Date of Degree

5-2019

Document Type

Dissertation

Degree Name

Ph.D.

Program

Chemistry

Advisor

Mark R. Biscoe

Committee Members

Stephen P. Fearnley

Ryan P. Murelli

Subject Categories

Inorganic Chemistry | Medicinal-Pharmaceutical Chemistry | Organic Chemistry | Other Chemistry

Keywords

cross-coupling, palladium, catalysis, Stille, stereospecificity, organotin

Abstract

Organometallic reagents containing the tin-carbon bond are used extensively in modern synthetic chemistry for the formation of new bonds to carbon. Over recent decades, transition metal catalyzed cross coupling reactions between two C(sp2) centers have been widely developed. However, the introduction of a C(sp3) center complicates the catalytic cycle, and opens unproductive chemical pathways which lead to isomerization, elimination, and racemization. Our lab has developed a modified-Stille reaction to combat the deleterious effects of β-hydride elimination. Our protocol enables unactivated 2° alkyl organotin nucleophiles to undergo efficient cross coupling reactions with C(sp2) electrophiles, avoiding the drawbacks commonly associated with such a synthetic approach. Analysis of the final products has shown our system to be highly stereospecific, which allows for translation of chiral information from our organometallic nucleophiles to the resulting arylation and acylation products. This specificity was also found to exist in an electrophilic halogenation reaction unrelated to the cross coupling mechanism.

This report will focus on our attempt to solve the major bottleneck for broader utility of our system, the preparation of enantioenriched tin precursors. Until recently, 2° alkyl tin compounds were not a synthetically useful species, as the rate of 2° alkyl transfer was simply too slow. With our nucleophiles exempt from that limitation, we began searching for a proper, general synthetic method for their preparation. We found that by utilizing a lithium-naphthalide catalyst, a tricarbastannatrane anion could be prepared from the corresponding chloride. By using this reagent, we observed the clean inversion of alkyl sulfonates from commercially available enantioenriched alcohols. No longer tethered to directed lithiation or chiral prep-HPLC separations, we were able to expand our library of tin nucleophiles with defined stereochemistry. This report will cover the development of the tricarbastannatrane anion and a discussion of the utility of enantioenriched 2° alkyl nucleophiles.

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