I. Total synthesis of (-)apicularen A and biological evaluation of side-chain analogs. II. Total synthesis of halipeptin D and oxazoline analogs

The total synthesis of apicularen A and halipeptin D is described in the following chapters. Apicularen A, a 10-member macrolactone, is part of a family of compounds containing a unique enamide side-chain and a benzolactone ring. An even more impressive quality of these compounds is the nanomolar potency against several different human cancer cell lines, including ovarian, prostate, lung, kidney, leukemia, cervix, and histocytic cell lines. The natural product contains within its framework a trisubstituted pyran ring embedded within the 10-member macrolactone ring and four stereogenic centers. Starting from 1,3 dihydroxybenzoic acid and after 20 steps the total synthesis of apicularen A was achieved. Some of the key reactions include a series of ozonolysis-allylation reactions, an axial substitution to make the 1,3 anti pyran ring, and a CuTC promoted coupling to form the crucial enamide bond. Analysis of several different side-chain analogs of apicularen A resulted in no compounds having a more potent profile than the natural product.; A second total synthesis of a marine natural product, halipeptin D, is also described. The synthetic challenges of this molecule include the construction of a trisubstituted amide bond and final approach to the macropeptide ring. Aside from these synthetic challenges, the ambiguity of several carbon centers posed additional complications requiring total synthesis as the only means to decipher its absolute configuration. Our synthesis was possible when an oxazoline tripeptide was synthesized by a Staudinger-Wittig reaction and subsequent oxazoline opening to a thioamide with H2S. The final approach to the natural product was met with several epimerizations occurring at two amino acid alpha-centers, nevertheless, culminated in the synthesis of the natural product. Originally, halipeptin D was assigned as a potential cytotoxic molecule but in our ensuing biological analysis no potency was discovered, prompting us to believe an error in the original analysis led to this false claim. In total and including halipeptin D, several different epimeric analogs as well as several oxazoline analogs were synthesized.