The overall objective of the proposed research is to develop new, efficient, organic synthetic methods using transition metal reagents and to apply these new methods to the synthesis of biologically-active compounds. Four major classes of biologically active compounds will be synthetic targets: (1) beta-lactams, (2) natural and unnatural amino acids, (3) small (2-3 amino acid) peptides, (4) nitrogen heterocycles derived from aminoketene and enaminoketeneprecursors. A major specific aim of the overall research program is the development of efficient methods for the induction of high degrees of asymmetry in all of the photolytic readctions of chromium carbene complexes discussed below.
The specific aims of the proposed beta-lactam studies are: (1) to develop reactions between newly developed, appropriately functionalized, chromium carbene complexes and imines to produce beta-lactams having functionality at the position alpha-to the carbonyl found in biologically active beta-lactams. These include the newly (by us) synthesized carbenes (CO)5CrC(OMe)2, (CO)5Cr(C(OMe)NR2)) and (CO)5CrC(H)(NH2). (2) To use this methodology to synthesize optically active biologically active natural and synthetic beta-lactams by new routes which are both more efficient and more direct than those currently in use. (3) To use this mehodology to synthesize key families of relay compounds, and their substituted analogs for use (by others) in making new members of known classes of biologically active beta- lactams in an efficient direct manner.
The specific aims of the proposed amino acid and small peptide synthetic studies are: (1) to develop syntheses of aminocarbene complexes having R-groups difficult to incorporate into alpha-amino acids by conventional methods. (2) To develop high yield, high ee trapping processes to produce chiral, optically active natural and unnatural alpha-amino acids by the photolytic decomposition of aminocarbene complexes in the presence of nucleophiles. (3) To develop this photolytic proces using chiral optically active alpha-amino acids as the nucleophiles, producing unusual dipeptides. (4) To use this system to synthesize unnatural amino acids and small peptides of use as enzyme inhibitors. (5) To synthesize unusual dialkyl amino acids from beta-lactams produced above.
The specific aim for the proposed aminoketene and enaminoketene synthetic studies is to develop new efficient routes to heterocycles having potential biological activity.
