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Short Paper | Special issue | Vol 99, No. 1, 2019, pp.638-648
Published online, 6th August, 2018
DOI: 10.3987/COM-18-S(F)17
Site-Selective Synthesis of Acacetin and Genkwanin through Lipase-Catalyzed Deacetylation of Apigenin 5,7-Diacetate and Subsequent Methylation

Rie Fujita, Susanta Mandal, Kengo Hanaya, Mitsuru Shoji, Shuhei Higashibayashi, and Takeshi Sugai*

*Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, 1-5-30 Shiba-Kouen, Minato-ku, Tokyo, Japan

Abstract

Candida antarctica lipase B-catalyzed deacetylation proceeded with high site-selectivity on the C-4’ acetyl group in apigenin triacetate to give apigenin 5,7-diacetate. Methylation of the liberated hydroxy group with the combination of trimethyloxonium tetrafluoroborate (Meerwein reagent) and 1,8-bis(dimethylamino)naphthalene (proton sponge) in CH2Cl2 proceeded in a quantitative manner to give the product methylated at the C-4’ hydroxy group (acacetin 5,7-diacetate). Even with the same precursor, a different methylation product at the C-7 hydroxy group (genkwanin 4’,5-diacetate) was obtained in 86% yield by applying iodomethane and Cs2CO3 in dimethyl sulfoxide (DMSO). The methylated products were deprotected to form acacetin and genkwanin. We inferred that the latter unexpected methylation was ascribable to the intermolecular migration of an acetyl group from C-7 to C-4’. DFT calculations indicated that the C-7 phenoxide ion was 12.6 kJ/mol more stable than the initially formed C-4’ phenoxide ion.