Synthesis of the optically active bicyclo[4.3.0]nonane derivative, regarded as the CD ring moiety of 12-oxygenated steroids

Article abstract of DOI:10.1016/S0040-4039(00)01413-1

The optically active bicyclo[4.3.0]nonane derivative, considered to be the CD ring moiety of 12-oxygenated steroids was synthesized in the present study, which involved stereo-controlled formation of bicyclo[2.2.2]octane derivative by sequential Michael reaction, formation of tricyclo[5.2.2.0^2,6]undecane derivative by intramolecular pinacol coupling reaction and the C-C bond cleavage by retro-aldol reaction. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01413-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8107–8110
Synthesis of the optically active bicyclo[4.3.0]nonane
derivative, regarded as the CD ring moiety of 12-oxygenated
steroids
Hidemichi Mitome, Hiroaki Miyaoka and Yasuji Yamada*
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji,
Tokyo 192-0392, Japan
Received 3 July 2000; revised 16 August 2000; accepted 18 August 2000
Abstract
The optically active bicyclo[4.3.0]nonane derivative, considered to be the CD ring moiety of 12-oxy-
genated steroids was synthesized in the present study, which involved stereo-controlled formation of
bicyclo[2.2.2]octane derivative by sequential Michael reaction, formation of tricyclo[5.2.2.02,6]undecane
derivative by intramolecular pinacol coupling reaction and the CꢀC bond cleavage by retro-aldol reaction.
© 2000 Elsevier Science Ltd. All rights reserved.
Keywords: steroids and sterols; bicyclic aliphatic compounds; Michael reactions.
Aragusterols A–H, isolated from an Okinawan marine sponge of the genus Xestospongia, are
structurally unique antitumor marine steroids, each possessing a 12b-hydroxyl group on the
steroidal nucleus and a side chain with a rare 26, 27-cyclo structure.1 Of these, aragusterols A
and C expressed potent antitumor activity toward L1210 leukemia in mice (T/C 220 and 257%
at 1.6 mg/kg)1a,b and it was demonstrated that the 12-oxygenated functionality plays an
important role in the antitumor activity. Aragusterols A–D were previously synthesized through
the enantioselective formation of a side chain segment and coupling of a steroidal nucleus
segment which was prepared from (+)-hecogenin with this side chain segment.2 For further
detailed pharmacological studies on aragusterols, we planned total synthesis of aragusterols
rather than using natural (+)-hecogenin as a starting material. Though a number of steroids
have been synthesized, no method for efficient synthesis of the 12-oxygenated steroidal nucleus
is reported. In the present study, as the first step of the total synthesis of aragusterols the
authors describe synthesis of bicyclo[4.3.0]nonane derivative regarded as the CD ring moiety of
aragusterols, which may be corresponded to the key component for the synthesis of the
12-oxygenated steroidal nucleus.
* Corresponding author. Tel: +81 426 76 3046; fax: +81 426 76 3069; e-mail: yamaday@ps.toyaku.ac.jp
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01413-1

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In our synthetic studies on natural products, bicyclo[2.2.2]octane derivatives as chiral building
blocks have been found to be quite useful for the stereoselective synthesis of substituted
cyclohexane derivatives3 and also applicable to the synthesis of the CD ring moiety of
12-oxygenated steroids. The synthetic strategy of the optically active bicyclo[4.3.0]nonane
derivative involved formation of bicyclo[2.2.2]octane derivative 4 by stereoselective sequential
Michael reaction, formation of tricyclo[5.2.2.02,6]undecane derivative 6 by intramolecular pina-
col coupling reaction, and subsequent cleavage of the C(6)ꢀC(12) bond4 in 9 by retro-aldol
reaction to afford the bicyclo[4.3.0]nonane derivative 10 as shown in Scheme 1.
i
Scheme 1. Reagents: A. TBDPSCl, imidazole, quant.; B. LDA then 3, 65%; C. NaBH4, 73%; D. MOMCl, Pr2NEt,
quant.; E. LiAlH4, 96%; F. cat. PPTS, MeOH, 96%; G. PCC, 62%; H. SmI2, THF–HMPA (10:1), 74%; I. Ph3P,
DEAD, 91%; J. Super-Hydride®, 99%; K. NaH, BnBr, 95%; L. B-bromocatecholborane, 79%; M. PCC, 89%; N. (1)
TMSCl, ZnCl2, Et3N, 110°C, (2) AcOH–THF–H2O (2:1:1), two steps, 72%
Optically active alcohol 15 ([h]D26 −94.2 (c 0.3, CHCl3), 99% ee), which was obtained by kinetic
resolution using lipase-catalyzed enantioselective esterification of ( )-1, was transformed into
cyclohexenone derivative 2 by protection of the hydroxyl group as TBDPS ether. A kinetic
enolate of 2 was treated with a,b-unsaturated ester 36 in THF at room temperature to afford
bicyclo[2.2.2]octane derivative 4, [h]D27 −17.8 (c 1.4, CHCl3) as the sole product in 65% yield.7
The stereochemistry of 4 was determined based on the correlations of H-15 with H-9 and with
H-19 in the NOESY spectrum.

