Preparation of C4'-modified nucleoside analogs

C4'-modified nucleoside analogs continue to attract global attention for treating infectious diseases and as components in oligonucleotide therapeutics. Current preparations mostly employ lengthy semi-synthetic approaches that do not allow for the efficient exploration of the chemical space associated with this valuable nucleoside subclass. Here we describe the pilot-scale (250 mg) and process-scale (85 g) preparation of 4'-methyl-ribothymidine (4',5-dimethyluridine) using a de novo strategy. Both L- and D-nucleoside analogs are accessible, and 10 different C4' modifications and 20 different nucleobases can be used interchangeably to create new analogs. This protocol involves the use of an enantioselective proline-catalyzed aldol between 2,2-dimethoxyacetaldehyde and a dioxanone. A 1,2-addition into the aldol product installs the C4' modification. Subsequent cyclization via intramolecular trans-acetalization delivers the modified ribose core of the nucleoside analog. Peracetylation, followed by Vorbrüggen glycosylation, completes the route. The pilot- and process-scale protocols can be completed in ~5 and ~7 d, respectively, to deliver C4'-modified nucleoside analogs in good yields and excellent enantiopurity.