FULL PAPER DOI: 10.1002/ejoc.201001102 Synthesis of Fused Oxa-Aza Spiro Sugars from D-Glucose-Derived δ-Lactone as Glycosidase Inhibitors A. P. John Pal, [a] Preeti Gupta, [a] Y. Suman Reddy, [a] and Yashwant D. Vankar* [a] Keywords: Glycosylation / Metathesis / Dihydroxylation / Spiro compounds / Azasugars / Enzyme inhibitors Four conformationally constrained fused oxa-aza spiro sugars have been synthesized from perbenzylated D-glucono- lactone involving C-glycosylation of ketoses by using Me 3 - SiCN, ring-closing metathesis, and diastereoselective di- Introduction In recent years an increasing interest in the design and synthesis of inhibitors of carbohydrate-processing en- zymes [1] (i.e., glycosidases and glycotransferases) has been witnessed. As glycosidases are essential for normal cellular development, glycosidase inhibitors have potential thera- peutic applications in a number of carbohydrate-mediated diseases such as cancer, [2] diabetes, [3] lysosomal storage dis- orders, [4] viral infection including influenza, [5] and HIV. [6] In the last few years a large number of glycosidase inhibi- tors has been designed and synthesized and tested for their activity against several glycosidases. As a result, glycosidase inhibitors such as Tamiflu, Zanamivir, Miglitol, Miglustat, Acarbose, Voglibose, and so on [7] have been approved as drugs to treat various carbohydrate-mediated diseases. Polyhydroxylated derivatives of nitrogen-containing heterocycles, such as piperidines, pyrrolidines, indolizidines, pyrrolizidines, calystegines, and azepanes, are probably the most fascinating class of active compounds towards glyco- sidases so far. For example, N-butyl-1-deoxynojirimycin (1, Zavesca) and N-hydroxyethyl-1-deoxynojirimycin (2, Migli- tol; Figure 1) have both been approved as medicines. [8] Be- sides these, isofagomine [9] (3) is the most potent β-gluco- sidase inhibitor found so far; swainsonine [10] (4) is a potent α-mannosidase inhibitor, alexine [11] (5) is also an effective thioglucosidase inhibitor, castanospermine (6) and its stereo- isomers also have potential therapeutic applications. [12] As part of our ongoing program of developing novel carbohydrate molecules [13] as glycosidase inhibitors and also our recent study on spiroaminal frameworks [14] as gly- cosidase inhibitors, we became interested in synthesizing [a] Department of Chemistry, Indian Institute of Technology, Kanpur 208016, India Fax: +91-512-259-0007 E-mail: vankar@iitk.ac.in Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ejoc.201001102. Eur. J. Org. Chem. 2010, 6957–6966 © 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 6957 hydroxylation as key steps. Two of the four spiro sugars were found to be highly selective but moderate inhibitors of α- mannosidase. Figure1. Some of the most important polyhydroxylated alkaloids. structurally interesting and conformationally constrained novel fused oxa-aza spiro sugars viz. 17, 25, 31, and 32 as glycosidase inhibitors. These spiro sugars were derived by carrying out spiroannulation at the anomeric center of monosaccharides. We can also consider these oxa-aza spiro sugars as “sugar-tethered azasugars” or “sugar-templated azasugars” (piperidine and azepane) or “spiro carbon linked oxa-aza disaccharides”. Due to the conformational rigidity of the spiro system, these spiro sugars should hold the hydroxy substituents in precisely defined arrangements and hence should have potential for specific interactions. Herein, we report the synthesis of four novel fused oxa-aza spiro sugars and their enzyme inhibition activity towards glycosidases. The key steps in their synthesis involved C- glycosylation of ketoses, which were derived from vinyl or allyl Grignard addition reactions of -gluconolactone (7), ring-closing metathesis reactions, and diastereoselective di- hydroxylations by using RuO 4 or OsO 4 . Results and Discussion As outlined in Scheme 1, target molecules 17 and 25 could be obtained from global deprotection of benzylated