Synthetic Oligosaccharides - ACS Publications - American Chemical

Chapter 3

Sugar Cyanoethylidene Derivatives Useful Tools for the Chemical Synthesis of Oligosaccharides and Regular Polysaccharides L. V. Backinowsky

Downloaded by RUTGERS UNIV on May 29, 2018 | https://pubs.acs.org Publication Date: May 5, 1994 | doi: 10.1021/bk-1994-0560.ch003

N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 117913 Moscow, Russia

Condensation of sugar 1,2-O-(1-cyano)ethylidene derivatives (CED's) with sugar trityl ethers catalyzed by triphenylmethylium salts (tritylcyanoethylidene condensation) is an efficient method of glycosylation. Methods are elaborated to make the starting materials readily accessible. The reaction is highly 1,2-trans-stereoselective. CED's of pyranose sugars with manno-configuration and glycofuranose CED's react stereospecifically; stereospecificity is also observed for reactions of gluco- and galacto-configurated CED's with primary trityl ethers. The role of various factors on the reaction stereoselectivity is examined. Synthesis of regular homo- and heteropolysaccharides can be performed by condensation polymerization of tritylated CED's as monomers.

The roles played by carbohydrates in life processes are extremely diverse, cell recognition and immunological activity being among the most important. Terminal fragments of polymeric carbohydrate structures, polysaccharides and glycoconjugates can produce specific serological activity and the polysaccharide chain itself (or its internal oligosaccharide sequences) is also involved in the antigen - antibody interactions (/, 2). It is not surprising therefore, that numerous studies aimed at synthesizing specific terminal oligosaccharide structures, which are known, or presumed, to be the immunodominant part of glycoconjugates, are complemented by the synthesis of internal fragments of immunologically active polymeric carbohydrates. Modified analogs of these oligosaccharides have also been the subject of extensive synthetic studies (3). The progress in achieving these goals to a great extent has depended on creation of novel, effective glycosylation methods, and contributions by Canadian (4), German (5, 6), Russian (7), and Swedish (8) groups cannot be overestimated. The other facet of the glycoside synthesis is the challenging problem of synthetic polysaccharides. Undoubtedly, polysaccharides exhibit broader spectum of biological 0097-6156/94/0560-0036$08.00/0 © 1994 American Chemical Society

Ková; Synthetic Oligosaccharides ACS Symposium Series; American Chemical Society: Washington, DC, 1994.


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Sugar Cyanoethylidene Derivatives

37

activity than the constituent oligosaccharides. Only few of the existing methods of glycosylation (such as orthoester (7) or thioglycoside (9) approaches) could be adopted to the synthesis of polysaccharides or higher regular oligosaccharides. Ringopening polymerization of anhydro sugars (70), which is only applicable to the synthesis of polysaccharides, is another approach. A method of glycosylation based on the use of l,2-0-(l-cyano)ethylidene derivatives (CED's) of sugars as glycosyl donors and sugar trityl ethers as glycosyl acceptors has already demonstrated its effectiveness in both the hypostases of the glycoside synthesis since the first publications in 1975 (77, 72). Prior to 1975, the only known reaction, which made use of sugar trityl ethers as glycosyl acceptors, was introduced by Bredereck (73), wherein an acylglycosyl halide served as the glycosyl donor and silver perchlorate (or tetrafluoroborate) as the glycosylation promoter. The organic solvent-soluble silver salt generates the actual glycosylation species (cations A and/or B, scheme 1) by detachment of the halide from C(l). Scheme 1

-O -Ha!

