Part I: Synthesis of Cyclobutyl Nucleoside and NucleotideAnalogues as HIV-1 Reverse Transcriptase InhibitorsPart II: Improvement of Glycosylation Regioselectivity in PurineNucleoside Analogue SynthesisPart III: Enantioselective Synthesis ofβ-D-Dioxolane-T andβ-D-FDOC Open Access

Davis, Kimberlynn Becnel (2008)

Permanent URL: https://etd.library.emory.edu/concern/etds/0c483j77q?locale=en
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Abstract

Part I of this dissertation describes the synthesis and biological activity of novel cyclobutyl nucleoside analogues. The cyclobutane portion of the analogues was synthesized via a [2+2] ketene cycloaddition and an SN2 coupling strategy for glycosylation. The EC50 values in human PBM cell lines ranged from 6.5 to >100 µM with no toxicity in PBM, CEM, and Vero cells up to 100 µM (with the exception of the 6-chloropurine derivative, which showed some toxicity). The guanine derivative was proven as the most active compound in the entire cyclobutyl series, including previously synthesized pyrimidine analogues. Ring-expanded nucleobases, including tricyclic and bicyclic with an extended chain (fatty), were also explored. None showed significant anti-HIV activity without an accompanying cytotoxicity. Certain compounds that showed significant cytotoxicity were evaluated for anti-cancer activity. Triphosphates of each class of compounds were synthesized as well, in order to determine if these derivatives serve as substrates for reverse transcriptase. It was found that the purine and tricyclic compounds are suitable as nucleoside reverse transcriptase inhibitors; however, the fatty base analogue was not incorporated into the elongating DNA chain.

Part II of this dissertation describes efforts toward the improvement of regioselective base coupling of purines. A problem often encountered in glycosylation reactions with purines is the N9 vs N7 competition. This issue was addressed by synthesizing the purine with a bulky silane group in the C-6 position. This should allow a method of blocking the N7 position to accomplish selective N9 glycosylation, but also a strategy to create a variety of derivatives through the easily substituted silyl group. The synthesis of the silyl purine was explored through a variety of methods, including cross-coupling reactions and organometallic/halogen exchanges. The product was synthesized, but was not able to be isolated as the pure silyl purine due to decomposition.

Part III of this dissertation depicts the studies performed towards enantioselectively synthesizing β-D-FDOC and β-D-dioxolane-T. This was explored in both the glycosylation and lactonization steps of the synthesis. Chiral auxiliaries on the dioxolane component as well as chiral Lewis acids to induce enantioselectivity were employed.

Table of Contents

Part I: Synthesis of Cyclobutyl Nucleoside and Nucleotide Analogues as HIV-1 Reverse Transcriptase Inhibitors 1.1 Statement of purpose ………………………………………….. 1 1.2 Introduction ……………………………………………………... 3 1.2.1 Current status of the HIV/AIDS pandemic…………………. 3 1.2.2 HIV replication cycle …………………………………………… 5 1.2.3 FDA approved anti-HIV treatments ………………... 7 1.2.4 NRTI mechanism of action ……………………………………. 11 1.2.5 Mechanism of NRTI resistance ………………………………. 12 1.3 Background …………………………………………………….. 16 1.3.1 Carbocyclic oxetanocins as nucleoside analogues ………… 16 1.3.2 Synthesis of 2,3-disubstitutedcyclobutanes as nucleoside analogue intermediates ………………………………………... 16 1.3.3 Synthesis of modified cyclobutanes as intermediates for nucleoside reverse transcriptase inhibitors ……………. 24 1.3.4 Methods of synthesizing carbocyclic cyclobutyl nucleoside analogues ……………………………………………………….. 27 1.3.5 Methods of synthesizing nucleoside triphosphates …………. 31 1.3.6 Synthesis and anti-HIV activity of 3'-hydroxymethyl cyclobutyl nucleosides ………………………………………….. 35 1.4 Results and Discussion ………………………………………… 40 1.4.1 Design and synthesis of purine cyclobutyl nucleosides …….. 40 1.4.2 Design and synthesis of tricyclic nucleobase cyclobutyl analogues ………………………………………………………... 48 1.4.3 Design and synthesis of ring expanded ("fat") nucleoside analogues ………………………………………………………… 65 1.4.4 Synthesis of 4'-O-triphosphate of cyclobutyl nucleosides ….. 67 1.4.5 Biological activity of synthesized compounds ……………… 69 1.5 Conclusion ………………………………………………………. 74 1.6 Experimental …………………………………………………….. 75 1.7 References ……………………………………………………. 138 Part II: Improvement of Glycosylation Regioselectivity in Purine Nucleoside Analogue Synthesis 2.1Statement of purpose ……………………………………….... 148 2.2Introduction and Background ………………………………... 150 2.2.1Organolithium reagents ……………………………………..... 151 2.2.2 Organomagnesium reagents ………………………………... 152 2.2.3 Organozinc reagents …………………………………………. 153 2.2.4 Organostannane reagents …………………………………….154 2.3Results and Discussion …………………………………….... 155 2.3.1 Organolithium generation ……………………………………...155 2.3.2 Palladium catalyzed cross-couplings ………………………...161 2.3.3 Halogen/magnesium exchange ………………………………..163 2.4 Conclusion ………………………………………………………....167 2.5 Experimental …………………………………………………….....168 2.6 References ………………………………………………………....173 Part III: Enantioselective Synthesis of β-D-Dioxolane-T and β-D-FDOC 3.1Statement of Purpose …………………………………………… 178 3.2Introduction and Background …………………………………... 180 3.3Results and Discussion ………………………………………….184 3.3.1 Asymmetric glycosylation ………………………………………. 184 3.3.2 Asymmetric lactonization ……………………………………….. 188 3.4 Conclusion ……………………………………………………….. 190 3.5 Experimental …………………………………………………….. 191 3.6 References ……………………………………………………….. 203

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