Defense Date

2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Chemistry

First Advisor

Dr. Joshua D. Sieber

Second Advisor

Dr. Thomas D. Roper

Third Advisor

Dr. Vladimir Sidorov

Fourth Advisor

Dr. Julio Alvarez

Abstract

The carbon scaffold of many drugs and natural products contain multiple stereogenic centers bearing heteroatoms. As a result of this, chemists have long sought methods to efficiently install these multi-heteroatom functionalities. Reductive coupling reactions have been extensively studied over the past decades, and the allylation of carbonyls via the reductive coupling approach has been a key method for generating chiral allylic alcohols. This work utilizes inexpensive Cu for the asymmetric reductive coupling of allenamides with carbonyls or imines to simultaneously install two heteroatoms (either oxygen and nitrogen or nitrogen and nitrogen, respectively) onto the product. These molecules have a polarity profile that makes them difficult to make using traditional methods. Herein, we report a method for the asymmetric reductive coupling reactions. Chapter 1 describes the development of a regio- and diastereoselective CuH-catalyzed reductive coupling of N-based allenes and imines, where stereoselectivity is controlled by a chiral auxiliary. This protocol provides access to branched products bearing the 1,2-diamine motif. Chemical transformations were performed on one of the branched products to furnish an aminopiperidine derivative that is a valuable intermediate to a major fragment of the potent NK-1 inhibitor compounds CP-99,994 and CP-122,721. Chapter 2 details the development of an asymmetric enantioselective aminoallylation of ketones, which builds on work previously published by our laboratory. This new protocol massively increases the enantiocontrol over this transformation by preventing an on-cycle carbamate migration that eroded enantioselectivity in the previous work and used allenamide protecting groups that were easier to cleave. This protocol provides an atom-economical approach for the synthesis of 1,2-aminoalcohols. Chapter 3 describes ongoing attempts to develop an asymmetric enantioselective aminoallylation of aldimines. This protocol would provide the same branched 1,2-diamine motif, as stated previously, but in a manner that would be more atom economical due to the chirality being provided by the catalyst instead of a chiral auxiliary.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

5-5-2024

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