9.2 Carbasugars: Synthesis and Functions

9.2 Carbasugars: Synthesis and Functions Yoshiyuki Kobayashi Daiichi Sankyo Research Institute, 4250 Executive Square, La Jolla, California 92037, USA [email protected] 1 Introduction ............................................................... 1915 2Overview.................................................................. 1915 3 Synthesis of Carbasugars: New Generations of Glycosidase Inhibitors . 1916 3.1 New Generations of Glycosidase Inhibitors Bearing 6-Membered Cyclitol . 1916 3.1.1 Cyclophelitol: A β-Glucosidase Inhibitor..................................... 1916 3.1.2 Tamiflu: A Neuraminidase Inhibitor .......................................... 1933 3.2 New Generations of Glycosidase Inhibitors Bearing 5-Membered Cyclitols . 1951 3.2.1 Allosamizoline: The Aglycone of the Chitinase-Specific Glycosidase Inhibitor, Allosamidin........................................... 1952 3.2.2 Trehazolin, Trehalamine and Its Aminocyclitol Moiety, Trehazolamine: A Trehalase-Specific Glycosidase Inhibitor ................................... 1964 4 New Methods for Conversion of Sugars to Carbasugars .................... 1982 4.1 Carbasugar Formation via SnCl4-Promoted Intramolecular Aldol Condensation 1982 4.2 SmI2-Mediated Carbasugar Formation ....................................... 1983 4.2.1 Cyclization between Carbonyl Compounds and α, β-Unsaturated Esters ....... 1985 4.2.2 Cyclization between Carbonyl Compounds and Simple Olefins ................ 1986 4.2.3 Cyclization between Carbonyl Compounds and Oximes ....................... 1987 4.3 SmI2-Mediated Pinacol Coupling ............................................ 1988 4.4 SmI2- or Zirconium-Mediated Ring Contraction of Hexapyranoside Derivatives to 5-Membered Carbosugar.................... 1988 5Conclusion................................................................. 1992 Abstract It is well recognized that glycosidase inhibitors are not only tools to elucidate the mechanism of a living system manipulated by glycoconjugates but also potential clinical drugs and insecticides by inducing the failure of glycoconjugates to perform their function. In this chapter, the syntheses and functions of natural glycosidase inhibitors (cyclophelitol, allosamidine, and tre- hazoilin), which possess highly oxygenated and functionalized cyclohexanes or cyclopentanes in their structures and are defined as carbasugars, and the structure and activity relationships (SAR) of their derivatives are described. Also, recently much attention has been focused on In: Glycoscience. Fraser-Reid B, Tatsuta K, Thiem J (eds) Chapter-DOI 10-1007/978-3-540-30429-6_49: © Springer-Verlag Berlin Heidelberg 2008 1914 9 Glycomimetics neuraminidase inhibitors as anti-influenza drugs since relenza, which was derived from sialic acid, and also, tamiflu, which is the artificial carbasugar designed as a transition state analogue in the hydrolysis pathway of substrates by neuraminidase, were launched in the market. Here- in, the medicinal chemistry efforts to discover tamiflu and some efficient syntheses applicable to process chemistry are described. Finally, useful synthetic methodologies for carbasugar formation from sugars are also introduced in this chapter. Keywords Carbasugars; Cyclitols; Glycosidase inhibitors; Cyclophelitol; Allosamidin; Trehazolin; Neuraminidase inhibitor; Tamiflu; Intramolecular [3+2] cycloaddition; The Ferrier reaction Abbreviations CDMA catalytic desymmetrization of meso-aziridine Chx cyclohexyl DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DDMPO diisobutylaluminum 2,6-di-tert-butyl-4-methoxyphenoxide DEIPS diethylisopropylsilyl DIBALH diisobutylaluminum hydride DIPEA diisopropylethylamine DMAP N, N-dimethylaminopyridine DMF N, N-dimethylformamide 2,2-DMP 2,2-dimethoxypropane DMSO dimethylsulfoxide HA hemagglutinin HPLC high pressure liquid chromatography KHMDS potassium (1,1,1,3,3,3)-hexamethyldisilazide mCPBA m-chloroperbenzoic acid MOM methoxymethyl NA neuraminidase NBA N-bromoacetamide NBS N-bromosucciimide NIS N-iodosucciimide NMO 4-methylmorpholine N-oxide PPTS pyridinium p-toluenesulfonate RCM ring-closing metathesis SEMCl 2-(trimethylsilyl)ethoxymethyl chloride TBAI tetrabutylammonium iodide TBAF tetrabutylammonium fluoride TBDMS t-butyldimethylsilyl TBDPSCl t-butyldiphenylsilyl chloride TFA trifluoroacetic acid TFAA trifluoroacetic anhydride THAB tetrahexylammonium bromide TMSCN trimethylsilyl cyanide Carbasugars: Synthesis and Functions 9.2 1915 1 Introduction Recently, a great deal of attention has been focused on the glycosidase inhibitors under the premise that glycoconjugates such as oligosaccharides, glycolipids, and glycoproteins play pivotal roles in living systems, and recently a scientific field called “glycogenomics” has been developed as a part of genomics