合成路线1

The reduction of the chiral propionic acid (VII) with NaBH4 in THF gives the primary alcohol (XXIX), which by reaction with SOCl2 and pyridine in CHCl3 yields the chloride (XXX). Condensation of (XXX) with the butyrolactone intermediate (XXVII) by means of Mg and dibromoethane affords the ketonic adduct (XXXI). Reduction of the exocyclic carbonyl group of (XXXI) with NaBH4 in THF/ methanol provides a 3:1 diastereomeric mixture of the desired chiral alcohol (XXXII) and its OH-epimer (XXXIII) that are separated by flash chromatography. Reaction of (XXXII) with MsCl and TEA, followed by treatment with NaN3, affords the azido derivative (XXXIV), which is condensed with 4-amino-3,3-dimethylbutyramide (XIX) by means of 2-hydroxypyridine and TEA to provide the adduct (XXXV). Finally, the azido group of (XXXV) is reduced with H2 over Pd/ in MeOH to yield the target amino alcohol. An extensive study on the stereoselective reduction of the ketonic adduct (XXXI) has been performed. No better diastereoselectivity than 3:1 has been obtained for the synthesis of the chiral alcohol (XXXII). However, excellent diastereoselectivity (97:3) has been obtained for the synthesis of its OH-epimer, alcohol (XXXIII), with K-selectride in THF, which could potentially provide access to the target amino alcohol via a double inversion protocol.

合成路线2