Our work required a reliable efficient preparation of 2-trimethylsilyloxymethyl((2R,3S)-3-(trimethylsilyloxy)-2,3-dihydrofuran. The best literature protocol for the preparation of this furanoid glycal is the treatment of thymidine with 20 mol% (NH4)2SO4 in (TMS)2NH (HMDS) at reflux. Unfortunately, this procedure was found to be unreliable on scale-up. The need for removal of ammonia formed during reactions using HMDS was identified as critical to the success. A high through-put screening prototype enabling release of the gaseous ammonia was developed allowing rapid screening of reaction conditions. Extensive screening initially identified 1 mol% (PhSO2)2NH (DBSI) in heptane at reflux gave more reliable and improved results. Despite this, these conditions still suffered from disadvantages such as the formation of a bis-glycosylated by-product, the need for a wiped film distillation to isolate the glycal and the need to expel the formed NH3 gas from the reaction mixture. Further screening revealed an unprecedented catalyst 1 mol% (Ph2PS)2NH (PTPI) with bistrimethylsilylacetamide (BSA) in heptane-toluene at 100 °C gave rapid and virtually quantitative conversion to the glycal. Throughout, process analytical technology (PAT) was extensively employed to improve process understanding and inform development from bench scale through over three orders of magnitude scale-up. Thus, a new class of novel silylation organocatalysts for the conversion of 2’-deoxynucleosides to furanoid glycals has been discovered. These phosphorimides, (Ph2PS)2NH and (Ph2PSe)2NH 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 synthesis of glycals with various substitution patterns while minimizing the formation of undesired by-products and expanding the scope of this methodology.

Discovery and development of an unusual novel organocatalyst for the conversion of nucleosides to furanoid glycals

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ACS Fall 2022

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