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Synlett 2008(14): 2175-2177  
DOI: 10.1055/s-2008-1078249
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of Mucin Glycans from the Protozoon Parasite Trypanosoma cruzi

Renate M. van Wella, Beatrice Y. M. Colleta, Robert A. Field*a,b
a School of Chemical Sciences and Pharmacy, University of East Anglia, Norwich NR4 7TJ, UK
b Department of Biological Chemistry, John Innes Centre, Colney Lane, Norwich NR4 7UH, UK
Fax: +44(1603)450018; e-Mail: rob.field@bbsrc.ac.uk;
Further Information

Publication History

Received 2 June 2008
Publication Date:
05 August 2008 (online)

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Abstract

A short, blockwise, 2+2-glycosylation approach to the synthesis of a tetrasaccharide component of Trypanosoma cruzi mucin is reported. Despite the use of a 1,2-linked disaccharide donor, high yield (79%) and good stereocontrol (>10:1, β:α) were achieved in the key glycosylation step. Preliminary studies indicate that this branched tetrasaccharide can serve as a substrate for enzymatic sialylation by the parasite cell surface trans-sialidase.

Key words

oligosaccharide - synthesis - parasite - mucin - trans-sialidase - drug target

1

http://www.who.int/topics/chagas_disease/en/.

Scheme 3 Action of recombinant T. cruzi trans-sialidase on synthetic mucin tetrasaccharide 1. [7d]

16

The studies reported herein have been conducted in parallel with efforts that replace the reducing terminal N-acetyl-glucosamine unit with mannose, which offers more straightforward entry to an α-linked amino acid-glycan linkage.

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In the parallel series with a mannose at the reducing terminus, the corresponding coupling gave complete
β-stereocontrol albeit in lower yield (54%).

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Selected Analytical Data
Imidate 3: [α]D ²0 +41.0 (c 1, CHCl3). ¹H NMR (400MHz, CDCl3): δ = 8.65 (s, 1 H, NH), 6.51 (d, 1 H, H1, J 1,2 = 3.6 Hz), 4.66 (d,1 H, H1′, J 1 ′ ,2 ′ = 7.8 Hz). ¹³C NMR (100 MHz, CDCl3): δ = 160.7 (C=NH), 101.3 (C1′), 94.9 (C1). HRMS: m/z calcd for C28O18NCl3H36 [M + NH4]: 797.1336; found: 797.1339.
Tetrasaccharide 5: [α]D ²0 -4.0 (c 1 in CHCl3). ¹H NMR (600 MHz, CDCl3): δ = 4.78 (d, 1 H, H1c, J 1,2 = 8.0 Hz), 4.70 (d, 1 H, H1a, J 1,2 = 10.0 Hz), 4.60 (d, 1 H, H1b, J 1,2 = 7.7 Hz), 4.55 (d, 1 H, H1d, J 1,2 = 7.9 Hz). ¹³C NMR (100 MHz, CDCl3): δ = 101.7 (C1b), 100.9 (C1c), 100.3 (C1d), 85.5 (C1a). MS (ES): m/z = 1372.5 [M + Na]+.
Tetrasaccharide 1: [α]D ²0 +15.0 (c 1 in H2O). ¹H NMR, (400 MHz, D2O): δ = 4.87 (d, 1 H, H1a, J 1,2 = 10.4 Hz), 4.37 (d, 1 H, H1b, J 1,2 = 6.8 Hz), 4.34 (d, 1 H, H1c, J 1,2 = 8.0 Hz), 4.31 (d, 1 H, H1d, J 1,2 = 7.9 Hz). ¹³C NMR (75 MHz, D2O): δ = 175.1 (C=ONHAc), 104.2 (C1c), 103.8 (C1d), 102.2 (C1b), 85.9 (C1a). HRMS: m/z calcd for C32H49N3O20S [M + Na]+: 822.2461; found: 822.2487.