J. Am. Chem. Soc. 2000, 122, 4813-4814
4813
Communications to the Editor
Scheme 1
Cyclozirconation of a Computationally-Designed
Diene: Synthesis of (-)-Androst-4-ene-3,16-dione
Douglass F. Taber,* Wei Zhang, Carlton L. Campbell,
Arnold L. Rheingold,† and Christopher D. Incarvito†
Department of Chemistry and Biochemistry,
UniVersity of Delaware, Newark, Delaware 19716
ReceiVed July 15, 1999
We report a new approach to the stereoselective construction
of polycyclic systems, illustrated by the cyclozirconation/carbo-
nylation1 of a computationally-designed diene 1 to give the
tetracyclic ketone 2. Ketone 2 was converted over several steps
to (-)-androst-4-ene-3,16-dione (3).2
Scheme 2
We3 and others4 have reported that intramolecular diene
cyclozirconation can be carried out under conditions of either
kinetic or thermodynamic control. We have also shown3b,c that
semiempirical calculations (ZINDO)5 can be used to predict the
relative stabilities of diastereomeric zirconacycles. We describe
here a computational approach to the design of a diene such that
cyclozirconation is directed toward a desired diastereomer.
Our initial objective was the construction of the steroid skeleton
(e.g., 3) with control of both relative and absolute configuration.
We first considered a B f BCD construction, starting with diene
4. Unfortunately (Scheme 1), computational analysis (ZINDO)5
predicted that the undesired cis-fused zirconacycle 6 would be
more stable than the desired trans-fused zirconacycle 5. The
prospects did not improve with the acetonide 7. Again (Scheme
1), computational analysis (ZINDO) predicted that the cis-fused
9 would be more stable than the desired trans-fused 8.
* Corresponding author: Telephone: 302-831-2433. Fax: 302-831-6335.
E-mail: taberdf@udel.edu.
† X-ray crystallography.
(1) (a) For an overview of carbonylative diene and enyne cyclometalation,
see: Hegedus, L. S. Transition Metals in the Synthesis of Complex Organic
Molecules, 2nd ed; University Science Books: Sausalito, 1999. For other recent
references to carbonylative cyclometalation, see: (b) Zhao, Z.; Ding, Y.; Zhao,
G. J. Org. Chem. 1998, 63, 9285. (c) Negishi, E.-I.; Montchamp, J.-L.;
Anastasia, L.; Elizarov, A.; Choueiry, D. Tetrahedron Lett. 1998, 39, 2503.
(d) Shiu, Y.-T.; Madhushaw, R. J.; Li, W.-T.; Lin, Y.-C.; Lee, G.-H.; Peng,
S.-M.; Liao, F.-L.; Wang, S.-L.; Liu, R.-S. J. Am. Chem. Soc. 1999, 121,
4066. (e) Murakami, M.; Itami, K.; Ito, Y. J. Am. Chem. Soc. 1999, 121,
4130. (f) Hicks, F. A.; Kablaoui, N. M.; Buchwald, S. A. J. Am. Chem. Soc.
1999, 121, 5881.
It was clear that the protecting group on the diol had to
introduce steric bulk underneath the ring system of the tricyclic
zirconacycle, to destabilize the cis diastereomer. After considering
several other alternatives, we settled on the menthonide 1. This
introduced steric interactions such the desired trans-fused 10 was
predicted to be more stable than the cis-fused 11. For each of
these three dienes (1, 4, and 7), the other two diastereomeric
zirconacycles were predicted to be significantly less stable (from
1, the other trans-fused diastereomer (12) was calculated at 9.6
kcal/mol, and the other cis-fused diastereomer (13) was calculated
at 9.9 kcal/mol, compared to 10).
(2) For recent examples of steroid total synthesis, see: (a) Kurosu, M.;
Marcin, L. R.; Grinsteiner, T. J.; Kishi, Y. J. Am. Chem. Soc. 1998, 120,
6627. (b) Grieco, P. A.; May, S. A.; Kaufman, M. D. Tetrahedron Lett. 1998,
39, 7074. (c) Zoretic, P. A.; Fang, H.; Ribeiro, A. J. Org. Chem. 1998, 63,
7213. (d) Heinemann C.; Demuth, M. J. Am. Chem. Soc. 1999, 121, 4894
and references therein.
(3) For references to our previous work on intramolecular diene cyclo-
zirconation, see: (a) Nugent, W. A.; Taber, D. F. J. Am. Chem. Soc. 1989,
111, 6435. (b) Taber, D. F.; Louey, J. P.; Wang, Y.; Nugent, W. A.; Dixon,
D. A.; Harlow, R. L. J. Am. Chem. Soc. 1994, 116, 9457. (c) Taber, D. F.;
Wang, Y. Tetrahedron Lett. 1995, 36, 6639.
(4) For leading references to work by others on intramolecular diene
cyclozirconation, see: (a) Rousset, C. J.; Swanson, D. R.; Lamaty, F.; Negishi,
E.-i. Tetrahedron Lett. 1989, 30, 5105. (b) Knight, K. S.; Wang, D.;
Waymouth, R. M.; Ziller, J. J. Am. Chem. Soc. 1994, 116, 1845. (c) Kim, S.;
Kim, K. H. Tetrahedron Lett. 1995, 36, 3725. (d) Bird, A. J.; Taylor, R. J.
K.; Wei, X. D. Synlett 1995, 1237. (e) Mirza-Aghayan, M.; Boukherroub, R.;
Etemad-Moghadam, G.; Manuel, G.; Koenig, M. Tetrahedron Lett. 1996, 37,
3109. (f) Luker, T.; Whitby, R. J. Tetrahedron Lett. 1996, 37, 7661. (g)
Nishihara, Y.; Aoyagi, K.; Hara, R.; Suzuki, N.; Takahashi, T. Inorg. Chim.
Acta 1996, 252, 91. (h) Yamaura, Y.; Hyakutake, M.; Mori, M. J. Am. Chem.
Soc. 1997, 119, 7615. (i) Martin, S.; Brintzinger, H. H. Inorg. Chim. Acta
1998, 280, 189. (j) Grepioni, F.; Grilli, S.; Martelli, G.; Savoia, D. J. Org.
Chem. 1999, 64, 3679.
The cis allylic alcohol 146 (Scheme 2) was prepared by
coupling (Z)-4-chloro-2-buten-1-ol7 with methallyl magnesium
chloride. Epoxidation with D-(-)-diethyl tartrate8 gave the enan-
tiomerically enriched epoxide 15. Grignard opening followed by
(6) Lozanova, A. V.; Surkova, A. A.; Moiseenkov, A. M. IzV. Akad. Nauk,
Ser. Khim. 1992, 2751.
(7) Cologne, J.; Poilane, G. Bull. Soc. Chem. Fr. 1955, 953.
(8) (a) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765. (b) Jung, M. E.; Fahr,
B. T.; D’Amico, D. C. J. Org. Chem. 1998, 63, 2982.
(5) Both ZINDO and molecular mechanics were used as implemented on
the Tektronix CAChe workstation (ref 3b).
10.1021/ja992491x CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/03/2000