t -Bu t -Bu
O O
O

O O

1. TrOOH, 1 N NaOH
t -Bu o t -Bu
acetone, -30 C

H H
H 2. recrystallization O H
O from PhH/hexane O
A
o
[α]23D -151.9 (c 0.9, MeOH)
o
mp 111 C , 100% ee

2. Total synthesis of (±)-ginkgolide A (Ref. 3):

Based on the successful total synthesis of ginkgolide B, ginkgolide A was made by two different
routes.

i. From the bislactone B:

N
N N
O S O
HO H O O H
O H N N H
O O
t-Bu S t-Bu (n-Bu)3SnH
O Me O
Me
H H
PhCH3 , Py, 45 C
o dioxane, ∆
HO O H HO O H

O O

10.12

227
 O

HO
O O
1. OsO4 , Py
O O H
H o O
O 60 C (PhSeO)2O
t-Bu t-Bu
O Me O
Me
H 2. I2 , CaCO3 H o
Py, PhCl, 80 C
HO O H MeOH/H 2O HO O H

O O

O O

O HO
O O
O H O H
O NaBH4 O
t-Bu t-Bu
Me O O
Me
H o H
EtOH, -45 C
HO O H HO O H

O O

Ginkgolide A

ii. From ginkgolide B:

O O O

HO HO MOMO
O O O
O HO H MOMCl O MOMO H
H O HO H
H
H O O
O CH3CN
t-Bu t-Bu t-Bu
O Me O O
Me Me
H (i-Pr)2NEt H H
HO O H HO O H + HO O H

O O O

Ginkgolide B 1 : 3 mixture, separated by SGC

O O

MOMO HO
O O
1. KH, THF
o o O H O H
2. CS2 , 23 C ® 45 C O
BF2 . Et2O, PhSH
O
t-Bu t-Bu
Me O O
Me
3. BnBr H o H
CH2Cl2 , -10 C
4. (n-Bu)3SnH HO O H HO O H
dioxane, ∆
O O

Ginkgolide A

References:
1. E. J. Corey, M.-c. Kang, M. C. Desai, A. K. Ghosh, and I. N. Houpis, J. Am. Chem. Soc.
1988, 110, 649.
2. E. J. Corey and A. V. Gavai, Tetrahedron Lett. 1988, 29, 3201.
3. E. J. Corey and A. K. Ghosh, Tetrahedron Lett. 1988, 29, 3205.
10.13

228
 Bilobalide

O OH OH
t -Bu
O H

O
O

Despite the structural relationship between ginkgolide B and bilobalide, retrosynthetic analysis
of the latter produced a totally different collection of sequences. A successful synthesis of bilobalide
was implemented using a plan which depended on stereochemical and FG-based strategies. A process
for enantioselective synthesis was based on an initial enantioselective Diels-Alder step in combination
with a novel annulation method.

CO2Me
LDA, (2 eq.) - CO2Me t-Bu CO2Ph

HMPA (3 eq.), THF

-
CO2Me CO2Me

t -Bu MeO2C t -Bu

MeO2C
NaBH4 O3 , NaHCO3

o o
MeOH / i-PrOH, 0 C CH2Cl2 / MeOH, -78 C;
MeO2C O MeO2C OH Me 2S
A B

t -Bu t -Bu
OHC (MeO)2HC
o
MeO2C MeO2C 1. LAH, Et2O, 0 C
MeO2C TsOH, HC(OMe) 3 MeO2C 2. (COCl)2 , DMSO

O MeOH O o
CH2Cl2 , -78 C;
o o
OH OMe Et2N, -78 C ® 0 C

4 : 1 mixture at C*

MeO
t -Bu t -Bu
(MeO)2HC
O H
OHC
O
OHC 1. 1% aq. HCl, THF aq. KOH, THF / EtOH
O
O 2. PDC, HOAc, CH2Cl2 O
mol. sieves
OMe OMe

