9.

9
The ethylene acetal A was also prepared by an alternative approach.

DMSO / THF ZnBr2 , PhH, ∆

Me2S=CH2O
O
H H O
NaCH2SOCH3
DMSO

+ -
Me2S I

OH
HO

TsOH, PhH, ∆ O

CHO H
H H O

References:
1. E. J. Corey and S. Nozoe, J. Am. Chem. Soc. 1963, 85, 3527.
2. E. J. Corey and S. Nozoe, J. Am. Chem. Soc. 1965, 87, 5728.

166
 9.10
dl - Sirenin

H
OH

OH

Sirenin is the sperm attractant produced by the female gametes of the water mold, Allomyces.
Its synthesis has been accomplished by the use of an internal [2 + 1] cycloaddition step.

O
Me
(EtO) 2P
OAc o OAc
O3 , Py, CH2Cl2 , -78 C; CO2Et

o o o
Zn, HOAc, -78 C ® 23 C NaH, THF, 0 C
O

1. MesCOCl, Py
OAc OTHP o
1. K2CO3 , EtOH CHCl3 , 0 C

2. DHP, TsOH, Et2O o

2. TsOH, MeOH, 0 C
o
CO2Et 3. LAH, AlCl3 , Et2O, 0 C

88 : 12 OH
(E,E / Z,E) selectivity
A

OH o
1. PBr3 , Et2O, 0 C 1. TsOH, MeOH

2. Li 2. H2 , Ni2B (P-1)
OTHP
OTHP aq. EtOH
THF
OCOMes OCOMes

1. CrO3 . 2Py, CH2Cl2 1. NaH; (COCl)2 , PhH

HO
2. AgO, THF / H2O 2. CH2N2 , Et2O
OH O

OCOMes OCOMes

167
9.10

CuSO4 NaH, DME;

H

N2 cyclohexane, ∆ (EtO)2CO
O O

OCOMes OCOMes

H H

NaBH4 1. BzCl, Py
H H
CO2Et CO2Et
o 2. t-BuOK, t-BuOH
EtOH, -20 C
O OH

OCOMes OCOMes

H H

LAH, AlCl3 , Et2O

H H
OH
CO2Et o o
0 C ® 25 C

OCOMes OH

The intermediate A was also made by the following method:

OAc OH
1. PH3P=CHCl, Et2O 1. n-BuLi, Et2O

2. NaOMe, MeOH 2. DHP, TsOH, Et2O

O CHCl

1. LAH, AlCl3 , THF

OTHP OTHP o o
n-BuLi, THF; 45 C ® 55 C

(CH2O)n o
OH 2. I2 , -78 C

OTHP Me2CuLi, Et2O OTHP

OH OH
I

168
 9.10
A shorter synthesis of sirenin was achieved following the sequence shown below (Ref. 2):

1. n-BuLi; Br
TMSCl, Et 2O, ∆
LiCH2 TMS
2. n-BuLi, TMEDA o
Et2O, 0 C
o
Et2O, -5 C

o
1. AgNO3 , EtOH n-BuLi, THF, -78 C;

2. NaCN o o
(CH2O)n , -78 C ® 25 C
TMS H

(Ref. 3)

Ni(CO)4 , HOAc 1. CH2N2 , Et2O

o CO2H o
EtOH / H2O, 70 C OH 2. MnO2 , hexane, 0 C

OH

o
1. NH2NH2 , Et3N, EtOH CuI, THF, 35 C
CO2Me o CO2Me
O 2. MnO2 , CH2Cl2 , 0 C N2

H H

1. SeO2 , EtOH
H H
OH
CO2Me o
2. LAH, AlCl3 , 0 C
(Ref. 4)

OH

References:
1. E. J. Corey, K. Achiwa, and J. A. Katzenellenbogen, J. Am. Chem. Soc. 1969, 91, 4318.
2. E. J. Corey and K. Achiwa, Tetrahedron Lett. 1970, 2245.
3. E. J. Corey and H. A. Kirst, Tetrahedron Lett. 1968, 5041.
4. J.J. Plattner, U. T. Bhalerao, and H. Rapoport, J. Am. Chem. Soc. 1969, 91, 4933.

169
9.11
dl - Sesquicarene

Br
1. DHP, HCl
HO THPO
Li
o THF
2. n-BuLi, THF, -78 C

1. TsOH, MeOH 1. CrO3 . 2Py, CH2Cl2

OTHP
2. H2 , NiB (P-1), EtOH 2. AgO, THF / H2O
OH

1. NaH; (COCl)2 , PhH CuSO4

HO
2. CH2N2 , Et2O N2 cyclohexane, ∆
O O

H H

NaH, DME; NaBH4

H H

(EtO)2CO CO2Et o
EtOH, -20 C
O O

170
 9.11
H H
o
1. BzCl, Py 1. LAH, AlCl3 , Et2O, 0 C
H H
CO2Et 2. t-BuOK, t-BuOH CO2Et o
2. SO3 . Py, THF, 0 C
OH

H H

LAH, Et2O
H - H
OSO3
o o
0 C ® 25 C

Sesquicarene was also synthesized from (Z,E)-farnesol as shown below:

MnO2 1. NH2NH2 , Et3N, EtOH

o o
OH hexane, 0 C O 2.MnO2 , CH2Cl2 , 0 C

CuI, THF
H
o
N2 35 C

References:
1. E. J. Corey and K. Achiwa, Tetrahedron Lett. 1969, 1837.
2. E. J. Corey and K. Achiwa, Tetrahedron Lett. 1969, 3257.