science. Glycosidase inhibitors possess interesting enzyme- specific inhibitory activities, therefore, they are expected not only to be tools to elucidate the mechanisms of a living system manipulated by the glycoconjugates but also to be potential clinical drugs and insecticides by inducing the failure of glycoconjugates to perform their function: anti-obesity drugs, anti-diabetics, anti-fungal, and anti-viral including substances active towards the human immunodeficiency virus (HIV) [1,2,3,4,5,6,7]. Most of the glycosidase inhibitors are isolated from natural sources, and they possess interesting structures in their molecules. Some of them possess the highly functionalized and oxygenated cyclohexane or cyclopentane moieties. In general, these moieties are called cyclitols, and also in this chapter, glycosidase inhibitors possessing cyclitols in their molecular structures are defined as carbasugars. Biochemically, carbasugars and cylitols themselves are recognized as the pseudo-sugars in a living system, and they show interesting biological activities based on the structure similarity to sugars. In the meantime, chemically, such highly functionalized molecules are quite challenging targets for synthetic studies. The most interesting and signif- icant points for the synthesis of glycosidase inhibitors possessing cyclitols are how we can form the frameworks of the cyclitols and how we can introduce the functional groups essential to generate their specific and interesting biological activities. In the last few decades new generations of glycosidase inhibitors, e. g., cyclophelitol, allosamidin, mannnostatin, and trehazolin, have been isolated from natural sources, and the appearance of these natural products has contributed to the development of the new methodologies needed to perform the aforementioned synthetic tasks. Also, due to tech- nical developments in the field of structure biology, the interaction between enzymes and inhibitors can now be visualized. This is helpful in the design of new scaffolds and eluci- dation of the detailed mechanisms of action involved. The creation of tamiflu, which is an artificially designed carbasugar showing neuraminidase (NA) inhibitory activity, is a good example favored by structure biology, and it has already been approved by US Food and Drug Administration (FDA) as an orally available anti-influenza drug. Herein, I will describe a variety of synthetic strategies directed to total syntheses and chemi- cal modifications of these glycosidase inhibitors and the structure and activity relationships of their derivatives. Also, the methodologies of carbasugar formation from sugars will be described. 2Overview One of the key points in the synthesis of carbasugars is the formation of the scaffolds of the cyclitol moieties, and three types of synthetic strategy can be considered: (a) Transformation of sugars to cyclitols; (b) Synthesis from nonsugar substrates by using asymmetric synthetic methodologies; (c) Utility of the framework of intact cyclitols. 1916 9 Glycomimetics Also, in addition, much attention should be focused on the structure-activity relationships (SAR) on enzyme inhibitory activities influenced by their stereochemistry and their functional groups. Therefore, the synthetic strategies should be applicable to the synthesis of their stereoisomers and congeners, and, in practice, some of the synthetic strategies have also been designed in consideration of this point. In this chapter, case studies on total synthesis of cyclophelitol, tamiflu, allosamidin, and trehazolin, including the synthesis of their stereoisomers and congeners, will be described, and SAR of these compounds will be discussed. Finally, SnCl4-promoted cyclitol formation and SmI2-mediated cyclitol formation will be described as useful methodologies for the conversion of sugars to cyclitols as well as SmI2-mediated carbasugar formation. 3 Synthesis of Carbasugars: New Generations of Glycosidase Inhibitors 3.1 New Generations of Glycosidase Inhibitors Bearing 6-Membered Cyclitol 3.1.1 Cyclophelitol: A β-Glucosidase Inhibitor Cyclophelitol (1)isaβ-glucosidase inhibitor isolated from a culture filtrate of the mushroom strain, Phellinus sp., and shows inhibitory activity towards almond β-glucosidase. In general, a series of β-glucosidase inhibitors such as castanospermine and 1-deoxynojirimycin have been reported to inhibit syncytium formation and infection with human immunodeficiency virus (HIV), possibly by perturbing the gp 120-linked glycan structure [8]. The structural fea- ture of cyclophelitol is the fully oxygenated cyclohexane, which possesses the stereochemistry of the hydroxyl groups corresponding to that of D-glucose and the β-epoxy group at the C1, C6 positions. This β-epoxy group is recognized to be

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