One-Pot Synthesis of Acyclic Nucleosides from Carbohydrate Derivatives, by Combination of Tandem and Sequential Reactions

Abstract

The design of processes which combine tandem and sequential reactions allows the transformation of readily available precursors into high-profit products. This strategy is illustrated by the one-pot synthesis of acyclic nucleosides, which are potential antiviral compounds, from readily available carbohydrates. The reaction conditions are mild, compatible with most functional groups. Depending on the starting sugar, both common and uncommon acyclic chains can be prepared. These polyhydroxylated chains can be combined with different bases to generate diversity.

“Cut and Paste” Processes in the Search of Bioactive Products: One-Pot, Metal-free O-Radical Scission-Oxidation-Addition of C, N or P-Nucleophiles

“…Nitrogen bases can also add to oxycarbenium ions, as shown in the conversions 58→ 59 and 60→ 61 ( Boto, Hernández et al, 2007b ). Both purine and pyrimidine bases reacted in good to excellent yields.…”

“…In effect, the scission generates a C -radical that can be readily oxidized to a cationic intermediate when the latter is stabilized by adjacent groups. This is the case for tertiary C -radicals, or those adjacent to nitrogen or electron-rich oxygen functionalities ( Boto et al, 1999 – 2004 ; 2005a ; 2007a ; 2007b ; 2007c ; 2007d ; Francisco et al, 2001 ; Romero-Estudillo, 2013 , 2015a , 2015b ; Kiyokawa et al, 2017 ; André-Joyaux et al, 2019 ). When the substrates are aminoacids or β-hydroxyamines, an intermediate iminium ion is formed, while carbohydrate substrates afford oxycarbenium ion intermediates.…”

Glycosylation reactions mediated by hypervalent iodine: application to the synthesis of nucleosides and carbohydrates

“…Boto et al applied the reaction to the one-pot synthesis of acyclic nucleosides that belong to an important class of nucleosides with antiviral activity [ 74 ]. First, they tried to synthesize acyclic nucleosides in a stepwise manner.…”

“…Based on the conditions for the stepwise fragmentation and glycosylation procedure, Boto et al explored the one-pot version of the reaction [ 74 ]. When the β-fragmentation, the first step of oxidative glycosylation, was carried out in CH 2 Cl 2 and then the Lewis acid and the silylated base were added, the acyclic nucleosides were obtained in low yields.…”

Synthesis of orotidine by intramolecular nucleosidation

“…We prepared three derivatives of 1-acyl-D-ribofuranose, 4a, 4b and 4c (Scheme 3) 11,12 in order (1) to probe the propensity of the leaving group for intramolecular nucleosidation and ( 2) to check the interference from a competing transacylation (from the 1-to the 5-position) during deprotection of the 5-O-silyl group, a process that would block the 5-O-position and prevent the formation of required 5 0 -O-orotate ester bond (such as B in Scheme 1). [13][14][15] The desired ribosides 5b and 5c were formed using Et 3 NÁ3HF (with 14% of benzoyl and 0% acetyl migration by-products) respectively; 5a was synthesized using TBAF with no by-product. The exact position of acyl groups in compounds 5a-5c was confirmed by HMBC NMR spectroscopy (Fig.…”