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

Abstract

Our work required a reliable efficient preparation of 2-trimethylsilyloxymethyl((2R,3S)-3-(trimethylsilyloxy)-2,3-dihydrofuran (glycal 1). The best literature protocol for the preparation of this dihydrofuran glycal is the treatment of thymidine with 20 mol % (NH₄)₂SO₄ in (TMS)₂NH (HMDS) at reflux. Unfortunately, this procedure was found to be extremely unreliable and messy on scale-up. The need for removal of ammonia formed during reactions using HMDS was identified as critical to the success of these reactions. A high throughput screening prototype setup enabling release of the gaseous ammonia byproduct was developed, allowing rapid screening of reaction conditions. Extensive high throughput screening initially identified 1 mol % (PhSO₂)₂NH (DBSI) in heptane at reflux gave more reliable and improved results. Despite this, this improvement still suffered from disadvantages such as the formation of a bisglycosylated byproduct, 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 3 orders of magnitude scale-up.