Total synthesis of brevisamide and herboxidiene

Jianfeng Li, Purdue University

Abstract

Brevisamide is a recently discovered natural product. It is believed to play an important role in the biosynthesis of marine polyether toxins, such as brevenal. We have accomplished an asymmetric total synthesis of brevisamide. The synthesis is convergent and involves the efficient sp2-sp 3 type coupling of fragments via Suzuki reaction. The stereogenic tetrahydropyran ring was synthesized via a highly stereoselective hetero Diels-Alder reaction using Jacobsen’s chiral Cr catalyst. The synthesis also involved a stereoselective Rubottom oxidation to install the hydroxyl group on the tetrahydropyran ring and a modified Wolff-Kishner reaction to remove a carbonyl group under very mild conditions. A regioselective oxidation was utilized in the synthesis to oxidize a primary hydroxyl group without affecting the secondary one. Sonogashira reaction and Negishi carboalumination reaction were utilized to synthesize the diene moiety in the molecule. This thesis work also involved the total synthesis of herboxidiene, which possesses a broad range of biological activities. Those biological activities include herbicidal activity, LDL receptor activating ability and antitumor activity. The synthesis utilized lipase resolution to establish the intial chirality in the synthesis. An Achmatowicz reaction was used to construct the pyran skeleton. An efficient-radical induced cyclopropyl ring opening reaction was used to install the methyl group on the tetrahydropyran ring. A stereochemically mismatched Brown asymmetric crotylboration was investigated. The results showed that stereochemical induction by (+)-Ipc chiral auxiliary in the reagent overruled the induction by the chiral substrate. Such results favored our synthesis. A highly stereoselective allylic chlorination was conducted to construct the tri-substituted olefin moiety. Olefin cross metathesis was utilized to synthesize the requisite boronate for the Suzuki cross coupling. An sp2-sp2 type Suzuki cross coupling was conducted to complete the carbon skeleton in herboxidiene. A highly stereoselective epoxidation of a bis-homoallylic alcohol was conducted, based on the allylic strain and hydroxyl group directing effect. Mild conditions for hydrolysis of esters were used in the reaction to give the final product herboxidiene in near quantitative yield.

Degree

Ph.D.

Advisors

Ghosh, Purdue University.

Subject Area

Organic chemistry

COinS