171
9.12
(±)-α-Copaene (±)-α-Ylangene (±)-β-Copaene (±)-β-Ylangene

1. Total synthesis of (±)-α-copaene and (±)-α-ylangene:

o OH
O
150 C, -CO2 HO

+
O O TsOH, PhH, ∆
H
CO2Me
CO2Me

O o
MCPBA 1. LAH, Et2O / THF, 0 C
O O
CH2Cl2 o
2. ClCO2Et, Py, 0 C
H O H O
CO2Me CO2Me
diastereoselection 9 : 1

OH O
o
DMSO Li, NH3 , -78 C
O O
Ac2O EtOH / THF
H O H O
OCO2Et

OH OTs
o
1. TsCl, Py, 0 C NaCH2SOCH3
O
2. 1 N HCl, HOAc, THF o
O DMSO, 75 C
H O H

O
CN
(EtO)2P
Me 1. Mg, MeOH

O NaH, DME 2. Dibal-H, hexane

o o
CN -78 C ® 23 C

172
 9.12

1. TsNHNH2 , THF
+
2. LAH, dioxane, ∆
CHO

(±)-α-Copaene (±)-α-Ylangene

2. Total synthesis of (±)-β-copaene and (±)-β-ylangene:

O O

Zn, HOAc Na, i-PrOH, ∆

O O

H O H O

OH OTs
o
1. TsCl, Py, 0 C NaCH2SOCH3

2. 1 N HCl, HOAc, THF o

O O DMSO, 75 C
H H

O
CN
(EtO)2P
Me 1. Mg, MeOH

O NaH, DME 2. Dibal-H, hexane

o o
CN -78 C ® 23 C

1. TsNHNH2 , THF
+
2. LAH, dioxane, ∆
CHO

(±)-β-Copaene (±)-β-Ylangene

References:
E. J. Corey and D. S. Watt, J. Am. Chem. Soc. 1973, 95, 2303.

173
9.13
(±) - Occidentalol

H OH

OH
1. HO
o TsOH, PhH, ∆
O 150 C, -CO2
+
O O O 1. LAH, Et2O
H
CO2Me CO2Me

o
SO3 . Py, THF, 0 C; 1 N HCl, HOAc

O O
LAH, THF
H O H O

HO

EtO
EtO P SMe

O HgCl2

o SMe CH3CN / H2O

O HMPA, DME, 62 C
H H

MeLi
+ o
COCH 3 COCH 3 Et2O, -70 C
H H H OH

diastereoselection 1 : 2.9
the β-isomer was removed by SGC

References:
D. A. Watt and E. J. Corey, Tetrahedron Lett. 1972, 4651.

174
 9.14
(±) - β - trans - Bergamotene

O O

o CO2H
LDA, THF, -78 C; Ph3P=CH2 , PhCH3

+ o o
CO2 ; H3O -50 C ® 25 C

O
CO2H
1. (COCl)2 , PhH

2. (i-Pr)2NEt
PhCH3 , ∆

1. NH2NH2 , HOAc, EtOH

2. t-BuOK, DMSO
O

References:
E. J. Corey and M. C. Desai, Tetrahedron Lett. 1985, 26, 3535.

175
9.15
(±) - Fumagillin

O
O

HO2C O
H O
OMe

The retrosynthetic analysis of fumagillol, the alcohol from which the antibiotic fumagillin is
derived, has been outlined in Section 2.3. The experimentally demonstrated synthesis of fumagillol
was derived by T-goal directed search to apply the Diels-Alder transform.

O O Br
1. , base SeO2 , DME / H2O, ∆
OMe CO2Me
2. NaOEt, EtOH, ∆

CHO
1. Ph3P , THF Br
OHC
CO2Me CO2Me
o
2. 80 C, isomerization K2CO3 , PhH, ∆

OTMS
Br Br
CHO 1. NaBH4 , THF / H2O MCPBA, NaHCO3

2. TMSCl, Et3N, THF o

CH2Cl2 , 0 C
H H

CO2Me CO2Me

OTMS OTMS
Br Br
1. (n-Bu)4NF, THF
+
2. NaOMe, MeOH
H O H O

CO2Me CO2Me

diastereoselection 1 : 9
the undesired minor isomer was removed
after the osmylation reaction

176
 9.15
O O
OsO4 , Py i-AmONa, THF;

HO MeI
H O H O
OH
CO2Me CO2Me

O 1. MeLi, THF O 1. MsCl, Et 3N

o o
-78 C THF, -15 C

HO AcO 2. (n-Bu)4NBr, THF

H O
2. Ac2O, Py H O
OMe o OMe
CO2Me
50 C
OH

O O
1. K2CO3 , MeOH
+
AcO AcO 2. separation by HPLC
H O H O
OMe OMe

1 : 3

O O
MeLi;
t
HO t HO2C(CH=CH)4CO2
H O HO2C(CH=CH)4COCl H O
OMe o OMe
THF, -78 C

(±)-Fumagillol (±)-Fumagillin

References:
E. J. Corey and B. B. Snider, J. Am. Chem. Soc. 1972, 94, 2549.

177
9.16
(±) - Ovalicin

O OH

O
H
OMe

The synthesis of ovalicin was accomplished following a line of analysis which was totally
different from that employed for the synthesis of the structural relative fumagillol. The plan for
ovalicin was based on S-goal, appendage, stereochemical and functional group derived strategies. A
key requirement for the synthesis was the stereospecific construction of the E-1,4-
pentadienyl subunit, which was achieved by a method of potentially wide utility.

