An improved stereodivergent and practical synthesis of α- and β-pseudouridines

An improved stereodivergent and practical synthesis of both alpha- and beta-pseudouridines has been achieved from a common intermediate. This practical approach features a highly diastereoselective Grignard reaction using inexpensive protected d-ribose under non-cryogenic conditions and a divergent one-pot, acid-mediated global deprotection-cyclisation and anomerization to give beta-pseudouridine, or a Mitsunobu cyclisation followed by deprotection to provide alpha-pseudouridine. Detailed H-1 NMR kinetic studies provide insight into the cyclisation and anomerization steps.

Automated summary

An improved method for synthesizing both alpha- and beta-pseudouridines from a common intermediate has been developed. This practical approach involves a highly diastereoselective Grignard reaction using inexpensive protected D-ribose, followed by a one-pot, acid-mediated deprotection-cyclization and anomerization to obtain beta-pseudouridine, or a Mitsunobu cyclization and subsequent deprotection to obtain alpha-pseudouridine. Detailed H-1 NMR kinetic studies provide insights into the cyclization and anomerization steps.