Stereocontrolled synthesis of syn-β-Hydroxy-α-amino acids by direct aldolization of pseudoephenamine glycinamide

Abstract

β-Hydroxy-α-amino acids figure prominently as chiral building blocks in chemical synthesis and serve as precursors to numerous important medicines. Reported herein is a method for the synthesis of β-hydroxy-α-amino acid derivatives by aldolization of pseudoephenamine glycinamide, which can be prepared from pseudoephenamine in a one-flask protocol. Enolization of (R,R)- or (S,S)-pseudoephenamine glycinamide with lithium hexamethyldisilazide in the presence of LiCl followed by addition of an aldehyde or ketone substrate affords aldol addition products that are stereochemically homologous with L- or D-threonine, respectively. These products, which are typically solids, can be obtained in stereoisomerically pure form in yields of 55-98 %, and are readily transformed into β-hydroxy-α-amino acids by mild hydrolysis or into 2-amino-1,3-diols by reduction with sodium borohydride. This new chemistry greatly facilitates the construction of novel antibiotics of several different classes.

Keywords: aldol reaction; amino acids; asymmetric synthesis; chiral auxiliaries; synthetic methods.

Scheme 1

Synthesis of pseudoephenamine glycinamide (1).

Scheme 2

Esterification and N-Boc protection of amino carboxylates.

Scheme 3

Cyclic carbamate formation followed by hydrolysis under neutral conditions affords protected α-amino acid derivatives. X₃₊ = (R,R)-pseudoephenamine. [a] Product contained ≤8% TBDPS-OH after aqueous extraction.

Scheme 4

Mild reductive cleavage of aldol adducts applied to the syntheses of chloramphenicol and thiamphenicol.