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Access Type
WSU Access
Date of Award
January 2024
Degree Type
Dissertation
Degree Name
Ph.D.
Department
Chemistry
First Advisor
Hien Nguyen
Abstract
Forging quaternary stereocenters has long been sought after in the realm of modern synthetic chemistry. Among the fundamental structural motifs in organic chemistry, the synthesis of -tertiary amines poses a surprisingly formidable challenge. Nonetheless, -tertiary amines are privileged structures present myriad of bioactive molecules. A highly effective diene-ligated rhodium catalyst was developed to catalyze the asymmetric allylic amination of tertiary allylic trichloroacetimidates with secondary aliphatic amine nucleophiles. This method offers precise control over regioselectivity and enantioselectivity to furnish -trisubstituted -tertiary amines. The synthetic utility is showcased by efficient preparation of -tertiary amines featuring pharmaceutically relevant secondary amine cores with good yields and excellent selectivities (branched:linear >99:1, up to 99% enantiomeric excess). In depth mechanistic investigations were conducted using synergistic experimental and computational studies. DFT calculations and kinetic experiments showed that the rate of conversion of the less reactive -allyl intermediate to the more reactive isomer via -- interconversion was faster than the rate of nucleophilic attack onto the more reactive intermediate. These data imply that the Curtin-Hammett conditions are met in the amination reaction, thereby leading to dynamic kinetic asymmetric transformation. The thermodynamically more stable -allyl intermediate was found to be kinetically more reactive, leading to the major (S)-enantiomer of the product. Isotopic labeling experiments established that the nucleophilic addition occurs via an outersphere nucleophilic addition with an inversion of -allyl stereochemistry. The observation of complete branched selectivity is noteworthy and as corroborated by computations might be attributed to the hydrogen bonding interactions between -oxygen of allylic substrate and amine-NH that greatly assist the delivery of amine nucleophile onto more hindered internal carbon of the -allyl intermediate. In summary, a robust catalytic approach has been developed for asymmetric construction of tertiary amines that would otherwise be difficult to access under synthetically useful conditions. It is anticipated this protocol would provide an attractive synthetic tool for medicinal chemists to explore new chemical space and develop novel therapeutic drugs.
Recommended Citation
Ketipe Arachchi, Thanuja Madhawee Madhawee, "Mechanistically Driven Development Of Rhodium-Catalyzed Asymmetric Allylic Amination For -Tertiary Amine Synthesis" (2024). Wayne State University Dissertations. 3973.
https://digitalcommons.wayne.edu/oa_dissertations/3973