AgCI0

4

4. R

- r ,

it

3K Β

Meerwein's data (14) on the formation of dioxolenium ionsfrom2-cyanodioxolanes and cyanophilic triphenylmethylium salts (Scheme 2) led to the idea (77) of employing sugar CED's as the precursors of glycosylation species type B: Scheme 2

I 0

1 0

τι* » >

4)-a-linked xylobiosides was 2.1:1 and 2.3:1 for endo- and exo-CED's 13, respectively, with overall yields of ca. 90%. Downloaded by RUTGERS UNIV on May 29, 2018 | https://pubs.acs.org Publication Date: May 5, 1994 | doi: 10.1021/bk-1994-0560.ch003

Scheme 10

OAc

O—l—CU R1

12 R • Ac

13 R1 = Me, R » A c

21 R - B n

u Rl=Me,R2=Bz

2

17 R -Me,R =Ac 1

2

18 R - Ph, R =Bz 1

2

15 R1 = M e , R 2 « B n 16 R l = P h , R « B z 2

Other D-xylose CED's (14, 15) gave β- and α-linked disaccharides in ca. 80% overall yield and β:α-τάΰο of 7.7:1 and 2.1:1, respectively. In the xylosylation of 12 by cyanobenzylidene derivative 16, the lowest amount of the α-linked disaccharide (ca. 10%) was observed . This lack of specificity was not unique to D-xylose CED's [note that with many other acceptors it behaved as highly stereoselective, l,2-//-aws-glycosylating agent (36)], but D-glucose, D-galactose, and L-rhamnose CED's also gave mixtures of 1,2trans- and 1,2-c/s-linked disaccharides (57). The only exceptions were L-arabinofuranose cyanoethylidene and cyanobenzylidene derivatives 17 and 18, both reacted virtually stereospecifically (52). Nonstereospecificity of the glycosylation of xyloside 12 by xylose CED 13 mani fested itself in the condensation polymerization of the corresponding 4-O-tritylated xylose CED as the monomer (53). The resulting (l-»4)-D-xylan contained up to 26% of l,2-C7.s-linked xylose units. Of note also is the nonstereospecific polycondensation of isomeric, 3-O-tritylated xylose CED (ca. 11% of a-xylosidic units), whereas the proportion of (l->3)-a-linked xylobioside in a model disaccharide synthesis amounted to only ca. 6% (36). The formation of 1,2-c/s- and l,2-/r4)- and (l->3)-xylans the only exceptions, since other monomers also produced anomerically mixed polysaccharides (55, 56).



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SYNTHETIC OLIGOSACCHARIDES

The results obtained allow one to make following conclusions on stereoselectivity of trityl-cyanoethylidene condensation. It is exceptionally high for mannopyranose, rhamnopyranose, and glycofuranose CED's and almost any type of acceptors. Pyranose CED's with gluco- and ^α/ac/o-configuration are stereospecific glycosylating agents, as a rule, with respect to acceptors with primary trityloxy groups. This follows from model disaccharide syntheses and is supported by syntheses of regular polysaccharides. Attempts were made to correct the deviation from the desired 1,2-transstereospecificity. The replacement of a perchlorate anion in the catalyst (triphenylmethylium salt) by a non-nucleophilic tetrafluoroborate (53, 54, 57) or a less nucleophilic trifluoromethanesulfonate (57, 58) decreased or even eliminated 1,2cw-linkages in some synthetic disaccharides and polysaccharides. Conducting the reaction under high pressure (14 kbar) also resulted in stereospecific syntheses of disaccharides (59) and polysaccharides (60). Introduction of an O-benzyl group instead of an 0-acetyl group at a position vicinal to O-trityl in an acceptor molecule greatly diminished the content of 1,2-cw-linked disaccharides (6J; Kitov, P.I.; Tsvetkov, Yu.E.; Backinowsky, L.V., unpublished results). l,2-0-(aCyano)benzylidene derivatives with electron-donating groups in the aromatic nucleus (58) can be regarded as favorable substitutes for the cyanoethylidene derivatives. The knowledge of the scope and limitations of trityl-cyanoethylidene condensation and promising results on correction of the deviations from stereospecificity allow one to make realistic prognosis in regards to the design and synthesis of complex, regular polysaccharides. The potential and value of this approach has not been fully exploited. Examples of a novel application of the condensation polymerization are the syntheses of regular polysaccharides and block-polysaccharides as glycosides bearing a functionalized spacer-arm (62, 63). The former involved the condensation of a tritylated CED as a monomer in the presence of a tritylated aglycon-acceptor, which served as a "primer" for a polysaccharide chain growth. When following the condensation of one monomer, another monomer was introduced, it resulted in the formation of a block-polysaccharide. Thus, initial model syntheses with monosaccharide monomers were followed with oligosaccharide monomers, which correspond to repeating units of a group Α-variant streptococcal polysaccharide (-2-L-Rhaa 1 -3 -L-Rhaa 1 -) (64) or a common polysaccharide antigen of Ps. aeruginosa (-2-D-Rhaa 1 -3-D-Rhaa 1 -3-D-Rhaa 1 -) (65). In the latter case, the poly saccharide produced was identical in its NMR spectral parameters to the natural one. This was coupled to bovine serum albumin by virtue of a 6-aminohexyl spacer at the "reducing" terminus and the neoglycoprotein thus obtained was used to raise polysaccharide-specific antibodies (Makarenko, T.A., et al, FEMS Immunol Med. Microbiol., 1993, in press). With new targets, new problems have arisen, and preferential coupling of a monomer to the aglycon-acceptor as opposed to its self-condensation, became the problem of primary importance. Therefore, the relative reactivity of acceptors toward CED's had to be evaluated. It was shown, for example, that the tritylated rhamnoside 19 (Scheme 11) is preferentially selected by a rhamnose CEDfroman equimolar mix ture of 19 and 6-0-trityl-mannoside 20, the yield of a rhamnosyl-rhamnoside being


