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Pure Appl. Chem., 2002, Vol. 74, No. 7, pp. 1219-1225

Design and synthesis of new sweeteners

Tomoya Machinami1*, Takashi Fujimoto1, Aya Takatsuka1, Takeshi Mitsumori1, Takako Toriumi1, Tetsuo Suami2 and Leslie Hough3

1 Department of Chemistry, College of Science and Technology, Meisei University, Hino, Tokyo 191-8506, Japan
2 Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi, Yokohama 223-0061, Japan
3 Department of Chemistry, King's College London, University of London, Strand, London WC2R 2LS, UK

Abstract: Sweet taste induction by alkyl 2,3-di-O-(l-aminoacyloxy)-α-d-glucopyranosides requires a combination of hydrophobic α-alkoxy and hydrophilic vicinal, diequatorially oriented, l-aminoacyloxy units. Pyranoside chair conformations afford the preferred stereochemical arrangements of these residues for optimum interaction with the receptor. For the design of new sweeteners based on sweetness inhibitors, the introduction of a di-O-aminoacyloxy unit as the hydrogen-bonding component was applied to effect their intertransformation. Thus, the known sweetness inhibitor, methyl 4,6-dichloro-4,6-dideoxy-α-d-galactopyranoside, was successfully transformed into sweet-tasting 2,3-di-O-(l-aminoacyl) derivatives. The inhibition of the 4,6-dichloro derivative is therefore competitive. Amongst the related amino-chloro-deoxysugars, methyl 6-chloro-6-deoxy-2,3-di-O-(l-alanyl)-α-d-gluco-pyrano side was found to be a full agonist. Our studies were then extended to disaccharide derivatives based on trehalose. This approach led to new highly intense sweeteners, as dimeric forms of the full agonist 2,3,2',3'-tetra-O-(l-alanyl)-6,6'-dichloro-6,6' -dideoxytrehalose. The derivatives with effective hydrophobic groups on the C-6 and C-6' positions, were found to be up to 800­1000 times sweeter than sucrose.