Deoxyribonucleic Acid as a Model for the Design of Functional, Degradable Polymers

Abstract

A grand challenge that crosses synthetic chemistry and biology is the scalable production of functional analogues of biomacromolecules. This dissertation has focused on the use of deoxynucleoside building blocks bearing non-natural bases to develop a synthetic methodology that allows for the construction of high molar mass deoxynucleotide polymers. Two thymidine-derived bicyclic monomers, (R)- and (S)- 3′,5′-bicyclic 3-(3-butenyl) thymidine ethylphosphate, were synthesized in two steps directly from thymidine, via butenylation and diastereoselective cyclization promoted by N,N-dimethyl-4-aminopyridine. Poly(3′,5′-bicyclic 3-(3-butenyl) thymidine ethylphosphate)s with low dispersities (Ð < 1.10) were obtained from ring-opening polymerizations of the more thermodynamically unstable (R)-monomer, catalyzed by 1,5,7-triazabicyclo[4.4.0]dec-5-ene at ambient temperature. These studies established a reliable synthetic pathway to thymidine-derived polydeoxyribonucleotide analogues from a six-membered bicyclic phosphoester.

Regioregularity is a crucial property in the synthesis of DNA analogues, as natural DNA is synthesized exclusively in 5′-to-3′ direction. From the ³¹P resonance frequency assignments of 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, 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. 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. 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 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. Furthermore, this dissertation provides a fundamental understanding of the polymerization behavior of sixmembered cyclic phosphoesters, and broadens the scope of DNA analogues from the ring-opening polymerization of 3′,5′-bicyclic phosphoesters.