Background: Phthalides are pervasive benzolactone structural frameworks in nature and
have a broad profile of biological activities. Catalytic asymmetric reduction with the in situ lactonization
of 2-acylarylcarboxylate compounds is an efficient strategy for chiral phthalide synthesis. The tartaric
acid-derived reagent TarB–X is capable of mediating the asymmetric reduction of aromatic ketones
using either LiBH4 or NaBH4 as the reductant. Up until now, the asymmetric reduction by Tarb-
H/NaBH4 had not been applied to the synthesis of chiral phthalides.
Methods: The requsite substrate, methyl 2-acetylbenzoate was obtained by a two step reaction starting
from phthalic anhydride and maloninc acid. Tarb-H was obtained by treatment of L-(+)-tartaric acid
with phenylboronic acid. The catalyst and NaBH4
were reacted with methyl 2-acetylbenzoate at room
temperature for 1 h. The structure of (R)-3-Methylphthalide was established by NMR and mass spectrometry
and its enantiomeric excess was determined by HPLC. The relative configuration was deduced
by comparison of the optical rotation with data given in the literature.
Results: (R)-3-Methylphthalide was obtained in moderte yield and high enantiomeric excess.
Conclusion: (R)-3-methylphthalide was prepared in high enantiomeric excesses using an inexpensive
and easily synthesized tartaric acid derived boronic ester (TarB–H) with sodium borohydride. The chiral
phthalide was obtained in an open flask by reductive cyclization of a 2-acylarylcarboxylate.