Convenient syntheses of metabolically important quercetin glucuronides and sulfates Paul W. Needs * and Paul A. Kroon BBSRC Institute of Food Research, Norwich Research Park, Colney Lane, Norwich, Norfolk NR4 7UA, UK Received 7 November 2005; revised 18 April 2006; accepted 28 April 2006 Available online 19 May 2006 Abstract—Synthetic approaches to the major human plasma metabolites of quercetin, quercetin 3 0 -sulfate and the b-D-glucopyranosiduronic acid derivatives 3 0 -methylquercetin 3-glucuronide (isorhamnetin 3-glucuronide), quercetin 3-glucuronide and quercetin 3 0 -glucuronide are described. This is the first report of the chemical synthesis of quercetin 3 0 -glucuronide. All procedures start from the same precursor, 4 0 ,7-di-O-benzylquercetin, and all are more convenient than existing methods. Ó 2006 Elsevier Ltd. All rights reserved. 1. Introduction The human diet includes several classes of plant flavonoids; many appear to be protective against coronary heart disease and/or a variety of carcinomas. 1 Quercetin 1 (Scheme 1) is the major flavonol found in plants (though usually in glyco- sylated forms) 2 and is thus a ubiquitous part of the human diet. In the past, the majority of evidence for the health bene- fits of quercetin came from in vitro experiments on free quer- cetin. Recent work has studied the human absorption and metabolism of quercetin derivatives and has shown that quercetin itself is not present in human plasma, but is found instead in various glucuronidated and sulfated forms. 3 In order to better determine the biological effects of quercetin, we required 100 mg quantities of the most abundant circulat- ing forms—the b-D-glucopyranosiduronic acid derivatives quercetin 3-glucuronide 2, quercetin 3 0 -glucuronide 3 and 3 0 -methylquercetin 3-glucuronide (isorhamnetin 3-glucuro- nide) 4, together with quercetin 3 0 -sulfate 5. Although quercetin glucuronides have been synthesised using liver microsomal preparations, 4,5 this is not convenient if larger quantities of glucuronides are needed; and existing chemical syntheses of both the sulfate and the glucuronides, where available, are either involved and/or low yielding. We describe convenient syntheses from a common easily pre- pared precursor, 4 0 ,7-di-O-benzylquercetin 6 (Scheme 2). O O H OH O OH OH OH 1 3' 4' 3 2' 5' 6' 7 8 6 5 1 Scheme 1. Structure of quercetin 1 (showing ring numbering). 2. Results and discussion 2.1. 4 0 ,7-Di-O-benzylquercetin, 6 4 0 ,7-Di-O-benzylquercetin, 6, was prepared as described by Jurd. 6 Although the yields were modest (17–29%), gram quantities of pure 6 were easily obtained without the need for chromatography. 2.2. Quercetin 3-glucuronide, 2 Wagner et al. first reported the synthesis of 2 in 1970. 7 Glu- curonidation of 6 with methyl 2,3,4-tri-O-acetyl-a-D-gluco- pyranosyluronate bromide 7 in the presence of silver oxide (Ag 2 O), gave 9 in 44% yield (Scheme 2); debenzylation and deacetylation afforded 2 in 24% overall yield. When we attempted this procedure, we failed to obtain any glu- curonidated products, or to recover 6. To ensure anhydrous conditions, we had stirred 6, Ag 2 O and a desiccant (either calcium sulfate, CaSO 4 , or 3 A ˚ molecular sieves) in pyridine for 2 h before adding 7. Conversely, when we added 7 imme- diately, the reaction gave two mono-glucuronidated prod- ucts, 8a and 8b, in 18 and 19% yields, respectively, after Keywords: Quercetin glucuronide; Quercetin sulfate; Quercetin 3-glucuro- nide; Quercetin 3 0 -glucuronide; Isorhamnetin 3-glucuronide; Quercetin 3 0 -sulfate; Glucuronidation; Sulfation; Synthesis. * Corresponding author. Tel.: +44 1603 255066; e-mail: needsp@bbsrc. ac.uk 0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2006.04.102 Tetrahedron 62 (2006) 6862–6868