10.13

229
HO CO2H
t-Bu t-Bu
O H O H
O o
1. MsCl, Et 3N, -30 C O O2N NO2

O O
O 2. (i-Pr)2NEt, CH3CN, ∆ O
NaHCO3 ,CH2Cl2

OMe OMe

O AcO OAc
t-Bu t-Bu
O H O O H O
o
O 1. 0.5 N HCl, THF, 60 C O MCPBA, BF3 . Et2O

O 2. Ac2O, DMAP, CH2Cl2 O

O O CH2Cl2 , Et2O

OMe OMe

AcO OAc O OAc

t-Bu t-Bu
O H O 1. 0.5 N HCl, HOAc O H O
o o
O THF, 80 C O Et3SiH, PhCH3 , 300 C

O 2. PDC, CH2Cl2 O
O O

O O

O O OAc
OAc
t-Bu OH
O H O H t-Bu
1. MeO2CCOCl, (i-Pr)2NEt
OH o
O O CH3CN, 0 C
OsO4 , Py, Et2O

O O
O O 2. (n-Bu)3SnH, PhCH3 , ∆

O O

O OAc O OH
OH OH
O H t-Bu O H t-Bu

O 3 N HCl, ∆ O

O O
O O

O O

10.12

230
 The enantioselective synthesis of (-)-bilobalide was achieved based on successful synthesis of
the chiral enone A and the highly stereoselective reduction of enone A to the desired α-alcohol B.
Further transformation to (-)-bilobalide was accomplished following the route used for racemic
bilobalide (Ref. 2).

O
R CO2Men
(i-Bu)2AlCl
+ O
CH2Cl2 / hexane
O R CO2Men

O o
[α]23D +25.5 (c 8.0, CHCl3)

MenO2C MenO2C t-Bu

o H
1. 1 eq. LDA, THF, -78 C t-Bu KN(TMS)2

o
2. t-Bu CO2Ph THF, -45 C
MenO2C MenO2C OH
O
A
o
[α]23D +89.9 (c 0.9, CHCl3)

Ph
H Ph
1. O3 , NaHCO3
O
N B t-Bu CH2Cl2/MeOH t-Bu
MenO2C (MeO)2HC
o
H -78 C; Me2S
MenO2C
MenO2C
BH . THF, THF 2. TsOH, HC(OMe) 3
MenO2C MeOH O
O

B, >99% ee OMe

10 : 1 mixture at C*

MeO O OAc
t-Bu t-Bu
O H O H O

O O

O O (-)-Bilobalide
O O

OMe O

o o
[α]23D +145.5 (c 1.45, CHCl3) [α]23D -110 (c 0.41, CHCl3)

References:
1. E. J. Corey and W.-g. Su, J. Am. Chem. Soc. 1987, 109, 7534.
2. E. J. Corey and W.-g. Su, Tetrahedron Lett. 1988, 29, 3423.
10.14

231
 Forskolin

O
OH
O

OH
OAc
H
OH

Forskolin is an activator of the enzyme adenylate cyclase which has therapeutic utility.
Outlined below are stereocontrolled routes to racemic and natural chiral forms of forskolin derived by
multistrategic retrosynthetic analysis.

