A grand challenge that crosses synthetic chemistry and biology is the scalable production of functional analogs of biomacromolecules. We have focused our attention on the use of deoxynucleoside building blocks bearing non-natural bases to develop a synthetic methodology that allows for the construction of high molecular weight deoxynucleotide polymers. Our 6-membered cyclic phosphoester ring-opening polymerization strategy will be demonstrated, herein, by an initial preparation of novel polyphosphoesters, comprised of butenyl-functionalized deoxyribonucleoside repeat units, connected via 3’,5’-backbone linkages. A thymidine-derived bicyclic monomer, 3’,5’-cyclic 3-(3-butenyl) thymidine ethylphosphate, was synthesized in two steps directly from thymidine, via butenylation and diastereoselective cyclization promoted by N,N-dimethyl-4-aminopyridine. Computational modeling of the 6-membered 3’,5’-cyclic phosphoester ring derived from deoxyribose indicated strain energies at least 5.4 kcal/mol higher than the 6-membered monocyclic phosphoester, 2-ethoxy-1,3,2-dioxaphosphinane 2-oxide. These calculations supported the hypothesis that the strained 3’,5’-cyclic monomer can promote ring-opening polymerization to afford the resulting poly(3’,5’-cyclic 3-(3-butenyl) thymidine ethylphosphate)s with low dispersities (PDI &lt; 1.10). This advanced design combines the merits of natural product-derived materials and functional, degradable polymers to provide a new platform for functional, synthetically-derived polydeoxyribonucleotide-analog materials.

Synthetic, functional thymidine-derived polydeoxyribonucleotide analogs from a 6-membered cyclic phosphoester

254th National Meeting (2017)

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