合成路线1

The chiral precursor (X) has been obtained from pyridine (V) by two different strategies. Heck coupling of 2,6-diethyl-4-bromopyridine (V) with benzyl 3(S)-cyclopentyl-3-hydroxy-4-pentenoate (XXIV) in the presence of Pd(OAc)2, Bu4NCl and (c-Hex)2NMe in DMA at 90 °C affords benzyl 3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3(R)-hydroxypent-4-enoate (XXV), which finally undergoes double bond reduction and O-debenzylation by means of H2 over Pd/C in EtOH .
Alternatively, coupling of 4-bromo-2,6-diethylpyridine (V) with 1-cyclopentyl-2-propen-1-ol (XXVI) in the presence of Pd(OAc)2, LiBr and Et3N in DMA/H2O gives rise to 1-cyclopentyl-3-(2,6-diethyl-4-pyridinyl)-1-propanone (XXVII). Subsequent condensation of ketone (XXVII) with ethyl acetate (XXVIII) by means of LiHMDS in THF affords the hydroxy ester (XXIX), which by hydrolysis with NaOH in H2O/THF yields the racemic free acid (XXX). Finally, fractional crystallization of carboxylic acid (XXX) with (1R,2R)-2-amino-1-(4-nitrophenyl) propane-1,3-diol in THF provides the desired (R)-enantiomer (X). The undesired (S)-enantiomer (XXXI), obtained from the mother liquors of resolution of compound (XXX), can be recycled by esterification with EtOH and H2SO4 in refluxing THF, followed by retroaldol reaction of the obtained hydroxy ester in the presence of t-BuOK in MTBE to produce ketone (XXVII) .