8109
Ketoester 4 was converted to dialdehyde 5, [h]2D8 −41.8 (c 1.8, CHCl3), in the following five
steps: (1) NaBH4 reduction of 4 to afford an alcohol as the sole product,8 (2) protection of the
hydroxyl group as MOM ether, (3) LiAlH4 reduction of ester to give primary alcohol, (4)
deprotection of TBDMS ether by PPTS in MeOH and (5) PCC oxidation of two primary
hydroxyl groups thus obtained dialdehyde 5. The formation of cyclopentane corresponding to
the D ring of the 12-oxygenated steroidal nucleus was carried out by intramolecular pinacol
reaction9 of 5. Dialdehyde 5 was treated with SmI2 in the presence of HMPA at room
temperature to afford tricyclo[5.2.2.02,6]undecan derivative 6, [h]D27 −39.4 (c 2.1, CHCl3), as the
sole product in 74% yield.10 The absolute configurations of the newly formed stereocenters in 6
were assigned as 16S,17S based on the correlation of H-17 with H-19 in the NOESY spectrum
1
1
and the H–1H coupling constant (J=0 Hz) between H-16 and H-17 in the H NMR spectrum.
Diol 6 was treated with Ph3P and DEAD to give epoxide 7 in 91% yield.11 The stereochem-
istry of this epoxide was determined as 16R,17S based on the correlation of H-17 with H-19 in
the NOESY spectrum. Treatment of 7 with Super-Hydride® provided the corresponding alcohol
as the sole product in 99% yield.12 Regioselectivity in this epoxide-opening reaction may be
explained as an attack of hydride ion on the less hindered carbon of the epoxide. The hydroxyl
group thus obtained was protected as benzyl ether to give 8 in 95% yield. Deprotection of the
MOM ethers13 of 8 followed by PCC oxidation of the secondary hydroxyl group afforded
b-hydroxyketone 9, [h]2D7 −33.4 (c 1.2, CHCl3).
Regioselective CꢀC bond cleavage through retro-aldol reaction was performed by treating 9
with ZnCl2, Et3N and TMSCl14 to provide TMS enol-ether of bicyclo[4.3.0]nonane derivative 10.
Subsequent hydrolysis gave the desired compound 10, [h]2D7 −23.3 (c 1.3, CHCl3) in two steps
(72% yield). When 9 was subjected to retro-aldol reaction with NaH in the presence of
15-crown-5-ether as catalyst,15 the reaction proceeded smoothly to give the aimed for product in
84% yield. The product, however, was an inseparable mixture of epimers at H-8 (b:a=2:1).
Bicyclo[4.3.0]nonane derivative 10 is equivalent to the CD ring moiety of 12-oxygenated
steroids and has the necessary functional groups for the construction of A and B rings and the
side-chain. The total synthesis of aragusterols using this compound as an intermediate is
presently being studied.
Acknowledgements
This work was supported in part by Grant-in-Aids for Scientific Research (Grant No.
11771398) from the Ministry of Education, Science, Sports and Culture of Japan.
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8110
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