Process for the preparation of (1<i>S</i>,4<i>R</i>)-2-oxa-3-azabicyclo[2,2.1]hept-5-enes

摘要

Enantiomerically enriched (1 S,4R)-2-oxa-3-azabicyclo[2.2.1]hept-5-ene of formula wherein PG1 is an amino-protective group, are prepared from cyclopentadiene via hetero-Diels-Alder cycloaddition with protected 1-C-nitroso-β-D-ribofuranosyl halides of formula wherein X is a halogen atom selected from fluorine, chlorine, bromine and iodine, PG2 is a hydroxyl-protective group and PG3 is a 1,2-diol-protective group.;;

主权项

1. A process for preparing an enantiomerically enriched (1S,4R)-2-oxa-3-azabicyclo [2.2.1] hept-5-ene of formula wherein PG1 is an amino-protective group, the process comprising the steps of (i) reacting a protected 1-C-nitroso-β-D-ribofuranosyl halide of formula wherein X is a halogen atom selected from the group consisting of fluorine, chlorine, bromine and iodine, PG2 is a hydroxyl-protective group, and PG3 is selected from the group consisting of methylene, ethylidene, isopropylidene, cyclopentylidene and cyclohexylidene; with cyclopentadiene to obtain a (1S,4R)-3-(1-C-halo-α-D-ribofuranosyl)-2-oxa-3-azabicyclo[2.2.1]hept-5-ene of formula wherein X, PG2 and PG3 are as defined above; (ii) hydrolyzing the compound obtained in step (i) to obtain free (1S,4R)-2-oxa-3-azabicyclo[2.2.1]hept-5-ene (I; PG1=H) or the corresponding hydrohalide and the corresponding 5-O-protected D-ribonolactone by phase separation, wherein the enantiomeric excess of (I) or corresponding hydrohalide is at least 80%; and (iii) introducing the amino-protective group PG1; wherein step (i) is carried out at a temperature between about −80° C. and about 0° C.