DOI: 10.1021/jo100566c Published on Web 05/06/2010 J. Org. Chem. 2010, 75, 3781–3785 3781 r 2010 American Chemical Society pubs.acs.org/joc Enantioselective Synthesis of Iclaprim Enantiomers;A Versatile Approach to 2-Substituted Chiral Chromenes Chouaib Tahtaoui,* ,† Arnold Demailly, † Carole Guidemann, † C ecile Joyeux, ‡ and Peter Schneider* ,†, ) † ARPIDA AG, Duggingerstrasse 23, 4153 Reinach, Switzerland, and ‡ Laboratoire de Chimie Organique, Bioorganique et Macromol eculaire, Ecole Nationale Sup erieure de Chimie de Mulhouse, 3 rue Alfred Werner, 68093 Mulhouse, France. ) Present address: Ki Consulting Ltd., Postfach 821, CH-4153 Reinach BL, Switzerland chouaib@hotmail.com; peter.schneider@intergga.ch Received March 25, 2010 Both enantiomers of the DHFR inhibitor iclaprim (R)-1 and (S)-1 were synthesized from the cyclopropyl homoallyl alcohols (R)-6 and (S)-6, respectively. As key steps these transformations include a Mitsunobu reaction and the formation of the diaminopyrimidine unit prior to a novel cyclization procedure to obtain the desired chromene heterocycle. The moderate enantioselectivity of the products (R)-1 and (S)-1 is related to the Mitsunobu reaction, which unfortunately did not proceed with complete inversion of configuration. Introduction Iclaprim and trimethoprim are diaminopyrimidine deri- vatives which are active against a broad panel of bacteria. 1 Trimethoprim (TMP) is successfully used in combination with sulfamethoxazole in the sequential blockade of the de novo synthesis of tetrahydrofolic acid to treat bacterial infections. Since the discovery of trimethoprim in 1965 many companies have initiated programs to synthesize derivatives within the benzyldiaminopyrimidine series to improve physi- cochemical and pharmacological profiles. 1,2 As a result of these activities several new inhibitors of dihydrofolate re- ductase (DHFR) have recently progressed into clinical de- velopment due to their potent anticancer or antibiotic properties. 1,3 ARPIDA AG developed iclaprim 1 (Figure 1) as a race- mate for complicated skin and skin structure infections (cSSSI) caused by Gram-positive organisms, especially methicillin-resistant (MRSA) and TMP-resistant Staphylo- coccus aureus. This chromene-benzyldiaminopyrimidine shows submicromolar activities against pathogenic micro- organisms such as Staphylococci, Enterobacter, Neisseria, Pneumocystis carinii, Streptococcus pneumoniae, and Hae- mophilus influenza. Both enantiomers of iclaprim exhibit similar activity against the DHFR enzymes of S. aureus and a similar antimicrobial profile against a broad range of bacteria. 4 FIGURE 1. Enantiomers of iclaprim. *To whom correspondence should be addressed. Phone: þ33(0)389446830/ þ41 76 308 7363. Fax: þ41 61 421 8781. (1) Kompis, I. M.; Islam, K.; Then, R. L. Chem. Rev. 2005, 105, 593–620. (2) Masciadri, R. U.S. Patent 5,773,446; Hoffmann-La Roche, June 30, 1998. (3) Schneider, P.; Hawser, S.; Islam, K. Bioorg. Med. Chem. Lett. 2003, 13, 4217–4221.