J. Am. Chem. SOC. 1993,115, 8487-8488
8487
Solution Conformations of &@-Trehaloseand Its C-Disaccharide Analog from Optical Rotation Christopher A. Dudat and Eugene S. Stevens' Department of Chemistry, State University of New York a t Binghamton, New York, 13902-6000 Received June 4, I993 HO
We report evidence that @,@-trehalose1a(Figure l a ) and its C-disaccharide analogIb (Figure 1b) adopt similar "zigzagn2 conformations in aqueous solution, the implication being that the exo-anomeric effect, necessarily absent in the latter, cannot be presumed to be conformation determining in the former. In addition to their role as model compounds for elaborating conformational determinants in saccharides, C-disaccharides are of interest as potential active-site-directed inhibitors of glycosidases and, thereby, as pharmacological regulators of glycoprotein processing and cell surface expre~sion.~ The N M R equivalence of residues in @,@-trehaloseprecludes determination of its solution conformation through conventional N M R techniques involving the measurement of chemical shifts, relaxation times, coupling constants, or NOES. Attempts to make the two glucose rings distinguishable by NMR, as through isotopic substitution, have not yet been reported. Martin and Lai,4 by exploiting the magnetic nonequivalence of the methylene bridge protonsin C-@,@-trehalose(H7, H7'), simulated their N M R signal to determine the extent of coupling with H 1 and Hl'. Values of J 1 , 7 = J1',7! = 9.6 Hz and J1.7' = J1',7 = 2.4 Hz indicate unambiguously that each H7 proton is anti with respect to one H1 and gauche with respect to the other; a relatively inflexible linkage is evidenced by the nearly maximal value of 9.6 Hz.4 Two linkage conformations5 are compatible with the N M R results: approximately $, $ = 60°, 60' and -60°, -60'. Citing unfavorable steric interactions between 0 2 and H1' in the latter conformation, the authors assigned the conformation to $, = 60°, 60'. In that conformation, the Cl-C2 bond of each glucose ring is trans to the C7-C 1 bond of the other, and the C7-C1 bond of each ring is gauche to the C1-05 bond of the other; the result is an extended zigzag arrangement2 of seven carbon atoms, C3 through C3'. MM3 flexible-residue vacuum calculations6 on the parent disaccharide, @,@-trehalose,indicate a global energy minimum at 4, $ = 44', 44O. The next lowest energy minimum is 3.9 kcal mol-' higher, near $, $ = 60°, 180'. The recently reported X-raydetermined solid-state conformation7 is $, $ = 45', 45' (-76' for 05-C1-01-Cl'; 167' for C2-C1-01-Cl'). Therefore, in the absence of a direct N M R determination of the @,@-trehalose solution conformation, only indirect evidence exists for concluding that the two compounds have similar conformations in solution. The molar rotations of the two compounds in solution are, however, significantly different: [MID = -138 deg cm2 dmol-l
+
t Present address: NOAA/NESDIS, Suitland, MD 20746.
(1) (a) 8-D-Glucopyranosyl-(I-c1)-8-~glucopyranoside;isotrehalose. (b) C-fl,@-Trehaloseor bis(8-D-glucopyranosy1)methane. (2) (a) Wu, T.-C.; Goekjian, P. G.; Kishi, Y. J . Org. Chem. 1987, 52, 4819-4823. (b) Goekjian, P. G.; Wu, T.-C.; Kang, H.-Y.;Kishi, Y. J . Org. Chem. 1987,52,4823-4825. (c) Babirad, S. A.; Wang, Y.; Goekjian, P. G.; Kishi, Y. J . Org. Chem. 1987, 52, 4825-4827. (3) Walker, B. D.; Kowalski, M.; Goh, W. C.; Kozarsky, K.; Krieger, M.; Rosen, C.;Rohrschneider,L.; Hazeltine, W. A.; Sodroski, J. Proc. Natl. Acad. Sci. U.S.A. 1987, 84, 8120-8124. (4) Martin, 0. R.; Lai, W. J . Org. Chem. 1993, 58, 176-185. (5) In trehalose, 4 and $ are the dihedral angles H1-C1-01-C1' and C1-0141'-Hl', respectively. In C-trehalose, 4 = Hl-Cl-C'I-Cl' and J. = Cl-C741'-Hl'. (6) Dowd, M. K.; Reilly, P. J.; French, A. D. J . Compu?.Chem. 1992,13, 102-114. (7) Lee, C.-K.; Koh, L. L. Acta Crystallogr. 1993, C49, 621-624.
(b)
Figure 1. (a) 6,fl-Trehalose. (b) C-@,@-Trehalose.
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