Enantioselective total synthesis of peloruside A and spongidepsin

Xiaoming Xu, Purdue University

Abstract

Peloruside A is a potent microtubule stabilizer with nanomolar IC50 value. Recent studies show that it binds to the non-taxoid site and shows synergistic effect with Taxol. We have accomplished an enantioselective synthesis of peloruside A. The synthesis is convergent and involves the assembly of C1-C10 segment and C11-C24 segment by a novel aldol protocol developed by us. The sequence involved reduction of the enone to provide an enolate which upon reaction with the aldehyde provided the hindered aldol product with high yield (92%) and good selectivity (4:1). The resulting aldolate was converted to a seco-acid and subsequent Yamaguchi macrolactonization provided the corresponding macrolactone. Selective methylation of hemi-ketal followed by removal of the protecting groups led to the synthesis of peloruside A. This thesis work also involved the synthesis of spongidepsin and assignment of absolute configuration of this natural product. Spongidepsin, a 13-membered depsipeptide isolated from the Vanuatu marine sponge Spongia sp., has shown potent antitumor properties against a variety of NCI tumor cell lines. Our synthesis is convergent, and the absolute stereochemistry of four of the five chiral centers was assigned through synthesis. The synthesis features enzymatic desymmetrization of a meso-diol in excellent enantiomeric purity. We have carried out a diastereoselective alkylation and a halolactonization reaction to set the C7 and C9 stereochemistry. An efficient cross-metathesis of functionalized substrates constructed the 13-membered ring. Several analogs were also synthesized.

Degree

Ph.D.

Advisors

Ghosh, Purdue University.

Subject Area

Organic chemistry

COinS