Direct Access to Unique C‐5’‐Acyl Modified Nucleosides through Liebeskind–Srogl Cross‐Coupling Reaction

Abstract

The chemical functionalization at C‐5’ position of nucleosides has been significantly less studied compared to the C‐1’, C‐2’ and C‐3’ sugar positions in spite of its potential important role for biological activity. We describe here the synthesis of new carbothioate nucleosides which were then engaged in a Liebeskind‐Srogl reaction with various boronic acids for the preparation of diversely modified C‐5’‐acyl nucleosides. Applied to pyrimidine nucleosides in the DNA and RNA series, the reaction showed a broad substrate scope and more than 25 examples were synthesized in good‐to‐excellent isolated yields. This general and efficient Pd‐catalyzed and Cu(I)‐mediated cross‐coupling represents a convenient method to prepare a diverse set of 5’‐modified nucleosides and paves the way for further transformation into a variety of potentially bioactive compounds via the possible conversion of the C‐5’‐ketone.

Serendipitous Synthesis of 5-Hydroxyuridine from 2′,3′-O-Isopropylidene N4-Acetylcytidine by Hypervalent Iodine(III)-Mediated Reaction

“…Heating 3 in dimethylformamide for an unspecified time gave 5-acetoxy-2′,3′- O -isopropylidene uridine 4 , although the obtained yield was not reported. In the course of our studies dedicated to the synthesis of C-5′-acyl-modified nucleosides, 10 we wanted to prepare several 5′-carboxylic acid nucleosides 11 by following the efficient 2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO)–[bis(acetoxy)iodo]benzene (BAIB) method described by Epp and Widlanski. 12 The C-5′-oxidation proceeded smoothly for all studied pyrimidine nucleosides, except for the cytidine protected by N 4-acetyl-2′,3′- O -isopropylidene groups, which led to a complex mixture of compounds.…”

Rapid plugged flow synthesis of nucleoside analogues via Suzuki-Miyaura coupling and heck Alkenylation of 5-Iodo-2’-deoxyuridine (or cytidine)

“…The introduction of aromatic or heteroaromatic functionalities on the nucleosides (that help enhance the fluorescent properties) via metal-catalyzed cross-coupling reactions [5,6] (especially palladium-catalyzed Suzuki-Miyaura coupling) has been extensively explored [7,8]. Contributions by the research groups of Len [9][10][11][12], Shaughnessy [13][14][15][16], Lakshman [17][18][19][20][21][22] and many others [18][19][20][21][22] are acknowledged for their advances in the area of nucleoside modification. We have also been active in the development of several catalytic systems (palladium-based) allowing efficient cross-coupling [23][24][25][26][27][28][29][30].…”

Ferrocene as a potential electrochemical reporting surrogate of abasic sites in DNA

“…Interest in chemical modification of nucleic acids stems from early developments of nucleoside and nucleotide-based antiviral drugs as well as of antisense oligonucleotide therapeutic agents. [1][2][3][4] The need for synthesizing oligonucleotides equipped with chemical alterations has been spurred further by the recent advent of mRNA-based vaccines. 5,6 In this context, besides solid-phase synthesis, [7][8][9] modified oligonucleotides can be constructed using polymerase-catalysed incorporation of unnatural nucleoside triphosphates ((d)N*TPs).…”