TETRAHEDRON LETTERS Tetrahedron Letters 42 (2001) 1279–1281 Pergamon Total synthesis of isotopically labelled flavonoids. Part 3: † 13 C-labelled (-)-procyanidin B3 from 1-[ 13 C]-acetic acid Vale ´rie Arnaudinaud, Bastien Nay, Alain Nuhrich, Ge ´rard Deffieux, Jean-Michel Me ´rillon, Jean-Pierre Monti and Joseph Vercauteren* GESNIT, EA 491, Faculte ´ de Pharmacie, Universite ´ Victor Segalen Bordeaux 2, 146, rue Le ´o Saignat, F -33076 Bordeaux, France Received 17 October 2000; accepted 8 December 2000 Abstract—The regioselectively 13 C-labelled (-)-procyanidin B3 was prepared in eight steps from 1-[ 13 C]-acetic acid. © 2001 Elsevier Science Ltd. All rights reserved. Epidemiological studies have established strong correla- tions between wine drinking and lower risks of cardio- vascular, 2 cancer 3 or Alzheimer 4 diseases. Because red wines are particularly rich in flavonoids, some authors have considered that they could be responsible for these observations. Indeed, many of these molecules, in vitro, demonstrate important biological properties (anti- atherosclerotic, 5 anti-thrombotic, 6 anti-inflammatory 7 and anti-carcinogenic 8 ). But this opinion is not shared unanimously and, on the contrary, other authors have shown that some wine flavonoids even promote atherosclerosis. 9 There is yet almost no direct proof of their gut resorp- tion and their metabolism in humans is poorly known. Information on these issues could be obtained by using non-radioactive isotopically labelled compounds, detectable in human biological fluids by NMR as well as by mass spectrometry. Several reports dealt with the synthesis of deuteriated flavonoids such as catechin 1 or its dimer procyanidin B3 2 (Scheme 1), 10,11 but their 2 H NMR signals lack sensitivity. Moreover, in our group, [ 13 C]-biolabelling of anthocyanidins and stilbenoids was made by Vitis vinifera cell cultures. 12,13 As large amounts of 13 C-labelled procyanidins (the most abun- dant flavonoids in wine) were not attainable by this method, we built them up by total synthesis. This letter reports the first total synthesis of [ 13 C]-labelled natural (-)-procyanidin 2, by coupling a C 6 –C 2 labelled ace- tophenone (from 1-[ 13 C]-acetic acid) with a C 1 –C 6 benz- aldehyde unit. This method allowed us to improve the yields and to decrease the number of steps to reach the pivotal intermediate chalcone 7, with respect to our previous synthesis of racemic 13 C-labelled catechin, from K 13 CN. 1 Benzylated [ 13 C]-phloroacetophenone 4 (Scheme 2) was synthesised (60% yield) from phloroglucinol tribenzyl ether 3 (obtained by the Kawamoto method 14 ) and activated 1-[ 13 C]-acetic acid by formation of a mixed anhydride upon treatment with trifluoroacetic anhy- dride (TFAA). Selective deprotection of 4 by TiCl 4 gave phloroacetophenone 2,4-dibenzylether 5 (80%). Croton- isation of 5 with 3,4-dibenzyloxybenzaldehyde 6 in the presence of NaH led to the tetrabenzylated chalcone 7 (89%). Flavan-3,4-diol 9 was obtained in 58% yield in three steps from 7 by the Clark–Lewis method: 15 boro- hydride reduction of 7 and Lewis acid catalysed cycliza- tion into racemic flavene 8, which was then directly transformed into the glycol 9 by an osmium-catalysed dihydroxylation with high diastereoselectivity. As ex- pected, 8 was revealed to be too labile a compound to be purified. Scheme 1. * Corresponding author. Fax: +33-5/56 96 09 75; e-mail: joseph.vercauteren@gnosie.u-bordeaux2.fr † For Part 2, see Ref. 1. 0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII:S0040-4039(00)02263-2