Cycloamyloses derivatives

In an attempt to prepare a catalytically active cycloamylose derivative which would retain the binding properties of an unmodified cycloamylose,7 Gruhn and Bender (1971) attached a relatively small hydroxamate function to a secondary hydroxyl group of cyclohexaamylose. The initial and most important step in the synthetic sequence is the reaction of ionized cyclo-... 

The reactions of the cycloamyloses may also be useful in achieving stereoselective organic synthesis or they may serve as models for hydrophobic interactions in aqueous solution. As the scope of cycloamylose catalysis is extended to include other reaction types and other cycloamylose derivatives, additional applications will undoubtedly be revealed for the cycloamyloses as catalysts. 

In accord with the current interest in stereochemistry at phosphorus a number of optical studies on phosphonous derivatives have been carried out. Benschop and his group have achieved a partial resolution of alkyl alkylphosphinates (133) by stereospecific inclusion in cycloamyloses. Optical purities in the range 20—80% were obtained. 

Because of the conformational restraints imposed on the cycloamyloses by their looped arrangement, it is reasonable to assume that the structural features derived for the crystalline state will be retained in solution. This has been confirmed in recent years by means of a variety of spectroscopic techniques. Nuclear magnetic resonance (Rao and Foster, 1963 Glass,... 

A final source of evidence for the formation of inclusion complexes in solution has been derived from kinetic measurements. Rate accelerations imposed by the cycloamyloses are competitively inhibited by the addition of small amounts of inert reagents such as cyclohexanol (VanEtten et al., 1967a). Competitive inhibition, a phenomenon frequently observed in enzymatic catalyses, requires a discrete site for which the substrate and the inhibitor can compete. The only discrete site associated with the cycloamyloses is their cavity. 

From scheme I, together with the experimentally observed first-order dependence on the total ester concentration, the rate relationship illustrated in Eq. (1) may be derived. In applying this equation, the cycloamylose concentration must be at least tenfold greater than the initial substrate concentration to ensure first-order conditions. Equation (1) may be rearranged in two ways to yield linear forms which permit graphical evaluation of fa, the maximal rate constant for release of phenol from the fully com-plexed ester and Kd, the cycloamylose-substrate dissociation constant (defined in Scheme I as A i/fa). These two methods are illustrated in Eqs. (2) and (3) and may be attributed to Lineweaver and Burk (1934) and to Eadie (1942), respectively. Although in theory both methods should give... 

The conclusions derived from the preceding experiments may be summarized with the aid of the reaction mechanism illustrated in Scheme II. The ester undergoes a rapid, reversible association with the cycloamylose, C—OH. An alkoxide ion derived from a secondary hydroxyl group of the cycloamylose may then react with an included ester molecule to liberate a phenolate ion and produce an acylated cycloamylose. This reaction is characterized by a rate constant, jfc2(lim), the maximal rate constant for the appearance of the phenolate ion from the fully complexed ester in the pH range where the cycloamylose is completely ionized. Limiting rates are seldom achieved, however, because of the high pK of cycloamylose. 

More recently, Kaiser and coworkers reported enantiomeric specificity in the reaction of cyclohexaamylose with 3-carboxy-2,2,5,5-tetramethyl-pyrrolidin-l-oxy m-nitrophenyl ester (1), a spin label useful for identifying enzyme-substrate interactions (Flohr et al., 1971). In this case, the catalytic mechanism is identical to the scheme derived for the reactions of the cycloamyloses with phenyl acetates. In fact, the covalent intermediate, an acyl-cyclohexaamylose, was isolated. Maximal rate constants for appearance of m-nitrophenol at pH 8.62 (fc2), rate constants for hydrolysis of the covalent intermediate (fc3), and substrate binding constants (Kd) for the two enantiomers are presented in Table VIII. Significantly, specificity appears in the rates of acylation (fc2) rather than in either the strength of binding or the rate of deacylation. 

Cycloamylose-induced rate accelerations are by no means limited only to the hydrolysis of carboxylic acid derivatives. Indeed, one of the first ob-... 

In contrast to the reactions of the cycloamyloses with esters of carboxylic acids and organophosphorus compounds, the rate of an organic reaction may, in some cases, be modified simply by inclusion of the reactant within the cycloamylose cavity. Noncovalent catalysis may be attributed to either (1) a microsolvent effect derived from the relatively apolar properties of the microscopic cycloamylose cavity or (2) a conformational effect derived from the geometrical requirements of the inclusion process. Kinetically, noncovalent catalysis may be characterized in the same way as covalent catalysis that is, /c2 once again represents the rate of all productive processes that occur within the inclusion complex, and Kd represents the equilibrium constant for dissociation of the complex. 

Accelerations (or decelerations) imposed by the cycloamyloses on the rate of an intramolecular reaction may be derived from a conformational effect. The rate of an intramolecular reaction depends not only on the proximity of the reactive groups but also on their relative orientation. For example, Bruice and Bradbury (1965) have shown that the rates of formation of cyclic anhydrides from mono esters of 3-substituted glutaric acids depend on the size of the substituent at the 3-position. This observation was interpreted as a change in the ground state population of reactive and non-reactive conformers as the 3-substituents are varied (Scheme IX). Reason-... 

