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Stereocontrolled Synthesis of syn-β-Hydroxy-α-Amino Acids by Direct Aldolization of Pseudoephenamine Glycinamide

Authors


  • We gratefully acknowledge the NSF for partial financial support. We express our gratitude to Dr. Shao-Liang Zheng for his exceptional work in conducting X-Ray crystallographic analyses. J.A.M.M. acknowledges Pfizer for financial support through the ACS SURF program. I.B.S. acknowledges postdoctoral fellowship support from the National Institutes of Health (F32M099233). Z.Z. is a Howard Hughes Medical Institute International Student Research fellow.

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.

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