OH OH OH
CO2H MeI, K2CO3 CO2H
Red-Al
OH

acetone, ∆ Et2O, ∆
HO MeO MeO

O O
O O
NaIO4 , THF / H2O KO2CN=NCO2K

o
MeO HOAc, DME, 45 C MeO

o
1. n-BuLi, DME, -78 C;
i-Pr i-Pr
1. I2 , CH2Cl2
H Br
N
N SO2 o
2. n-BuLi, TMEDA; (n-Bu)3Sn 2. t-BuLi, Et2O, -78 C
i-Pr (n-Bu)3SnCl

O OH
o o
A, PhCH3 , -78 C 1. NBS, MeOH, 0 C

2. TsOH, acetone / H2O

Li
OMe

diastereoselection 17 : 1

178
 9.16
O OH 1. NH2OH . HCl, O OH
HOAc-KOAc, pH 6 TiCl3 , NH4OAc

2. Et3N, MeOH OMe MeOH / H2O, pH 6

Br

O NOH

O O O OH
OMe
+
O O OMe OMe
OH OH
O
1 : 1 mixture

K2CO3 , MeOH

O OH
VO(acac)2 , t-BuOOH
O
H
PhCH3 / PhH OMe

References:
E. J. Corey and J. P. Dittami, J. Am. Chem. Soc. 1985, 107, 256.

179
9.17
Picrotoxinin Picrotin

OH HO OH

CO CO
O O
O O
O O
O O

Picrotoxin, a potent antagonist of γ-aminobutyric acid at neural synapses, has been synthesized
from (R)-(-) carvone as SM-goal (Sections 3.1 and 6.5).

180
 LDA, HMPA
o o
Me2NNH2 , TFA THF, -78 C ® 0 C;

PhCH3 , ∆ Br OMe

O N OMe
NMe2
(R)-(-)-Carvone o
-60 C ® 0 C
o

1. NaOAc, HOAc/THF/ H2O

2. aq. HCl, THF/DME Li
OMe
H
3. BzCl, Py o
THF, -78 C
MeO N 4. HPLC separation O
NMe2 OBz
H
o
diastereoselection 3 : 2 [α]23D -72 (c 5, CHCl3)

Br
1. (Cy-Hex)2BH, THF
OH o
NBS, THF O 0 C; H2O2 , NaHCO3
H H
SH
OBz
2. HS
OBz
H H BF3 . Et2O, CH2Cl2
o o
0 C ® 25 C
Br Br

O o O
1. K2CO3 , MeOH, 70 C O2 , t-BuOK, t-BuOH
H H
o THF, Me2S
S 2. PDC, DMF, 0 C
OBz S
O
H
S S

Br

O 1. HgO, BF3 . Et2O Br O

H THF / H2O H NaOCl
OC CO
S OBz H2O / THF
O 2. BzCl, Py, DMAP
S O

9.17

181
 CO2H
Br O Br O
H H
Pb(OAc)4 (i-Pr)2NEt
CO
OBz OBz
CH3CN o
CO2H O DME, 50 C
O
O

Br O Br O

CO CF3CO3H, Na2HPO4 Zn, NH4Cl,

CO
o O EtOH / H2O, ∆
O CHCl3 , 50 C O
O O
O O

OH OCOCF 3
1. Hg(OCOCF3)2
TFAA, DMAP PhH / THF
CO CO
O o O 2. KCl, H2O
O
Py, 45 C O
O O
O O

Picrotoxinin
o
[α]23D -6.3 (c 0.27, CHCl3)

ClHg

CF 3COO OCOCF 3 OCOCF 3 CF 3COO OCOCF 3

(n-Bu)3SnH
CO CO CO
O
+ O
O o
O
EtOH, 0 C O O
O O O
O O O
60% 35%

NaHCO3 NaHCO3
EtOH / H2O EtOH / H2O

HO OH
Picrotoxinin
CO
O
O
O
O
Picrotin

References:
1. E. J. Corey and H. L. Pearce, J. Am. Chem. Soc. 1979, 101, 5841.
2. E. J. Corey and H. L. Pearce, Tetrahedron Lett. 1980, 21, 1823.

182
9.18
9-Isocyanopupukeanane 2-Isocyanopupukeanane

9 NC
Me Me NC

Me 2 Me
H H

The co-occurring marine allomones 2- and 9-isocyanopupukeanane have been synthesized

from a common intermediate. This condition along with topologically based strategic disconnection
had a major impact on the retrosynthetic analysis.

1. Total synthesis of 9-isocyanopupukeanane (Ref. 1):

1. MgCl , CuSPh O
OMe o OMe
THF, -15 C TsCH2NC, t-BuOK

o o o o
MeO2C Me 2. PPA, 65 C ® 91 C Me DME, 0 C ® 25 C;
HOAc

NC 1. KOH, H2O2 MeO2C

OMe OMe o
H2O / EtOH LDA, THF, -78 C;

2. CH2N2 , Et2O o
Me Me MeI, HMPA, -78 C

CO2Me CO2Me
Me Me
OMe BBr3 , CH2Cl2 OH H2 , 200 atm, Rh-Pt

o o HClO4 , HOAc
Me
-78 C ® 0 C
Me

diastereoselection 6 : 1

O OTs
O
Me o Me
H 1. LAH, THF, 0 C O
t-BuOK, t-BuOH

o
Me 2. 1 eq. TsCl, Py, 0 C Me
3. PCC, CH2Cl2

183
 9.18
O NH2
Me o
Me 1. NH2OH . HCl, Py, EtOH HCOOAc, -10 C
Me Me
H H
2. H2 , Rh-Pt, HOAc

NHCHO NC
Me Me
MsCl, Py
Me Me
H H

2. Total synthesis of 2-isocyanopupukeanane (Ref. 2):

The total synthesis of 2-isocyanopupukeanane was accomplished starting from the same
lactone A which was used for the synthesis of 9-isocyanopupukeanane.

