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Chemical Synthesis of Oligosaccharides: Efficiency and Selectivity Due to the Significant Roles They Play in Various Biological

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Chemical Synthesis of Oligosaccharides: Efficiency and Selectivity Due to the Significant Roles They Play in Various Biological Chemical Synthesis of Oligosaccharides: Efficiency and Selectivity Osamu Kanie, Tomoya Ogawa and Yukishige Ito The Institute of Physical and Chemical Research (RIKEN) Abstract: Due to high demand to access biologically important oligosaccharide structures, efficient and stereoselective synthetic methods are required. This article addresses these two issues from our recent studies. The first part deals with ƒÀ-mannosylation and ƒ¿-sialylation known as the two most difficult glycosylation reactions which were now made possible by means of an "intramolecular aglycon delivery" system and control by "auxiliary", respectively. In the second part, the remarkably efficient "orthogonal glycosylation strategy" which was developed based on tactical analysis of oligosaccharide synthesis is described. 1. Introduction Due to the significant roles they play in various biological events (ref. 1), glycoconjugates are attracting wide attention and multidisciplinary research areas called glycobiology and glycotechnology have emerged (ref. 2). These molecules include glycolipids, glycoproteins and proteoglycans and each of these groups has a high degree of structural diversity. Most typically, they exist on the cell surface and their oligosaccharide portions (glycans) are extruded into the outer region of the cell. This particular feature allows them to participate in various cell surface recognition events such as cell-cell and cell- matrix adhesion, bacterial and virus invasion, cancer cell migration, cell differentiation, sperm-oocyte interaction, and others (ref. 3). In addition, it is now well known that the glycan portions serve as functional parts in a majority of glycoproteins, to stabilize them and tune their activity by controlling three-dimensional structures and participate in intra- and inter-cellular transportation (ref. 4). Even in higher-order biological phenomena like signal transduction, not only the gross structure but also the fine structure of glycoprotein glycans is important (ref. 5). Considering the structural diversity of glycan chains as well as the limited quantity and heterogenicity of samples available from biological sources, synthetic approach to this group of molecules is expected to be a key driving force in glycoconjugate-related research area (ref. 6). Chemical synthesis should be able to secure the supply of a large amount of materials, including non-natural structures, with higher degree of structural homogeneity. 2. Stereoselectivity of 0-Glycosylation 2.1 General Discussion In order to synthesize oligosaccharides with defined structures, iterative ƒ•-glycosylation reactions are required, where free OH-carrying sector 1 called glycosyl acceptor is coupled with glycosyl donor 2 to afford ƒ•-glycoside 3. Active investigations in the last two decades resulted in development of the so- called modern glycosylation technology that utilizes non-classical glycosyl donors 2 [X=F, OC(NH)CC13, SR, S(0)Ph, OP(OR)2, etc.] which are relatively stable but can be activated into highly reactive glycosylating entities, under mild reaction conditions (ref. 7). For example, glycosyl fluoride, which used to attract little attention in synthetic carbohydrate chemistry, has been proved as a powerful glycosyl donor. In 1981, Mukaiyama and coworkers demonstrated that it can be activated by combined use of AgC104 and SnC12 to afford a-glycoside with a significant level of stereoselectivity (ref. 8). The utility of this system was quickly demonstrated in synthesis of glycolipids and natural products (ref. 9). Further refinement was achieved by Suzuki and coworkers, who introduced a combination of Cp2MC12 (M=Ti, Zr, Hf)-Ag+ as an activator and made glycosyl fluoride as one of the most strong glycosyl donors 952 ( 88 ) J . Synth . Org . Chem . , Jpn Scheme 1 2 3 (ref. 10). Meanwhile, hard Lewis acids are also demonstrated to be effective to promote the activation of glycosyl fluorides (ref. 11). Likewise, thioglycoside (ref. 12) and trichloroacetimidate (ref. 13) are now recognized to be highly effective glycosyl donors in oligosaccharide synthesis. Combination of these methodologies allows us to design synthetic routes to even more highly complex oligosaccharide structures. This aspect was clearly exemplified in our synthesis of blanched polylactosamine type oligosaccharide which consists of as many as 25 sugar residues (ref. 14). Although such advancement has dramatically improved the overall efficiency of oligosaccharide synthesis, these modern methodologies are still not free of stereochemical problems inherent in 0- glycosylation reactions (ref. 15). Among 0-glycosides found in naturally occurring glycoconjugates a- glycoside of sialic acid and 13-glycosideof mannose are considered to be "difficult sequences", because neither stereoelectronic control nor neighboring effect is available to control the stereochemistry in these particular cases. In the following sections, our efforts to solve the problem of stereoselective synthesis of sialic acid (NeuAc) glycoside 4 and 13-mannoside5 will be summarized. 