Large Scale Synthesis of gal Trisaccharide Derivative

Although a-d-Galp-(1^3)-|8-d-Galp-(1^4)-|6-d-Glc^ and a-d-Galp-(1^3)-^-d-Galp-(1^4)-^-d-GlcNAcp sequences had been synthesized chemically [90-94], these synthetic methods failed to produce a large quantity of oligosaccharides effectively. In addition to our successful efforts in the enzymatic synthesis of several a-gal oligosaccharides using a recombinant a1,3-GT, we have developed a practical and efficient route for chemical synthesis of derivatives of a-gal trisaccharide 2 on a 50 g scale. Synthesis of a-gal epitope derivatives 35 and 37 was achieved by utilizing a stereoselective and high-yielding glycosylation method, with the acceptor prepared through an efficient dibutylin oxide mediated regioselective protecting scheme [95]. In preparation of the glycosylation acceptor 33 (Fig. 13), lactosyl bromide 29 was converted to azide 30 [51] and then deacetylated to generate lactosyl azide 8. The regioselective monoalkylation of the C3 hydroxy group of galactose with p-methoxybenzyl chloride (MPMCl) was achieved through a one-pot reaction m i o

Figure 11 Synthesis of a-gal tri- and pentasaccharide epitopes with the bifunctional protein ga/E-a1,3-GT.

Compound a-D-Galp-( 1 —>3)-ß-D-Galp-( 1 ^-d-GIcNH^ (13)

a-D-Galp-( 1 —>3)-ß-D-Galp-(l -^4)-ß-D-GlcNH2p-(1^3)-ß-D-Galp-( 1^4)-ß-D-Glcp-N3 (28) a-D-Galp-(l—>3)-ß-D-Gal/>-(l—>4)-D-GlcNHAcp (11)

a-D-Galp-(l—>3)-ß-D-Galp-(l—>4)-ß-D-GlcNHAcp-(l—>3)-ß-D-GaIp-(l—>4)-ß-D-Glcp-N3 (22)

Figure 12 Comparing inhibitory activity of N-acetylated a-gal epitopes and those bearing a free amino group.

sequence involving a dibutylstannylene acetal intermediate. The selectively protected azide 31 was peracetylated to give compound 32, which was selectively deprotected at C3-OH through oxidative cleavage of the MPM ether with cerium(IV) ammonium nitrate (CAN) [96] to yield acceptor building block 33 (Fig. 13). Large scale (50 g) glycosylation between perbenzylated phenyl thiogalactoside donor 34 [97] and acceptor 33 (Fig. 14) was carried out under activation of V-iodosuccinimide/triflic acid

Ac9 OAc .OAc NaN3, TBAHS AcO 0Ac .OAc

OAc OAc Br 95% OAc OAc

OAc Br 95%

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