Synthetic studies of (+)-discodermolide: Gram -scale synthesis, solution conformation, and analog design, synthesis, and evaluation

The dissertation contained herein describes synthetic studies of (+)-discodermolide (1), a deep-sea marine sponge metabolite possessing potent anticancer activity. First, a triply convergent total synthesis of (+)-discodermolide (1) has been achieved, exploiting a common precursor ( CP) to permit the rapid and efficient construction of three advanced subtargets (A, B, C). Importantly, this first preparative-scale synthesis of (+)-discodermolide is highly efficient, proceeding in 6% overall yield (longest linear sequence, 24 steps; 33 steps overall), stereocontrolled, and has produced 1.043 g of crystalline 1, available for further evaluation of the biological profile.* Secondly, studies were performed to elucidate the conformation of (+)-discodermolide in solution. A combination of 1 and 2-D NMR techniques and computational studies revealed that in McCN (+)-discodermolide exists in a helical conformation remarkably similar to the solid-state. Conformational analysis of the solution and solid-state conformational properties of (+)-discodermolide suggests that A1,3 and syn-pentane nonbonded interactions, in addition to intramolecular hydrogen bonding, play a major role in defining the overall conformation.* Having achieved a highly efficient, gram-scale synthesis in addition to defining the solution conformation of the natural product, we turned our attention to the design and synthesis of four distinct series of analogs. In our first-generation analogs, structural simplifications to the C(1–7) and C(14) regions were implemented and resulted in better or no significant loss of cytotoxicity. The second series of analogs consisted of fragment C congeners in which five stereocenters were removed from the C(1–7) region via the utilization of aromatic scaffolds as δ-lactone mimics. These congeners also displayed potent cell growth inhibitory activity. In the third series of analogs, photoaffinity and fluorescent congeners were designed and synthesized that hold the promise of labeling the respective tubulin and cellular sites of (+)-discodermolide binding. The final series of analogs included structural simplifications in the fragment A C(14–24) region, in addition to a C(19) carbamate functional group scan. Taken together, the analogs described herein further develop structure-activity relationships, contribute to the definition of the minimum structure element required for cytotoxicity, and hold the promise of characterizing the (+)-discodermolide-tubulin binding pocket.* *Please refer to dissertation for diagrams