Chemical Synthesis of : 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 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 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 ĥ-glycosylation reactions are required, where free OH-carrying sector 1 called glycosyl acceptor is coupled with 2 to afford ĥ- 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 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- 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 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 "stable" leaving groups which can be used as an anomeric protecting group until exposed to certain activation conditions. The thioglycoside is a typical example of this class of leaving groups. Thioglycosides can be activated under alkylating or oxidative conditions but are stable under the traditional glycosylation conditions such as the KOenigs-Knorr method, so that halides can be chemoselectively activated in the presence of thioglycosides. In addition, they can be transformed into halides or other leaving groups when required (ref. 31,32). For this reason, thioglycosides and other stable leaving groups possessing such characteristics are ideal candidates as intermediates in this flexible chemoselective strategy. The strategy is closely related to the so-called armed-disarmed concept in terms of the realization of stable leaving groups and the efficiency (ref. 33). An ideal strategy taking advantage of the efficiency and eliminating the limitations arising from combinatorial numbers of differentiated reactivities of leaving groups would be to combine two chemically distinct glycosylation reactions where one of the leaving groups is activated while the other behaves as a protecting group and vice versa (Scheme 5). To fulfill the requirement for this orthogonal system, each selected leaving group should be unaffected under the conditions used to activate the other. Also, both leaving groups should be stable enough to be compatible with routine manipulations of temporary protecting groups. For this orthogonal strategy, a set of leaving groups and activation conditions for each group; L1, phenylthio group and L2, fluoride, and (a), NIS-TfOH (or AgOTf) (ref. 34) and (b) , Cp2HfC12-AgC104 (ref. 10,35) was selected.

3.2 Orthogonal Glycosylation Strategy (ref. 36) In order to assess the orthogonality of the above-mentioned combination of reactions, the interconversion reactions of two anomeric potential leaving groups such as the phenylthio and fluoro groups were examined and shown to be useful. Thiophenyl glycoside 22 was treated under (a) Nicolaou's conditions (ref. 37) to yield the glycosyl fluoride 23 quantitatively. On the other hand, the fluoride could be activated under (b)Mukaiyama's conditions (ref. 8) in the presence of thiophenol to give the thioglycoside 22 in 93% yield (Scheme 6). Using this orthogonal set of reactions, a set of glycosylation reactions was investigated using 22 and 23 as donors and 24 and 25 as acceptors. In this manner, the glycosylation reactions based on the orthogonality of anomeric leaving groups were carried out and each coupling was shown to give the desired disaccharide while still keeping one of the potential leaving groups attached at the anomeric center (Scheme 7). These results also indicate that less reactive acyl protected donors were activated preferentially compared to the potentially more reactive ether nrotected acceptors, thereby clearly distinguishable from armed-disarmed reactions. The chosen set of reactions is, Scheme 6 therefore, proven as orthogonal, chemoselective in both directions In order to show the applicability of the present strategy to the synthesis of longer chain oligosaccharides, iterative couplings 22 23

956 ( 92 ) J . Synth . Org . Chem . , Jpn Scheme 7

24 26

25 27 were further examined by constructing the heptasaccharide 33 where all synthons were derived from 22 (Scheme 8). First, thioglycoside donor 28 was coupled with acceptor fluoride 24 under condition (a) to give disaccharide fluoride 29 which was then reacted with the acceptor 25 to produce 30 [condition (b)]. Subsequent reaction of 30 with 24 [condition (a)] gave tetrasaccharide 31. Having accomplished the synthesis of a tetrasaccharide, we next examined a block condensation approach. Tetrasaccharide acceptor 32, prepared by deacetylation of 31, was coupled with its precursor 30 to give compound 33 [condition (a)], which is again ready for further use as an Scheme 8 oligosaccharide donor. Synthesis of a tetrasaccharide, which is a partial structure of a novel mammalian blood group related glycosphingolipid was also achieved in order to verify the 28 generality of the orthogonal strategy (ref. 38). Three iterative orthogonal glycosylation reactions successfully afforded trisaccharide as an octyl 29 glycoside which was incorporated at the end of the synthesis enabling rapid isolation and enzyme assay. Deprotection of the levulinoyl group and the 30 a-fucosylation reaction followed by complete deprotection afforded the target compound. Thus, the applicability of the strategy was demonstrated in the synthesis of the antigenic 31 32 tetrasaccharide achieved in seven steps (38% overall yield) from protected monosaccharide units.

3.4 Polymer Supported (a) NIS (1.3 equiv.)-AgOTf (0.1 equiv.) Oligosaccharide (b) Cp2HfCl2(1.3 equiv.)-AgCIO4 (2.6 equiv.) Synthesis Organic synthesis inevitably requires tedious 33 purification process and becomes