Recently, an example of cycloamylose-induced catalysis has been presented which may be attributed, in part, to a favorable conformational effect. The rates of decarboxylation of several unionized /3-keto acids are accelerated approximately six-fold by cycloheptaamylose (Table XV) (Straub and Bender, 1972). Unlike anionic decarboxylations, the rates of acidic decarboxylations are not highly solvent dependent. Relative to water, for example, the rate of decarboxylation of benzoylacetic acid is accelerated by a maximum of 2.5-fold in mixed 2-propanol-water solutions.6 Thus, if it is assumed that 2-propanol-water solutions accurately simulate the properties of the cycloamylose cavity, the observed rate accelerations cannot be attributed solely to a microsolvent effect. Since decarboxylations of unionized /3-keto acids proceed through a cyclic transition state (Scheme X), Straub and Bender suggested that an additional rate acceleration may be derived from preferential inclusion of the cyclic ground state conformer. This process effectively freezes the substrate in a reactive conformation and, in this case, complements the microsolvent effect. 

The successful selective modification of the cycloamyloses must overcome rather severe synthetic difficulties derived primarily from the multiplicity of potentially reactive cycloamylose hydroxyl groups. Utilizing techniques developed for the modification of acyclic carbohydrates, the cycloamyloses... 

The rate effects imposed by this derivative, however, are dependent on the structure of the substrate. For example, the hydrolysis of 8-acetoxy-5-quinoline-sulfonate (AQS), a large substrate which cannot be included within the cyclohexaamylose cavity, is not enhanced by this derivative. Moreover, in contrast to the effects of unmodified cycloamyloses on the hydrolyses of nitrophenyl acetates, the rate accelerations imposed by this... 

In a preliminary attempt to improve the catalytic properties of the cycloamyloses Bunting and Bender (1968) and, subsequently, Kice and Bender (1968) replaced, in separate experiments, both a primary and a secondary cyclohexaamylose hydroxyl group with a thiol group which has a pKa closer to neutrality than a hydroxyl group. Unfortunately, neither derivative catalyzed the hydrolysis of m-nitrophenyl acetate to any greater extent than unmodified cyclohexaamylose. 

As recently as 1965, Thoma and Stewart predicted that alterations in reaction rates [in the presence of the cycloamyloses] should be anticipated whose magnitude and sign will fluctuate with the reaction type, and added that at the present juncture, it is impossible to sort out confidently. . . which factors may contribute importantly to raising or lowering the activation energy of the reaction. In the short interval between 1965 and the present, a wide variety of cycloamylose-induced rate accelerations and decelerations have, indeed, been revealed. More importantly, rate alterations imposed by the cycloamyloses can now be explained with substantially more confidence. The reactions of derivatives of carboxylic acids and organo-phosphorus compounds with the cycloamyloses, for example, proceed to form covalent intermediates. Other types of reactions appear to be influenced by the dielectric properties of the microscopic cycloamylose cavity. Still other reactions may be affected by the geometrical requirements of the inclusion process. 

Phenyl acetates, hydrolysis of, and derivatives, catalytic action of cycloamyloses on, 23 222-228, 254 Phenylacetylene hydration, 41 155... 

An interesting bisimidazole adduct has been reported by Breslow et al. (12). The imidazole derivative (3) was prepared from the capped disulfonate (2) originally made by Tabushi et al. (97). The cycloamylose (3) was used as... 

Berger L, Lee J (1960) Cycloamylose sulfates and derivatives thereof. USA Hoffmann - La Roche... 

Trimethylsilylation is adversely affected by moisture, and therefore, hydrolyzates should be evaporated to dryness as completely as possible. If trimethylsilylation is catalyzed by trifluoroacetic acid, instead of chlorotrimethylsilane, moderate proportions of water may be tolerated,117,127-129 but, even under these conditions, extra peaks may be obtained from partly trimethylsilylated derivatives.130 Catalysis with trifluoroacetic acid is useful when aqueous aliquots from a reaction are to be trimethylsilylated.131 A further advantage of this method, which has been used in the determination of 1,6-anhydro-jS-D-glucopyranose in corn syrup,132 for cycloamyloses,133 and for a series of malto-oligosaccharides,134 is that ammonium trifluoroacetate is soluble in pyridine. 

Although several advantages of dimethylsilyl (Me2HSi) ethers have been claimed,191 few examples of their use have been reported, except for the separation of cycloamyloses.133 Thus, dimethylsilyl derivatives (which are more volatile than trimethylsilyl ethers) require lower column-temperatures and have shorter retention times for example, for glucose, the per(trimethylsilyl) derivative has a retention time of 11.4 min, and the per(dimethylsilyl) derivative, 5.10 min. Both types of derivative may be analyzed on the same column, and, in certain cases, compounds inseparable as their O-trimethylsilyl derivatives may be separated as their dimethylsilyl ethers. The potential of di-methylsilylation for converting oligosaccharides into volatile derivatives should be examined. 

In most cases, complete trimethylsilylation is desired, and with O-trimethylsilyl derivatives, steric hindrance does not arise, but, with larger groups, such as tricyclohexylsilyl, it may be very significant.198 The fact that cycloamyloses yield several peaks when converted into the trimethylsilyl ethers, but only a single peak as their di-methylsilyl ethers, has been attributed to possible steric hindrance.195... 

Crystallography, of melezitose, II, 14 Cuto-cellulose, III, 187 Cyanohydrins, in synthesis of higher-C sugars, I, 1-36, 37, 38 Cyclization, of hexose derivatives, III, 53 Cycloamyloses, III, 254 305 V, 266 Cyclohexane, 1,3-diamino-2,4,5,6-tetra-hydroxy-. See Streptamine. 

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