Synthesis of a Long Acting HIV Protease Inhibitor via Metal or Enzymatic Reduction of the Appropriate Chloro Ketone and Selective Zinc Enolate Condensation with an Amino Epoxide

Abstract

This paper describes a new convergent approach to the synthesis of an HIV protease inhibitor which was designed to be suitable in long acting formulations. Unique features in the synthesis include an asymmetric hydrogenation as well as enzymatic reduction of a key chloro ketone intermediate, to set the threo stereochemistry in the corresponding epoxide and the diastereoselective coupling of the latter with the zinc enolate of a suitable functionalized amide derivative.

Hydrogen

“…49 (19) to the methyl ketone was the predominant reaction, but use of rhodium catalysts provided the desired product in good yield and selectivity (eq 21). 50 In a relatively recent development, tethered ruthenium catalysts (such as those in eq 22) have proven highly effective for the asymmetric reduction of ketones and for selective reduction of aldehydes. 51 Iron catalyzed hydrogenation of ketones is currently under development in an effort to move away from the platinum group metals (due to their cost, low abundance, and toxicity).…”

Rh(iii)-Catalyzed diastereoselective transfer hydrogenation: an efficient entry to key intermediates of HIV protease inhibitors

“…The combination of enzyme catalysis and asymmetric hydrogenation was also disclosed in 2003, albeit with low efficiency. 11 Scheme 1 Previous work and this work.…”