Dearomative Photocatalytic Hydroalkylation and Lipophilic Prodrugs Open Access

Abstract

Dearomatization has become a powerful technique to create dimensional complexity from inexpensive, abundant aromatic precursors. Here, we employed intramolecular cyclization of alkyl radicals for dearomatization of benzylacetamides to form spirocyclic lactams. A strongly reducing organic photocatalyst with a stoichiometric amine reductant was used to afford the 1,4-cyclohexadiene moieties by a reductive radical polar crossover mechanism. The reaction was optimized to favor the dearomatized product over hydrodehalogenation and dimer byproducts. The regioselective method proceeds efficiently on a range of substituted benzylacetamides. Additionally, the dearomatized products can be functionalized to afford a variety of scaffolds, including the commonly prescribed anticonvulsant drug, Gabapentin.

Nucleoside analogues have emerged as effective therapeutics by interfering with endogenous nucleosides to prevent viral replication and tumor proliferation. Here we develop nucleoside prodrug analogues to increase selectivity, and decrease degradation and toxicity. A Tenofovir prodrug was developed with a glycerol backbone with oxygen linkers connecting TFV to inhibit reverse transcriptase, a lipophilic chain to improve cell permeability, and varying lipophilic groups to increase lipoprotein association and direct transport to systemic circulation. The 5-fluorouracil prodrug analogue incorporates the active metabolite FdUMP prevent 5-FU degradation, steric bulk to limit kinase activity, and a metabolically stable chain to decrease premature drug release.

Table of Contents

Dearomatization of Unactivated Arenes via Photocatalytic Hydroalkylation………1

Introduction……………………………………………………………………………,,,,,…..1

Results and Discussion……………………………………………………………………....7

Conclusion and Future Work……………………………………………………………....16

Lipophilic Tenofovir Prodrugs…………………………………………………………………18

Introduction………………………………………………………………………......………18

Results and Discussion…………………………………………………………….....……..26

Conclusion and Future Work…………………………………………………………....….31

Fluorodeoxyuridine Monophosphate Prodrugs………………………………...…………32

Introduction…………………………………………………………………………......…....32

Results and Discussion………………………………….…………………………....……..39

Conclusion and Future Work…………………………………………………………....….41

References………………………………………………………………...…………………..…..42

Experimental ……………………………………………………………..………………...…….48

About this Master's Thesis

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School	Laney Graduate School
Department	Chemistry
Degree	M.S.
Submission	Master's Thesis
Language	English
Research Field	Chemistry, Organic
Keyword	Photochemistry Dearomatization Prodrugs
Committee Chair / Thesis Advisor	Liotta, Dennis, Emory University
Committee Members	Wuest, William, Emory University Blakey, Simon, Emory University

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