Enantiomeric Selection Properties of β‐homoDNA: Enhanced Pairing for Heterochiral Complexes

Abstract

The analysis of the physicochemical properties of sugarmodified nucleic acids is currently at the core of intense multidisciplinary investigations including chemistry, biology, biotechnology, and medicine. On one side, synthetic polymers acting as RNA/DNA mimics have extensively been devised for applications in therapy, diagnostics, and synthetic biology. On the other side, the construction of alternative pairing systems has been explored either to consider their use as orthogonal nucleic acid candidates or with the aim to potentially yield insights into the chemical evolution criteria ultimately leading to the current genetic system. In all cases, structural changes of natural (deoxy)ribose cores have been established to determine profound consequences in the pairing potential of the resulting artificial nucleic acids. In some noteworthy examples, oligonucleotide systems endowed with six-membered sugars in the backbone have been observed to hold the singular property (unique of its kind) of pairing with homochiral complements having opposite sense of chirality. Relevant to etiology-oriented investigations on nucleic acid structure, these findings could suggest the existence of a relationship between nature of the sugar backbone and chiral-selection properties of nucleic acids, thereby providing insights to enrich our understanding of the structural prerequisites for base pairing. From a comparative analysis of the pairing behavior of six-membered nucleic acids we perceived that, despite the large structural differences, oligonucleotide systems capable of isoand heterochiral hybridization (Figure 1) shared preorganized carbohydrate conformations with equatorially-oriented nucleobases. This observation took us to wonder if such an arrangement of the aglycon moiety, especially whereas inducing strong backbone-base inclination or even enabling formation of quasilinear oligomeric structures, could lead sugar chirality not to be crucial in hybridization processes. In view of systematic investigations aimed at addressing this question, we herein considered the chiral selection properties of the well-known pairing system composed of (6’!4’)-linked b-erythro-hexopyranosyl nucleotides (b-homoDNA; Figure 1). Based on above assumptions and early experimental data, we reasoned that the strongly inclined complexes provided by the “allequatorial” pyranose backbone of b-homoDNA could make the latter an interesting candidate displaying potential for heterochiral hybridization. An investigation into the enantioselectivity of the hybridization processes of b-homoDNA required access to oligomeric sequences in both enantiomeric forms (b-dand b-lhomoDNA). From a synthetic standpoint, while access to d-hexopyranosyl nucleosides was easily obtained by a carbohydrate-based route, the synthesis of the corresponding lenantiomers under the same reaction conditions was hampered by the limited commercial availability of almost all lhexoses. In an alternative path, our long studied de novo approach to l-monosaccharides and other structurallyrelated compounds was recently exploited for the preparation of the l-nucleosides 2a,b (T and A acting as model nucleobases) from the homologating agent 1 (Scheme 1). Figure 1. Sugar-modified nucleic acids displaying pairing aptitude for homochiral complements of opposite chirality.