Highly stereoselective synthesis of spiro-alpha-methylene-gamma-butyro-lactones: the role of alpha-hydroxy substitution

Abstract

An alpha-alkoxy substituent provides acceleration and greater diastereoselectivity in organometallic additions to chiral ketones. We find that alpha-hydroxy substitution also plays a similar role. Whereas the addition of a Reformatsky reagent to unsubstituted steroidal ketones does not yield the desired products, alpha-hydroxy substitution provides the alpha-methylene-gamma-butyrolactone steroid in good yields and very high diastereoselectivity. The alpha-methylene-gamma-butyrolactone moiety has been synthesized at several positions on the steroid nucleus. The stereochemistry can be explained through a chelated transition state, while the enhancement in the rate may be due to both the electron-withdrawing nature of the Reformatsky reagent and the neighbouring group effect.