Hemiacetals stable cyclic

Compounds that contain both carbonyl and alcohol functional groups are often more stable as cyclic hemiacetals or cyclic acetals than as open chain compounds Examples of several of these are shown Deduce the structure of the open chain form of each... 

The position of equilibrium, i.e. whether the carbonyl compound or the addition product is favoured, depends on the nature of the reagents. The equilibrium constant is often less than 1, so that the product is not favoured, and many simple hemiacetals and hemiketals are not sufficiently stable to be isolated. However, stable cyclic hemiacetals and hemiketals... 

If the aldehyde group and the hydroxyl group are part of the same molecule, a cyclic hemiacetal results. Cyclic hemiacetals are particularly stable if they result in five-or six-membered rings. In fact, five- and six-membered cyclic hemiacetals are often more stable than their open-chain forms. 

A particularly successful synthesis of Epothilone A is based on two DERA-cata-lyzed steps. In these two of the seven stereocentres of Epothilone A were established. When a racemic aldehyde was released in situ from its acetal, DERA converted only the R-enantiomer into the stable cyclic hemiacetal. This is a combined kinetic resolution and carbon-carbon bond formation yielding a building block with two chiral centers. Since the alcohol function was oxidized, the optical information obtained from the kinetic resolution was lost. Thus, for the overall yield it would have been better if DERA had displayed no stereoselectivity towards the acceptor (Scheme 5.32). In the DERA-catalyzed synthesis of another part of Epothilone A DERA is again highly stereoselective. Fortunately its preference is for the S-enan-tiomer of the acceptor aldehyde, the enantiomer that has to be submitted to the carbon-carbon bond formation in order to obtain the desired building block, again a stable hemiacetal (Scheme 5.32). Indeed, both DERA-catalyzed reactions yield open chain products that form stable cyclic hemiacetals. This ensures that the equilibria of these aldol reactions are shifted towards the desired products. Further synthetic manipulations converted these intermediates into Epothilone A [55]. 

A particularly elegant application of DERA is the sequential synthesis of thermodynamically stable cyclic hemiacetal. Two DERA-catalyzed aldol reactions convert one equivalent of acceptor and two equivalents of acetaldehyde into this stable compound. A mild subsequent oxidation yielded the corresponding lactone in ex-... 

There is no generally useful nonhydride method for the direct reduction of carboxylic acid esters to aldehydes. There are, however, procedures which are valuable under particular circumstances. An important example is the one-electron reduction of aldonolactones to aldoses. Two factors presumably contribute to the success of these reactions firstly the presence of electron-withdrawing substituents in the substrates, raising the reactivity of the carbonyl group, and secondly the ability of the products to form cyclic hemiacetals stable to further reduction. 

In the presence of oxygen, intermediate 10 can undergo oxidation and give rise to the formation of the aminoketo compound 11 and subsequently an acid, the so-called Strecker acid [36], The formation of Strecker acid, however, is not possible if dicarbonyls such as 4 are present in form of their stable cyclic hemiacetals, as shown by Hofmann and co-workers [36]. The same group revealed also that Strecker aldehydes can be formed via an oxidative degradation of Amadori compounds, as shown for the Amadori compound of phenylalanine and glucose [37],... 

We showed you glucose as on p. 137 an example of a stable, cyclic hemiacetal. matic hydrolysis of starch or cellulose, which are themselves polyacetals made... 

Draw the most stable conformation of the most stable cyclic hemiacetal form of tagatose. 

FIGURE 22.11 Intramolecular hemiacetal formation is analogous to hydration and intermolecular hemiacetal formation. Cyclic hemiacetals having five or six atoms in the ring are easily made and are often more stable than their open forms. 

Problem 21.40 Two naturally occurring compounds that contain stable cyclic hemiacetals and acetals are... 

The simplest carbohydrates are the sugars, or saccharides. As chain length increases, the increasing number of stereocenters gives rise to a multitude of diastereomers. Fortunately for chemists, nature deals mainly with only one of the possible series of enantiomers. Sugars are polyhydroxycarbonyl compounds and many form stable cyclic hemiacetals, which affords additional structural and chemical variety. 

The key to a successful two-step aldol strategy is that the first aldol reaction product must not form a stable cyclic hemiacetal (Table 10.19) [167,168]. The starting aldehyde acceptor must therefore be carefully selected or strategically protected to prevent the reaction stopping after the first addition step. Higher order sequences are usually impossible after two successive additions due to... 

Experiments designed to clarify the situation were carried out by Wittig and Mayer (40). It was shown that changing the molar ratio of amine (diethylamine, di- -butylamine, or diisobutylamine) to -butyraldehyde from 1 1 to 2 1 did not affect the yield of enamine (53- 64%, based on the aldehyde). Contrariwise, changing the ratio of amine (morpholine, piperidine, or pyrrolidine) to n-butyraldehyde from 1 1 to 2 1 boosted the yields from 52-57 % to 80-85 %. The authors interpret these data as indicating that the cyclic amines form aminals with n-butyraldehyde, while the open-chain do not. Infrared evidence is stated as having shown that the aminal originates not from attack of excess amine on the enamine, which is stable under the conditions of the reaction, but from the N-hemiacetal (17). 

If the carbonyl and the hydroxyl group are in the same molecule, an intramolecular nucleophilic addition can take place, leading to the formation of a cyclic hemiacetal. Five- and six-membered cyclic hemiacetals are relatively strain-free and particularly stable, and many carbohydrates therefore exist in an equilibrium between open-chain and cyclic forms. Glucose, for instance, exists in aqueous solution primarily in the six-membered, pyranose form resulting from intramolecular nucleophilic addition of the -OH group at C5 to the Cl carbonyl group (Figure 25.4). The name pyranose is derived from pyran, the name of the unsaturated six-membered cyclic ether. 

When catalyzed by acids, low molecular weight aldehydes add to each other to give cyclic acetals, the most common product being the trimer. The cyclic trimer of formaldehyde is called trioxane, and that of acetaldehyde is known as paraldehyde. Under certain conditions, it is possible to get tetramers or dimers. Aldehydes can also polymerize to linear polymers, but here a small amount of water is required to form hemiacetal groups at the ends of the chains. The linear polymer formed from formaldehyde is called paraformaldehyde. Since trimers and polymers of aldehydes are acetals, they are stable to bases but can be hydrolyzed by acids. Because formaldehyde and acetaldehyde have low boiling points, it is often convenient to use them in the form of their trimers or polymers. 

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