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.
Stereocontrolled Synthesis of syn-β-Hydroxy-α-Amino Acids by Direct Aldolization of Pseudoephenamine Glycinamide†
Article first published online: 1 APR 2014
© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Volume 126, Issue 18, pages 4730–4735, April 25, 2014
How to Cite
Seiple, I. B., Mercer, J. A. M., Sussman, R. J., Zhang, Z. and Myers, A. G. (2014), Stereocontrolled Synthesis of syn-β-Hydroxy-α-Amino Acids by Direct Aldolization of Pseudoephenamine Glycinamide. Angew. Chem., 126: 4730–4735. doi: 10.1002/ange.201400928
- Issue published online: 25 APR 2014
- Article first published online: 1 APR 2014
- Manuscript Received: 27 JAN 2014
- National Institutes of Health. Grant Numbers: F32M099233, Howard Hughes Medical Institute International Student Research fellow
- Asymmetrische Synthesen;
- Chirale Auxiliare;
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.