Diastereoselective Synthesis of (–)-Bestatin, Epibestatin, Phebestin and (3S,4R)-4-Amino-3-hydroxy-5-phenylpentanoic Acid from an Aldehyde Derived from d-Phenylalanine

Abstract

Abstract A convenient and efficient method for the synthesis of (–)-bestatin, epibestatin, phebestin, and (3S,4R)-4-amino-3-hydroxy-5-phenylpentanoic acid is reported. The key step is a proline-catalyzed α-hydroxylation of an aldehyde derived from d-phenylalanine, which leads to incorporation of a hydroxyl group at the α-position of that aldehyde with good yield and very high diastereoselectivity. Bestatin and its dia­stereomer epibestatin are synthesized from the same starting material using the same sequence of reactions, except for proline as the catalyst. An O-MOM and Boc-protected amino acid, a common intermediate for bestatin, was coupled with a dipeptide, H-Val-Phe-OMe followed by global deprotection to yield phebestin. (3S,4R)-4-Amino-3-hydroxy-5-phenylpentanoic acid was also synthesized in eight steps from the same starting material. The reported synthetic route offers a general method for the synthesis of such types of compounds and their analogues by changing the proline catalyst and/or the starting material from d- to l-phenylalanine.

Keywords

• asymmetric hydroxylation
• organocatalysis
• reductive cleavage