Pergamon BlODRGANlC& MEDICINALCHEMISTRY Bioorganic & Medicinal Chemistry Letters 8 (1998) 2569-2572 LElTERS Synthesis of 13C labelled Daidzein and Formononetin Jacqueline L. Whalley, Timothy J. Bond1 and Nigel P. Batting,* School of Chemistry, University of St. Andrews, St. Andrews, Fife, KY16 9ST, UK Received 29 May 1998; accepted 5 August 1998 Abstract: Effkient methods are described for the synthesis of daidzein and formononetin labelled with a single 1%~ atom at the 4-position, to prepare material for metabolic studies. 0 1998 Elsevier Science Ltd. All rights reserved. Recent studies have shown that the phytoestrogens present in soya-based foods may have a considerable impact on human health. In particular the isoflavonoid phytoestrogens daidzein (1; RI= H, R2 = OH) and genistein (1; R1 = OH, R2 = OH) have been identified as modulators in the growth of hormone dependent cancers,1 as well as implicated in the prevention of cardiovascular disease,2 lessening the symptoms of the menopause3 and protection against oestreoporosis.4 In addition, recent evidence suggests a role in the central nervous system, stimulating nerve growth, and action as an antioxidant against endogenous toxins that produce free radicals in the CNS which are associated with the development of Alzheimer’s disease. 5 Due to the growing interest in the potential for isoflavones as pharmaceuticals there is need for the development of an efficient synthesis of labelled daidzein for use in routine analysis and metabolic studies. A number of synthetic routes towards the isoflavones have been developed previously and it was proposed that labelled daidzein and formononetin (1; R1 = H, R2 = OCH3) would be prepared by adapting existing methodologies (Scheme 1). The final step of most isoflavone syntheses involves the formylation and cyclisation of a suitable deoxybenzoin precursor (2). Various reagents have been used to provide the necessary one carbon fragment including dimethyl formamide dimethylacetal in THF,6 dimethyl formamide followed by mesyl chloride7 and 1,3,5triazine with boron trifluoride etherate. Preliminary studies were therefore carried out to investigate the first two methods to examine the possibility of using 13C-labelled dimethyl formamide to introduce the label in the final step. Unfortunately preliminary studies with unlabelled material demonstrated that a large excess of dimethyl formamide, or its dimethyl acetal, were required in order to obtain reasonable yields. This would be feasible if recovery of unreacted labelled starting material was also efficient but this was not the case. a) DMF dimethylacetal, THF, reilux or DMF then Mesyl Chloride or BF,.Et,O, 1,3,5-triazine SCHEME 1 * e-mail: npb@st-andrews.ac.uk; Fax: +44 334 463808 0960-894X/98/$ - see front matter 0 1998 Elsevier Science Ltd. All rights reserved. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQ PII: SO960-894X(98)00453-3