Enantiotopos differentiation

This approach sets the stage for an enantiotopos-differentiating olefin metathesis which would allow the enantioselective synthesis of 258. However, the realization of such an approach has not yet been successful [132]. The second building block (259) containing the A ring was synthesized diastereoselectively by a diastereoface-differentiating intramolecular Heck-Mizoroki reaction of the enantiomerically enriched furan 260 [120]. 

Me o-epoxides, nucleophilic ring-opening reactions by aryllithium/(—)-sparteine (11) have been realized by Alexakis and coworkers with very good differentiation between the enantiotopic positions . Eliminative desymmetrization reactions of me o-oxacycles such as 144 or 147, which are triggered by an enantiotopos-differentiating deprotonation... 

According to Widdowson, [(methoxymethoxy)benzene]tricarbonylchromium (448) was deprotonated with enantiotopos differentiation by n-BuLi/(—)-sparteine (11), and the lithium intermediate 449 was trapped by various electrophiles to give the products 451 with ee values up to 97% (equation 122) . Surprisingly, opposite enantiomers are formed when stoichiometric or excess amounts of base are applied. The authors presume that in the dilithium intermediate 450 the C—Li bond (in the rear) has a higher reactivity than the other one (pointed to the front). The deprotonation procedure was also applied to a couple of 1,4-disubstituted chromium complexes . 

Quite obviously, this is simultaneously an enantiotopos- and diastereoface-differentiating (enantio- and diastereoselective) reaction3. Similar combinations can be found in Table 15. Section 1.2.2.3 (p 54). Thus, the transformation of 12 into 13 is a diastcreotopos-diastereoface-... 

The ill-defined term meso-trick and the related term chiral economy should be avoided when a stereoselective reaction rather than a separation step is involved. Preferably, the well-defined term enantiotopos-differentiating reaction should be used. 

As is apparent from a recent review there are many examples of this lype of reaction known see R. S. Ward, Client. Soe. Rev. 19, 1 (1990). Concerning terminology, the title of this article is interesting "Non-Enzymatic Asymmetric Transformations Involving Symmetrical Bifunctional Compounds". Using the Izumi-Tai system the title could have been much shorter and precise Non-Enzy-matic Enantiotopos-Differentiating Reactions. 

I. Enantiodifferentiating Reactions (Enantiotopos-, F.nantioface-, Enantiomer-Differentiating Reactions)... 

Pig liver esterase (PLE, E.C. 3.1.1.1) is one of the most successful enzymes for the enantiotopos-differentiating hydrolysis of dicarboxylic diesters and diacetates of diols as exemplified by the two examples, dimethyl cv. y-4-cydohexene-l,2-dicaiboxylate (I)100 - " 2 and (l/ ,2.S,3S)-l,3-di-acetoxy-2-nitrocyclohexane (3)113. The monoester 2 is obtained with the same results when prepared on a 100 mol scale114. The ee values of the monoester 2 may be determined conveniently by H-NMR spectroscopy in the presence of (+)- or ( )-ephedrine and that of the monoacetate 4, after conversion to the corresponding Mosher ester, by 19F-NMR spectroscopy. 

By enantiotopos-differentiating deprotonation the lithiated complex is formed in a reagent-controlled reaction with excellent selectivity. The lithiated center of the complex is assumed to have the S configuration, as follows from the carboxylation, to give an (7 )-lactic acid derivative based on the reasonable assumption of metalloretentive electrophilic attack. Trapping with chlorotrimethylstannane gave the corresponding chiral (.S -SjS-dimethyl-l-trimethylstannyl-alkyl-l-oxa-4-azaspiro[4.5]decane-4-carboxylates. Enantioselectivity of the overall transformation is excellent. 

The classification of stereo-differentiation (63) (see Section VII) is as follows enantiomer-differentiation includes enantioface-difTerentiation, enantiotopos-dilferentiation, and enantiomer-differentiation diastereo-differentiation includes diastereoface-differentiation, diaster-eotopos-differentiation, and diastereomer-differentiation. 

A related enantiotopos-differentiating desymmetrization, the CBS-reduction of cyclic meso imides, was reported in 1997 by Hiemstra et al. [18]. 