O
OH
Me O Me
H o OH NBS, aq. DME
LAH, THF, 0 C

Me Me

OH O

Me Me
O O
PCC, CH2Cl2 K2CO3 , MeOH

Me Me

SH
O 1. HS
Me OH o
BF3 . Et2O, 0 C Me OH PCC, CH2Cl2
Me Me
H H
2. Ra Ni, DME, ∆

184
9.18
O o
Me 1. NH2OH . HCl, Py, 100 C Me X HCOOAc
Me Me
H 2. H2 , 100 atm, Rh-Pt, HOAc H o
Py, -10 C

X = NH2
1 : 1 mixture

Me X MsCl, Py Me NC Me

H
Me
H
Me + H
Me

NC

X = NHCHO 2-Isocyano- epi-2-Isocyano-

pupukeanane pupukeanane

References:
1. E. J. Corey, M. Behforouz, and M. Ishiguro, J. Am. Chem. Soc. 1979, 101, 1608.
2. E. J. Corey and M. Ishiguro, Tetrahedron Lett. 1979, 2745.

185
 9.19
(E)  γ - Bisabolene (Z)  γ - Bisabolene

Me Me

The stereoselective synthesis of γ-bisabolenes was made possible by the development of a new
method for the carbosilylation and double alkylation of an acetylenic function coupled with ring
closure, overall addition of three carbon substituents to two acetylenic carbons.

1. Total synthesis of (E)- γ-bisabolene (Ref. 1):

O
O O CO2Me o
2 eq. LDA, THF; 1. KH, 18-C-6, THF, 0 C
OMe
BrH2C TMS o
2. (PhO)2POCl, -78 C
o
THF, 0 C TMS

P OPh
O
OPh
o
LiFeMe3 , Et2O 1. Dibal-H, CH2Cl2 , -78 C

CO2Me o o CO2Me o
-78 C ® -95 C 2. (n-Bu)4NF, THF, 0 C
TMS TMS

TBDMSCl, Et3N n-BuLi, THF;

OH DMAP, CH2Cl2 OTBDMS

B
3
A

186
9.19

TMSOTf n-BuLi; CuI;

OTBDMS OTBDMS
TMS
(EtO)3P, HMPA, MeI
-
B
+ 3 B
Li 2

OTBDMS
TMS o
1. (n-Bu)4NF, THF, 0 C 99.6% (E) by capillary VPC analysis

Me 2. TiCl4 , PhNHCH3 , CH2Cl2 Me

An alternative route to (E)-γ-bisabolene was demonstrated starting from the acetylene B, which
was made from 5-hexyn-2-one as shown:

OTBDMS
O
o
1. MgBr , Et2O, 0 C n-BuLi, THF;

2. TBDMSOTf, Et3N, CH2Cl2

B
3
B

OTBDMS OTBDMS

TMSOTf n-BuLi; CuI;

TMS
- (EtO)3P, HMPA, MeI
B
+ 3 B
Li
2

187
 9.19
OTBDMS

1. (n-Bu)4NF, THF
TMS
S
Me F Me
2. N+ -
TfO
Me
97.5% (E) by capillary VPC analysis
Et3N, CH2Cl2

2. . Total synthesis of (Z)- γ-bisabolene (Ref. 2):

The acetylenic alcohol A, which was used as a key intermediate in the synthesis of (E)-γ-
bisabolene, served as the starting point of this synthesis.

o
Br2 , Ph3P PhLi, THF, -78 C;

o
OH CH2Cl2 , 0 C Br B
2

A o
-78 C

o o
Br -78 C ® 23 C o
n-BuLi, -30 C; CuI;
-
B (EtO)3P, HMPA;
2 B Me
MeI; NaOH, H2O2
+
Li

79 : 21 mixture of
(Z)- and (E)-
Bisabolenes

References:
1. E. J. Corey and W. L. Seibel, Tetrahedron Lett. 1986, 27, 905.
2. E. J. Corey and W. L. Seibel, Tetrahedron Lett. 1986, 27, 909.

