Synthetic, Functional Thymidine-derived Polydeoxyribonucleotide Analogues from a Six-Membered Cyclic Phosphoester


Yi-Yun Timothy Tsao (1), Travis H. Smith (1), and Karen L. Wooley (1)

1.Departments of Chemistry, Chemical Engineering

2.Materials Science & Engineering,

Texas A&M University, College Station, TX 77842, United States



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 six-membered cyclic phosphoester ring-opening polymerization strategy will be demonstrated, by an initial preparation of novel polyphosphoesters, comprised of butenyl-functionalized deoxyribonucleoside repeat units, connected via 3’,5’-backbone linkages.  Computational modeling of the six-membered 3’,5’-cyclic phosphoester ring derived from deoxyribose indicated strain energies at least 5.4 kcal/mol higher than the six-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 the synthesis of DNA analogues, as natural DNA is synthesized exclusively in the 5’ to 3’ direction.  The regioisomeric preference was investigated by comparison to synthesized 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 were then conducted to afford the corresponding ring-opened unimer adducts and to gain understanding of the regioselectivity during the ring-opening polymerization.  1H−31P heteronuclear multiple-bond correlation spectroscopy showed ethanol and 4-methoxybenzyl alcohol initiation to yield only the P−O5’ bond cleavage product, whereas attack by isopropyl alcohol afforded both P−O3’ and P−O5’ bond cleavage products, supporting our hypothesis that the increased steric hindrance of the propagating species dictates the regioselectivity of the P−O bond cleavage.  Overall, this work provides a fundamental understanding of the polymerization behavior of six-membered cyclic phosphoesters and broadens the scope of DNA analogues from the ring-opening polymerization of 3’,5’-cyclic phosphoesters.

Keywords: DFT calculation, DNA analogue, natural product, polymer, polyphosphoester, regioisomeric preference, ring-opening polymerization, synthetic polymer, thymidine

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