Enantiotopic carbonyl groups

Desymmetrization of prochiral cyclic anhydrides In the presence of the chiral nucleophilic catalyst (e.g. A, Scheme 13.1, top) one of the enantiotopic carbonyl groups of the prochiral (usually meso) cyclic anhydride substrate is selectively converted into an ester. Application of catalyst B (usually the enantiomer or a pseudoenantiomer of A) results in generation of the enantiomeric product ester. Ideally, 100% of one enantiomerically pure product can be generated from the starting anhydride. No reports of desymmetrizing alcoholyses of acyclic meso anhydrides appear to exist in the literature. 

As exemplified in Scheme 13.4, attack of the nucleophile methanol occurs uniformly at one or the other of the two enantiotopic carbonyl groups of the meso-anhydride (affording the hemi-esters 10 and mt-10, respectively), depending on whether (—)-quinine (2) or (+)-quinidine (3) is employed as catalyst. 

Even higher multiplicities of specificity combinations are possible. In Scheme 49, conversion of (115) to (116) involves regiospecific reduction of an enantiotopic carbonyl group concurrently with enantiotopic face specificity. This transformation can also be achieved using Saccharomyces species, with the level of (116) produced being enhanced by the addition of unsaturated carbonyl compounds, such as acrolein. ... 

Tanaka, K., Ohta, Y., and Fuji, K., Differentiation of enantiotopic carbonyl groups by the Horner-Wadsworth-Emmons reaction. Tetrahedron Lett., 34, 4071, 1993. 

The ability to differentiate between two enantiotopic carbonyl groups in a symmetrical dicarboxylic anhydride in order to generate a chiral product is extremely useful, since the resulting product can be subsequently converted into either enantomeric species by selective transformations of the chemically distinguishable functional groups. (i )-2-Methoxy-l-phenylethanol (98), prepared from 63 by a four-step sequence, reacts in the presence of a... 

The catalyst we will use Is the amino acid L-proline—no derivatization or protection required. It was actually back in 1971 that it was first noted that L-proline will catalyse asymmetric aldols, but until the year 2000 examples were limited to this one cyclization. Treatment of a triketone with proline leads to selective cyclization onto one of the two enantiotopic carbonyl groups. A molecule of proline must condense with the least hindered ketone, and in this case an enamine (rather than an iminium ion) can form. The chiral enamine can select to react with only one of the two other carbonyl groups, and it turns out that it chooses with rather high selectivity the one coloured green in the scheme below. Cyclization, in the manner of a Robinson annelation, and hydrolysis of the resulting iminium ion follow on, releasing the molecule of L-proline to start another catalytic cycle. The isolated product is the bicyclic ketone, in 93% ee. 

The first approach is based on differentiation of enantiotopic carbonyl groups in symmetrical molecules such as meso compounds, and is therefore referred to as the desymmetrization of symmetric organic molecules. Discrimination of the n-faces of symmetrically substituted carbonyl groups constitutes the second type of approach leading to dissymmetric compounds having axial chirality, and is referred to as dissymmetrization. The third type of asymmetric carbonyl oiefination... 

Most optically active olefinic products possess axial or planar chirality, which can be easily converted into central chirality by further appropriate chemical transformation without any serious loss of optical purity. The products obtained by the discrimination of enantiotopic carbonyl groups or kinetic resolution already have central chirality as well as reactive functional groups such as olefinic or unsaturated carbonyl systems. Consequently, asymmetric olefination provides an efficient methodology for the construction of useful chiral synthons applications along these lines in the asymmetric construction of useful and complex chiral molecules have just started and will be extensively investigated in the future. 

For example, the two carbonyl groups in methyl l-methyl-2,5-dioxocyclopentane acetate are enantiotopic and the two faces of each carbonyl group are diastereotopic. Yeast reduction furnished 1 (albeit in low chemical yield), by attack of the pro-R carbonyl group from its sterically less hindered Re-face. The immediate lactone formation indicates the relative configuration at the two stereogenic centers, while the absolute configuration of the yeast reduction product had to be determined (see p 437)133. 

One can also compare faces of a molecule in the same way as groups, since the comparison actually applies to environments. Thus, the two faces of the carbonyl groups of aldehydes, unsymmetrical ketones, esters, and other acid derivatives are enantiotopic. Reaction at the two faces by a chiral nucleophile will take place at different rates, resulting in asymmetric induction. 

SE.3.1.2. Desymmetrization of gem-Dwarboxylates An equivalent of asymmetric carbonyl addition can be achieved by the alkylation of gem-dicarboxylates (Scheme 8E.17). The alkylation of gem-dicarboxylates, which are easily prepared by the Lewis acid-catalyzed addition of acid anhydrides to an aldehyde, converts the problem of differentiating the two enantiotopic 7t-faces of a carbonyl group into that of asymmetric substitution of either enantiotopic C-O bond of the gem-dicarboxylate. Although asymmetric induction may be derived from enantio-discrimination in the ionization step or in the alkene coordination step, the fast and reversible nature of alkene coordination suggests that the ionization step is more likely to be the source of enantio-discrimination. 

But the product from the enzymatic reaction is optically active. The two faces of pyruvic acid s carbonyl group are enantiotopic and, by controlling the addition so that it occurs from one face only, the reaction gives a single enantiomer of lactic acid. 

Asymmetric Desymmetrization. Desymmetrization of an achiral, symmetrical molecule is a potentially powerful but relatively unexplored concept for the asymmetric catalysis of carbon-carbon bond formation. While the ability of enzymes to differentiate between enantiotopic functional groups is well known, little is known about the similar ability of nonenzymatic catalysts to effect carbon-carbon bond formation. The desymmetrization by the enantiofacial selective carbonyl-ene reaction of prochiral ene substrates with planar symmetry provides an efficient access to remote internal asymmetric induction which is otherwise difficult to attain (eq 6). The (2R,5S)-xyn product is obtained in >99% ee along with more than 99% diastereoselectivity. The desymmetrized product thus obtained can be transformed stereoselectively by a more classical diastereoselective reaction (e.g., hydroboration). 

The two carbonyl groups of symmetrical diketones are distinguishable, with the carbonyl group undergoing reduction doing so with enantiotopic specificity. Some acyclic and monocyclic examples are shown in Scheme 9.- 2,44.49.50 Once more, enantiomeric products can be selected by the use of organisms with opposite enantiotopic face specificities, as shown for the reduction of (19) to (/ )- or (S)-(20) (Scheme 10). ... 

Q2. Are the faces of the carbonyl groups in compounds 66-71 homotopic, enantiotopic or diastereotopic ... 

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