D-Gluco- and D-xylopyranosylidene-spiro-hydantoins and -thiohydantoins were prepared from the parent sugars in a six-step, highly chemo-, regio-, and stereoselective procedure. In the key step of the syntheses C-(1-bromo-1-deoxy-beta-D-glycopyranosyl)formamides were reacted with cyanate ion to give spiro-hydantoins with a retained configuration at the anomeric center as the major products. On the other hand, thiocyanate ions gave spiro-thiohydantoins with an inverted anomeric carbon as the only products. On the basis of radical inhibition studies, a mechanistic rationale was proposed to explain this unique stereoselectivity and the formation of C-(1-hydroxy-beta-D-glycopyranosyl)formamides as byproducts. Enzyme assays with a and b forms of muscle and liver glycogen phosphorylases showed spiro-hydantoin 12 and spiro-thiohydantoin 14 to be the best and equipotent inhibitors with K(i) values in the low micromolar range. The study of epimeric pairs of D-gluco and D-xylo configurated spiro-hydantoins and N-(D-glucopyranosyl)amides corroborated the role of specific hydrogen bridges in binding the inhibitors to the enzyme.

vs. pH profile (zero buffer) in Figure 2 in the pH region from 7.5 to 8.0, i.e., that for rate-limiting attack of OH" on the oxocarbonium ion.At pH >10 the ring opening reaction becomes independent of pH. Similar pH-independent reactions have been found in .the hydrolysis of acetals and ketals subject to general acid catalysis.7,8•10 These reactions involve rate-determining unimolecular C-O bond breaking.8 Thus the analogous reaction of II may also involve a unimolecular decomposition (VIII). Such a reaction would be 8-/VQ, z=\ /H-\_J~N(CH3>2 VIII due to the significant oxocarbonium ion stabilization and the ease of C-O bond breaking brought about by relief of steric strain in the acetal of trans-1,2-cyclohexanediol. An alternative possibility is that water is acting as a general acid, which would require a second-order rate constant of 1.1 X "6 M"1 s'1 (kj55.5 M). This second-order rate constant fits reasonably well on a Bronsted plot of slope -0.7 including points for the general acids and hydronium ion.In summary, in the plot of log kobsd vs. pH for the hydrolysis of trans-1,2-cyclohexanediol p-(dimethylamino)benzylidene acetal in H20 there are seven inflections, only one of which is due to an ionizable group (the p-dimethylamino group conjugate acid). As discussed, the other inflections are produced by two changes in rate-determining step and four changes in mechanism as pH is increased. This novel situation comes about because of steric strain in the acetal, so that ring opening is rapid, and the cyclic structure of the acetal, which can lead to reversibility of ring opening. The resultant compromise between these opposing factors is one in which each step becomes rate limiting in turn as pH is increased. Hemiacetal breakdown can only be rate determining at pH <6 because of OH" catalysis at higher pH. Rate-limiting hydrolysis of the protonated and neutral species of the hemiacetal at low pH is brought about because of the rapid hydronium ion catalyzed ring opening or L•2aH > k2. As the pH is increased above 6 attack of a water molecule on the oxocarbonium ion intermediate becomes rate limiting because at those pH values the hydroxide ion catalyzed breakdown of the hemiacetal is rapid with fc3(OH~) > fc-2flH• The mechanism changes at pH >7 to attack of OH" on the oxocarbonium ion, and as the concentration of OH" becomes larger the hydronium ion catalyzed ring opening becomes rate determining, i.e., &oh(OH~) > The ring-opening is also catalyzed by general acids. Finally at pH >10 the mechanism changes to pH-independent rate-determining ring opening. Thus, alt of the mechanisms and rate-determining steps for the hydrolysis of an acetal are represented on one remarkable log kobsd vs. pH profile (Figure 2).

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