ZUSCHRIFTEN Angew. Chem. 2000, 112, Nr. 6  WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000 0044-8249/00/11206-1131 $ 17.50+.50/0 1131 1,2-Seleno Migrations in Carbohydrate Chemistry: Solution and Solid-Phase Synthesis of 2-Deoxy Glycosides, Orthoesters, and Allyl Orthoesters** K. C. Nicolaou,* Helen J. Mitchell, Konstantina C. Fylaktakidou, Hideo Suzuki, and Rosa M. Rodríguez In the field of antibiotics lead compounds derived from natural sources, for example, vancomycin and penicillin, provide a starting point from which a library of analogues can be synthesized and screened for biological activity. The naturally derived everninomicin 13, 384-1 (Ziracin, 1), [1] a potent antibiotic against methicillin-resistant staphylococci and vancomycin-resistant enterococci, is rapidly advancing through clinical trials as a new weapon against multidrug resistant bacteria. With the total synthesis of this antibiotic now accomplished, [2] the feasibility of constructing semisyn- thetic analogues for biological investigations through solution and solid-phase combinatorial chemistry can be put to the test. Furthermore, the synthesis of libraries of compounds representing novel regions, such as the 2-deoxy glycoside and orthoester moieties, of this complex molecule for general screening purposes is deemed highly desirable and important. Herein we report a general method for the stereocontrolled construction of 2-deoxy glycosides and orthoesters, both in solution and on a solid support, which is facilitated by a 1,2- selenium migration. Based on the observation of the 1,2-phenylseleno migra- tion [3] and its application to the synthesis [2] of everninomicins orthoester moieties in solution together with recognizing the potential use of our previously synthesized polystyrene-based selenium resin, [4] we designed the chemistry shown in Scheme 1. A general method employing this novel 1,2- selenium migration reaction was envisioned for both the O O OR Se Se F O O O F III O O O O Se O R 1 O OR 1 OR 1 R 1 O O O OR 1 A B C DAST ROH I: R = H II: R = SF 2 NEt 2 IV VI V OR OR 1,2-seleno- migration glycosidation VII R 1 = H R 1 = PG reductive cleavage oxidative cleavage; ring closure oxidative cleavage; ring closure/ Ferrier-type rearrangement Scheme 1. General concept for the stereoselective synthesis of 2-deoxy glycosides (V), orthoesters (VI), and allyl orthoesters (VII) via 1,2- selenium migrations. PG  protecting group. solution (  phenyl) and solid-phase (  polystyrene) syn- thesis of 2-deoxy glycosides, 2-deoxy orthoesters, and 2,3-allyl orthoesters from structures of general type I. Thus, treatment of the readily available 2-hydroxy-1-seleno glycoside (I) with diethylaminosulfur trifluoride (DAST) [5] should result in a stereospecific 1,2-migra- tion of the selenium group, with simultaneous installa- tion of a fluoride group at C-1, to furnish III. Expo- sure of these reactive do- nors (III) to various alco- hols in the presence of Lewis acids should then selectively afford the de- sired a-glycosides IV through participation of the seleno group. From IV , one of the following three paths may be followed: path A should furnish the 2-deoxy glycosides V in O O O O O O RO O O OR orthoesters 2-deoxy glycosides OR 2,3-allyl orthoesters high yield, via radical deselenation, facilitated with nBu 3 SnH; path B would first require removal of the protecting group R, followed by oxidation of the selenium to the selenoxide and heating to promote the syn-elimination and cyclization, to furnish 2-deoxy orthoesters (VI); and path C would require that both protecting groups (R and R 1 ) be removed before subsequent oxidation and heating, and should afford the 2,3- [*] Prof. K. C. Nicolaou, H. J. Mitchell, Dr. K. C. Fylaktakidou, Dr. H. Suzuki, Dr. R. M. Rodríguez Department of Chemistry and The Skaggs Institute for Chemical Biology The Scripps Research Institute 10550 North Torrey Pines Road, La Jolla, CA 92037 (USA) Fax: ( 1) 858-784-2469 E-mail: kcn@scripps.edu and Department of Chemistry and Biochemistry University of California San Diego 9500 Gilman Drive, La Jolla, CA 92093 (USA) [**] We thank Drs. D.H. Huang and G. Siuzdak for NMR spectroscopic and mass spectrometric assistance, respectively. We gratefully thank Nicolas Winssinger for helpful discussions and preparation of the selenium bromide resin. This work was financially supported by the Skaggs Institute for Chemical Biology, the National Institutes of Health (USA), postdoctoral fellowships from M.E.C., Spain (R.M.R. , Fullbright), the Japan Society for the Promotion of Science (H.S.), the George Hewitt Foundation (K.C.F.), and grants from Schering Plough, Pfizer, Glaxo, Merck, Hoffmann ± La Roche, DuPont, Abbott Lab- oratories, and Boehringer ± Ingelheim. O O O O HO Cl Cl OMe Me O Me OMe NO 2 Me Me O Me HO O Me O OH O OMe OH OMe O O OH O O O O O O O O O O O O Me OH Me HO OH Me MeO A C D B G A 1 E A 2 F 1: everninomicin 13,384-1 (Ziracin) H