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.
|School:||The Ohio State University|
|School Location:||United States -- Ohio|
|Source:||DAI-B 79/10(E), Dissertation Abstracts International|
|Keywords:||Annulation, Conformation, Dna, Enantioselective, Pestalotiopsin, Pestalotiopsin a, Restriction, Spirocyclic, Spirocyclic nucleosides|
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