O
1. CH3CO3H, EtOAc O3 , MeOH

2. NaBH4 , CeCl3 , MeOH CH2Cl2 ; Me2S

O OH

α-Ionone

OH
O

1. KOH, MeOH CHCl3

O
o Ts CO2H
2. Ph3P=CH2 , THF, 0 C

1. n-BuLi, THF
o o
A -105 C ® -95 C
o o
2. CO2 , -95 C ® 0 C
+
3. H3O
Ts H

O O
O O
1. Me 2CuLi, BF3 . Et2O
Ts o o o
Et2O, -35 C ® 0 C hv, O2 , CHCl3 , 0 C

2. DBN, CH2Cl2 0.1% methylene blue

O
O HO

Al / Hg, THF / H2O Bz2O, Py, DMAP

O OH
CO
O
o
ClCH2CH2Cl, 50 C
O

10.14

232
 BzO BzO

PCC, ClCH2CH2Cl 1. Al/Hg, THF/H2O

CO OH CO
o o 2. CH2N2 , Et2O
80 C ® 90 C
O O
O

O
CO2Me O
BzO
o
Dibal-H, PhCH3 , -78 C t-BuOOH, Mo(CO)6

o
PhH, 68 C
H H
O OH

O O
O O
1. Li OTBDMS
o
1. KOH, MeOH THF, 0 C
O
2. Me 2C(OMe)2 2. Me 2NCOCl, AgOTf
O
H TsOH, acetone H 2,6-lutidine, CH2Cl2
OH O

O OTBDMS O
O
O O
Me2N O Me2N O
O 1. 2 N (CO2H)2
OTBDMS
OH o
HO acetone, 60 C

O K2CO3 , THF O 2. TBDMSCl

H H
O O imid, DMF

O O

O OTBDMS O OTBDMS
Me2N O Me2N O

OH OAc hv, O2 , CHCl3

o
1. EtOTl, PhCH3 10 C

O 2. AcCl, Et2O O 2% methylene

H H
O o O blue
-45 C

10.14

233
 O O
AcO OTBDMS AcO OTBDMS
Me2N O Me2N O
O
O
O O
1O2 NaOEt, (n-Bu)3P

o
O O EtOH, 0 C
H H
O O

O
O
O OTBDMS O OTBDMS
Me2N O HO O
O
O O
HOAc, Ac2O MeCu . P(n-Bu)3

O
o
100 C O
BF2 . Et2O
H H o o
O O Et2O, -78 C ® -50 C

O O
O OTBDMS O SeAr
O O
O o O
O 1. HF, CH3CN/H2O, 0 C O H2O2 , THF

2. o-O2NC6H4SeCN
o
O (n-Bu)3P, THF, 0 C O
H H
O O

O O
O O
O O
O O
o
O HOAc, H2O, 70 C O 0.14 N LiOH

H2NCONHNH2 THF/H2O/i-PrOH
OH
O
H H
O OH

O O
OH OH
o
O Ac2O, Py, 0 C O
OH OH
OH OAc
H H
OH OH

10.14

234
 The hydroxydiene A could be obtained by enantioselective CBS reduction of dienone B in
90% ee, which led to an enantioselective synthesis of the natural occurring from of forskolin.

Ph
H Ph
Ts CO2H
O 10 mol.% O OH
N B Ph3P . I2 , CH2Cl2
5
o o
Me -35 C ® 23 C

0.6 eq. BH3 . THF, THF

t-Bu N t-Bu
B (S)-A
o
[α]23D -53 (c 1.0, CHCl3)
enantioselectivity 95 : 5

O I O
i-Pr
N
O Ts i-Pr i-Pr O
N N
Ts 1. CH2Cl2
i-Pr i-Pr

o 2. recrystallization
CH2Cl2 , -35 C from PhH/hexanes

O O
O O
Ts Me2CuLi, BF3 . Et2O Me

o
Et2O/PhCH3 , -35 C

o o
[α]23D +8.7 (c 1.0, CHCl3) [α]23D -70.7 (c 1.0, CHCl3)
o o
mp 153 C - 154 C, 100% ee

References:
1. E. J. Corey, P. Da Silva Jardine, and J. C. Rohloff, J. Am. Chem. Soc. 1988, 110, 3672.
2. E. J. Corey, P. Da Silva Jardine, and T. Mohri, Tetrahedron Lett. 1988, 29, in press.

10.15

235
 Venustatriol

OH
H
O
O
H OH
O H OH
O
H H
Br
H

O CHO

H
O H H
O Li Br
O O
H H + OH
O O
H OH H
Br
H
A B

Venustatriol, a marine-derived antiviral agent, as with many polyether structures, is a

straightforward problem for retrosynthetic analysis. The major issues, clearance of stereocenters and
topologically strategic disconnection, were readily resolved to generate the pathway of synthesis
described below.

