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

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 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 (D < 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.

Monomer design strategies to create natural product-based polymer materials.

Covering: 2010-Aug. 2016In an effort towards enhancing function and sustainability, natural products have become of interest in the field of polymer chemistry. This review details the blending of chemistries developed through synthetic organic chemistry and polymer chemistry. Through synthetic organic chemical transformations, such as functional group interconversion, a protection/deprotection series, or installation of a functional group, various designs towards novel, synthetic, bio-based polymer systems are described. This review covers several classifications of natural products - oils and fatty acids, terpenes, lignin, and sugar derivatives - focusing on exploring monomers prepared by one or more synthetic steps.

Regioisomeric Preference in Ring-Opening Polymerization of 3',5'-Cyclic Phosphoesters of Functional Thymidine DNA Analogues.

Regioregularity is a crucial property in the synthesis of DNA analogues, as natural DNA is synthesized exclusively in the 5' to 3' direction. We have focused our attention on the determination of the regioisomeric distribution of poly(3',5'-cyclic 3-(3-butenyl) thymidine ethylphosphate)s obtained from the ring-opening polymerization of (R)-3',5'-cyclic 3-(3-butenyl) thymidine ethylphosphate. The regioisomeric preference was investigated by comparison to synthesized model compounds of 3',3'-, 3',5'-, and 5',5'-linkages, where the model 3'-phosphoester linkages were to the secondary alcohol of 3-hydroxytetrahydrofuran and the model 5'-linkages derived from coupling to the primary alcohol of tetrahydrofurfuryl alcohol. From the 31P resonance frequency assignments of those small molecule model compounds, 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 the propagating alcohol relative to the initiator, 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 upon (R)-3',5'-cyclic 3-(3-butenyl) thymidine ethylphosphate 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. Further model reactions suggested that the P-O5' bond cleavage products can be detected upon the formation of dimers during the ring-opening polymerization. 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.