Synthesis of annelated pyranosides: a rapid and efficient entry to highly functionalized optically pure branched-pyrazoles Issa Samb, Nadia Pellegrini-Moı ¨se * and Yves Chapleur * Groupe S.U.C.R.E.S, UMR 7565 Nancy Universite ´, CNRS, BP 239, F-54506 Nancy Vandoeuvre, France Received 10 July 2007; revised 13 August 2007; accepted 7 September 2007 Available online 12 September 2007 Abstract—Pyrazolo-pyranosides prepared from methyl-2,3:4,6-di-O-benzylidene-a-D-mannopyranoside were functionalized to design new scaffolds suitable for peptidomimetic construction. Under certain acidic conditions, they undergo only pyranose ring- opening generating highly functionalized optically pure pyrazoles bearing an aldehyde function. Ó 2007 Elsevier Ltd. All rights reserved. The use of scaffolds for the construction of biologically active compounds is now a well-accepted concept. 1 Chi- ral carbohydrate-based scaffolds are well suited for introducing stereodiversity in the final compounds. 2–4 Our preliminary results on the design of peptidomimet- ics based on sugar scaffolds led us to the conclusion that a challenge in this area is to construct platforms larger than a single pyranose ring. 5,6 In this regard pyranose- fused ring systems deserve some attention. 7,8 We have successfully used keto-sugars for pyranosidic homologa- tion using hetero Diels–Alder reactions. 9–11 More recently, we became interested in the construction of nitrogen containing heterocycles fused to the pyranose ring and pyrazole has been chosen as the first target. Pyrazole derivatives are known to exhibit a wide range of biological properties such as anti-hyperglycemic, analgesic, anti-inflammatory, anti-pyretic and sedative- hypnotic activities. Particularly, arylpyrazoles were re- ported to have non-nucleoside HIV-1 reverse transcrip- tase inhibitory activity. 12,13 The most common method to prepare pyrazole heterocycles involves the condensa- tion of hydrazine derivatives with b-dicarbonyl compounds or with a,b-unsaturated carbonyl com- pounds. 14–16 However, the generality of this method is somewhat vitiated by the severe reaction conditions or the multistep sequence usually required to access the starting materials. Thus, continuing efforts have been made to develop efficient synthetic methods for preparing functionalized pyrazole derivatives. In this context, we report our preliminary results in the con- struction of pyrazolo-pyranose which lead to new scaf- folds and afford a direct route to acyclo-pyrazole nucleosides. 17 Starting from the known methyl 2,3:4,6-di-O-benzyl- idene a-D-mannopyranoside 1, 2-deoxy-3-ulo derivative 2 was prepared by the action of BuLi on 1 as previously described. 9,10 The condensation of N,N-dimethylform- amide dimethylacetal gave branched-chain ulose 3 in good yield. Pyrazole-annelated pyranoside4 was pre- pared in 80% yield by the treatment of 3 with hydrazine hydrate (Scheme 1). 18 In order to construct scaffolds for peptidomimetic design, the reactivity of compound 4 was explored 0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2007.09.048 Keywords: Pyrazoles; Pyranosides; Ring pyran opening; Scaffold. * Corresponding author. Tel.: +33 383 68 47 76; fax: +33 383 68 47 80; e-mail: nadia.pellegrini@sucres.uhp-nancy.fr i ii 70% 81% 80 % iii 1 3 2 1 2 3 4 5 6 7 8 O O O Ph OMe O O Ph O O O Ph OMe O O O O Ph OMe N O O O Ph O OMe 4 N N H H Scheme 1. Reagents and conditions: (i) 1/BuLi/THF/30 °C; 2/ NH 4 Cl; (ii) HCNMe 2 (OMe) 2 /CH 2 Cl 2 ; (iii) NH 2 NH 2 /MeOH. Tetrahedron Letters 48 (2007) 7978–7981