Enantioselctive Syntheses of Sulfur Analogues of Flavan-3-Ols.docVIP

Molecules 2010, 15, 5595-5619; doi:10.3390/moleculeOPEN ACCESS molecules ISSN 1420-3049 /journal/molecules Article Enantioselctive Syntheses of Sulfur Analogues of Flavan-3-Ols Pradeep K. Sharma 1,2,*, Min He 1, Jurjus Jurayj 1, Da-Ming Gou 1, Richard Lombardy 1, Leo J. Romanczyk Jr. 3 and Hagen Schroeter 3 1 Chemical Process Research Development and Analytical Development, Johnson Matthey Pharmaceutical Materials Inc., 25 Patton Road, Devens, MA 01434, USA 2 Chemical Process RD and CMC Regulatory, ARIAD Pharmaceuticals Inc., Cambridge, MA 02139, USA 3 MARS Incorporated, 6885 Elm Street, McLean, VA 22101, USA * To whom correspondence should be addressed; E-Mail: sharmap76@; Tel.: 978 394 9341. Received: 26 July 2010; in revised form: 12 August 2010 / Accepted: 12 August 2010 / Published: 13 August 2010 Abstract: The first enantioselective syntheses of sulfur flavan-3-ol analogues 1–8 have been accomplished, whereby the oxygen atom of the pyran ring has been replaced by a sulfur atom. The key steps were: (a) Pd(0) catalyzed introduction of –S t-butyl group, (b) Sharpless enantioselective dihydroxylation of the alkene, (c) acid catalyzed ring closure to produce the thiopyran ring, and (d) removal of benzyl groups using N,N-dimethylaniline and AlCl3. The compounds were isolated in high chemical and optical purity. Keywords: flavan-3-ols; 5,7-dideoxythiocatechin; 5,7-dideoxythioepicatechin; thiocatechin; thioepicatechin; asymmetric dihydroxylation 1. Introduction Oligomeric and polymeric proanthocyanidins are some of the most ubiquitous groups of all the plant phenolics [1] and their health benefits are well known. A large number of in vitro studies have characterized flavanols as powerful antioxidants capable of efficient scavenging of both reactive oxygen and reactive nitrogen species [2-8]. The mechanism of their action as radical scavengers involves the donation of a hydrogen a