A highly stereoselective synthesis of a cyclic dinucleotide (CDN) STING agonist containing two chiral thiophosphoramidate linkages is described. These rare, yet key functional groups were, for the first time, installed efficiently and with high diastereoselectivity using a specially designed P(V) reagent. By utilizing this strategy, the CDN was prepared in greater than sixteen-fold higher yield than the prior P(III) approach, with fewer hazardous reagents and chromatographic purifications. File list (2) download file view on ChemRxiv BMS Diastereoselective Synthesis Thiophosphoramidat... (396.86 KiB) download file view on ChemRxiv BMS Diastereoselective CDN Synthesis-Supporting Inform... (1.83 MiB)
The
stereoselective and divergent synthesis of two aza-nucleosides
is reported. Starting from xylofuranose 9, aza-adenosine 2 was prepared in 13 steps and 7% overall yield, and aza-guanosine 3 was prepared in 13 steps and 7.8% overall yield. Compared
to the original syntheses, some advantages of these new routes are
significant yield improvement, overall step-count reduction, an optimized
protecting group strategy, the development of a versatile platform
for nitrogenous base incorporation, and the elimination of hazardous
reagents (e.g., benzyl isocyanate, Et3N·HF).
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