Synthesis of .alpha.-benzyl .gamma.-lactam, .alpha.-benzyl .delta.-lactam, and .alpha.-benzylproline derivatives as conformationally restricted analogs of phenylalaninamide

Abstract

The ready availability of N-(trifluoroacetyl)-α-allylphenylalaninamide (4) via a dehydration/hetero-Cope rearrangement/ammonolysis sequence starting with N-(trifluoroacetyl) phenylalanine allyl ester made it an attractive intermediate for elaboration into C-α to N- or C-α to N'-bridged products as conformationally restricted phenylalaninamide analogues. Oxidative one-carbon degradation of the side-chain olefin followed by acid-catalyzed silane reduction afforded C-α to N'-bridged γ-lactam. Hydroboration/oxidation of the side-chain olefin provided an intermediate that could be cyclized selectively either to a δ-lactam or a proline analogue depending on choice of dehydrating conditions. For preparation of a target dipeptide containing the α-substituted proline moiety, a preferred route involved N-deprotection of 4 and coupling to Boc-Asp(OBn)-OH to give a dipeptide intermediate, which similarly could be elaborated selectively to either the α-benzyl δ-lactam analogue or the α-benzylproline analogue