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Dissertation/Thesis Abstract

I. Restriction of DNA Conformation by Spirocyclic Annulation at C-4'. II. Studies Toward the Enantioselective Synthesis of Pestalotiopsin A
by Dong, Shuzhi, Ph.D., The Ohio State University, 2007, 432; 10836009
Abstract (Summary)

The demand for antisense oligonucleotides with efficient and selective recognition of complementary nucleic acid sequences for diagnostic or therapeutic purposes has motivated significant research activity. We have designed a new class of conformationally restricted nucleoside analogues based on modification of the glycosyl moiety by spirocyclic annulation at C-4' to explore their potential use as antisense therapeutics, as well as antiviral agents.

A divergent strategy has been implemented to provide access to DNA- and RNA-configured spirocyclic thianucleosides in both the syn and anti series from a common sulfide acetonide intermediate. This intermediate is accessible in enantiopure form via a thionium ion-induced pinacolic ring expansion reaction, subsequent optical resolution, chemoselective oxidation of olefin in the presence of sulfur, and a series of functional group interconversions.

Elaboration of the sulfide acetonide to the spirocyclic 2'-deoxy-4'-β-thianucleosides was achieved via thiaglycal intermediates bearing adequate protecting groups. Electrophilic glycosidation reactions mediated by PhSeCl led to incorporation of nucleobases in a stereoselective fashion. The stereoselective synthesis of spirocyclic 4'-thia-β-ribonucleosides was realized via key sulfoxide intermediates bearing a 2,4-dimethoxybenzoyl substituent at C-2. Pummerer rearrangement with nucleobases was effected with TMSOTf and triethylamine to deliver β-configured ribonucleosides through anchimeric assistance.

Overall, twenty spirocyclic 4'-thianucleosides were synthesized and submitted to the NIH for antiviral evaluation. Uridine 2.65 has been shown to be an inhibitor of herpes virus VZV and EBV. In addition, a 2'-deoxy syn-5' configured 4'-β-spironucleoside was synthesized stereoselectively through an NIS-mediated glycosidation reaction of a TIPDS-protected spiroglycal. This nucleoside, as well as other thianucleosides, can be incorporated into oligonucleotides to study their potential as antisense therapeutics.

A study toward an enantioselective total synthesis of pestalotiopsin A was undertaken. Starting from D-glyceraldehyde acetonide, both antipodes of the polysubstituted cyclobutanol were obtained via zirconocene-mediated ring contraction of a pair of 4-vinylfuranosides. The upper and lower side chains were incorporated via stereocontrolled nucleophilic addition and anti-aldol reactions, respectively. The advanced intermediate possessing all the skeletal carbons of pestalotiopsin A was transformed into a series of dienes, and these dienes were examined for the challenging construction of the (E)-cyclononene ring via ring-closing metathesis.

Indexing (document details)
Advisor: Paquette, Leo
School: The Ohio State University
Department: Chemistry
School Location: United States -- Ohio
Source: DAI-B 79/10(E), Dissertation Abstracts International
Subjects: Chemistry
Keywords: Annulation, Conformation, Dna, Enantioselective, Pestalotiopsin, Pestalotiopsin a, Restriction, Spirocyclic, Spirocyclic nucleosides
Publication Number: 10836009
ISBN: 978-0-355-97193-4
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