2.2 Stereoselective Synthesis of NeuAc Glycoside (ref. 16) At the outset of our investigation on this subject, we assumed proper functionalization of the NeuAc donor is 4 5 required. As shown in Scheme 2, NeuAc donors having a PhSe or PhS group at the C-3 position were designed and synthesized. Having the neighboring participation active functional group as an auxiliary, glycosylation should proceed via the episelenonium or episulfonium ion to afford the desired a-glycoside. Requisite stereochemical control at the C-3 position can be easily obtained by having hemiketal 6 as an intermediate, because this position can be epimerized into thermodynamically more stable (and desired) 7, irrespective of the stereochemical outcome of the preceding addition reaction. In this sense, our synthetic scheme can be viewed as translating thermodynamically disfavored equatorial glycoside into thermodynamically favored C-3 equatorial vol .56, No.11 (November 1998) ( 89 ) 953 Scheme 2 Stereoselective Synthesis of NeuAc Glycoside 6 9 7 8a NeuAcƒ¿2-48NeuAcƒ¿2•¨3Gƒ¿1ƒÀ1•¨4GIcƒÀ1•¨1Cer (GD3, 10) stereochemistry. NeuAc donors 8a,b afforded a-glycosides in a highly stereoselective manner, and in an unprecedentedly high yield in the case that 8a was utilized. In particular, stereoselective synthesis of the NeuAca2-48NeuAc sequence (i.e. 9) was realized for the first time and the first chemical synthesis of disialoganglioside GD3 (10) was achieved (ref. 17). Subsequently, a similar strategy was reported from other groups (ref. 18), and it was demonstrated by Magnusson (ref. 18c) and ourselves (ref. 19) that incorporation of thioglycosiclde functionality as a leaving group (i.e. 11) further improves the glycosylation efficiency. Meanwhile, a research team lead by Hasegawa and Kiso first demonstrated that glycosylation with NeuAc thioglycoside 12 gives a-glycoside with substantial stereoselectivity when it was conducted in acetonitrile (ref. 20). They have extensively applied this protocol to systematic synthetic studies of various gangliosides (ref. 21). 2.3 Stereoselective Formation of 13-Manno glycoside (ref. 22) 13-Manno glycoside exists as a central 11 12 core unit of all types of asparagine (Asn)-linked glycoprotein oligosaccharides (ref. 23). Therefore, stereoselective synthesis of this particular type of glycoside is of fundamental significance aiming at chemical synthesis of glycoprotein-related molecules (ref. 24). Our approach depicted in Scheme 3 is based upon the concept called intramolecular aglycon delivery (IAD) which was first developed by Baressi and Hindsgaul (ref. 25) and later by Stork and coworkers.(ref. 26) In our version of IAD, mannosyl donor 13 that has a p-methoxybenzyl group (PMB) was utilized. The p-methoxybenzyl group has been extensively investigated as a valuable OH 954 ( 90 ) J . Synth . Org . Chem. , Jpn protecting group which is removable under nearly neutral conditions by the action of a certain oxidant, most typically DDQ (ref. 27). Since deprotection is believed to proceed through a hydrolytic quench of the quinonemethide-like intermediate 14, it was assumed treatment of 13 with alcohol (glycosyl acceptor) Scheme 3 ƒÀ-Manno Glycosylation via Mixed Acetal 15a,b 13a,b 16 17a-d 14 18 20 19 would give us mixed acetal 16 which serves as a tethered intermediate for IAD. According to this expectation, PMB-carrying mannosyl donors 13a,b were prepared and subjected to a two-step sequence (1. DDQ, molecular sieves 4A/CH2C12; 2. Me0Tf , DBMP/Cl(CH2)2Cl) using 15a,b as glycosyl acceptors. In all cases, the desired p-glycoside products 17a-d were obtained as single isomers. (ref. 22b) Even p-mannosylations of disaccharide with a trisaccharide donor was successful. (ref. 22c) These products were further converted into the core pentasaccharide structure 18 commonto Asn-linked glycans. Likewise, fucose-containing hexasaccharidic asparagine 19,(ref. 28) as well as"bisecting" GlcNAc-containing hexasaccharide 20 (ref. 29), both of which stand for the most significant structural modifications found in Asn-linked glycans, were achieved. More recently, the efficiency of f3-mannosylation was further improved by using a 4,6-0- cyclohexylidene carrying mannosyl donor 21, which gives 13-manno glycoside in •„80% yield (ref. 30). Scheme 4 21 Vol.56, No .11 (November 1998) ( 91 ) 955 3. Efficiency of Glycosylation Strategy 3.1 Background of The Tactical Scheme 5 Aspect One important advancement in oligosaccharide synthesis was the introduction of
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