Date of Degree

9-2020

Document Type

Dissertation

Degree Name

Ph.D.

Program

Chemistry

Advisor

Mark R. Biscoe

Committee Members

Qiao-Sheng Hu

Shengping Zheng

Subject Categories

Organic Chemistry

Keywords

stannylation, stereospecific, cross-coupling, heterocycles

Abstract

α-Substituted oxygen-containing heterocycles are commonly present in biologically active molecules. Statistics shows that at least one α-substituted ether moiety appears in over 20% of the top 200 small-molecule pharmaceuticals. This project illustrates a reliable regioselective method to introduce simple cyclic ethers towards the diversification of small molecules. Aryl halides bearing various functional groups were well tolerated independent of their electronic properties. It was found that cyclohexyl spectator ligands on tin selectively slows transmetallation of undesired units, circumventing the competitive transfer of n-butyl group from nBu3SnR reagents. Compared to the normally used nBu3SnR reagents, Cy3SnR organometallics benefits from lower toxicity and significantly higher crystallinity, which should become more appealing to synthetic chemists.

Nitrogen is the most abundant heteroatom among FDA approved pharmaceuticals. Particularly, α-chiral pyrrolidines are not only useful building blocks of pharmaceuticals, but also chiral controlling ligands in asymmetric synthesis. The second project reveals a general approach to stereospecific palladium catalyzed cross-coupling reactions of enantioenriched nitrogen-containing heterocycles. α-Stannylated pyrrolidine and azetidine organometallic reagents perform stereospecific arylation and acylation reactions against a variety of aryl and heteroaryl electrophiles. High stereofidelity is achieved with predictable reagent-control stereochemistry regardless of electronic properties of electrophiles and existing stereocenter on chiral substrates. Late stage functionalization could benefit from this protocol through a streamlined synthetic approach, avoiding the requisite time and labor consuming resolution of desired enantiomer from the corresponding racemic mixtures.

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