Carbohydrate Reaction Intermediates: Effect of Ring-Oxygen Protonation on the Structure and Conformation of Aldofuranosyl Rings Jamie Kennedy, † Jian Wu, ‡ Kenneth Drew, † Ian Carmichael, § and Anthony S. Serianni* ,† Contribution from the Department of Chemistry and Biochemistry, UniVersity of Notre Dame, Notre Dame, Indiana 46556, Department of Human Biological Chemistry and Genetics, UniVersity of Texas Medical Branch, GalVeston, Texas 77555-1157, and Radiation Laboratory, UniVersity of Notre Dame, Notre Dame, Indiana 46556 ReceiVed October 28, 1996. ReVised Manuscript ReceiVed June 11, 1997 X Abstract: The effect of ring-oxygen protonation on the structure and conformational properties of a model deoxyaldofuranose, 2-deoxy--D-glycero-tetrofuranose 2, has been examined with the use of NMR spectroscopy and ab initio molecular orbital calculations conducted at the HF/6-31G* level of theory. The computational method was validated by comparing the conformational behavior of 2 derived from PSEUROT treatment of 3 J HH values measured in 2 ( 2 H 2 O solvent) with that predicted from the theoretical calculations. Coupling data indicate that 2 favors S forms in solution (∼89% 4 T 3 , ∼11% E 2 ), while MO data indicated more comparable populations of the same or very similar N and S forms. Protonation of 2 at the ring oxygen (O4), yielding 1, gave two distinct protonated forms which differed in the orientation of the proton about O4. Both forms showed substantial changes in ring structure and conformation compared to 2. Protonated forms almost exclusively prefer S forms (E 3 ), and energy barriers for N/S interconversion were found to be considerably higher than those for 2, leading to the conclusion that 1 is more conformationally constrained than 2. Bond lengths in the vicinity of O4 changed significantly upon conversion of 2 to 1; for example, the C1-O4 bond length increases by ∼14%, the C1-H1 and C1-O1 bond lengths decrease by 1-5%, and the C4-O4 bond length increases by ∼5%. These results indicate that O4 protonation predisposes 2 toward ring opening by inducing specific structural and conformational modifications, thus providing a more concise explanation of the role of acid catalysis in furanose anomerization (i.e., 1 resembles the transition state of the acid-catalyzed anomerization reaction more than 2). The molecular orbital data obtained in this investigation also provide evidence for a new structural factor (a 1,3-effect involving oxygen lone-pair orbitals) that influences bond lengths in carbohydrates. Introduction Furanosyl rings are common scaffolds upon which many biologically-important compounds, both simple and complex, are constructed. For example, cell metabolites such as D- fructose 1,6-bisphosphate and D-ribose 5-phosphate contain a single furanose ring, whereas biopolymers such as nucleic acids and some polysaccharides (e.g., inulin) are comprised of many furanose building blocks. In contrast to most pyranosyl rings, 1 furanosyl rings are not conformationally homogeneous in solu- tion, but exist in various nonplanar envelope and twist conform- ers that are similar in energy (energy barriers < ∼4 kcal/mol). 2 The spontaneous interconversion between these forms in solution proceeds via a pseudorotational itinerary 2a (Figure 1) in which nonplanar forms (E, envelope; T, twist) interconvert with other nonplanar forms, that is, the less stable planar form is not involved as an intermediate. An alternative, and presumably less preferred, mode of conformer exchange (i.e., inversion) describes conformer interconversion via the planar form. 2c The fluxional behavior of furanosyl rings confers considerable flexibility to molecules that contain them, and this flexibility may have important implications for biological recognition. For example, given the relative ease of interconversion of nonplanar furanose conformers, it is energetically possible that confor- mational change may occur in substrates containing a furanose constituent upon initial binding by enzymes. In contrast, conformational change is less likely for most pyranosyl rings, at least for 4 C 1 and 1 C 4 interconversion, where the energy barrier for interconversion is considerably greater. 2e Likewise, chem- istry performed on a furanose ring during an enzyme-catalyzed reaction might be accompanied by significant change in ring shape, again facilitated by the low barriers for conformer interconversion. These changes, if they occur, might represent an important element in the underlying molecular processes affecting catalytic efficiency. Indeed, such structural and/or conformational changes have been implicated in transition state analyses of enzyme reactions involving oxycarbonium ion intermediates derived from furanose-containing substrates. 3 * Address correspondence to this author. † Department of Chemistry and Biochemistry, University of Notre Dame. ‡ Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch. § Radiation Laboratory, University of Notre Dame. X Abstract published in AdVance ACS Abstracts, August 1, 1997. (1) Many aldopyranosyl rings, such as those having the gluco, manno, and galacto configurations, are considered highly conformationally con- strained to a single chair form (e.g., 4 C1 for D-gluco). In contrast, a few rings, such as those having the ribo, ido, and altro configurations, exhibit considerable conformational mobility. (2) (a) Altona, C.; Sundaralingam, M. J. Am. Chem. Soc. 1972, 94, 8205- 8212. (b) Harvey, S. C.; Prabhakaran, M. J. Am. Chem. Soc. 1986, 108, 6128-6136. (c) Westhof, E.; Sundaralingam, M. J. Am. Chem. Soc. 1983, 105, 970-976. (d) Levitt, M.; Warshel, A. J. Am. Chem. Soc. 1978, 100, 2607-2613. (e) The free energy barrier for chair interconversion of cyclohexane has been estimated at ∼10 kcal/mol (Jensen, F. R.; Noyce, D. S.; Sederholm, C. H.; Berlin, A. J. J. Am. Chem. Soc. 1962, 84, 386); barriers for aldopyranose chair interconversion are expected to be considerably higher (Dowd, M. K.; French, A. D.; Reilly, P. J. Carbohydr. Res. 1994, 264,1-19). 8933 J. Am. Chem. Soc. 1997, 119, 8933-8945 S0002-7863(96)03727-4 CCC: $14.00 © 1997 American Chemical Society