188
 CHAPTER TEN

Polycyclic Isoprenoids

10.1 Aphidicolin ...................................................................................................................188

10.2 Stemodinone and Stemodin ..........................................................................................191
10.3 K-76 .............................................................................................................................193
10.4 Tricyclohexaprenol ......................................................................................................195
10.5 Atractyligenin ..............................................................................................................198
10.6 Cafestol ........................................................................................................................204
10.7 Kahweol .......................................................................................................................204
10.8 Gibberellic Acid ............................................................................................................205
10.9 Antheridic Acid .............................................................................................................212
10.10 Retigeranic Acid ...........................................................................................................215
10.11 Diisocyanoadociane ......................................................................................................218
10.12 Ginkgolide B and Ginkgolide A ....................................................................................221
10.13 Bilobalide ......................................................................................................................227
10.14 Forskolin ......................................................................................................................230
10.15 Venustatriol ..................................................................................................................234
10.16 Pseudopterosin A ..........................................................................................................237
10.17 α-Amyrin ......................................................................................................................239
10.18 β-Amyrin ......................................................................................................................241
10.19 Pentacyclosqualene .......................................................................................................243
10.20 Dihydroconessine ..........................................................................................................246

187
10.1
(±) - Aphidicolin

HO
CH2OH

Me

H
A B
HO
Me H

HO

Aphidicolin, a potent antiviral and antimitotic agent, possesses an interesting arrangement of

fused, spiro and bridged rings. The synthesis shown below followed from the concurrent application of
topological, transform-based, stereochemical and FG-based strategies. Noteworthy steps include
stereospecific double annulation to from the A/B ring pair, introduction of the CH2OH group at a
highly hindered carbonyl carbon, and position-selective enolate generation.
1. TBDMSCl, Et3N
o
DMAP, CH2Cl2 , -20 C
o
1. SeO2 , EtOH, ∆ 2. K2CO3 , MeOH, 0 C
OAc OAc
2. NaBH4 3. MsCl, Et 3N
o
HO CH2Cl2 , -40 C
4. LiBr, THF

- - CO2Me
O O
O
OMe
NaH, (EtO)2POCl
Br
o o
THF, 0 C Et2O, 0 C
TBDMSO TBDMSO

CO2Me CO2Me
OEt 1. Hg(OCOCF3)2 Me OH
O O 1. HO
OEt o
P MeNO2 , 0 C TsOH, PhH, ∆
O
2. NaCl, H2O ClHg
Me H 2. NaBH4 , DMF, O2
3. PDC, CH2Cl2
TBDMSO TBDMSO

CO2Me CO2Me
Me O Me O

O 1. (n-Bu)4NF, THF O
t-BuCHO, TsOH

O HO CH2Cl2
Me H 2. L-Selectride
o
Me H
THF, -78 C
TBDMSO HO

188
 10.1
CO2Me CHO
Me O Me
1. LAH, Et2O O 1. MVK, DBU, K2CO3
O 2. PCC, CH2Cl2 THF / t-BuOH
O
.
O
Me H 3. HClO4 Me H
H2O/acetone 2. NH HOAc
t-Bu O t-Bu O
THF / MeOH

O S
S

1. TMSCN, ZnI2
Me Me
O o
O CHCl3 , 40 C
TMSS STMS

ZnI2 , CHCl3 2. Dibal-H,

O O o
Me H Me H PhCH3 , 0 C
t-Bu O t-Bu O

S S
S S

Me 1. LiSiMe 3 , HMPA,
CHO Me
o H
OTMS -35 C 1. NaBH4 , EtOH/THF
CHO

2. LDA, HMPA, THF; 2. TBDMSCl, DMAP,

O O
Me H H2O / HOAc Et3N, CHCl3
Me H
t-Bu O t-Bu O

S O
S O

Me IN NI Me
1. 1. (n-Bu)4NF,
OTBDMS OTBDMS THF
O

O acetone/ THF/ H2O O 2. TsCl, DMAP,

Me H 2. H2 , Pd/C Me H Et3N, CHCl3
t-Bu O t-Bu O

O O

Me Me O Li
o
OTs LiN(t-Bu)2 , -120 C H 1.
OEt

O O 2. HOAc, MeOH/ H2O

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

189
10.1
HOH 2C HO
OH CH 2OH
16

Me Me OMe
, PPTS
H
+ H

HO HO
Me H Me H
HO HO

C16-epi-(±)-Aphidicolin (±)-Aphidicolin
1 : 1 mixture, inseparable by chromatography.

O
O
O HO
O CH2OH

Me Me Me

H H 2N HCl, MeOH
+ H

O O HO
Me H Me H Me H
O O HO

removed by chromatography (±)-Aphidicolin

References:
E. J. Corey, M. A. Tius, and J. Das, J. Am. Chem. Soc. 1980, 102, 1742.

190
 10.2
(±) - Stemodinone (±) - Stemodin

HO HO
Me Me

Me Me
O H HO H

H H

The syntheses of stemodin and stemodinone, structural relatives of aphidicolin, were

accomplished using the A/B double annulation and B/C spiro annulation processes developed for the
assembly of aphidicolin.

CO2Me 1. Hg(OCOCF3)2 CO2Me

OEt o Me
O OEt MeNO2 , -20 C O 1. KI3 , aq. dioxane
P

O 2. NaCl, H2O 2. NaHSO3

ClHg
H

(Ref. 2)

