Carbohydrate Research 337 (2002) 459 – 465 www.elsevier.com/locate/carres Note Stereospecific synthesis of ( + )-oxybiotin from D-xylose  Velimir Popsavin,* Goran Benedekovic ´, Mirjana Popsavin, Dus ˇan Miljkovic ´ Faculty of Sciences, Institute of Chemistry, Uniersity of Noi Sad, Trg D. Obradoica 3, YU-21000 Noi Sad, Yugoslaia Received 22 October 2001; accepted 14 December 2001 Abstract A new 14-step synthesis of ( +)-oxybiotin, an oxygen analogue of ( +)-biotin, was achieved starting from D-xylose by use of selected 2,5-anhydro sugar derivatives as key intermediates. © 2002 Elsevier Science Ltd. All rights reserved. Keywords: ( +)-Oxybiotin; Protected 2,5-anhydro pentoses; 2,3,4-Trisubstituted tetrahydrofuranes; D-Xylose Oxybiotin, a biotin analogue in which oxygen re- places sulfur, was synthesized by Hofmann 2 and shown to exhibit a high biotin-like activity towards some microorganisms. 3 Accordingly, it was assumed that the biologically active oxybiotin has the same absolute configuration as that of the natural biotin. This as- sumption was definitely proved by a stereospecific syn- thesis of ( +)-oxybiotin (18, Scheme 3) from D-glucose. 4 Apart of this 19-steps sequence, no further attempts were made directed towards more efficient preparations of the enantiopure ( +)-18. Herein we report a new 14-step stereospecific synthesis of ( +)- oxybiotin, based on D-xylose as a chiral precursor, 1 by way of selected 2,5-anhydro sugars † as convenient intermediates. Earlier we have described 6,7 the five-step conversion of D-xylose to the 2,5-anhydro-D-xylose ethylene acetal derivative 1 (Scheme 1). The key step of the sequence (stereospecific formation of the trisubstituted tetra- hydrofuran system) has been achieved according to the methodology similar to that developed by Defaye and Hildesheim. 8 Compound 1 has the correct stereochem- istry at C-2, as well as the functionalities suitable for further introduction of the carboxyalkyl side chain, as well as for building the final ( +)-oxybiotin ureido system. Hydrolytic removal of the dioxolane protective group in 1 gave a hydrated form of the corresponding alde- hyde 2. Due to its instability, ‡ the intermediate 2 was promptly treated with 3-methoxycarbonyl-2-propenyli- dene triphenylphosphorane, 9 (generated in situ from the corresponding phosphonium bromide), to afford the ,-unsaturated ester 3 as a mixture of E and Z iso- mers. Subsequent catalytic hydrogenation of 3 over PtO 2 gave the corresponding saturated ester 4 (32% from 1). Solvolysis of 4 in wet N,N -dimethylfor- mamide, in the presence of calcium carbonate as a proton acceptor, gave a mixture of regioisomers 5 with inverted configuration at C-3. O -Debenzoylation of 5 with sodium methoxide in methanol afforded the ex- pected diol 6. Reaction of 6 with mesyl chloride in dichloromethane, in the presence of triethylamine, gave the corresponding di-O -mesyl derivative 7 (15.3% from 1), a potential intermediate for the further introduction of two azide functions with inversion of configuration at C-3 and C-4. An alternative six-step sequence for the preparation of intermediate 7 is presented in Scheme 2. Solvolysis of 1 in wet N,N -dimethylformamide, under the same reac-  For a preliminary account, see Ref. 1. * Corresponding author. Fax: +381-21-54065. E -mail address: popsavin@ih.ns.ac.yu (V. Popsavin). † For a review on 2,5-anhydro sugars, see Ref. 5. ‡ Compound 2 decomposes slowly on prolonged standing at room temperature turning into tar. 0008-6215/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved. PII:S0008-6215(01)00331-7