Solid Support Oligosaccharide Synthesis

Scheme 2.23 Solid-phase synthesis of glycopeptides.

give glycopeptide 86. Retrieval from the solid support afforded trisaccharide– octapeptide 87 in 18% overall yield from 10.

The methodology described above has proved to be effective for other glycosylation sequences. Scheme 2.23 shows conversion of a variety of disaccharides to their respective glycopeptides. For example, lactal derivative 31 was transformed into a lactosamine-linked glycopeptide where C6 of the glucosamine residue is protected as its benzyl ether, in 24% overall yield. Disaccharides 56 and 90, with a β-(1→3) glycosylation pattern, differ in their mode of attachment to the solid support. In compound 56 the linkage was established via a silyl ether, while in 90 it was fashioned via a silylene linkage. They can both be elaborated to disaccharide–pentapeptide 93 in 20% and 44% yields, respectively, based on the initial loading of polymer-bound galactal carbonate.

2.11 CONCLUSIONS

In this chapter we have described the progress that our laboratory has made in the solid support synthesis of oligosaccharides and glycopeptides using glycal assembly. Protocols for the effective transformation of glycals into powerful glycosyl donors such as 1,2-anhydrosugars and thioethylglycosides have been developed. A variety of

38 THE GLYCAL ASSEMBLY METHOD ON SOLID SUPPORTS

glycosidic linkages may now be fashioned in a selective manner and bring complex structures within reach. The flexibility and capabilities of our synthetic approach were demonstrated on some select structures of biological interest.

Glycal assembly on a solid support eliminates the repetitive purifications usually associated with oligosaccharide synthesis. As a method, it has a certain generality as it does not require any specific enzymes or complex starting materials. Both natural and nonnatural sugars may be used in the constructions.

A number of challenges still remain before a flexible, high-yielding, and absolutely selective strategy for the synthesis of oligosaccharides on the solid support becomes available. Once these problems are solved, the construction of an automated oligosaccharide synthesizer will become feasible.

The rapid access to complex glycoconjugates will open the door to detailed studies concerning the structure and function of this class of biooligomers.

ACKNOWLEDGMENTS

This work was supported by the National Institutes of Health (grant numbers AI 16943, CA 28824, HL 25848). We thank our coworkers whose names are cited in the footnotes.

REFERENCES

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REFERENCES 39

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A.K., Hakomori, S., and Paulson, J. C., Proc. Natl. Acad. Sci. (USA) 88, 6224–6228 (1991); (e) Hindsgaul, O., Norberg, T., Le Pendu, J., and Lemieux, R. U., Carbohydr. Res. 109, 109–142 (1982).

17.For a review, see Lloyd, K. O., Am. J. Clin. Pathol. 87, 129–139 (1987).

18.For syntheses of H-type determinants, see (a) Petrakova, E., Spohr, U., and Lemieux, R. U., Can. J. Chem. 70, 233–240 (1992); (b) Zemlyanukhina, T. V., and Bovin, N. V., Bioorg. Khim. 16, 1096–1104 (1990).

19.Randolph, J. T., and Danishefsky, S. J., Angew. Chem., Int. Ed. 33, 1470–1473 (1994).

20.Seeberger, P. H., Eckhardt, M., Gutteridge, C. E., and Danishefsky, S. J., J. Am. Chem. Soc. 119, 10064–10072 (1997). For the activation of thiodonors, see (a) Lonn, H., Carbohydr. Res. 139, 115–121 (1985); (c) Lonn, H., J. Carbohydr. Chem. 6, 301–306 (1987); (d) Fugedi, P., and Garegg, P. J., Carbohydr. Res. 149, C9–C12 (1986).

21.Kunz, H., and Harreus, A., Liebigs Ann. Chem. 41–48 (1982).

22.Kunz, H., and Harreus, A., Liebigs Ann. Chem. 717–730 (1986).

23.Zheng, C., Seeberger, P. H., and Danishefsky, S. J., J. Org. Chem. 63, 1126–1130 (1998).

24.(a) Griffith, D. A., and Danishefsky, S. J., J. Am. Chem. Soc. 112, 5811–5819 (1990);

(b) Hamada, T., Nishida, A. and Yonemitsu, O.,J. Am. Chem. Soc. 108, 140–145 (1986).

25.Zheng, C., Seeberger, P. H., and Danishefsky, S. J., Angew. Chem., Int. Ed. 37, 786–789 (1998).

26.Boren, T., Falk, P., Roth, K. A., Larson, G., and Normark, S., Science 262, 1892–1895 (1993).

40THE GLYCAL ASSEMBLY METHOD ON SOLID SUPPORTS

27.Alper, J., Science 260, 159–160 (1993).

28.(a) Graham, D. Y., Lew, G. M., Klein, P. D., Evans, D. G., Evans, D. J., Saeed, Z. A., and Malaty, H. M., Ann. Int. Med. 116, 705–708 (1992); (b) Hentschel, E., Brandstatter, G., Dragosics, B., Hirschl, A. M., Nemeg, H., Schutze, K., Taufer, M., and Wurzer, H.,

N.Engl. J. Med. 328, 308–312 (1993).

29.Sharon, N., in The Lectins: Properties, Functions and Applications in Biology and Medicine, Liener, I. E., Sharon, N., and Goldstein, I. J. (Eds.), Academic Press, New York, 1986, pp. 494–525.

30.Bernstein, M. A., and Hall, L. D., Carbohydr. Res. 78, C1–C4 (1980).

31.Bremer, E. G., Levery, S. B., Sonnino, S., Ghidoni, R., Canevari, S., Kannagi, R., and Hakomori, S., J. Biol. Chem. 259, 14773–14777 (1984).

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3.1 INTRODUCTION 43

Figure 3.1 Oligosaccharides synthesized using the sulfoxide glycosylation method.

Scheme 3.2 Synthesis of nucleoside analogs.

Sulfoxides have also been used in the synthesis of nucleoside analogs (Scheme 3.2). Chanteloup and Beau reported the synthesis of ribofuranosyl sulfoxide 13 and its use in the glycosylation of a series of silylated pyrimidine and purine bases.7 Although 16 is not an anomeric sulfoxide, its reaction with cytosine derivative 17 is conceptually related.8

OH hikizimycin (26)

Scheme 3.3 Synthesis of glycoside natural products.

The sulfoxide method has come to the rescue in the syntheses of some complex glycoside natural products, where many other glycosylation methods failed. Two examples are shown in Scheme 3.3. Boeckman and Liu reported an enantioselective synthesis of cassioside (22).9 While the focus of the synthesis was the assembly of the aglycone 20, utilizing a highly diastereoselctive cycloaddition of a trienol silyl ether, the glycosylation turned out to be a challenge in its own right. They initially performed this glycosylation using the perbenzylated glucose sulfoxide 2 (see Table 3.1); but found that the hydrogenolytic removal of the benzyl protecting groups was not compatible with other functionality in the molecule. Similar problems were reported in the synthesis of ciclamycin 0.10 The solution, in both cases, was found in the p-methoxybenzyl ether protecting group, which can be removed oxidatively.11 Ikemoto and Schreiber encountered a challenging glycosylation in their synthesis of hikizimycin (26); sterically hindered alcohol 24 was ultimately glycosylated using sulfoxide 23.12

3.2 SYNTHESIS OF SULFOXIDE DONORS

The preparation of thioglycosides was thoroughly reviewed by Garegg.13 These versatile glycosides can be used directly in glycosylation reactions, or can be converted to a number of other glycosyl donors, including sulfoxides.