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Synthetic, Functional Thymidine-Derived Polydeoxyribonucleotide Analogues from a Six-Membered Cyclic Phosphoester
journal contribution
posted on 2017-04-10, 14:24 authored by Yi-Yun
Timothy Tsao, Karen L. WooleyA 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 is 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 six-membered 3′,5′-cyclic
phosphoester ring derived from deoxyribose indicated strain energies
at least 5.4 kcal/mol higher than those of the six-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 (Đ <
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-analogue
materials.
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strain energiesweight deoxynucleotide polymersdegradable polymersdiastereoselective cyclization2-dimethyl -4-aminopyridine Computational modelingring-opening polymerizationscalable productionsix-membered monocyclic phosphoesterSix-Membered Cyclic Phosphoesterproduct-derived materialssix-membered cyclic phosphoester ring-opening polymerization strategypolydeoxyribonucleotide-analogue materialsFunctional Thymidine-Derived Polydeoxyribonucleotide Analoguesthymidine-derived bicyclic monomerbutenyl-functionalized deoxyribonucleosidenon-natural basesnovel polyphosphoestersthymidine ethylphosphatedeoxynucleoside building blocks
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