1. Synthesis of the fragment A:

(S,S)-(-)-DET
Ti(Oi-Pr)4
t-BuOOH O 1. CrO3 . 2Py, CH2Cl2
OH OH
mol. sieves 2. Ph3P=CHCO2Me
CH2Cl2 CH2Cl2
(E, E) - Farnesol

1. H2 , Rh-Al2O3 1. NaCN, HOAc

O Py, THF O THF / H2O
CO2Me CHO
2. Dibal-H 2. TsOH, CH3CN
PhCH3
o
-78 C

CN CN
O O
H H (S,S)-(-)-DET
Ti(Oi-Pr)4 , TrOOH
HO HO
H + H mol. sieves, CH2Cl2

1 : 1 mixture
o
1. KN(TMS) 2 , THF, -23 C

o
2. EtCO2H, -10 C

10.15

236
 O
Br Br

CN CN
O O H
H
O OH Br Br

HO MsOH O
H H H
o CH3NO2
CH2Cl2 , 0 C

Zn, HOAc
Et2O

CN CN
O O CN
H H O H
Br
O O
O O O
H H + H H + O
H H
Br H
H Br

26% 5% 61%
separated by SGC and purified
by recrystallization
o o
[α]23D +9.82 (c 1, CHCl3) Dibal-H, -23 C
CH2Cl2

CHO
O H

O
O
H H
Br
H
A

2. Synthesis of the fragment B:

(S,S)-(-)-DET
Ti(Oi-Pr)4 , t-BuOOH 1. NaH, BnBr, THF
O
HO HO
mol. sieves, CH2Cl2 2. HClO4 , THF/H2O

Geraniol

OH

PCC, CH2Cl2 1. NaH, THF

H
BnO
H BnO O 2. MOMCl, CH 2Cl2
OH OH o o
H OH 0 C ® 55 C

10.15

237
 1. H2 , Pd/C, EtOH
H 2. (COCl)2,DMSO H Ph3P=CH2
OHC
BnO O O
o o o
H O O CH2Cl2 , -78 C H O O THF, -78 C ® 23 C
o o
3. Et3N, -78 C ® 0 C

1. 9-BBN, THF;
H H2O2, NaOH H
Br
O O
O O 2. CBr4, Ph3P, CH2Cl2 O O
H H

B
o
[α]23D +79.8 (c 2.5, CHCl3)

3. Coupling of the fragments A and B and the completion of the synthesis:

HO H
H
O
t-BuLi, Et2O O
H o H
Br -78 C; O H O O
O O
H H
H O O CeCl3
o o Br
-78 C ® 0 C; H
B A, Et2O
o o
-78 C ® 0 C

O
H
O
(COCl)2 , DMSO O
o H
CH2Cl2 , -78 C; O H O O
O
H H
o o
Et3N, -78 C ® 0 C Br
H

OH
H
O
O
H OH OH
o o O H
1. MeMgBr, THF, -78 C ® 0 C O
H H
o
2. TsOH, THF / H2O, 40 C Br
H

o
synthetic sample: [ α]23D +9.3 (c 0.6, CHCl3)
o
natural Venustatriol: [α]23D +9.4 (c 3.2, CHCl3)

References:
E. J. Corey and D.-C. Ha, Tetrahedron Lett. 1988, 29, 3171.
10.16

238
 Pseudopterosin A

Me
H

Me
H

Me O O
HO OH
OH OH

Pseudopterosin A is a member of a group of marine natural products which show potent

antiinflammatory properties, but which are not prostaglandin biosynthesis inhibitors. Structurally
similar to phosphatidyl inositol, they may function as phospholipase inhibitors, and, as such, may be
the forerunners of a new class of therapeutic agents.

