FULL PAPER DOI: 10.1002/ejoc.201403689 The First Total Synthesis of Sophoflavescenol, Flavenochromane C, and Citrusinol Van-Son Nguyen, [a,b] Lin-Pei Dong, [a] Sheng-Chun Wang, [a] and Qiuan Wang* [a] Keywords: Total synthesis / Natural products / Sigmatropic rearrangement / Cyclization / Fused-ring systems / Oxygen heterocycles The first total syntheses of sophoflavescenol (1), flaveno- chromane C (2), and citrusinol (3) were achieved. These three naturally occurring prenylated or prenyl-cyclized flavonoids have important biological activities such as cyto- toxicity against some cancer cell lines, or are lead com- pounds for the treatment of erectile dysfunction. Starting from 2,4,6-trihydroxyacetophenone and substituted benzal- dehydes, the synthesis involved methoxymethyl protection, aldol condensation, cyclization, oxidation with dimethyl- Introduction Prenylated flavonoids are a unique class of naturally oc- curring flavonoids characterised by the presence of a pren- ylated side-chain on the flavonoid skeleton. C-Prenylation of flavonoids can enhance their binding affinity toward P- glycoprotein, and can remarkably improve the biological activity of the flavonoids. [1] Over the past few decades, an impressive number of biological activities and pharmaco- logical effects have been demonstrated for C-prenylated flavonoids, including antitumor, anti-inflammatory, and antiosteoporosis activities, enzyme inhibition, and vascular- protective and estrogen regulation activities. [2,3] Sophoflavescenol (1), a C-8-prenylated flavonoid isolated from S. flavescens , was the most potent and selective inhibi- tor of CGMP phosphodiesterase 5 (PDE5; IC 50 0.013 μ), and so it was considered as a lead structure for the treat- ment of erectile dysfunction. [4] Sophoflavescenol (1) also showed inhibitory activity against HL-60, LLC, and A549 tumor cells. [5] Flavenochromane C (2) is a prenyl-cyclized derivative of sophoflavescenol, and it showed potent cyto- toxicity against a panel of five human tumour cell lines with IC 50 values of 1.0–3.6 μ. [6] It also showed strong cytotoxic [a] College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. China E-mail: wangqa@hnu.edu.cn http://cc.hnu.cn [b] Faculty of Chemical Engineering, Industry University of Hochiminh City, Vietnam Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ejoc.201403689. Eur. J. Org. Chem. 2015, 2297–2302 © 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 2297 dioxirane, O-prenylation, microwave-assisted Claisen re- arrangement, deprotection, cyclization of the prenyl group, and dehydrogenation with 2,3-dichloro-5,6-dicyano-1,4- benzoquinone. The overall yields of 1, 2, and 3 were 23, 17, and 16%, respectively. All compounds were characterized by 1 H and 13 C NMR spectroscopy and MS. The key step of the synthetic route was a regioselective microwave-assisted Claisen rearrangement to form an 8-prenylated flavonoid from a 5-O-prenylflavonoid. activity against lung carcinoma (A549), ovarian carcinoma (1A9), and breast adenocarcinoma (MCF-7) cell lines with IC 50 values of 1.7–3.6 μ. [7] Citrusinol (3), the dimethyl pyrano derivative of C-8-prenylkaempferol, isolated from the stems and leaves of Desmodium caudatum, has been shown to have antibacterial and antifungal activities. [8] It has also shown cytotoxicity against KB cells and the HepG2 cell line. [9] Sophoflavescenol (1), flavenochromane C (2), and cit- rusinol (3) only occur at low levels in natural plants, and this has negatively influenced further evaluation of their biological activity. Therefore, the chemical synthesis of 1, 2, and 3 would be a very important way of addressing the problem of their availability. In this paper, we describe the first total synthesis of sophoflavescenol (1), flavenochrom- ane C (2), and citrusinol (3) in 10–11 steps, starting from commercially available 2,4,6-trihydroxyacetophenone and MOM-protected 4-hydroxybenzaldehyde. The key step is a regioselective microwave-assisted Claisen rearrangement to form an 8-prenylated flavonoid from a 5-O-prenylflavonoid. All the compounds synthesized were characterized by 1 H and 13 C NMR spectroscopy and MS. The synthetic route to sophoflavescenol (1), flavenochromane C (2), and cit- rusinol (3) is shown in Schemes 1 and 2. Results and Discussion Starting material 2,4,6-trihydroxyacetophenone is com- mercially available. 2-Hydroxy-4,6-bis(methoxymethoxy)- acetophenone (4) and 4-(methoxymethoxy)benzaldehyde were prepared according to literature procedures. [10,11] A