Nucleic‐Acid Analogues with Constraint Conformational Flexibility in the Sugar‐Phosphate Backbone (‘Bicyclo‐DNA’). Part 1. Preparation of (3S,5′R)‐2′‐Deoxy‐3′,5′‐ethano‐αβ‐D‐ribonucleosides (‘Bicyclonucleosides’)

Abstract

AbstractWe describe the synthesis of 2′‐deoxy‐3′,5′‐ethano‐D‐ribonucleosides 1–8 (= (5′,8′‐dihydroxy‐2′‐oxabicyclo‐[3.3.0]oct‐3′‐yl)purines or ‐pyrimidines) of the nucleobases adenine, thymine, cytosine, and guanine. They differ from natural 2′‐deoxyribonucleosides only by an additional ethylene bridge between the centers C(3′) and C(5′). The configuration at these centers (3S,5′R) was chosen as to match the geometry of a repeating nucleoside unit in duplex DNA as close as possible. These nucleosides were designed to confer, as constituents of an oligonucleotide chain, a higher degree of preorganization of a single strand for duplex formation with respect to natural DNA, thus leading to an entropic advantage for the pairing process. The synthesis of these ‘bicyclonucleosides’ was achieved by construction of an enantiomerically pure carbohydrate precursor 18/19 (Schemes 1), which was then converted to the corresponding nucleosides by known methods in nucleoside synthesis (Schemes 2 and 3). In all cases, both anomeric forms of the nucleosides were obtained in pure crystalline form, the relative configuration of which was established by 1H‐NMR‐NOE spectroscopy. A conformational analysis of the nucleosides with β‐configuration at the anomeric center by means of X‐ray and 1H‐NMR (including NOE) spectroscopy show the furanose part of the molecules to adopt uniformly a 1′exo‐conformation with the base substituents preferentially in the anti‐range in the pyrimidine nucleosides (anti/syn ca. 2:1) distribution in the purine nucleosides (in solution).