Chapter 9 First total synthesis of (+)-Amphidinolide T1

Abstract

Publisher Summary Amphidinolides are a series of unique cytotoxic macrolides, many of which have shown significant antitumor properties against a variety of NCI tumor cell lines. Amphidinolides A through W exhibit remarkable structural diversity, the range is from 12-membered to 29-membered ring systems. More than half of the amphidinolides possess an odd-numbered macrocyclic lactone ring, different from the general macrolide natural products that possess even-numbered rings. The absolute configurations of some amphidinolides have been determined by X-ray analysis and interconversion. This synthesis represents a well-convergent and stereocontrolled route to the first total synthesis of natural product amphidinolide T1. A number of synthetic technologies have been developed during the course of this endeavor. The functional group compatibility of the oxocarbenium ion-mediated alkylation reaction, efficient cross metathesis, diastereoselective aldol reactions, and the use of a cyclic bromoether as a novel protection of the exo-methylene group are noteworthy features. The first total synthesis of amphidinolide T1 was accomplished in 16 (longest linear sequence) steps and 5.6% overall yield, starting with a syn-aldol reaction developed in the laboratory. This chapter gives the chronology of events that led to its first total synthesis.