+ -
NO HSO4 , Py hv, Dabco

HO Me CH2Cl2 ONO Me o
PhCH3 , 15 C

(1S, 2R, 5S)-

(+)- Menthol

Me
1. NaHSO3 (5 eq.) Me H
o o
H2O, 50 C 1. Dibal-H, CH2Cl2 , -78 C
O
N 2. Br2 , CaCO3 Me
HO HO Me O Me 2.
Ph3P C , DMSO
THF/ H2O H
o SEt
3. LDA, THF, 0 C

Me Me
1. DMSO, TFAA, CH2Cl2 H
H
o
-60 C; Et3N 1. KH, THF/HMPA

C 2. TBDMSCl, THF
EtS HO Me 2. HgCl2, CH3CN/H2O O Me
Me H o
50 C
3. NaOMe, MeOH

1. TMSOTf
Me Me
H Me CHO H
o
CH2Cl2, -78 C; H2O KH, THF
H
O Me 2. PCC, CH2Cl2 O Me
TBDMS
O

Me

10.16

239
 Me Me
H H

1. cat. HClO4
(PhSeO)2O HOAc / H2O
O Me O Me
(TMS)2NH, PhH 2. aq. NaHSO3 , EtOH
Me OH Me O
NSePh

Me Me
H H

Me2C(OMe)2 1. Me 2S=CH2, THF

O Me O Me

o 2. BF3 . Et2O, CH2Cl2

Me OH PPTS, CHCl3 , 70 C Me O o o
-30 C ® 23 C
OH O

Me Me
H H
1. Ph3P=CMe2
o
O THF, 0 C TsCl, Et3N, CH2Cl2
Me Me
H H
o o o
H 2. 10% HCl, 70 C -30 C ® 23 C
Me O Me OH
THF / MeOH
O OH

Me Me
H H

1. NaH, CH3CN KOH

Me Me
H H
Br MeOH / H2O
2.
Me OH Me O O
O AcO OAc
AcO OAc
OTs OTs OAc
OAc

Me Me
H H

1. Na / Hg, MeOH
2. Ac2O, DMAP, CH2Cl2
Me Me
H H
3. SGC separation
Me O O 4. KOH, MeOH/ H2O Me O O
HO OH HO OH
OTs OH OH OH

References:
E. J. Corey and P. Carpino, Submitted for publication.
10.17

240
 Partial Synthesis of α-Amyrin Acetate
Proof of the Structure and Stereochemistry

AcO
H

The comparison of degradation products from α- and β-amyrin led to the conclusion that these
large classes of triterpenoids differed in absolute configuration. That such was not the case was
established by synthesis of α-amyrin from a β-amyrin derivative, glycyrrhetric acid, an obvious SM
goal. The synthesis of α-amyrin also demonstrated the relative stereochemistry beyond doubt. This cis
D/E ring of α-amyrin is thermodynamically more stable than the trans arrangement mainly because of
anchoring of ring E by the two equatorial non-angular methyl sudstituents on that ring.

CO2H CO2Me

O 1. KOH, EtOH
H 1. CH2N2 , Et2O H PhCH3 , ∆

H
2. H2 , PtO2 , HOAc H 2. Ac2O, Py, ∆

HO HO
H H

Glycyrrhetic Acid
(a known derivative
of β-Amyrin )

CO2H NCO

1. PCl5, dioxane, ∆ H LAH, THF, ∆

H

2. NaN3, acetone/ H2O

H H
3. xylene, ∆
AcO AcO
H H

10.17

241
 NMe3 I -
+
NHMe

H H 1. t-BuOK
K2CO3 , MeI t-BuOH, ∆
H H
EtOH, ∆ 2. Ac2O, Py, ∆
HO HO
H H

H H 1. KOH, dioxane
1. OsO4 , Py, Et2O MeOH, ∆
H H
2. NaIO4 , EtOH/H2O 2. BzCl, Py
AcO AcO
H H

O O

1. Ph3P=CH2
H H
TrNa, dioxane/Et2O; Et2O
H H
MeI 2. KOH
BzO BzO dioxane/MeOH
H H

1. Li, dioxane
H NH 2 H
H 2N

H H
2. Ac2O, Py
HO AcO
H H

α-Amyrin acetate

References:
1. E. J. Corey and E. W. Cantrall, J. Am. Chem. Soc. 1958, 80, 499.
2. E. J. Corey and E. W. Cantrall, J. Am. Chem. Soc. 1959, 81, 1745.

