Face selective 6,1′-(1-oxo)ethano bridge formation of uracil nucleosides under hypoiodite reaction conditions

Abstract

Synthesis of novel spiro uracil nucleosides with an anomeric orthoester structure in a stereoselective manner under the hypoio dite reaction conditions of Heusler-Kalvoda and Suárez is fully described. While 2′-deoxy-6-(hydroxymethyl)uridine 2 and 2′-deoxy-6-[(1-hydroxy-1-methyl)ethyl]uridine 4 gave β- and α-spiro nucleosides in 43–68% yields with low βα selectivity (11.3∼31), the secondary ary alcohols 3a and 3b showed 68–79% chemical yields with significantly better βα selectivity (6.51∼146). The βα orientation of the 6-(hydroxyalkyl)uridine counterparts 6–8, 16–17, and 19 seemed to be controlled not only by the 2′-substituent but also by the chirality at the C7-stereocenter of the C6-side chain like in the 2′-deoxyuridine series. The transition state geometries of the reaction were postulated based on the X-ray crystallographic structures of cyclized products 20α and 24β.