Follow the Silyl Cation: Insights into the Vorbrüggen Reaction

Abstract

To succeed in the development of a mechanistic model for the Vorbruggen reaction of thymine with an advanced furanose intermediate, a range of spectroscopic techniques were applied and found essential to understanding kinetically relevant, yet nonisolable, silylated reaction intermediates. Understanding of the dynamic nature of the interaction of trimethylsilyl trifluoromethanesulfonate with these functionally dense substrates allowed for the accurate prediction and straightforward explanation of the relationship between process parameters and the levels of key impurities.

Nitro-Activated Nucleobase Exchange in the Synthesis of 2′-Fluoro-2′-Deoxyribonucleosides

“…The mechanism of transglycosylation , is depicted in Scheme . Under Vorbrüggen conditions, BSTFA-silylated intermediate TMS-1bβ releases 5-nitro-2,4-bis­(trimethylsilyloxy)­pyrimidine ( C ) and forms glycosyl oxocarbenium ion pair IP , which is in equilibria with β-glycosyl triflate β - G-OTf and α-glycosyl triflate α - G-OTf .…”

“…Glycosylation of nucleobases with 2-fluorinated glycosyl donors bearing various common anomeric leaving groups (e.g., −Cl, −Br, −OAc, −OBz) offered access to sofosbuvir, clofarabine, gemcitabine, and other 2′-fluoro-2′-deoxypyrimidine and 2′-fluoro-2′-deoxypurine nucleosides. , The glycosylation normally requires higher temperatures and prolonged reaction times to give mixtures of regio- and/or stereo-isomeric products. This likely results from the slow formation of reactive oxocarbenium species , by the inductive effect of the 2′-fluoro substituent. Derivatization of simple or available 2′-fluoro-2′-deoxynucleosides represents another general approach to increase the complexity of the fluorosugar moiety that can limit off-target effects and improve safety profiles.…”

Competing interests during the key N-glycosylation of 6-chloro-7-deaza-7-iodopurine for the synthesis of 7-deaza-2′-methyladenosine using Vorbrüggen conditions

“…About a dozen patent applications filed between 2002 and 2010 report the synthesis based on these approaches; however, the preparation of the key epoxide intermediates can require 5 to 10 steps. Looking for a shorter process to produce compound 2 , we envisioned the traditional Vorbrüggen protocol for the key N -glycosylation reaction ( Vorbrüggen and Ruh-Pohlenz, 1999 ; Beutner et al, 2019 ). Although Bio and co-workers have described the lack of reactivity of 6-chloro-7-deazapurine ( 4a ) under these conditions ( Bio et al, 2004 ), the Hocek group succeeded in coupling perbenzoylated 2-methyl-ribose ( 5 ) with iodinated 6-chloro-7-deazapurine ( 6 ) ( Scheme 1 ) in the presence of TMSOTf and DBU in 48% yield ( Nauš et al, 2012 ).…”