10.18

242
 Olean - 11,12;13,18 - Diene,
a β-Amyrin Derivative

The first synthesis of a β-amyrin derivative was accomplished by a convergent route which
depended on cation-olefin cyclization to from the critical central ring. The plan of synthesis was
largely guided by the selection of SM goals for the A/B and E ring portions of the target.

O
CO2Me

O OH o o
1. NaOH, dioxane/ H2O, ∆ 1. POCl3 , Py, 0 C ® 25 C
H H
o
2. CH2N2 , Et2O, 0 C 2. KOH, EtOH/H2O, ∆
H H

(+)-Ambreinolide
(Ref. 3)

Br
CO2H

1. LAH, Et2O, ∆
H H
o
2. TsCl, Py, 0 C
H H
3. LiBr, acetone

CO2Me
1.
o
t-BuOK, t-BuOH PCl5 , 0 C;

O O 2. HCl, acetone/ H2O, ∆ O O then, ∆ O O

CO2H
O

10.18

243
 o
H2 , PtO2 , HOAc PCl5 , 0 C;

O
then, ∆ O

HO2C
O

Br MgBr
o
Mg, Et2O, ∆ B, Et2O, -70 C
H H

H H

O
t-BuOK, t-BuOH MeLi, Et 2O
H O H O

H H

HCl (gas), HOAc

H OH H
o o
25 C ® 55 C
H H

References:
1. E. J. Corey, H.-J. Hess, and S. Proskow, J. Am. Chem. Soc. 1959, 81, 5258.
2. E. J. Corey, H.-J. Hess, and S. Proskow, J. Am. Chem. Soc. 1963, 85, 3979.
3. P. Dietrich and E. Lederer, Helv. Chim. Acta 1952, 35, 1148.

10.19

244
 Pentacyclosqualene

Pentacyclosqualene, the symmetrical hydropicene corresponding to squalene, has not been made
by acid-induced cation-olefin cyclization of squalene, despite considerable experimental study. A
simple, convergent synthesis of pentacyclosqualene using cation-olefin cyclization to generate ring C
was developed. The C30-framework was constructed by radical coupling to a tetracyclic intermediate
that was also used for the synthesis of onoceradiene.
OH O

O
OH
(Ref. 3)

H H

Sclareol A

o
H2SO4 , HOAc, 85 C

O
CO2H

O
+
H3O 1. KOH, MeOH, ∆

2. NH3 , Et2O
H

α- or β-Monocyclo
homofarnesic acid

CO2- +NH 4
HO
OH
OH
electrolysis

MeOH, ∆ , -CO2
H H

B POCl3 , Py

HClO4
HOAc, PhH
H H

H
Pentacyclosqualene H
β-Onoceradiene
10.19

245
 Pentacyclosqualene was also obtained from the isomeric lactone A in a similar fashion as shown
below.

H
O

1. KOH, MeOH, ∆
O
2. NH3 , Et2O OH
OH
3. electrolysis
H MeOH, ∆, -CO2 H

POCl3 , Py
HClO4
HOAc, PhH

H H

H H

Pentacyclosqualene α-Onoceradiene

It was found later that the electrolytic coupling reaction gave better yield with the acetate
corresponding to B, since fragmentation was a major side reaction of the γ-hydroxy acid B (Ref. 2).

OH
CHO

OsO4 , NaIO4 KMnO4 , CO2

OAc
dioxane / H2O acetone
H H

Sclareol

10.19

246
 H
CO2H

OAc OAc
OAc

H H

LAH, Et2O
HClO4 , HOAc, PhH

H
H

HClO4 , HOAc, PhH

OH
OH H

H H

References:
1. E. J. Corey and R. R. Sauers, J. Am. Chem. Soc. 1957, 79, 3925.
2. E. J. Corey and R. R. Sauers, J. Am. Chem. Soc. 1959, 81, 1739.
3. L. Ruzicka and M. M. Janot, Helv. Chim. Acta. 1931, 14, 645.

