Defense Date

11-13-2019

Graduation Date

Fall 12-20-2019

Availability

Immediate Access

Submission Type

dissertation

Degree Name

PhD

Department

Chemistry and Biochemistry

School

Bayer School of Natural and Environmental Sciences

Committee Chair

Bruce D. Beaver

Committee Member

Jeffrey D. Evanseck

Committee Member

Shahed U. M. Khan

Committee Member

Patrick T. Flaherty

Committee Member

Fraser F. Fleming

Keywords

Metalated Nitriles, Alkylation, Arylation, Catalysis, Diastereoselectivity

Abstract

Development of an sp3 hybridized halogen-magnesium exchange route to Grignard reagents, chelation-controlled asymmetric induction of γ- and δ-hydroxynitriles as well as a diastereoselective arylation procedure for C-zincated nitriles have been explored. Sequential addition of i-PrMgCl and n-BuLi to 3- and 4-carbon iodoalcohols triggers a facile halogen-metal exchange to generate cyclic magnesium alkoxides capable of intercepting electrophiles to produce a diverse range of substituted alcohols. This work advances progress toward the synthesis of highly desirable chiral Grignard reagents.

Double deprotonation of γ- and δ-acyclic hydroxynitriles with i-PrMgCl effects highly diastereoselective alkylations via a singly-chelated magnesiated nitriles. These alkylations are electrophile-dependent with either syn- or anti-addition occurring depending upon the electronic properties of the electrophile. These alkylations are the first electrophile-dependent alkylations of acyclic nitriles and exhibit a unique reactivity depending upon the nature of the Grignard reagent used for deprotonation. The work presented here addresses the long-standing challenge of stereoselective installation of quaternary carbons in conformationally mobile, acyclic nitriles.

Lastly, deprotonating substituted cyclohexanecarbonitriles with the TMPZnCl·LiCl complex affords C-zincated nitriles that can couple in a diastereoselective manner with aryl bromides in the presence of catalytic Pd(OAc)2 and S-Phos. Ring substituents displaying a wide range of steric and stereoelectronic effects have been examined. Selectivity ranges from null to high depending upon the size and location of the substituent. The diastereoselectivity trends discovered here present an immense potential for the synthesis of substituted cyclohexanecarbonitriles, key intermediates and targets in active pharmaceutical agent synthesis.

Language

English

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