Conformations of cyclic acetals

The conformations of cyclic acetals have been discussed by us in Adv. Polymer Sci. 37 (1980). 

General reviews on cyclic acetals of carbohydrates have appeared. The cyclic acetals of the aldoses and aldosides have been treated in this Series by de Beider, but inclusion of cyclic acetals of ketoses was beyond the scope of his Chapter. Other articles, by Barker and Bourne, Mills, and Ferrier and Overend, have been concerned with the stereochemistry and conformation of cyclic acetals of the carbohydrate group. The purpose of the present article is to supplement de Beider s Chapter with a description of the pertinent original work, optimal laboratory preparations, properties, and applications of the cyclic acetals of ketoses, and to provide a summary of the known theoretical aspects of their formation, rearrangement, and hydrolysis. 

With due consideration of the explanations just presented for the observed, relative stabilities of cyclic acetals derived from polyols, in terms of their constitution and conformation, nearly all of the following observations on the selective hydrolysis of cyclic acetals of alditols and dialkyl dithioacetals may be readily understood. 

Several reviews have already been published on the subject, for example, the acetala-tion of alditols [4], of aldoses and aldosides [5,6], and of ketoses [7]. Some aspects of the stereochemistry of cyclic acetals have been discussed in a review dealing with cyclic derivatives of carbohydrates [8], also in a general article [9] and, more recently, in a chapter of a monograph devoted to the stereochemistry and the conformational analysis of sugars [10], Aspects on predicting reactions patterns of alditol-aldehyde reactions are reviewed within a general series of books on carbohydrates [11]. The formation and migration of cyclic acetals of carbohydrates have also been reviewed [12,13],... 

This sequence serves to exemplify the formation and aspects of reactivity of toluene-p-sulphonate esters in monosaccharide systems, and further to illustrate the selective protection afforded to hydroxyl groups by the formation of cyclic acetals by reaction with carbonyl compounds. Thus reaction of methyl a-D-glucopyranoside (26) with benzaldehyde in the presence of zinc chloride gives the 4,6-acetal (27) (Expt 5.118), wherein two fused six-membered rings of the frans-decalin type are present. As a cognate preparation the reaction of benzaldehyde with methyl a-D-galactopyranoside results in a similar conversion to a 4,6-acetal, but in this case the product is the conformationally flexible system of the cis-decalin type, the most likely conformation being that shown below. 

Barker, Bourne and Whiffen have shown that, if the preferred conformation of glycitols is that with the planar, zig-zag arrangement of carbon atoms characteristic of long-chain polymethylene compounds, it is possible to explain the main features of the observed pattern of cyclic-acetal formation. 

There is now enough evidence available to permit an analysis of the conformational factors concerned in the formation of cyclic acetals from all classes of polyhydroxy compounds likely to be encountered, and to allow the recognition of structural types for which more evidence is needed. It will be found that the empirical rules are all sound in principle and may be used to assess quickly the types of acetals likely to be encountered in a given situation, but that a study of conformations is necessary where alternative structures seem to be possible from the empirical rules. 

Barker, Bourne and Whiffen concluded that the empirical rules were soundly based by examining the consequences of a planar, zig-zag conformation of the carbon chain in glycitols. The writer feels that a study of the end-products of reaction is the safer approach to the problem of acetal formation, and of other reversible reactions, because deductions based on the conformations of the reactants will only be sound if these conformations, and the mechanism of the reactions, are well established. If all factors concerned could be accurately assessed, the two approaches would give identical answers. Formation of cyclic acetals seems to be the only instance in which both approaches to the problem of preferred ring structure are possible. 

The excellence of n.m.r. spectroscopy for elucidating structural and stereochemical problems is unsurpassed, and is nowhere better illustrated than in the field of cyclic acetals. There are many authoritative reviews on this topic,72a72e and, in this article, the discussion will be confined to two main aspects the application of n.m.r. spectroscopy to the study of (a) diastereoisomerism, and (b) conformation. 

The conformational equilibria of cyclic acetals have received much attention during the past decade, a development due essentially to improved instrumental techniques for n.m.r. spectroscopy. Several comprehensive reviews2 893-890 of this field have been published con-... 

Formation of cyclic acetals by sugar hydroxyls generally retards nucleophilic displacements at the anomeric centre of the same sugar residue. In the case of 4,6-benzylidene derivatives, the mechanism of deactivation appears to be that the dipole of the C6-06 bond is constrained with its positive end directed towards the anomeric centre.In the case of the 1,2-diketals, the deactivation arises from the increased difficulty of forming half-chair or boat conformations in a six-membered ring, which is part of a traw -fused decalin structure. 

The effect of the nature and size of 2-substituents on the preferred conformation of 1,3-dioxepans has been studied by i.r. and dipole-moment measurements.Carbon-13 n.m.r. spectroscopy provides a useful way to distinguish between ring sizes 5—7 of cyclic acetals, using both the chemical shift of the acetal carbon and the coupling constant with its attached proton. ... 

Formation and migration of cyclic acetals of carbohydrates has been reviewed. Molecular mechanical calculations have been used to calculate the energies of various conformations of bicyclic acetals of C4-C6 alditols with formaldehyde. The thermodynamic stabilities of the [4.4.0] products were predicted to be higher than for the [5,3.0] products in the gas phase. Discrepancies with experimentally observed data were ascribed to solvent effects. 

With the advent of NPGs, it was now possible to escape from the acid-lability restrictions and impose conformational restraints by strategic placing of cyclic acetals. Unrestrained, 8a, and restrained substrates 50 and 51 (Fig. 5) were... 

Treatment of methyl /l-D-glucopyranoside with benzaldehyde forms a six-membered cyclic acetal. Draw the most stable conformation of this acetal. Identify each new chiral center in the acetal. 

Notice that the eclipsed conformation of d ribose derived directly from the Fischer pro jection does not have its C 4 hydroxyl group properly oriented for furanose ring forma tion We must redraw it m a conformation that permits the five membered cyclic hemi acetal to form This is accomplished by rotation about the C(3)—C(4) bond taking care that the configuration at C 4 is not changed... 

Fig. 8. Stereoscopic illustration of the inclusion compound of host 5 (folded conformation) with acetic acid and 2 mol of water. Host-host and host-water hydrogen bonding interactions stabilize the structure. The solvation layers consist of cyclic carboxy dimers of acetic acid surrounded by water species (crystal data a = 7.857, b = 11.379,c = 13.831 A,a = 92.50,/i = 101.21, y = 101.12°, space group Pi taken from Ref. 351)...

Two other myo-inositol derivatives have been selectively alkylated. Reaction of DL-l,2 4,5-di-0-cyclohexylidene-myo-inositol with benzyl chloride-potassium hydroxide in benzene, followed by removal of the acetal groups, gave DL-1-O- and DL-4-O-benzyl-myu-inositol in the ratio of 5 2, whereas, under similar conditions, DL-1,2 5,6-O-cyclohexylidene-myo-inositol gave311 the same ethers in the ratio of 57 10. These results are not readily explicable in the absence of knowledge of the conformations adopted by the cyclic acetals. 

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