247
10.20
Dihydroconessine

Me
H
N Me

Me H

H H

Me2N
H

A simple synthesis of dihydroconessine from the SM goal 3β-acetoxyhisnorcholenic acid was

devised by applying concurrently the Hoffmann-Loeffler-Freitag transform to effect retrosynthetic
removal of the C(18) functional group of the target structure. In the course of demonstrating the
synthesis, a mild new method for the generation of isocyanides was discovered and the first
functionalization of a steroidal angular methyl group was achieved.

Me Me
Me CO2H Me H NHCHO
H

1. SOCl2, Py, Et2O

Me H Me H
2. NaN3 , H2O 1. K2CO3, MeOH
H H H H o
3. NaOH, H2O, ∆ 2. TsCl, Py, 0 C
AcO HCO2
4. AcOCHO

3β-Acetoxybisnorcholenic Acid

Me Me
Me N C Me H NHCHO
H
1. Me 2NH, DMF
Me H Me H o
HOAc, Et2O 80 C
H H H H
2. LAH, THF, ∆
TsO TsO

Cl
Me Me
NHMe Me H N
Me H Me
1. H2 , PtO2 Me H
Me H
HOAc hv, 90% H2SO4
H H H H
2. NCS, Et2O [ (n-Bu)2NCl ]
Me2N Me2N o
H 0 C

248
 10.20
Me
H Cl Me H
H NHMe N Me
H

Me H Me H

H H H H
Me2N Me2N
H H

References:
1. E. J. Corey and W. R. Hertler, J. Am. Chem. Soc. 1958, 80, 2903.
2. E. J. Corey and W. R. Hertler, J. Am. Chem. Soc. 1959, 81, 5209.

249
 CHAPTER ELEVEN
Prostanoids

11.1 Structures of Prostaglandins (PG’s) .............................................................................250

11.2 (±)-Prostaglandins E1, F1α, F1β, A1 and B1 ....................................................................251
11.3 Prostaglandins E1, F1α and Their 11-Epimers ...............................................................253
11.4 General Synthesis of Prostaglandins .............................................................................255
11.5 Refinements of the General Synthesis of Prostaglandins ..............................................258
11.6 Prostaglandins E3 and F3α .............................................................................................262
11.7 Modified Bicyclo[2.2.1]heptane Routes to Prostaglandins ............................................265
11.8 Synthesis of Prostaglandin A2 and Conversion to Other Prostaglandins ......................267
11.9 Alternative Synthesis of Prostaglandins F1α and E1 ......................................................272
11.10 Conjugate Addition-Alkylation Route to Prostaglandins ..............................................273
11.11 Bicyclo[3.1.0]hexane Routes to Prostaglandins .............................................................276
11.12 Prostaglandin F2α from a 2-Oxabicyclo[3.3.0]octenone ................................................278
11.13 11-Desoxyprostaglandins ..............................................................................................280
11.14 Prostacycline (PGI2) .....................................................................................................282
11.15 Major Human Urinary Metabolite of Prostaglandin D2 ...............................................284
11.16 Analogs of the Prostaglandin Endoperoxide PGH2 .......................................................286
11.17 12-Methylprostaglandin A2 and 8-Methylprostaglandin C2 ..........................................291
11.18 Synthesis of Two Stable Analogs of Thromboxane A2 ..................................................293
11.19 Synthesis of (±)-Thromboxane B2 .................................................................................295
11.20 Synthesis of Prostaglandins via an Endoperoxide Intermediate. Stereochemical
Divergence of Enzymatic and Biomimetic Chemical Cyclization Reactions ...................297
11.21 (±)-Clavulone I and (±)-Clavulone II ............................................................................303
11.22 (-)-Preclavulone-A .........................................................................................................305
11.23 Hybridalactone ..............................................................................................................307

249
11.1
Structures of Prostaglandins (PG’s)

