Reduction of an Enaminone:  Synthesis of the Diamino Alcohol Core of Ritonavir

Abstract

The reduction of (5 S )-2-amino-5-dibenzylamino-4-oxo-1,6-diphenylhex-2-ene was optimized for diastereoselectivity and overall conversion to (2 S,3 S,5 S )-5-amino-2-dibenzylamino-3-hydroxy-1,6-diphenylhexane ( 2a ). A two-step reduction sequence is described wherein the enamine is reduced with a borane-sulfonate derivative followed by reduction of the resulting ketone with sodium borohydride. The desired 2a was obtained with 84% diastereoselectivity and an acyclic 1,4 stereoinduction ratio of 14:1. This methodology has been used to produce multikilogram quantities of the diamino alcohol core of Ritonavir and should be general to the synthesis of related diamino hydroxyethylene isosteres.