A simple route to α-substituted-β-amino ester precursors of carbapenem antibiotics

Article abstract of DOI:10.1021/jo00125a043

A three-step process is presented for the preparation of α-substituted-β-amino esters which can serve as precursors to a key intermediate in carbapenem synthesis. The pivotal reaction in this sequence involves a highly diastereoselective conjugate addition reaction. Two series of alkenoates bearing a stereogenic substituent attached to C2 were prepared and their conjugate addition reactions with benzylamine studied under several different sets of conditions. Conjugate addition of benzylamine to alkenoates 7a and 7d, in methanol at room temperature, gave adducts 8a and 8d with virtually complete anti-diastereoselectivity. These two β-amino esters bear the correct relative stereochemistry and side chain to serve as precursors for carbapenem antibiotic synthetic intermediates. The role of the allylic substituents of the alkenoates 7a-e in determining the stereochemical outcome of these additions is discussed. These conjugate additions were explored further by the preparation and conjugate addition reactions of the α,β-disubstituted alkenoates 15a and 15b. It was found that the presence of a β-substituent led to a dramatic reduction in yield although the same anti-diastereoselectivity was maintained. The relative stereochemistry of the adducts was established by examination of the relevant coupling constants in the ¹H NMR spectra of their tetrahydro-1,3-oxazine derivatives.