Expeditious Stereoselective Synthesis of l-Iminosugar Precursors via a Mitsunobu Reaction

Abstract

An efficient stereoselective synthesis of L-imino-C-gulosides is disclosed. Starting from the 2,3:4,6-di-O-isopropylidene-Dmannopyranose the synthetic pathway involves first a Wittig reaction with CMPP to introduce the carbon at the pseudo-anomeric position, followed by a Michael reaction under ultrasound activation to introduce the nitrogen center, and finally a Mitsunobu reaction for the ring closure leading to the C-iminosugar from the L-series.Among carbohydrate mimetics, iminosugars (or azasugars), in which the endocyclic oxygen of the sugar is replaced by a nitrogen atom, attract considerable attention. Nojirimycin, a natural azasugar isolated from Streptomyces filtrate, was found to inhibit a-and b-glucosidase. 1 Extended researches have enlarged the range of biological activities of azasugars and demonstrated that those lowmolecular-weight compounds are powerful inhibitors of a variety of glycosidases. As a consequence, the therapeutical potentials of natural or synthetic azasugars are remarkable. 2-5 Compared to azasugars, aza-C-glycosides, which possess a C-linked aglycon, have shown to improve the selectivity of the inhibitors. Moreover, they offer the possibility of further functionalization and/or elongation in search of improved biological activities, inhibitory properties depending also on the nature of the substituents on the nitrogen atom. Since several decades, various synthetic methods focusing on azasugars and aza-C-glycosides have been developed. [6][7][8][9][10][11][12][13][14][15] Interest in finding simple and general ways to synthesize such carbohydrate mimetics has, of course, been prompted by their remarkable properties.The second aspect of our research deals with L-sugars. While D-sugars are abundant, L-sugars are rare and expensive. Moreover, the latter play important roles in therapy, and efforts are needed to develop the synthesis of these valuable sugars. [16][17][18][19][20][21] In this work, we were interested to find a direct and potentially general approach to aza-Cglycosides from the L-series using a strategy developed by our group. Thus, as part of our program devoted to develop new synthetic routes to sugar derivatives, we have recently published a powerful cascade sequence using (cyanomethylene)trimethylphosphorane (CMMP) for the synthesis of carba-C-glycosides. 22 However, in order to prepare azahexopyranoses using a comparable approach, a one-pot reaction could not be envisaged, and the conversion had to be separated into three sequential steps. The reaction involves (a) a ring-opening process with the aim to free the hemiacetal hydroxyl group; (b) nucleophile addition at the anomeric position in order to introduce the nitrogen with a variety of substituents, and (c) a ring closure (Scheme 1 and Scheme 2). Scheme 1To access the L-azahexopyranose system, we focused the methodology on mannose, using 2,3:4,6-di-O-isopropylidene-D-mannopyranose (1) as starting material. In order to achieve the ring opening, a Wittig reaction between (cyanomethylene)triphenylphosphorane (CMPP,...