Application of the asymmetric hydrogenation of enamines to the preparation of a beta-amino acid pharmacophore

(3R)-3-[N-(tert-Butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid 7a has been synthesized by an asymmetric hydrogenation of enamine ester 3 using chiral ferrocenyl ligands I and II in conjunction with [Rh(COD)Cl]2. The direct reduction of 3 provides amino ester 1b in 93% ee, which was isolated as an (S)-camphorsulfonic acid salt to upgrade the enantiomeric excess to >99%. A more concise approach was developed involving the in situ protection of 1b using di-tert-butyldicarbonate. This approach provided the desired N-Boc amino ester 7b directly from the hydrogenation with 97% ee, which was upgraded to >99% ee upon crystallization.

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Methyl (3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoate (1S)-(+)-10 camphorsulfonic acidC21H28F3NO6SEe = >99%[α]D = +15.7 (c 1.02, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R)

Methyl (3R)-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoateC16H20F3NO4Ee = >99%[α]D = +15.2 (c 1.0, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (3R)

(3R)-3-[N-(tert-Butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acidC15H18F3NO4Ee = >99%[α]D = +32.3 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R)