Graduation Year

2023

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Chemistry

Major Professor

Justin Lopchuk, Ph.D.

Committee Member

Xiaodong Shi, Ph.D.

Committee Member

James Leahy, Ph.D.

Committee Member

Jianfeng Cai, Ph.D.

Committee Member

Ernst Schönbrunn, Ph.D.

Keywords

Asymmetric Synthesis, Bifunctionalization, Grignard, Organolithium, SuFEx, Sulfur, Sulfoximine, Sulfonimidamide, Sulfinamide, Sulfonimidoyl Fluoride

Abstract

This dissertation mainly covers the latest methodology development in the field of sulfur-containing functional groups in synthetic chemistry. There are two parts. The first part is the asymmetric synthesis of sulfoximines, sulfonimidamides, sulfonimidoyl fluorides, and sulfinamides enabled by a versatile enantiopure S(VI) reagent. The second part is the Grignard reagent-triggered divergent S-editing synthesis via a bench-stable S(VI) reagent.

In the first part, the asymmetric synthesis of sulfoximines, sulfonimidamides, sulfonimidoyl fluorides, and sulfinamides is reported. This report focuses on the development of a bifunctional S(VI) reagent and its utility in synthesis. It employed the enhanced stability of sulfonimidoyl fluorides and the diversity of SuFEx chemistry to design a bifunctional and bench-stable reagent. The sterically congested sulfur center also required a reliable protecting group and new strategy for its application. We developed a unique protecting group and improved the stability of the reagent both for storage and reaction. A one-pot strategy was employed in the preparation of the S(VI) reagent, in situ protection and fluorination, and the decagram scale synthesis of the reagent, which ensured the investigation of its reactivity and application for solving practical issues. The S(VI) reagent allowed for the first functionalization with organolithiums. A one-pot strategy was highlighted and applied to stereospecifically transform the intermediates to sulfonimidoyl fluorides, sulfoximines and sufonimidamides quickly and maintained their enantiopurity. Lastly, the new protecting group was removed readily under mild conditions for all types of S-containing functional groups without loss of enantiopurity.

In the second part, the continued exploration of the S(VI) reagent led to the discovery of its new reactivity with Grignard reagents. Grignard reagents triggered the formation of a reactive intermediate from the S(VI) reagent and allowed access to a broad scope of sulfinamides. Then the sulfinamides were employed as divergent linchpins to deliver various S-containing compounds, such as sulfoximines, sulfonimidamides, sulfonimidoyl fluorides, sulfonamides, sulfilimines, imino-sulfinamides and sulfondiimines, under different activation strategies. This delivery, from sulfinamides to various S-containing compounds, is expected to help researchers quickly establish and extend their library for drug discovery and pharmaceutical science.

In summary, the dissertation explored two strategies involving the development of the versatile S(VI) reagent. Both methods demonstrated their excellent reactivity and diversity. These newly developed methods will boost the research in the field of sulfur chemistry.

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