NoteIsoliquiritigenin [ILG, (E)-1] is a naturally occurring antioxidant that belongs to the class of chalcones, 1) and is known to exhibit a wide spectrum of biological activities.2,3) For example, antiinflammatory, antitumor, antiatherosclerotic, antihistaminic, antidiabetic, antiplatelet aggregation, cardioprotective, estrogenic, quinone reductase-inducing, antiviral, antileishmanial, antimalarial, antiangiogenic, antibacterial, and antimitotic activities of ILG, (E)-1 have recently been reported by various authors. [4][5][6][7][8][9][10][11][12] reactions. In addition, improvement of the classical Claisen-Schmidt condensation is presented. As far as we know, our protocol constitutes the first report of the use of the HWE reaction for the synthesis of ILG [(E)-1]. [18][19][20][21][22] In our synthetic approach for ILG [(E)-1] and its Z-isomer [(Z)-1], several types of HWE reagents 5a-d were prepared from the commercially available 2,4-dihydroxybenzoic acid (2) by the following procedure (Chart 1). Hydroxy and carboxy groups of benzoic acid 2 were protected as the corresponding methoxymethyl (MOM) ether and ester by methoxymethyl chloride (MOMCl) in the presence of Hünig's base in quantitative yield. The resultant MOM benzoate 3 was reacted with (diethoxyphosphoryl)methanide generated by deprotonation of diethyl methylphosphonate (4a) by lithium hexamethyldisilazide (LHMDS) to afford diethyl 2-[2,4-bis(methoxymethoxy)phenyl]-2-oxoethylphosphonate (5a) in 68% yield. Similarly, phosphonate 5b was obtained in 70% yield by the reaction of dimethyl methylphosphonate (4b) and MOM benzoate 3. However, phosphonates 4c, d did not afford the corresponding HWE reagents 5c, d because of the lability of 4c, d under the same reaction conditions. Thus, phosphonates 4c, d in tetrahydrofuran (THF) were added slowly into the mixture of 3 and LHMDS in THF at Ϫ50°C. As a result, the HWE reagents 5c, d were successfully obtained in 86% and 84% yields, respectively. Recently, Milburn et al. 23) and Maloney et al. 24) independently reported the preparation of b -ketophosphonates by the condensation of alkyl phosphonates with various esters. However, phosphonates 4c, d have not been tolerated under their reaction conditions, and the corresponding b -ketophosphonates 6c, d and 7c have not been obtained at all. The synthesis of ILG [(E)-1] was performed via E-selective HWE reaction of phosphonates 5a, b with 4-formylpheny benzoate (8) utilizing NaH as a base. The reaction of 5b and 8 proceeded smoothly to furnish the desired E-olefin (E)-9 in 91% yield. In order to simplify the reaction procedure, with- Sho-machi, Tokushima 770-8505, Japan: and b Faculty of Engineering, Kagawa University; 2217-20 Hayashi-cho, Takamatsu, Kagawa 761-0396, Japan. Received March 4, 2011 accepted March 31, 2011; published online April 6, 2011 Isoliquiritigenin [ILG, (E)-1] was readily prepared via the Horner-Wadsworth-Emmons reactions using b b-ketophosphonates 5a, b. An improved protocol for the synthesis of (E)-1 via the Claisen-Schmidt condens...

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