Unveiling Incipient Reactivity via Tandem Hydrosilylation Reaction Cascades and the Progress Toward the Total Synthesis of (–)-Cylindrocyclophane A

Author: Casselman, Tyler Daniel

Year: 2023

Degree: Dissertation (Ph.D.)

Advisor: Stoltz, Brian M.

Committee Members: Reisman, Sarah E.; Agapie, Theodor; Fu, Gregory C.; Stoltz, Brian M.

Option: Chemistry

DOI: 10.7907/92b3-2d90

Abstract

The two pillars of synthetic organic chemistry, reaction methodology development and total synthesis of complex natural products, has remained the focus of chemical research for synthetic chemists since their fundamental inception. In particular, harnessing the reactivity of unstable, but useful, chemical intermediates through telescoping reaction conditions is emerging as an attractive approach to rapidly access complex molecular architecture from readily available building blocks. Herein is described two unique reaction methodologies relying on tandem hydrosilylation reaction cascades to synthesis saturated N-heterocyclic products in a stereoselective manner. We have developed a diastereoselective Mannich reaction combining α-substituted-γ-lactam pronucleophiles with N-silyl imine electrophiles generated in situ via catalytic hydrosilylation of aryl nitriles. Additionally, we have developed a tandem hydrosilylation, enantioselective allylic alkylation reaction of substituted pyridines to yield chiral tetrahydropyridine products. This serves as the first example of using hydrosilylation of pyridines to generate enamine nucleophiles that can undergo an asymmetric allylic alkylation reaction. The final portion of this thesis describes the progress toward a total synthesis of (–)-cylindrocyclophane using C–H functionalization logic. We were able to access the necessary [7.7]-paracyclophane core in 8 steps from a feedstock aryl diazoacetate compound and n-hexene. Through functional group manipulations, we were able to advance this paracyclophane core to an intermediate possessing the exact stereocenters and carbon framework in (–)-cylindrocyclophane A. We are currently modeling the necessary deoxygenation needed to advance this intermediate and complete the total synthesis.

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