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Monday, August 8, 2005
Douglass Taber
University of Delaware

Enantioselective Transformations of Prochiral Rings

Enantiomericallly-pure carbacyclic rings are important components both of physiologically-active natural products and of important pharmaceuticals. Often it is most effective to control the absolute configuration of the ring as it is formed. Recent developments in the enantioselective construction of carbacyclic rings will be covered next week and the week after. The focus this week is on the asymmetric transformation of preformed prochiral rings.

The power of such an approach is illustrated by the synthesis of (-)-pumiliotoxin C (3) recently reported (Tetrahedron 2004, 60, 9687. ) by Adriaan J. Minnaard and Ben L. Feringa of the University of Groningen in the Netherlands. Enantioselective conjugate addition of Me2Zn to the inexpensive cyclohexenone (1) gave the intermediate enolate, Pd-mediated coupling of which with allyl acetate gave the ketone 2 in 96% ee. Conversion of the ketone to the cis tosylamide followed by Pd-mediated cyclizative coupling with 1-bromo-1-propene and hydrogenation then gave 3. The intermediate tosylamide was recrystallized to >99% ee.

Stephen L. Buchwald at MIT has reported (Org. Lett. 2004, 6, 4809. ) a complementary approach. Enantioselective conjugate reduction of the inexpensive 3-methylcyclopentenone (4) led to the silyl enol ether 5, Pd-mediated coupling of which with the aryl halide gave the product 6. 3-Methylcyclohexenone gave the analogous product in 84% ee.

These approaches led to ternary stereogenic centers. Brian Stoltz has found (J. Am. Chem. Soc. 2004, 126, 15044. ) that the Pd-mediated conversion of 7 to 8 can be induced to proceed in high enantiomeric excess. This appears to be a general method for the preparation of quaternary stereogenic centers. Wacker oxidation followed by aldol condensation converted 8 into the bicyclic enone 9.

We have put forward (J. Am. Chem. Soc. 2004, 126, 13900. ) an alternative approach to the enantioselective construction of cyclic quaternary centers. Addition of phenylacetylene to cyclopentanone followed by dehydration and Shi epoxidation gave the epoxide 10. Opening of the epoxide with allylmagnesium chloride proceeded with inversion, to give 11. The alcohol 11 can also be carried on to bicyclic products, exemplified by the sulfone 12.

The power of asymmetric transformation of a preformed ring is further illustrated by the synthesis of (+)-allocyathin B2 (15) reported (Org. Lett. 2004, 6, 4897. ) by Masahisa Nakada of Waseda University, Tokyo. This bird nest fungi diterpene was assembled by convergent coupling of enantiomerically-pure 13 with enantiomerically-pure 14. The cyclohexane 14 was derived from the prochiral cyclohexane-1,3-dione 16. The cyclic quaternary stereogenic center was established by yeast reduction of 16 followed by diastereoselective reduction of the resulting hydroxy ketone, to give the diol 17. The two alcohols of 17 were differentiated by selective acetonide formation, giving 18. The chiral cyclopentane 13 was prepared by enantioselective intramolecular cyclopropanation.

D. F. Taber, Org. Chem. Highlights 2005, August 8.