Replace Apratoxin A And Its Analogues Synthesized And Series S_n2. / Michael Addition / Intramolecular Substitution Reaction

In this thesis we describe following two parts of work:1. Total synthesis and structure-activity relationship studies of apratoxin A.Apratoxin A is a cyclodepsipeptide bearing both peptide and polyketide moieties, isolated from the marine cyanobacterium Lyngbya majuscula by Moore and his co-workers. Through in vitro studies on cytotoxicity against several human tumor cell lines, apratoxin A was found to have IC50 values ranging from 0.36 to 0.52 nM. By using D-proline catalyzed enantioselective direct aldol reaction of acetone and trimethylacetaldehyde and Oppolzer's methodology for preparing anti-diols as the key steps, we assembled its 3,7-dihydroxy-2,5,8,8-tetramethyl nonanoic acid (Dtena) part. Connection of this intermediate with other amino acid residues followed by elaboration of thiazoline ring with Kelly's methodology, and macrocyclization at the N-Me-IIe-Pro site afforded apratoxin A and its oxazoline analogue.Followed the similar procedure three oxazoline analogues of apratoxin A were synthesized. However, these analogues displayed poorer antitumor activity. These results gave a prelimitary SAR pattern for Apratoxin A.2. A Sequential Reaction Process to Assemble Polysubstituted piperidine Analogues.In the second part of this thesis, we developed a novel tandem reaction process to synthesize piperidine alkaloids by a sequential S_N2/Michael addition/ S_N2 reaction process. This novel transformation can rapidly evolve molecule complexity in a stereocontrolled fashion, and shows convenience and generality.