Proline catalyzed direct diastereoselective 6-enolexo aldolization: toward the synthesis of the imino sugar DNJ Indresh Kumar   , Chandrashekhar V. Rode ⇑ Chemical Engineering & Process Development Division, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India article info Article history: Received 27 September 2010 Accepted 26 October 2010 abstract A L-proline catalyzed direct diastereoselective 6-enolexo aldolization reaction of differentiating dialdehy- des derived from tartaric acid is presented. This organocatalytic approach provides high levels of syn- selectivity (dr >10:1) with the stereocontrolled C–C bond formation between C4 and C5 intramolecularly, which can serve to synthesize imino-sugar skeleton quickly. Ó 2010 Elsevier Ltd. All rights reserved. 1. Introduction The aldol reaction is one of the important C–C bond forming reactions in organic chemistry, and several asymmetric and cata- lytic variants have been developed. 1 Recently, direct asymmetric aldol reaction catalyzed by small organic molecules, such as pro- line and its derivatives through an enamine intermediate, have been studied; in particular, intermolecular aldol reaction has been extensively explored by several research groups. 2 Regarding the direct intramolecular aldol reaction, there are two modes of cycli- zation, in which the enolendo mode remained as the first organo- catalytic reaction, 3 while the enolexo mode of cyclization remained undeveloped until the first report from List et al. in 2003. 4 In the case of the enolendo mode of cyclization, the enamine C–C bond constitutes a part of newly formed cyclic skeleton, while in the case of the enolexo mode of cyclization the enamine C–C bond does not constitute the part of ring system as shown in Figure 1. However, the later mode of cyclization reaction is mainly suitable for the asymmetric desymmetrization of meso- compounds. 5 Imino-sugars are biologically active compounds consisting of polyhydroxy piperidine and pyrrolidine skeletons. 6 Such com- pounds have been the subject of extensive interest over the past three decades, several comprehensive reviews and accounts on their synthesis and glycosidase inhibitors activities have been published. 7 Some of these imino-sugars have already been tested and approved for the treatment of diabetes, 8 Gauchers disease, 9 HIV infection, 10 viral infections, 11 and cancer. 12 They have also been used as chemical probes, in combination with protein crys- tallography and kinetic studies, to provide further insight into the glycosidase mechanism. 13,7b Although the quest for stronger gly- cosidase inhibitors has been the driving force for the synthetic ef- forts dedicated to this class of compound, 14 it is probable that several of their biological properties are not related to their abil- ity to inhibit glycosidase (Fig. 2). 15 During our continued studies on the direct aldol reactions for the synthesis of important biological skeletons, 16 we realized that the issue of differentiating between two C@O groups of a dialde- hyde using organocatalysts has not been explored much, except for the cross-aldol reactions developed by MacMillan and others. 17 Our aim was to differentiate between two intramolecular aldehyde 0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2010.10.024 ⇑ Corresponding author. Tel.: +91 20 2590 2349; fax: + 91 20 2590 3260. E-mail address: cv.rode@ncl.res.in (C.V. Rode).   Present address: College of Sciences, Shri Mata Vaishno Devi University, Katra 182 320, J&K, India. O O n enolendo O N n HO O n n enolexo n N n O O O O OH aldolization aldolization (1971) (2003) Figure 1. Enolendo and enolexo mode of cyclization. N HO OH 3 castanospermine NH HO OH HO OH 1 1-deoxynojirimycin (DNJ) HO OH NH HO OH HO OH 2 L-deoxyidonojirimycin Figure 2. Some important imino-sugars. Tetrahedron: Asymmetry 21 (2010) 2703–2708 Contents lists available at ScienceDirect Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy