Organocatalytic Conversion of Nucleosides to Furanoid Glycals

Abstract

A class of organocatalysts that are highly active for the conversion of 2′-deoxynucleosides to furanoid glycals have been discovered. These phosphorimides, (Ph 2 PS) 2 NH and (Ph 2 PSe) 2 NH, were shown to effectively mediate persilylation of 2′-deoxynucleosides allowing the elimination of the nucleobase giving the corresponding glycal. These mild conditions were demonstrated in the syntheses of glycals with various substitution patterns while minimizing the formation of undesired byproducts and expanding the scope of this methodology.

Discovery and Development of an Unusual Organocatalyst for the Conversion of Thymidine to Furanoid Glycal

“…Despite not being commercially available, both PTPI and PSePI are easily prepared in a one-pot operation from Ph 2 PCl and HMDS in toluene followed by addition of sulfur or selenium, respectively . Computational modeling to calculate the energetic preference of the position of TMS in these catalysts showed silicon–S and silicon–Se bonds are weaker than the silicon–oxygen bond as expected . Additionally, while Se- and S-derivatives prefer to position TMS on the nitrogen, respectively, the corresponding oxo-derivative POPI prefers to be silylated on the oxygen.…”

“…Since the new conditions require a minimal amount of catalyst and produce virtually pure product, 1 can often be used without further purification. These conditions have been extended to various substituted deoxynucleosides allowing rapid access to a variety of these useful furanoid glycals . The preparation of several unnatural nucleosides using these glycals will be reported in due course.…”

“…15 Computational modeling to calculate the energetic preference of the position of TMS in these catalysts showed silicon−S and silicon−Se bonds are weaker than the silicon−oxygen bond as expected. 16 Additionally, while Se-and S-derivatives prefer to position TMS on the nitrogen, respectively, the corresponding oxo-derivative POPI prefers to be silylated on the oxygen. In good agreement with the experimental results, we could conclude that catalysts that are more easily silylated on nitrogen, PSePI and PTPI, are more active in the transformation.…”

“…These conditions have been extended to various substituted deoxynucleosides allowing rapid access to a variety of these useful furanoid glycals. 16 The preparation of several unnatural nucleosides using these glycals will be reported in due course. Along the course of development, PAT and extensive high throughput experimentation were used to interrogate the process and provide valuable mechanistic insight which were leveraged to discover new, dramatically improved chemistry and over 3 orders of magnitude scale-up.…”

“…Organocatalysts PTPI and PSePI 15 were synthesized according to literature procedures. 16 Infrared spectra were recorded on a Nicolet 6700 FT-IR spectrometer and are reported in reciprocal centimeters (cm −1 ). 1 H NMR spectra were recorded on Bruker 400, 500, or 600 MHz spectrometers.…”