CO2Me CO2Me
Me Me
O O OH
LiCl, DMF HO

I TsOH, PhH, ∆
H H

5 : 1 mixture

CO2Me CHO
Me O 1. LAH, Et2O Me 1. MVK, DBU, K2CO3
O
2. PCC, CH2Cl2 THF/ t-BuOH
O

H
3. HClO4 , acetone/ H2O
H 2. .
NH HOAc

THF / MeOH

O S
S

Me Me 1. TMSCN
O O
TMSS STMS ZnI2 , CHCl3

ZnI2 , CHCl3 2. Dibal-H

o
H H PhCH3 , -10 C

191
10.2

S S
S S

Me 1. LiSiMe 3 , HMPA
CHO Me
o H o
OTMS
Et2O, -35 C 1. NaBH4 , EtOH/THF, 0 C
CHO

2. LDA, HMPA, THF; 2. TsCl, Py, DMAP, CHCl3

H H2O / HOAc H

S O
O
S
IN NI
Me Me

OTs O OTs 1. t-BuOK, THF

o o
acetone/THF/ H2O, -20 C 2. Li, NH3 , -78 C
H H

O HO Me
Me OH

O
Me Me Me
1. Me2S CH2 , DMSO H H
+
2. LiEt3BH, THF
H H H

diastereoselection 5 : 1

HO HO
Me Me

Me Me
O o HO H
1. AcNHBr, H2O/acetone H Na, THF/EtOH, 0 C

2. PCC, CH2Cl2
3. Zn, aq. NH4Cl, Et2O H H

(±)-Stemodinone (±)-Stemodin

References:
1. E. J. Corey, M. A. Tius, and J. Das, J. Am. Chem. Soc. 1980, 102, 7612.
2. E. J. Corey, M. A. Tius, and J. Das, J. Am. Chem. Soc. 1980, 102, 1742

192
 10.3
The Complement Inhibitor K - 76.

HO CHO

CHO
Me
HO O Me

HO
H

Otsuka K-76, a fungal product with strong anticomplement activity, was synthesized from the
A/B bicyclic precursor of stemodin. The aromatic subunit was retrosynthetically disconnected to a
symmetrical precursor. A surprising non-selectivity of olefinic hydroxylation by osmium tetroxide was
noted.

CO2Me CO2Me CO2Me

Me Me Me
o OTf Me
O 1. NaH, Et2O, 0 C Me2CuLi, Et2O

2. Tf2O o o
-78 C ® -30 C
H H H

(Ref. 2)

OH Br

Me o Me
LAH, Et2O Me 1. MsCl, Et 3N, CH2Cl2 , -50 C Me

o o
2. LiBr, THF, -50 C ® 0 C
H H

MeO OMe
CO2Me
1. MOMCl, NaOH, MeOH n-BuLi, TMEDA, THF
o o
2. LAH, Et2O -20 C ® 0 C;

3. PCC, NaOAc, CH2Cl2 o o

HO OH o MOMO OMOM A, HMPA, -78 C ® 0 C
4. TsOH, MeOH, 0 C

OMe

MOMO HO CHO
OMe

Me 1. TsOH, MeOH
Me
OMOM 1. 1 N HCl, THF O 2. (n-Bu)4NOMe;
Me
Me
OH (n-Bu)4NI3 , CH2Cl2/MeOH
2. HO
3. MOMCl
H 6 N HCl, THF H

193
10.3
OMe OMe

MOMO MOMO
OMe OMe

I CONH2
Me o Me
O 1. CuCN, HMPA, 85 C O OsO4 , Py
Me Me
2. KOH, t-BuOH, ∆

H H

OMe OMe
MOMO MOMO
OMe OMe

CONH 2 CONH 2 1. 1 N HCl, THF

Me Me 2. TsOH, MeOH
HO O HO O
Me Me
2 + 2
3. TsOH, acetone
3 3
Me 2C(OMe)2
HO HO
H H

1 : 1 mixture of 2 β, 3β and 2α, 3α diols which

were used to carry out the following reactions.

OMe OMe
MOMO MOMO
NH O
1. Dibal-H
PhCH3 ,
o
Me N2O4 , NaOAc Me -78 C
O O O O
O Me O Me
o 2. 1 N HCl,
CCl4 , 0 C
O O THF
H H

plus the 2 β, 3β isomer The 2β, 3β isomer was separated

easily at this stage

MOMO CHO HO CHO

CHO CHO
Me 6 N HCl, THF Me
O O
HO Me HO Me

HO HO
H H

References:
1. E. J. Corey and J. Das, J. Am. Chem. Soc. 1982, 104, 5551.
2. E. J. Corey, M. A. Tius, and J. Das, J. Am. Chem. Soc. 1980, 102, 7612.

194
 10.4
(±) - Tricyclohexaprenol

OH

H H

O
X
OH OR
H
+ X

H
B
A

Tricyclohexaprenol, a possible forerunner of sterols in the evolution of biomembranes, was

synthesized by construction of the cyclic network in one step using cation-olefin tricyclization and
subsequent stereocontrolled attachment of the C10 appendage to ring C.

1. Synthesis of the fragment A:

Br
- -
O O

OMe CO2Me TBDMSCl

THF imid, DMF

(Ref. 2)

OTBDMS O O
1. Hg(OCOCF3)2
o
H CH3NO2 , 0 C CO2Me CO2Me
CO2Me + H H
2. NaCl, H2O ClHg ClHg
H H

195
10.4
O O
OH
1. HO O O
TsOH, PhH, ∆
CO2Me CO2Me
2. NaBH4 , NaOH + H
o
THF, 0 C H H

removed by SGC

O O
1. MsCl, Et 3N,
o
1. Dibal-H, PhCH3 , 0 C OH CH2Cl2

H H
2. (CO2H)2 , acetone/ H2O 2. DBU, PhH
H H

2. Synthesis of the fragment B:

OH TBDPSCl, imid, DMF OTBDPS

Geraniol

1. SeO2 , Py, EtOH, ∆ CCl4 , Ph3P, ∆

OTBDPS
HO
o
2. NaBH4 , EtOH, 0 C

TMS
o
OTBDPS
Et2O, -60 C OTBDPS
Cl
TMSCu

1. MeLi, Et 2O B
o
HMPA, 0 C
2. CuI, Me2S

Me3Si - SiMe 3

196
 10.4
3. Coupling of the fragments A and B and the completion of the synthesis:

O O

o OTBDPS
1. TiCl4 , CH2Cl2 , -78 C
H H
o
2. B, CH2Cl2 , 8 C
H H

1. MeLi, Et 2O,
o o OTBDPS
0 C ® 23 C (n-Bu)4NF, THF
H
2. SOCl2 , Py,
o H
CH2Cl2 , -20 C

OH

References:
1. E. J. Corey and R. M. Burk, Tetrahedron Lett. 1987, 28, 6413.
2. E. J. Corey, J. G. Reid, A. G. Myers, and R. W. Hahl, J. Am. Chem. Soc. 1987, 109, 918.

