Stereoselective transformations of iminium ions via copper catalysis
Date
2022
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Publisher
University of Delaware
Abstract
This dissertation focuses on stereoselective transformations of iminium ions, which are mediated via copper(I) catalysts. Chapters 1–3 focus on developing stereoselective alkynylations to yield saturated, substituted N-heterocycles from commercial or easily-synthesized precursors. Chapter 4 describes discovery and examination of a novel kinetic resolution of benzoisoxazolines. ☐ Chapter 1 describes an enantioselective alkynylation of unstabilized cyclic iminium ions, formed in situ from cyclic α-methoxyaminals. This method utilizes a copper(I)/PyBOX catalyst to generate chiral copper(I) acetylides, which undergo an addition to the iminium ion to yield enantioenriched, substituted cyclic amines. Broad scope is demonstrated in both alkynyl partners and aminal identity under mild conditions and with high enantioselectivities. This research finds its utility in medicinal chemistry and total synthesis to synthesize saturated heterocycles with highly predictable stereochemical outcomes. ☐ Chapter 2 describes a diastereoselective alkynylation of β-bromoiminium ions, which are formed in situ from α,β-methoxy bromoaminals. This method uses a Lewis acid to cleave a C–O bond and form the iminium ion, which is stabilized and stereocontrolled by the bromide moiety. These factors result in a diastereoselective alkynylation using a copper(I) acetylide to yield β-bromo-alkynylated cyclic amines. This method offers broad scope under mild conditions, demonstrating stereoselectiveheterocyclic synthesis and facile derivatization of potentially bioactive compounds. ☐ Chapter 3 describes my efforts towards an enantioselective and diastereoselective halogenation-alkynylation of cyclic enecarbamates. I envisioned a dynamic kinetic resolution wherein the enecarbamate could react with a halide source via reversible halogenation. These intermediates could then interconvert between both enantiomers of the halo-iminium ion, where one of the intermediates could be preferentially attacked by a chiral copper(I) acetylide. Alternatively, I hypothesized a pathway in which the halogenation could be achieved via a chiral halogenating reagent, which would provide a single enantiomer of the halo-iminium ion. This reaction could then be followed by a diastereoselective alkynylation to yield enantioenriched halo-alkynylated piperidines. ☐ Chapter 4 describes a kinetic resolution of benzoisoxazolines, which employs a chiral copper(I)/PHOX catalyst to differentiate between two enantiomers of starting material. One enantiomer of starting material reacts to form a benzoxazepine while the other enantiomer remains untouched and enantioenriched. This method requires 1.) a stoichiometric amount of terminal alkyne and base and 2.) specific properties for the terminal alkyne for the overall reaction to be successful. Cleavage of the N-O bond may also lead to enantioenriched α-tetrasubstituted amines, allowing for further derivatization and pathways for bioactive synthesis.
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Keywords
Iminium ions, Enantioselective alkynylation, Bioactive compounds, Reversible halogenation