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47

ca. 90% and the recovery of 20 being 96.5%. This accounted for a low degree of (poly)rhamnosylation of a mannan anchored to a 6-phthalimidohexyl glycoside in an attempted synthesis of rhamnomannan, a block-polysaccharide (63). Benzylated xyloside 21 (Scheme 10) not only was almost stereospecifically glycosylated by xylose CED, it was also much more reactive than the diacetate 12. The recovery of the latter was 70% and the yield of a mono-0-benzylated xylobioside was 76% when an equimolar mixture of these two acceptors was subjected to glycosylation by xylose CED 13 (61).


Scheme 11

19

20

Some features of the synthesis of polysaccharide glycosides still remain unexplained. For example, despite obvious similarity in the acceptor sites in the monomer 11 and the tritylated acceptor glycoside 22 (Scheme 9), the yield of a polysaccharide glycoside is extremely low (38) with overall high efficiency of condensation polymerization of the monomer 11. Analogously, polymerization of a monomer 23 (Scheme 12), which represents the synthon of a repeating unit of a group A-variant streptococcal polysaccharide, in the presence of a 2-0-tritylated acceptor 24 resulted in polysaccharide glycoside in lower yield and lesser DP as compared to the polycondensation of the same monomer in the presence of an isomeric acceptor 25 (Backinowsky, L.V., unpublished results). Scheme 12 BzO

TrO

0(CH )6NPhth 2

•o

OBz

23

Recently we have begun the study of kinetics of this glycosylation aimed at solving the mechanistic problems and evaluation of the relative reactivity of CED's as




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glycosyl donors and trityl ethers as acceptors. Our preliminary results show that o f several ordinary C E D ' s studied, none exhibited exceptionally high or l o w activity (Kitov, P.I.; Tsvetkov, Y u . E . ; Backinowsky, L . V . ; Kochetkov, N . K . , Izv. Akad Nauk. Ser. Khim. [Russ. Chem. Bull.J, 1993, in press). A t the same time, the higher reactivity o f the galactose erafo-cyano-CED vs. its exo-cyano isomer was confirmed (cf. 37). Relatively great difference in reactivities o f various acceptors was observed, and the pattern found for one C E D does not necessarily hold for another C E D . Quite unexpected was the finding that the secondary trityl ethers are more reactive than the primary ones (though experimental data were documented, cf. 63). This allowed us to perform selective monoglycosylation o f some monosaccharide primary - secondary ditrityl ethers at the secondary sites (Tsvetkov, Y u . E ; K i t o v , P.I.; Backinowsky, L . V . ; Kochetkov, N . K . , Tetrahedron Lett., in press). This order o f reactivity contrasts that o f primary - secondary diols, and may open new possibilities, although additional studies are required to reveal characteristic features o f this version o f the synthesis o f oligosaccharides by trityl-cyanoethylidene condensation.

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