A grand challenge that crosses synthetic chemistry and biology is the scalable production of functional analogues 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. 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. These calculations supported the hypothesis that the strained 3’,5’-cyclic monomer can promote ring-opening polymerization to afford the resulting polymers with low dispersities. Regioregularity is a crucial property in these DNA analogues, as natural DNA is synthesized exclusively in 5’ to 3’ direction. The regioisomeric preference was investigated by the synthesis of model compounds of 3’,3’-, 3’,5’-, and 5’,5’-linkages. 31P NMR spectra revealed the major connectivity in the polymer backbone to be 3’,5’-linkages, with ≤30% of other isomeric forms. Model reactions employing a series of alcohol initiators imparting various degrees of steric hindrance, to mimic the increased steric hindrance of a propagating alcohol, yielded the corresponding ring-opened unimer adducts. 1H–31P HMBC spectroscopy showed ethanol and 4-methoxybenzyl alcohol initiation to yield only the P–O5’ bond cleavage product, whereas isopropyl alcohol initiation afforded both P–O3’ and P–O5’ bonds cleavage products, supporting our hypothesis that the increased steric hindrance of the propagating species during polymerization dictates regioselectivity of P–O bond cleavage. Overall, this work combines the merits of natural product-derived materials and functional, degradable polymers to provide a new platform for functional, synthetically-derived polydeoxyribonucleotide-analogue materials.

Synthetic, functional thymidine-derived polydeoxyribonucleotide analogues from a six-membered cyclic phosphoester

255th National Meeting (2018)

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