Title

The Z-selective [2,3] Wittig rearrangement of secondary allylic alpha-stannyl ethers, chiral alpha-alkoxy stannanes, and progress toward the enantiospecific total synthesis of (+)-mycotrieninol I

Date of Award

2003

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Advisor(s)

James Kallmerten

Keywords

Z-selective, Wittig rearrangement, Stannyl ethers-alpha, Alkoxy stannanes-alpha, Mycotrienins

Subject Categories

Chemistry | Organic Chemistry | Physical Sciences and Mathematics

Abstract

A study of the stereochemical consequences of the Still [2,3]-Wittig rearrangement of various related secondary α-lithio ether ethers is the focus of this dissertation. Unique to our work was the observation that trans -disubstituted olefins with a syn -α-alkoxy allylic relationship may rearrange producing cis -homoallylic alcohol products. The ability to prepare compounds stereospecifically with Z-olefins may provide an entry into the total synthesis of several natural products such as the immunosuppressive agent (+)-discodermolide and the tumor cell migration inhibitor (+)-migrastatin.

The basis for our Z-olefin stereocontrol is a reactive conformation that invokes a six-membered chelation between the α-alkoxy group and the lithium cation prior to the [2,3] Wittig rearrangement. This relationship, however, required a transition state model where the stereochemistry at the migrating carbon was maintained contrary to literature precedent. Chiral α-stannyl ethers were prepared in order to observe this stereochemical transfer and to determine whether the Still [2,3] Wittig rearrangement proceeds with retention or inversion of stereochemistry.

A highly convergent asymmetric synthetic approach toward the synthesis of (+)-mycotrienol 1, the core 21-member macrolactam of this family, will also be discussed. Members from the mycotrienin family of novel ansamycin antibiotics were first isolated in 1985 from a culture broth of Streptomyces sp. No. 83-16.

The construction of two key synthons, the C 8 -N 21 aromatic core and the C 1 -C 7 triene precursor will be described. The synthesis of the C 8 -N 21 fragment will explore allenyl and propargyl metal addition to aldehydes in order to prepare a suitable homoallylic alcohol for further functionalization in preparation for a Stille coupling. The planned Stille coupling would complete the carbon framework of the mycotrienol I core. Although calcium-based dissolving metal reduction allowed the cleavage of the C 17 benzyl ether bond in the presence of a terminal acetylene, we found that it was more efficient to introduce the acetylene functionality after the C 17 bond had been cleaved. The C 1 -C 7 synthon, derived from (+)-malic acid, was transformed into a useful ( E,E )-iodo diene in anticipation of the Stille coupling.

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