TETRAHEDRON: ASYMMETRY Tetrahedron: Asymmetry 14 (2003) 1037–1043 Pergamon Diastereoselective synthesis of protected 4-epi -vancosamine from (S )-N -Boc-N,O -isopropylidene--methylserinal Alberto Avenoza,* Jesu ´ s H. Busto, Francisco Corzana, Jesu ´ s M. Peregrina,* David Sucunza and Marı ´a M. Zurbano Departamento de Quı ´mica, Universidad de La Rioja, Grupo de Sı ´ntesis Quı ´mica de La Rioja, U.A.-C.S.I.C., 26006 Logron ˜o, Spain Received 5 December 2002; accepted 28 January 2003 Abstract—An efficient diastereoselective synthesis of methyl N,O-dibenzoyl-L-4-epi -vancosamine is described. The key step involves Sharpless asymmetric dihydroxylation of a Z olefin derived from (S )-N-Boc-N,O-isopropylidene--methylserinal. © 2003 Elsevier Science Ltd. All rights reserved. 1. Introduction During the last decade, glycopeptide antibiotics have been the subject of intensive investigation. 1 Two gly- copeptide antibiotics, vancomycin and teicoplanin, are in clinical use and are of great utility in the treatment of infections by bacteria that are resistant to many other classes of antibiotics. Indeed, vancomycin is considered to be the last line of defense for many severe bacterial infections. However, resistance to vancomycin is unfortunately now on the increase. 2 Although the SAR of the gly- copeptide antibiotics has been extensively studied, 3 the modifications necessary to improve the resistance situa- tion are not clear. Because of this, many investigations aimed at enhancing the activity of the vancomycin group of glycopeptide antibiotics are in progress. 4 In this sense, different vancomycin derivatives are cur- rently under investigation; for example A82846B (van- comycin plus one additional carbohydrate substituent: 4-epi -vancosamine) and LY333328 (a vancomycin derivative that features both the chlorobiphenyl side chain and the additional sugar substituent of A82846B) are highly efficient against vancomycin-resistant entero- cocci (VRE) and methicillin-resistant Staphylococcus aureus (MRSA) and are now undergoing clinical trials. 5 The structure of vancomycin is shown in Fig. 1 and consists of a disaccharide moiety (a glucose and a vancosamine) attached to a rigid cyclic heptapeptide framework aglycon. The structures of the vancomycin derivatives previously mentioned are also shown. Taking into account the importance of glycopeptide antibiotics, 6 and in order to construct combinatorial libraries of vancomycin analogs for biological screen- ing, the synthesis of vancosamine donors has been the focus of many researchers. To this end, several stereose- lective syntheses of protected vancosamines have been described. 7 Nevertheless, the synthesis of 4-epi -van- cosamine derivatives has received little attention. In fact, although some derivatives have been isolated from several antibiotics, 8 they have only been synthesized de novo on a few occasions 9 and these approaches have involved three methodologies. 10–12 2. Results and discussion In this context, we wished to explore the chemistry of our chiral building block (S )-N -Boc-N,O -isopropyli- dene--methylserinal 13 1 for the asymmetric synthesis of suitably protected 4-epi -vancosamine. Our synthesis started with the Wittig olefination of -amino aldehyde * Corresponding authors. Tel./fax: +34-941-299655; e-mail: alberto. avenoza@dq.unirioja.es; jesusmanuel.peregrina@dq.unirioja.es 0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0957-4166(03)00119-8