Asymmetric propionate aldol reactions of a chiral lithium enolate accessible from direct enolization with n-butyllithium

Abstract

The presented lithium enolate-based methodology is suitable for access to propionate syn-aldol motifs with high levels of stereocontrol. The reactive lithium enolate species is generated by direct treatment of a camphor-based chiral ethyl ketone with butyllithium, and is subsequently submitted to aldolization with a broad variety of aldehydes. The product aldols are obtained in uniformly high yields and high d.r. values (ranging from 91:9 to >98:2) irrespective of the aliphatic (both linear and branched chain), α,β-unsaturated, aromatic, or hetero-aromatic nature of the aldehyde employed. The crystallinity of most of the obtained adducts offers an easy access to almost 100% isomerically pure products upon a single recrystallisation. The auxiliary (1R)- (+)-camphor can be removed easily from the adducts for reuse, thereby producing the corresponding syn propionate aldols. This technology is implemented in the synthesis of a key subunit of the multi-drug resistance reversing agent hapalosin.