Vol.56, No .11 (November 1998) ( 93 ) 957 Approach A Approach B

time-consuming. Employment of solid-phase synthesis has been demonstrated to be extremely valuable for routine preparation of oligopeptides and oligonucleotides. Usefulness of polymer-support chemistry in combinatorial chemistry is also well recognized. From these points of view, oligosaccharide synthesis on polymer support has been attracting recent attention (ref. 39). In polymer-support synthesis of oligosaccharide, two approaches can be considered with respect to the direction of chain elongation; from reducing end to non-reducing end (approach A), and from non- reducing end to reducing end (approach B). Among them, the former approach is generally considered to be more advantageous because, as far as both polymer-supported aglycon and glycosyl donor are reactive enough to ensure completion of all (step 1) - otherwise capping has to be carried out, and selective deprotection to liberate the hydroxyl group for the next glycosylation (step 2) can be performed quantitatively, nearly homogeneous product can be obtained. On the other hand, the application of approach B is less straightforward due to the following considerations. First, every glycosylation (step 1) inevitably gives rise to side reaction(s) (13-elimination, , etc.) together with the formation of the desired product, all of which are accumulated on the polymer. In addition, transformation of the reducing-end anomeric position into a certain leaving group (step 2) is required after each glycosylation, which is by no means straightforward at the oligosaccharide stage.

3.4.1 Orthogonal Glycosylation Strategy on the Polymer Supported Synthesis (ref. 40). The elongation of the sugar chain from non-reducing end (approach B) in the polymer supported oligosaccharide synthesis is less straightforward as discussed previously. However, when the orthogonal glycosylation strategy is applied to the polymer supported synthesis, an important improvement, namely, preinstallation of the potential leaving group is achieved. This makes the methodology advantageous because having the leaving group attached, there will be 1) no need for the activation reaction and 2) no need for the protection of the anomeric hydroxyl group produced by hydrolysis. As the result, again only one reaction step is required as a coupling cycle as was shown for the solution synthesis. In addition, since only the last introduced sugar unit has a leaving group, one can introduce a tag to ease isolation of the final product after deprotection.

958 ( 94 ) J . Synth . Org . Chem . , Jpn . Scheme 9 Polymer Supported Orthogonal The first attempt was made using Oligosaccharide Synthesis polyethylene glycol (PEG) as a "soluble" polymer (ref. 39b), and the trimannoside portion of high-mannose type glycoprotein oligosaccharides was chosen 35 as the target. In addition, 2- (trimethylsily1) ethyl (SE) group was used as a hydrophobic tag in this case as well as the temporally protecting group 34 (Scheme 9). The coupling of the polymer, PEG monomethyl ether (average MW = 5,000), supported methylthio mannoside 34 with the fluoride 35 was performed in the presence of DMTST (a) to afford the disaccharide-PEG conjugate 3 6 . 37 Subsequent coupling with the reducing- end mannoside was performed by using SE-glycoside 37 as an aglycon under 36 conditions (b) to afford the trisaccharide- PEG conjugates 39. The PEG was then cleaved off from 39 under basic conditions and the crude trisaccharide was hydrogenated to afford unprotected compounds, from (a) DMTST which the desired product 40 w a s (b) Cp2HfCl2-AgOTf isolated by simple C18 reverse-phase silica gel column chromatography. The strategy featuring a novel combination of polymer support chemistry, the concept of orthogonal glycosylation, and simple 39 isolation of the final product by incorporating a hydrophobic tag has been achieved. Also to be noted is that the aglycon in 4 0 which is used as a hydrophobic tag can be selectively cleaved (ref. 41) in case one wants to conjugate the formed oligosaccharide with other structures. Another approach (approach A) was also examined using polystylene resin as solid-phase (ref. 42). Thus, the synthesis of a neolactosamine oligosaccharide was achieved using the trichroloacetimidate as a leaving group 40 throughout the synthesis. An approach to the synthesis of sialylated oligosaccharide has also been studied (ref. 43).

3.4.2 ƒÀ-Mannosylation on Polymer In connection with our program on solid-phase oligosaccharide synthesis, a polymer-supported version of IAD was devised. (Scheme 10) (ref. 22d). In this system, the isolation process is greatly simplified, because 1) the unreacted glycosyl acceptor can be removed after the mixed acetal formation step and 2) the desired product (13-mannoside) is specifically released into a non-polymeric phase while most of the by-products remain bound to the polymer. When fluorinated acceptor (R = F) was used in

Vol.56, No .11 (November 1998) ( 95 ) 959 the system, the product can be used as Scheme 10 ƒÀ-Manno Glycosylation via IAD on Polymer Support an acceptor itself or a donor after protection of released 2-OH in connection to the orthogonal strategy.

4. Conclusion As was summarized in this article, recent efforts including ours resulted in significant progress in chemical synthesis of glycan chains. However, once compared to the other two major classes of biological molecules (i.e., oligopeptides and oligonucleotides), there certainly remains much more to be investigated in this area. In particular, future investigation should be directed toward the establishment of simplified synthetic methodology which enables the preparation of biologically relevant oligosaccharides in a less time- consuming manner. Undoubtedly, solid-phase synthesis technology is going to give the solution. This should also open a way to the construction of an oligosaccharide library. However, again, many problems are waiting to be solved before it can gain generality as a practical tool. Another goal in synthetic would be the total chemical synthesis of glycoproteins. Since synthetic technologies in oligosaccharide and in oligepeptide/protein fields have been developed and refined separately, many of the key operations involved in an optimized synthetic protocol of each class of molecules are not compatible to each other. We hope collaborative efforts of the carbohydrate and peptide synthetic community will give a compromising answer to these problems and result in the successful achievement of the goal.

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