Acetals cyclic, conformation

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... 

In cyclic systems such as 1, the dominant conformation is the one with the maximum anomeric effect. In the case of 1, only conformation lA provides the preferred antiperiplanar geometry for both oxygens. Antiperiplanar relationships are indicated by including lone pairs in the oxygen orbitals. Other effects, such as torsional strain and nonbonded repulsion, contribute to the conformational equilibrium, of course. Normally, a value of about 1.5 kcal/mol is assigned to the stabilization due to an optimum anomeric interaction in an acetal. 

The hydrolysis of acetals and ortho esters is governed hy the stereoelectronic control factor previously discussed (see A and B on p. 427) though the effect can generally be seen only in systems where conformational mobility is limited, especially in cyclic systems. There is evidence for synplanar stereoselection in the... 

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. 

The C,C-coupling reactions of six-membered cyclic nitronates were studied in most detail (274, 478). Here silyl ketene acetal was also used as the test nucleophile. The configurations of most of the starting nitronates and the resulting nitroso acetals were determined by NMR spectroscopy and X-ray diffraction, and also a conformational analysis was performed (see Tables 3.24 and 3.25). 

Detailed configurational and conformational analyses of the starting six-membered cyclic nitronates (356) of cationic intermediates (357), and (decoupling products (357 + Nu), taking into account slow nitrogen inversion (Ijv) in nitroso acetals (see Section 3.4.3.4.4), made it possible to propose a mechanistic model based on the stereochemical outcome of the C,C-coupling process (Chart 3.23). 

When reacted with an alcohol in the presence of a catalytic amount of a strong acid, 3,4-dihydro-2/f-pyran yields a base-stable 2-alkoxytetrahydropyran (a cyclic acetal) (Scheme 4.13). The reaction is reversed if the acetal is treated with aqueous acid (see Section 3.3.4, page 54), so that this provides a simple way of protecting alcohols in syntheses where a strong base might otherwise deprotonate them. The conformational preferences of 2-alkoxytetrahydopyrans, mediated by the anomeric effect, were commented upon earlier (Section 1.5.3). 

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],... 

A number of methods for the synthesis of piperazic acid (7) and related derivatives are currently available as a result of growing interest in natural product chemistry and in their potential in medicinal chemistry. Their chemistry and conformational properties have been comprehensively reviewed. 2451 Racemic piperazic acid is obtained by condensation of penta-2,4-dienoic acid with phthalazinedione and subsequent reductive deprotection of the resulting A,A -bis(phthaloyl)-l,2,3,6-tetrahydropyridazine-3-carboxylic acid.12431 Resolution of racemic piperazic acid is achieved by fractional crystallization of the ephedrine salt of Nl-(benzyloxycarbonyl)piperazic acid from ethyl acetate. 246,2471 A typical route to enantiomerically pure (3S)-piperazic acid 56 starts from chiral 2-amino-5-hydroxyvaleric acid 55 as shown in Scheme 12.1248 Convenient stereoselective syntheses have been reported for 5-hydroxy- and 5-chloropiperazic acids as important constituents of natural cyclic peptides and depsipep-tides.1249,2521... 

Dorofeenko and his coworkers have extended this route to the synthesis of a range of cyclic analogues of pyrylium salts. Thus, cyclohexenylacetophenone affords the reduced isobenzopyrylium salt (635) on treatment with acetic anhydride (67MI22402) and 2-(indol-2-yl)cyclohexanone yields the indolo[2,3-rf]pyrylium salt (636) in the same way (69ZOB716). The yields in these reactions are much improved, a feature which may be attributable to the conformational preference for the structure shown for the enone rather than a conjugated arrangement of double bonds. 

Examples of the way these two entirely different approaches compliment each other are developing in conformation studies with the hormones angiotensin, oxytocin, and vasopressin. In 1964 Craig, Harfenist, and Paladini (7) published the comparative half-escape times shown in Table I in 0.01N acetic acid and another series in Table II using a different membrane less porous and not as selective as the first. Oxytocin and vasopressin are cyclic octapeptides with an S-S linkage closing the ring at the 1-6 positions (5, 6). Their size is thus limited except for the side... 

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