Synthetic Studies Toward Cyclobutyl Nucleoside Analogs for the Treatment of Hepatitis C Virus Open Access

Jones, Matthew James (2017)

Permanent URL: https://etd.library.emory.edu/concern/etds/vd66w0599?locale=en
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Abstract

Computational evaluations of novel cyclobutyl nucleoside analogs for the targeting of the hepatitis C virus (HCV) NS5B Rdrp led to the investigation of synthetic routes towards several target molecules. This work sought to determine a viable synthetic strategy for a highly functionalized cyclobutane core that was amenable to late stage elaboration for thorough SAR studies. Several strategies were evaluated, ultimately revealing the stereoselective [2+2] ketene cycloaddition with Stericol offering the most promising route despite several late-stage difficulties stemming from the labile auxiliary. An achiral route was initially employed that failed to allow facile α-functionalization to the intermediate cyclobutanone. Instead, performing the cycloaddition with a disubstituted enol ether removed the requirement for α-functionalization, and use of the chiral Stericol would provide the added benefit of stereoselective construction of the cylcobutyl ring. Further synthetic efforts provided an advanced intermediate that would allow for the investigation of different fluorination strategies once the critical Wittig olefination stage is optimized, at which point subsequent glycosylation and phosphorylation would yield analogs suitable for testing in an HCV replicon assay.

Table of Contents

1. Introduction

1.1 Cyclobutyl Nucleoside Analogs

1.2 Synthetic Routes Towards Cyclobutyl Nucleoside Analogs

1.3 Hepatitis C Virus

1.4 Project Goals

2. Results and Discussion

2.1 Initial Synthesis Efforts via an Achiral Route

2.2 Adoption of an Asymmetric Method via Stericol

2.3 Model System Synthesis

2.4 Synthesis of an Advanced Intermediate

3. Conclusions and Future Work

4. Supporting Information

5. References

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