Studies on the viability of cyclopropane-containing peptidomimetics and application of the vinylogous Mannich reaction to the syntheses of indolizidine natural products

1,2,3-Trisubstituted cyclopropanes have been previously incorporated into inhibitors of matrix metalloproteases, in order to mimic extended conformations of the peptide backbones and orient the amino acid side chains. Two reduced dipeptides, which are flexible analogues of these cyclopropane-containing peptidomimetics, were synthesized. Biological evaluation of the flexible compounds, the conformationally restricted peptidomimetics, and the parent inhibitor provided a deeper insight into the scope and limitation of cyclopropanecontaining replacements as mimics for peptide secondary structures. A concise enantiospecific synthesis of the angiotensin-converting enzyme inhibitor A58365A has been achieved. In the key step, a sequence involving a vinylogous Mannich reaction followed by a base-induced lactone–lactam rearrangement was applied to establish the indolizidine core of the molecule. A conceptually novel approach to the potent immunosuppressant FR901483 has been proposed. It has been demonstrated that an addition– vinylogous Mannich reaction sequence can be employed to obtain unsymmetrical α,α-disubstituted amines from carbamate-protected lactams. This sequence could be applied to the diastereoselective generation of one of the bridgehead centers in FR901483.