197
10.5
(±) - Atractyligenin

Me
HO

H OH

CO2H

Atractyligenin and its sulfated glucoside (actractyloside) are toxins which block the transport
of ADP into mitochondria and which occur in the coffee bean. Atractyligenin was synthesized
following a multistrategic retrosynthetic plan in which the disconnection of ring B was a major
objective. Novel stereocontrolled processes were employed for the critical cyclization to from the
tetracarbocyclic network and for introduction of the carboxylic substituent.

1. Li, t-AmOH
o Me
Me LAH, Et2O Me THF/NH3 , -45 C

CO2H 2. I2 , Ph3P, imid

OH I
Et2O/CH3CN
A

o Me o
LDA, THF, -78 C; 1. Dibal-H, CH2Cl2 , -78 C
CO2Me
A, HMPA (1 eq.) 2. (COCl)2 , DMSO
CO2Me o
CH2Cl2, -60 C; Et3N

1. LDA, N2CHCO2Et
Me o Me
THF, -78 C TsN3 , Et3N, EtOH
CHO COCH 2CO2Et
2. Rh2(OAc)4 , DME

t -Bu
N
O
Cu
O N
Me Me CO2Et
t -Bu LAH, Et2O
COCN2CO2Et
PhCH3 , ∆
O

198
 10.5
Me

Me Me
OH OTBDMS
TBDMSCl (1 eq.) t -Bu N t -Bu

H imid, DMF H o
OH OH Tf2O, n-PrNO2 , 0 C;
Et 3N
diastereoselection 15 : 1

1. hv, O2,
Me OTBDMS Rose bengal Me OTBDMS
MeOH / CH2Cl2 HO
CrO3 , Py

2. Al/Hg, THF/ H2O

OH

1. TFAA,
Me DMAP, Py, Me
OTBDMS OTBDMS
O CH2Cl2 O L-Selectride

2. Zn, THF/HOAc o
THF, -78 C
OH

1. COCl2
Me OTBDMS Et3N, Me
HO OTBDMS
PhSeCO2
THF (n-Bu)3SnH

2. PhSeH, Py AIBN, PhH, ∆

PhH

Me 1. (n-Bu)4NF, THF Me OH 1. H2 , Pd/C

OTBDMS
2. TrOOH, VO(acac) 2 EtOAc
O O O
2,6-lutidine 2. CBr4 , Ph3P
PhCH3 / PhH CH3CN
O O

199
10.5

Me Br Me 1. TBDMSOTf, CH2Cl2
o
Zn, THF / HOAc 2,6-lutidine, -78 C
O O O
H OH 2. K2CO3 , MeOH

O O

Me Me
HO O
PCC, CH2Cl2 SmI2 , THF / H2O

H OTBDMS H OTBDMS

CO2Me CO2Me

Me Me
HO HO
1. (n-Bu)4NF, THF

H OTBDMS 2. n-PrSLi, HMPA H OH

CO2Me CO2H

diastereoselection 13 : 1

References:
A. K. Singh, R. K. Bakshi, and E. J. Corey, J. Am. Chem. Soc. 1987, 109, 6187.

200
 10.6
(±) - Cafestol

Me OH
OH

The synthesis of cafestol, an antiinflammatory agent which occurs in coffee beans along with
related diterpenoids such as actractyloside and kahweol, was accomplished by the same strategic
approach which was applied to its companion atractyligenin.

O Me
aq. base LDA, THF
+ Cl
H o
O O
O O -78 C; MeI O O

Me Me
1. Li TMS KF.2H2O, DMSO

2. PPTS, MgSO4 , PhH, ∆ O O

TMS

o Me Me
Sia2BH, THF, 0 C; O 1. NaBH4 , MeOH

K2CO3 , H2O2 , H2O H 2. I2 , Ph3P, imid I

O O

Me 1. NaOH, THF/H2O/MeOH
o
LDA, THF, -60 C; 2. (imid)2CO, THF
CO2Me
o o o
CO2Me A, -60 C ® 0 C O 3. LiCH2CO2t-Bu, THF, -78 C

201
10.6
t -Bu
N
O
Me Me Cu
O N
TsN3 , DBU COCN 2CO2t -Bu t -Bu
COCH2CO2t -Bu
O O
CH2Cl2 PhCH3 , ∆

Me CO2t -Bu Me CO2t -Bu

o
1. NaBH4 , MeOH, 0 C Dibal-H
H
O 2. NaH, BnBr, DMF OBn o
O O CH2Cl2 , -10 C

Me Me
OH
Tf2O, 2,6-lutidine Li, EtOH (7 eq.)
H H
OBn o OBn o
O CH2Cl2 , -78 C O NH3 / THF, -78 C

Me Me
Na, H2O (5 eq.) 1. MsCl, Et 3N
H H
OH o 2. ZnI2 , CH2Cl2
NH3 / THF, -78 C OH
O O

Me I Me NHNH 2
NH2NH2 O2 , CH2Cl2

O DME / t-BuOH O

202
 10.6

NH
Me N Me
o
-N2 n-BuLi, THF, -40 C;

O O TIPSOTf

Me Me OH

1. OsO4 , THF OH

O 2. H2 , 5% Rh-Al2O3 , THF O
3. HF, THF / CH3CN
TIPS

References:
E. J. Corey, G. Wess, Y. B. Xiang, and A. K. Singh, J. Am. Chem. Soc. 1987, 109, 4717.