O O O
8
CO2H 9 CO2H CO2H
6 5
12 14
15
11
HO 13 HO
HO
OH OH OH

PGE1 PGE2 PGE3

HO HO O

CO2H CO2H CO2H

HO HO
OH OH OH

PGF1α PGF2β PGA2

O O HO

CO2H CO2H CO2H

O
OH OH OH

PGB2 PGC2 PGD2

OH
HO2C

CO2H CO2H
O
O
O HO O

n-Am OH OH

HO OH

PGI2 TXA2 TXB2

References:
1. A. Mitra, The Synthesis of Prostaglandins; J. Wiley-Interscience: New York, 1977.
2. J. S. Bindra and R. Bindra, Prostaglandin Synthesis; Academic Press: London, 1977.
3. New Synthetic Routes to Prostaglandins and Thromboxanes; S. M. Roberts and
F. Scheinmann Eds.; Academic Press: London, 1982.

250
 11.2
Total Synthesis of (±) - Prostaglandins
E1, F1α, F1β, A1, and B1

The first synthesis of pure primary prostaglandins was designed retrosynthetically to allow the
direct synthesis of E prostaglandins (PG’s) under the mildest possible conditions to ensure survival of
the sensitive β-ketol subunit (see Section 5.9 of Part One). The synthesis involved a number of novel
processes including mild methods for transketalization, aldol cyclization, dehydration of β-ketols,
amine oxidation, and cleavage of tetrahydropyranyl ethers. An important result leading to second
generation syntheses was the finding that PGE’s survive tetrahydropyranyl ether cleavage.

o n-Am
S n-BuLi, THF / pentane, -25 C;
n-Am S S

S Br

MeNO2 , KOH, MeOH;

NC O NC
Ac2O, cat. H2SO4 ;
NaHCO3 , EtOAc
NO2
B

o NC(CH2)6 n-Am
110 C 1. Al/Hg, Et2O/H2O/MeOH
A + B S S

O2N 2. HCOOAc

NC(CH2)6 n-Am NC(CH2)6 n-Am

HgCl2 , THF 1. OsO4 , Py
S S O O
HCONH OH HCONH 2. Pb(OAc)4
HO o
acetone, -50 C

NHCHO HCONH

(CH2)6CN (CH2)6CN 1. NaBH4 , EtOH

o o
1. DBN, CH2Cl2 , 0 C -20 C
n-Am n-Am
O H
2. Ac2O, Py AcO O O 2. H2SO4 , THF / H2O
O O O
O

251
11.2
HCONH
HCONH
(CH2)6CN
DCC, CuCl2 (CH 2)6CN Zn(BH4)2

n-Am Et2O diglyme

n-Am
AcO
OH O AcO
O

o 1. NBS, CH2Cl2
1. KOH, 30 C +
HCONH H 3N o
MeOH/H 2O 2. DBN, -40 C
(CH 2)6CN 2. DHP, TsOH (CH 2)6CO-2 3. aq. NaHSO3

n-Am dioxane n-Am t-BuOH

o o
AcO 3. KOH, 120 C THPO 4. HOAc, 40 C
OH OTHP
MeOH/H 2O THF / H2O

O O
CO2H CO2H

15
+
HO OH HO OH

(±)-15-epi-PGE1 HCl (±)-PGE1

H2O / THF
NaBH4
o
MeOH, 0 C

O HO
CO2H CO2H

OH HO OH
(±)-PGA1 (±)-PGF1α
KOH
MeOH, pH 9
+
O HO
CO2H CO2H

OH HO OH
(±)-PGB1 (±)-PGF1β

References:
1. E. J. Corey, N. H. Andersen, R. M. Carlson, J. Paust, E. Vedejs, I. Vlattas, and R. E. K.
Winter, J. Am. Chem. Soc. 1968, 90, 3245.
2. E. J. Corey In Proc. of the Robert A. Welch Foundation Conferences on Chemical Research.
XII. Organic Synthesis, November 11-13, 1968, pp 51-79 (1969).

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