Selectivity in enantiotopos-differentiating acylation and phosphorylation of meso-diols can rival that of enzymes. The organocatalysts employed include chiral phosphines, chiral diamines, chiral DMAP derivatives and peptides identified from combinatorial libraries. The highest selectivity in meso diol desymmetrization has been achieved with a planar-chiral Fu catalyst. It seems the substrate scope of this process is not yet broadly explored. Because of their sequential variability it is to be... 

The desymmetrization of meso-e poxides such as cyclohexene epoxide (55, Scheme 13.27) has been achieved both by enantioselective isomerization, e.g. to allylic alcohols (56, path A, Scheme 13.27) or by enantiotopos-differentiating opening by nucleophiles, affording trans-/ -substituted alcohols and derivatives (57, path B, Scheme 13.27). As indicated in Scheme 13.27, the allylic alcohols 56 can also be prepared from the ring-opening products 57 by subsequent elimination of the nucleophile. 

Important work concerning the question of the intermediacy of metal-bound ylides was published in 2001 (Scheme 98) [232]. It was found that the diastereoselectivity of the reaction was independent of the catalyst used, but markedly influenced by the size of the ester groups. (With R = CH(fPr)2 and Rh2(S-PTPI)4 the anti-398 syn-398 ratio was 94 6.) From these results it was deduced that after the enantiotopos differentiating yHde formation, the metal dissociates off and the absolute topicity of attack of the reactive sites on each other is controlled by the factors discussed for the free yHde pathway, as illustrated in Scheme 95. 

Scheme 11.1-4. Enantiotopos-differentiating hydrolysis of carboxylic acid esters.

Scheme 11.1-8. Enantiotopos-differentiating lactonization of hydroxy esters.

Numerous meso-configured or otherwise prochiral substrates, preferentially containing enantiotopic methoxycarbonyl groups, have been converted by a pig liver esterase- or lipase-catalyzed enantioselective hydrolysis in water to chiral monoesters (see Sect. 11.1.1.1.1., Tables 11.1-1 to 11.1-4 and Sect. 11.1.1.1.5, Tables 11.1-10 to 11.1-12). In nearly all cases investigated thus far the pig liver esterase-catalyzed hydrolysis of the substrate diester S terminates at the stage of the enantiomeric monoesters P and ent-P. In this case, where the products P and ent-P are not transformed further, the irreversible enantiotopos-differentiation may be described by the process depicted in Scheme 11.1-10167 691. 

Scheme 11.1-10. Hydrolase catalyzed enantiotopos-differentiating irreversible transformation167 .

In this case the ee value of the monoester P (or ent-P) depends on the extent of the conversion of the diester S to the monoesters P and ent-P and of the conversion of the latter to the achiral diol Q, and thus on all four rate constants. From the fact that a hydrolase usually retains the (R)- or (S)-group preference of the enantiotopos differentiation in the enantiomer-differentiating hydrolysis, i. e. the hydrolysis of the faster formed monoester P to the diol Q is slower than the hydrolysis of the slower formed monoester ent-P to the diol Q (fci > k2 and fc4 > k) or vice versa), it follows that the ee value of the monoester P (or mt-P) can be raised upon carrying the hydrolysis further to the diol Q, at the expense of the yield. This can be advantageously used to raise the ee value of the monoester to the point where it can be isolated enantiomer-ically pure (for practical purposes). The diol can in most cases be converted to the diester. A mathematical model for the prediction of the ee value of the monoester and the quantity of the individual products in such a combined enantiotopos- and enantiomer-differentiating hydrolysis, which allows one to find the optimum in regard to the ee value and the yield, has been developed on the basis of an irreversible reaction and the absence of product inhibition (Scheme 11.1-11) I8, s7 691. Required are the kinetic constants a, Ei and E2, which can be derived from a determination of... 

Scheme 11.1-11. Hydrolase-catalyzed enantiotopos- and enantiomer-differentiating irreversible transformations [67 69(...

Figure 11.1-1. Dependence of ee value of monoester (P) on yield of monoester in combined enantiotopos- and enantiomer-differentiation with different sets of kinetic parameters.

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