Synthesis of enantiopure phthalides including 3-butylphthalide, a fragrance component of celery oil, and determination of their absolute configurations

Enantiopure phthalides 2 and 5–8 were synthesized via enantioresolution of the corresponding alcohols with a chiral auxiliary of camphorsultam dichlorophthalic acid, (1S,2R,4R)-(−)-CSDP acid 3, followed by solvolysis with KOH in MeOH and the catalytic oxidation of chiral glycols with iridium complex 28. The absolute configurations of phthalides 2 and 5–8 were determined by applying the 1H-NMR anisotropy method of MαNP acid (4), 2-methoxy-2-(1-naphthyl)propionic acid, to the chiral synthetic precursory alcohols. In the case of 3-phenylphthalide (R)-(−)-7, the absolute configuration determined by the 1H-NMR anisotropy method using MαNP acid 4 agreed with that by the X-ray crystallographic method. By applying these methods, 3-butylphthalide (S)-(−)-2, a fragrance component of essential oil of celery, has been synthesized in an enantiopure form, and its absolute configuration was unambiguously determined. Chirality 17:218–232, 2005. © 2005 Wiley-Liss, Inc.