Synthesis of (R)-3-Methylphthalide by Reductive Cyclization of a 2-Acylarylcarboxylate Using the Chiral Boronic Ester TarB-H and Sodium Borohydride

Author(s): Aline Aparecida Nunes de Souza , Jason Guy Taylor .

Journal Name: Letters in Organic Chemistry

Volume 13 , Issue 9 , 2016

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Abstract:

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.

Keywords: Phthalides, asymmetric reduction, sodium borohydride, TarB–H, cyclization, lactonization.

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Article Details

VOLUME: 13
ISSUE: 9
Year: 2016
Page: [657 - 660]
Pages: 4
DOI: 10.2174/1570178613666161021154112
Price: $58

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