Acylnitrene route to vicinal amino alcohols. Application to the synthesis of (-)-bestatin and analogues

Bestatin, valinoctin A, and microginin are naturally occurring small peptid es containing a nonproteinogenic alpha-hydroxy-beta-amino acid at the N-ter minus of the peptide chain. We report here our development of a general met hod for the synthesis of alpha-hydroxy-beta-amino acids and exemplify this with a synthesis of (-)-bestatin and analogues. Our synthesis utilizes an i ntramolecular acylnitrene-mediated aziridination to generate a key bicyclic aziridine in excellent yield and stereoselectivity. This bicyclic aziridin e can be opened with a number of organometallic reagents to provide a serie s of substituted oxazolidinones. The oxazolidinones are readily converted t o bestatin and a series of bestatin analogues. As part of this approach, we have developed a new method for the synthesis of azidoformates. We have al so demonstrated that oxazolidinones can be selectively hydrolyzed in the pr esence of peptide bonds. This acylnitrene route to bestatin should prove us eful for the synthesis of a variety of analogues of bestatin as well as oth er alpha-hydroxy-beta-amino acids and their corresponding peptides.