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N-Silylated amines as valuable synthons in methods development toward pharmaceutically relevant small molecules

University of British Columbia

This thesis focuses on two distinct methods which were developed to access both a series of diheteroarylamides and a series of primary and secondary amines with a tertiary α-carbon. Crucial to the methods development for their synthesis was the use of N-silylated amines. The diheteroarylamides served as structural alternatives to a reference diheteroarylamide which showed potency against HIV-infected cells and the resulting primary and secondary amines were used as precursors to heterocyclic derivatives. In Chapter 1, an introduction on the catalytic synthesis and chemistry of the N-silylated amines is presented. Modern catalytic reactions to access N-silylamines and the type of transformations the resulting N-silylated amines can be engaged in are discussed. In Chapter 2, the value of N-silylated amines is highlighted with their use in amide bond formation of diheteroarylamides derived from electron deficient amines. The negative charge unveiled upon the desilylation of the above amines is a necessity for them to be engaged in the amidation reaction. In Chapter 3, the focus is centered on secondary N-silylated α-arylated amines which are used as substrates in zirconium catalyzed hydroaminoalkylation of alkenes to access primary α-arylated amines with a tertiary center on the α to the nitrogen carbon. Efforts to cyclize the resulting primary amines with the goal to access relevant heterocycles in organic and pharmaceutical chemistry are presented. In Chapter 4, N-aryl and N-alkylamines with a secondary α-carbon are used as substrates in zirconium catalyzed hydroaminoalkylation of alkenes to afford secondary α-arylated amines with a tertiary α to the nitrogen carbon. In analogy with the primary amines, some of the resulting secondary amines can further be cyclized into heterocyclic derivatives. Chapter 5 provides a summary and describes the future direction the two methods presented in Chapter 2 and 3&4 can take. For Chapter 2, the ongoing synthesis of diheteroarylamides will serve as a platform for the identification of the interactions with their target. For Chapters 3&4, there is space for the methodology improvement to control both regio- and diastereoselectivity in the resulting compounds. Further strategies on how to construct heterocycles with the resulting amines are discussed.

Text

2021-10-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/69862

Pharmaceutical Sciences

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/