203
10.7
Kahweol

Me OH
OH

Kahweol, a “coffee” diterpenoid, was synthesized from the co-occurring natural product
cafestol.

Me
OMe Me O t-BuLi, THF
OH 1. o
Me O -50 C;
OH
POCl3 , CH2Cl2 O
TIPSOTf
O 2. TsOH

Cafestol
(Ref. 2)

Me O Me O
AcO
DDQ cat. H2SO4
O O

PhCH3 / HOAc PPTS, CH2Cl2

O O

TIPS TIPS

OH
Me 1. HO Me
O OH

O
HCl, THF OH

2. (n-Bu)4NF O
O
THF

TIPS

References:

204
 1. E. J. Corey and Y. B. Xiang, Tetrahedron Lett. 1987, 28, 5403.
2. E. J. Corey, G. Wess, Y. B. Xiang, and A. K. Singh, J. Am. Chem. Soc. 1987, 109, 4717.

10.8
Gibberellic Acid

CO
HO OH

Me CO2H

The plant growth regulator gibberellic acid was synthesized along the lines of the plan
discussed in Section 6.4 of Part One.

205
 1. NaIO4 , OsO4
o
THF/ H2O, 0 C
o o
1. 230 C 2. NaBH4 , EtOH, 0 C
OMe 2. NaH, MEMCl, THF OMe 3. NaH, BnBr, THF, ∆
o o
O 0 C ® 25 C OMEM 4. TFA, CH2Cl2

OH
O2 , DMF

BnO OMe BnO OMe

PhH, ∆
OH O O O
Co
N N

o
O o O 1. LAH, Et2O, -10 C
H 1. DHP, TsOH, CH2Cl2 , 0 C H 2. MsCl, Et 3N
o
2. NaBH4 , EtOH, 0 C o
THF, -58 C

OMe OMe
3. MOMCl, ( i-Pr)2NEt 3. NaHCO3 , H2O
O CH2Cl2 , ∆ OMOM
o
-58 C ® 0 C
o
HO THPO
BnO BnO

H H
CrO3 . 2Py
1. H2 , Rh / C, THF Celite, CH2Cl2
O OH o o
o
2. Li, NH3 , -78 C -45 C ® -25 C
OMOM
THPO t-BuOH / THF THPO
BnO HO

10.8

206
 1. DMSO, (Cl 3CCO)2O
H H o o
CH2Cl2 , -60 C ® -50 C;
o o
1. Ti (from TiCl 3 + K), THF Et3N, -50 C ® 23 C

O OH
2. MeOH; aq. K2CO3 2. MEMCl, ( i-Pr)2NEt
CHO OH CH2Cl2 , ∆
THPO THPO

H H
1. OsO4 , NMO
OHC - +
acetone / H2O CF3CO2 NH Bn 2 2
OHC
OMEM o OMEM o
2. Pb(OAc)4 , PhH, 5 C PhH, 50 C
O O
THPO THPO

OHC H H
1. Ph3P=CH2
o
HMPA / THF, ∆ n-BuLi, THF, -40 C;

OMEM o OMEM
2. HOAc, THF/ H2O, 35 C O o
, -40 C
THPO O HO
Cl Cl

Cl
H H
O
LICA, HMPA
o
THF, -78 C;

O OMEM o Cl OMEM
PhH, 160 C MeI,
O o o
-78 C ® 0 C
O O

1. COCl2 , DMAP,
ZnBr2 CH2Cl2

OMEM CHCl3/Et 2O/CH3NO2 OH NH2

Me H
Me 2. (S)-(-)-
O O Ph Me
O O
3. SGC separation

10.8

207
 O Me
H Cl3SiH 1. 1 N KOH, ∆
O N Ph Et3N, PhH OH
Me H Me 2. Na2RuO4
1 N NaOH
O O O O

synthetic sample:
o
[α]20D + 162 (c 0.58, CHCl3)
derivative from natural
Gibberellic Acid (GA3):
o
[α]20D + 161 (c 0.49, CHCl3)

1.TsCl, Et3N
o o
-78 C ® -50 C MCPBA, CH2Cl2

OH 2. MeOH OH o o
Me o o Me -20 C ® 25 C
CO2H CO2H -50 C ® 23 C CO2H CO2Me

I
O
1. 0.1 N NaOH, HO 1. TFAA, Py
o
O
EtOH CO THF, 0 C

HO OH 2. I2 , aq. NaHCO3 HO OH o
2. Zn, THF, 0 C
Me CO2Me THF / CH2Cl2 Me CO2Me
O

O O

CO 1. 10% NaHCO3 , H2O CO

CF 3CO2 OH 2. n-PrSNa HO OH
o
Me CO2Me HMPA, 0 C Me CO2H

Gibberellic Acid (GA 3)

10.8

208