An expeditious synthesis of 3′-α-carboxymethyl-2′-O-methyl ribonucleosides

Amide-Linked Ribonucleoside Dimers Derived from 5‘-Amino-5‘-deoxy- and 3‘-(Carboxymethyl)-3‘-deoxynucleoside Precursors1

“…The Novartis group 7 have shown that oligomers containing amide-linked 2‘-deoxynucleoside analogues exhibited increased duplex stability (0.4−0.9 °C/dimer) and resistance to degradation by (endo and exo)nucleases. Additional enhancements of duplex stability observed with oligomers containing amide-linked dimers with 2‘- O- methyl substituents on both sugar rings were attributed to increased population of the 3‘-endo (ribo-like) furanose conformation range 7e. NMR and molecular modeling studies were consistent with similar trends observed with oligonucleotides with analogous 2‘-substituents …”

“…Stereoselective reduction 10,14 of 3 (10% Pd−C/MeOH) gave 6 , whose ribo configuration was indicated by difference NOE (6% enhancement of the H3‘ resonance upon irradiation of H2‘) and corroborated by conversion to lactone 10 . This two-step sequence (Wittig olefination and stereoselective hydrogenation) provides a valuable alternative to free-radical coupling methods 15 used for the preparation of 3‘-substituted 2‘,3‘-dideoxynucleosides. , Monomers prepared by free-radical methods are obtained with high α-facial diastereoselectivity at C3‘ from 5‘-O - protected 2‘-deoxynucleosides. However, analogous treatment of 2‘,5‘-di-O - protected ribonucleosides resulted in coupling at the opposite (β) face to give contaminating 15f or predominant 7e formation of xylofuranosyl products.…”

“…We and others , became interested in amide-linked oligonucleotide analogues for potential antisense applications. The Novartis group 7 have shown that oligomers containing amide-linked 2‘-deoxynucleoside analogues exhibited increased duplex stability (0.4−0.9 °C/dimer) and resistance to degradation by (endo and exo)nucleases.…”

“…We have communicated 10 synthesis of the γ-butyrolactone-fused (3.3.0) nucleosides 9 and 10 and their application for the preparation of amide-linked ribonucleoside dimers (Scheme ) that were expected to have a favorable 3‘-endo conformational bias, 7e, resistance to nucleases, and enhanced membrane permeability (no backbone charge) . We had hoped that the lactones would be readily susceptible to ring opening with 5‘-amino-5‘-deoxynucleosides by analogy with model reactions. , However, 9 and 10 proved to be unreactive with 5‘-amino-5‘-deoxyadenosine at ambient temperature under a number of reaction conditions, including addition of several acylation promoters.…”

Glucose-Derived 3‘-(Carboxymethyl)-3‘-deoxyribonucleosides and 2‘,3‘-Lactones as Synthetic Precursors for Amide-Linked Oligonucleotide Analogues1

“…Free radical-mediated coupling of [3‘- O- (aryloxy)thiocarbonyl or 3‘-deoxy-3‘-iodo)]-2‘-deoxynucleoside precursors with (allyl4a or styryl 4b )tributyltin/AIBN has been employed to introduce substituents at C3‘ that were modified to generate internucleoside linkages for ribonucleotide-dimer mimics. 4b, Such radical couplings are highly stereoselective and give 3‘-branched derivatives with the desired β- d -erythro configuration with 5‘-O - protected 2‘-deoxynucleoside substrates. However, analogous couplings with 5‘-O - protected 3‘- O- [(aryloxy)thiocarbonyl]ribonucleosides that have 2‘-O - substituents gave 3‘-branched derivatives with contaminating 5d or predominant6a formation of the opposite (xylo) configuration, presumably resulting from the more sterically demanding effects of 2‘-substituents on the α-face.…”