Total synthesis of microtubule stabilizing agent laulimalide and total syntheses of proposed structure of cytotoxic macrolide iriomoteolide-1a and -1b

Hao Yuan, Purdue University

Abstract

Laulimalide is a potent microtubule stabilizing agent similar to paclitaxel with nanomolar IC50 values against various cancer cell lines. Laulimalide also retains activity against multidrug-resistant cell lines including paclitaxel resistant cells. Recent studies reveal that laulimalide binds at a binding site distinct from the taxoid site actually showing a synergistic effect with paclitaxel. We have completed a convergent enantioselective synthesis of laulimalide. This concise synthesis is achieved by a Still-Gennari modified Horner–Wadsworth–Emmons reaction to form the C2-C3 Z-enoate followed by macrocyclization using an asymmetric Sakurai reaction at C14-C15 position. An efficient cross metathesis was applied to form the C16-C17 trans-olefin. A modified retro-Michael reaction was used to remove the chiral auxiliary and a “matched” Sharpless asymmetric epoxidation furnished the final product without affecting the C20 olefin. This thesis also involves the synthesis of the proposed structure of iriomoteolide-1a and -1b. Iriomoteolide-1a is a 20-membered macrolide newly isolated from a benthic HYA024 strain of dinoflagellate Amphidinium sp. It shows potent cytotoxicities against a variety of cancer cell lines with IC50 values in the nanomolar range. The unique structural features and potent cytotoxicities of iriomoteolide-1a attracted considerable attention from the synthetic chemists. A number of synthetic stratagies are reviewed in this chapter. Our synthetic study of the proposed structure of iriomoteolide-1a is discussed in detail. The completion of the synthesis is achieved by Julia-Kocienski olefination followed by Yamaguchi macrolactonization as the key steps. The synthesis of the C1-C15 fragment features a Sakurai followed by a Julia-Kocienski olefination. A more efficient and economic ene reaction was used to replace the Sakurai reaction later as the key step. The trisubstituted Z-enoate of fragment C1-C6 is introduced by a carbocupration of the corresponding acetylene ester utilizing freshly prepared Gilman reagent. The separate syn- and anti- geometry on C16-C23 fragment are introduced by successive Brown asymmetric crotylboration reactions. Efforts towards the elucidation of the correct structure of iriomoteolide-1a including the syntheses of different diastereomers are also described.

Degree

Ph.D.

Advisors

Ghosh, Purdue University.

Subject Area

Toxicology|Surgery|Biochemistry|Organic chemistry

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