Pure &App/. Chern.,Vol. 66,Nos lO/ll, pp. 2119-2122, 1994.
Printed in Great Britain.
@ 1994 IUPAC
Enantiocontrolled route to natural products
using chiral equivalents of cyclopentenone
and cyclohexenone
Kunio Ogasawara
Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980, Japan
Abstract: Efficient preparation of two tricyclic dienones, (1) and (2), in both
enantiomeric forms has been developed by employing lipase-mediated
resolution. A variety of natural products have been synthesized in
enantiocontrolled manners by utilizing the former as a chiral equivalent of 2cyclopentenone (as well as cyclopentadienone) and the latter as a chiral
equivalent of 2-cyclohexenone (as well as 2,5-cyclohexadienone).
Enantiocontrolled functionalization of cyclopentane and cyclohexane derivatives is one of the most
important subjects in the synthesis of optically active materials. In this regard the enantiotopical
preparation of two tricyclic dienones 1 and 2 was investigated with intent to use the former as a chiral
equivalent of cyclopentenone (as well as cyclopentadienone) and the latter as a chiral equivalent of
cyclohexenone (as well as 2,5-~yclohexadienone)in the chiral synthesis of natural products. Because
of their biased framework and thermal susceptibility, they allowed highly stereoselective
functionalization and generation of the olefin functionality which led to enantiocontrolled synthesis of
a variety of natural products.
SYNTHESIS OF OITICALLY PURE SUBSTRATES
(a) Synthesis of Optically Pure "Cyclopentenone" (1) -Treatment of the readily
accessible exo-alcohol (4) with vinyl acetate in the presence of lipase PS (pseudomonas, sp.) or
lipase MY (candida cylindraceae) in organic solvent yielded the optically active acetate (5) and the
optically active alcohol (4) both in ca. 80% ee. Fortunately, the alcohol (4) crystallized and the
optically pure 4 could be obtained after recrystallization. "Cyclopentenone"(1) was obtained from 4
in a satisfactory yield on oxidation. Moreover, the configuration of 1 could be inverted by a 1,3ketone transposition via the Wharton reaction.
21 19
2120
K. OGASAWARA
b
!OH
( +)-4
+
PCC
BubMe
SeO2
,'
( 4 - 3(X-H)
(f)-4 (X-OH)
w
0'
(-)-5 (R=Ac)
(-)-4 (R=H)
(-1-1
(b) Synthesis of Optically Pure "Cyclohexenone" (2) -Treatment of the readily
accessible meso-diol (7) with vinyl acetate in the presence of lipase PS in acetonitrile furnished the
optically pure (>99%ee) mono-acetate (8) in 79% yield. Oxidation of 8 gave the "4-substituted
cyclohexenone" (9), while on sequential pivaloylation deacetylation, and oxidation, 8 afforded 12
which may be taken as enantiomer of 9. The "cyclohexenone" (2) was obtained excellently in a
rather surprising way when 8 was refluxed with ammonium formate in the presence of palladium
dichloride (1.5 mol%) in acetonitrile. Similarly, the enantiomer was obtained excellently from the
pivalate (11) under the same conditions. Deuterium labeling experiment revealed that this interesting
reaction involved unprecedented suprafacial 1,4-hydrogen shift pathway.
2121
Chiral equivalents of cyclopentenone and cyclohexenone
c
- ACOH
___)
Q?D(H)
&
0
15
PdLn
&$
0
16
-Pd(O),
%
PdLn
0
J
2
SYNTHESIS OF NATURAL PRODUCTS
"Cyclopentenone" (1) and "cyclohexenone" (2) allowed highly stereospecific nucleophilic p and
electrophilic a functionalizations of the enone system from the exo-face and also allowed a'
functionalization under appropriate conditions. Moreover, Fischer indolization and Diels-Alder
reactions also proceeded exclusively from the exo-face. Retro-Diels-Alder cleavage occurred
generally at 200-250 "Cin diphenyl ether to generate the double bond by removal of cyclopentadiene.
BrmH
MeErD*J
\
\
-
a-cuparenone (18)
P-cuparenone (19)
aplysin (20)
1
7
l
glutamic acid (17)
HO
Y H Y
Me Me
physostigmine (21)
Me'.
physovenine (22)
aphanorphine (23)
estrone (26)
HO
equilenin (25)
goniomitine (24)
2122
K. OGASAWARA
T n B u 3 "
27
carvone (32)
q i M e 3
0
0
29
2 (R=H)
10 (R=OAc)
13 (R=OPiv)
H G O H
,-,
OH
OH
conduritol C (30)
H
eutipoxide B (31)
Natural products belonging to alkaloids, terpenes, and alkaloids, were prepared by standard a-and
p-functionalization procedures, by a-arylation under the Fischer indolization conditions and by DielsAlder functionalization,prior to retro-Diels-Alderreaction.
ACKNOWLEDGMENTS
I am greatly indebted to Professor Seiichi Takano, Director of the Department, for his kind
encouragement and to my dedicated students whose tireless efforts led to the present results. I also
wish to acknowledge the Ministry of Education, Culture, and Science, Japan for financial support.
REFERENCES
1. "Cyclopentenones": a) S. Takano, K. Inomata, and K. Ogasawara, J. Chem. SOC.,Chem.
Commun. 271 (1989). b) S. Takano, K. Inomata, M. Takahashi, and K. Ogasawara, Synlett 636
(1991). c ) S. Takano, K. Inomata, T. Sato, M. Takahashi, and K. Ogasawara, J. Chem. Soc.,
Chem. Commun. 290 (1990). d) S. Takano, K. Inomata, and K. Ogasawara, J . Chem. SOC.,
Chem. Commun. 1544 (1990). e) S. Takano, T. Sato, K. Inomata, and K. Ogasawara, J. Chem.
SOC.,Chem. Commun. 462 (1991). f ) S. Takano, M. Moriya, and K. Ogasawara, J. Org.
Chem. 56, 5982 (1991). g) S. Takano, M. Moriya, and K. Ogasawara, Tetrahedron Lett. 33,
329 (1992). h) S. Takano, M. Moriya, and K. Ogasawara, Tetrahedron Lett. 33, 1909 (1992).
2. "Cyclohexenones": a) S. Takano, M. Moriya, Y. Higashi, and K. Ogasawara, J. Chem. SOC.,
Chem. Commun. 177 (1993). b) S. Takano, Y. Higashi, T. Kamikubo, M. Moriya, and K.
Ogasawara, Synthesis, in press. c) S . Takano, M. Moriya, and K. Ogasawara, J. Chem. SOC.,
Chem. Commun. 614 (1993). d) S. Takano, M. Moriya, and K. Ogasawara, Synlett, in press.