Highly stereoselective synthesis of spiro-α-methylene-γ-butyrolactones: the role of α-hydroxy substitution

Abstract

An α-alkoxy substituent provides acceleration and greater diastereoselectivity in organometallic additions to chiral ketones. We find that α-hydroxy substitution also plays a similar role. Whereas the addition of a Reformatsky reagent to unsubstituted steroidal ketones does not yield the desired products, α-hydroxy substitution provides the α-methylene-γ-butyrolactone steroid in good yields and very high diastereoselectivity. The α-methylene-γ-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.