Date of Award

Spring 5-27-2020

Track

Chemistry

Degree Type

Thesis

Degree Name

Master of Science in Chemical Sciences (MSCB)

Department

Chemistry

Committee Chair

Christopher W. Alexander

Committee Member

Daniela Tapu

Committee Member

Michael Van Dyke

Abstract

Tetrahydroquinolines (THQs) are a group of N-heterocyclic molecules derived from natural sources. They show a wide range of interesting biological activity and have been the basis for a variety of different medications including antibacterial and antiparasitic drugs. The Hancock alkaloids, Galipinine, Galipeine, Cuspareine and Angustureine, are natural 1,2,3,4- tetrahydroquinoline compounds that are found in the South American Angostura tree. Extracts containing these alkaloids have been used to treat fever, dysentery and other ailments. Interestingly, These compounds have shows in vitro antimalarial activity. However, it does not appear in the literature that they have been evaluated for their potential antibiotic activity.

The synthetic utility of α-aminocycloalkylcopper reagents derived from tert-butylformamidines has not been extensively explored and a limited number of examples have been reported in the chemical literature. It was hypothesized that the racemic Hancock alkaloids could be synthesized using α-aminocycloalkyl cuprate cross-coupling chemistry as a synthetic exercise to expand the utility of this class of cuprate reagents.

Initially the t-butylformamidine (TBF) functionalized tetrahydroquinoline (THQ-TBF) starting material was synthesized from 1,2,3,4-tetrahydroquinoline. This THQ-TBF was treated with t-butyllithium to give the α-aminocarbanion which was reacted with a copper (I) salt to form the α-aminocycloalkyl cuprate in situ. This cuprate reagent was then cross-coupled with alkyl iodides, that corresponded to the requisite side chains of each alkaloid target to afford the 2-position functionalized THQ-TBFs. The TBF group was subsequently hydrolyzed to an N-formyl intermediate and then reduced to give the targeted Hancock alkaloids in good yields.

Part I of this thesis briefly describes the discovery and medicinal history of the Hancock alkaloids and how they are prevalent in modern medicine. Part II describes the synthesis of TBF-THQ starting to produce the N-formyl THQ followed by treatment with Meerwein’s reagent to afford the formamidine functionalized THQ. Part III describes the new cuprate cross-coupling process used to produce the α-substituted THQ systems. Part IV describes the removal of the TBF group through hydrolysis and lithium aluminum hydride reduction to afford the target alkaloids.

Available for download on Thursday, January 28, 2021

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