SYNTHESIS OF A DIVERSITY OF IMINOSUGAR C-GLYCOSIDES OF BIOLOGICAL INTEREST BY WAY OF CROSS-METATHESIS Philippe Compain , Guillaume Godin, and Olivier R. Martin Institut de Chimie Organique et Analytique, Université d’Orléans - CNRS, BP6759, 45067 Orléans, France Fax : + 33 2 38 41 72 81 - Email : philippe.compain@univ-orleans.fr Historically, iminosugars are best known for their role as powerful glycosidase inhibitors [1], but more recently the scope of their biological activities has been extended to the inhibition of other carbohydrate-processing enzymes such as glycosyltransferases [2] or nucleoside phosphorylases. Since these enzymes are involved in a number of fundamental biological processes, iminosugars and related compounds have recently entered the clinical field for assessment of their therapeutic potential in a wide range of diseases including viral infection, tumor metastasis and lysosomal storage disorders [3]. Recently, we reported a general strategy for the practical synthesis of nojirimycin C-glycosides bearing an olefinic group at C1 using the 2-naphthalenemethyl (NAP) group as a new versatile amino protecting group [4,5]. Starting from these advanced intermediates, we investigated olefin cross-metathesis as a powerful methodology to access a wide range of new functionalized iminosugar-based building blocks [6]. PREPARATION OF KEY PRECURSORS In conclusion, we have reported the first example of cross-metathesis reactions with iminosugar C-glycosides. The results obtained from α-1-C-allyl-1- deoxynojirimycin analogues demonstrated the simplicity and the power of cross- metathesis reaction to generate rapidly iminosugar C-glycosides with a great degree of structural diversity in the aglycon moieties. This practical and selective methodology provides new avenues for the synthesis of glycoconjugate mimetics of biological interest. Efforts towards this aim are currently in progress in our laboratory. CROSS-METATHESIS REACTIONS INTRODUCTION O O O N OBn H OBn NAP NNAP AcO BnO BnO NZ AcO BnO BnO N H AcO BnO BnO O O O O OBn OBn L-sorbose 7 steps 64% Ref. 4 AcO AcO a, b c, d, e Reagents and conditions: (a) NAPNH 2 (1.05 eq.), molecular sieves, 4°C, 2h. (b) AllMgBr or vinylMgBr (3 eq.), ether, 0°C to 20°C, 24h. (c) TFA/H 2 O (9/1), 30h. (d) NaBH 3 CN (4 eq.), AcOH (1 eq.), MeOH, 30h. (e) Ac 2 O (6 eq.), Py, 5h. (f) DDQ (3 eq.), CH 2 Cl 2 /MeOH, 1h. (g) HCOONa (2.5 eq.), PivCl (2.5 eq.), CH 2 Cl 2 , 8h. (h) TrocCl (1.5 eq.), Py, 2h. de > 98% Z= CHO n = 1 95% Z= Troc n = 1 95% Z= Troc n = 0 93% g or h Z= CHO n = 1 Z= Troc n = 1 Z= Troc n = 0 f n = 1 86% n = 0 83% H ( ) n n ( ) n ( ) AcO n ( ) n = 1 75% n = 0 68% n = 1 76% n = 0 66% NAP N H O H OH BnO BnO NCHO AcO OAc BnO BnO O O O RHN OBn H OBn O O O O OBn OBn O O O N OBn OBn 76% 66% d, e Reagents and conditions: (a) AllylNH 2 (1.1 eq.), molecular sieves, 4°C, 2h. (b) vinylMgBr (3 eq.), ether, 0°C to 20°C. (c) Pd(PPh 3 ) 4 , NDMBA (2.1 eq.), 35°C, 3h. (d) TFA/H 2 O (9/1), 36h. (e) NaBH 3 CN (4 eq.), AcOH (1 eq.), MeOH, 24h. (f) HCOONa (2.5 eq.), PivCl (2.5 eq.), CH 2 Cl 2 , 8h. (g) Ac 2 O (6 eq.), Py, (2.5 eq.), CH 2 Cl 2 , 8h. (g) Ac 2 O (6 eq.), Py, 20°C, 16h. de > 98% R= allyl quant. a 74% R= H c b f, g 80% N N Ru Ph PCy 3 Cl Cl Mes Mes N OAc AcO Z BnO BnO R N OAc AcO Z BnO BnO R Z = CHO, Troc 5-20% cat. Grubbs II CH 2 Cl 2 , 40°C, 16-24h (2-5 equiv.) Grubbs II NTroc AcO OAc BnO BnO NZ AcO OAc BnO BnO CO 2 Et NTroc AcO OAc BnO BnO SO 2 Ph NTroc AcO OAc BnO BnO P(OMe) 2 O NTroc AcO OAc BnO BnO Br NTroc AcO OAc BnO BnO N O NTroc AcO OAc BnO BnO AcO NTroc AcO OAc BnO BnO N OAc OBn OBn NTroc AcO OAc BnO BnO O O Z = CHO 96% Z = Troc 92% 50% 71% 45% 70% Boc 87% Troc 88% 85% 82% ( ) n n = 5 N OAc AcO Z BnO BnO R N OAc AcO Z BnO BnO R Z = CHO, Troc 5-20% cat. Grubbs II CH 2 Cl 2 , 40°C, 16-24h (3-5 equiv.) α or β X In sharp contrast with findings for α-1-C-allyl-1-deoxynojirimycin analogues, exposure of the corresponding α- or β-1-C-vinyl derivatives to various olefins using 5 to 20 mol% of Grubbs catalyst II led to almost complete recovery of the starting material. These results may be explained by greater Ru-O chelation possibilities and increased steric hindrance due to close proximity of the reacting alkene and the bulky iminosugar moiety CONCLUSION REFERENCES [1] Stütz, A.E., Iminosugars as Glycosidase Inhibitors: Nojirimycin and Beyond; Wiley-VCH:Weinheim, 1999. [2] For a review see: Compain, P.; Martin, O. R. Bioorg. Med. Chem. 2001, 9, 3077. [3] Iminosugars: Recent Insights Into Their Bioactivity and Potential As Therapeutic Agents in Curr. Top. Med. Chem.; Martin, O. R.; Compain, P. Eds.; Bentham, Neth., 2003, 3, (5). [4] Godin, G.; Compain, P.; Masson, G.; Martin, O. R. J. Org. Chem. 2002, 67, 6960. [5] Godin, G.; Compain, P.; Martin, O. R Synlett 2003, 2065. [6] Godin, G.; Compain, P.; Martin, O. R Org. Lett. 2003, 5, 3269 .