Enantiotopic group discrimination

Speranza, G., Manitto, P, Fontana, G., Monti, D. et al (1996) Evidence for enantiomorphic-enantiotopic group discrimination in diol dehydratase-cataiyzed dehydration of meso-2, 3-butanediol, Tetrahedron Lett., 37,... 

Asymmetric synthesis (1) Use a chiral auxiliary (chiral acetal—the synthetic equivalent of an aldehyde chiral hydrazone—the synthetic equivalent of a ketone) covalently attached to an achiral substrate to control subsequent bond formations. The auxiliary is later disconnected and recovered, if possible. (2) Use a chiral reagent to distinguish between enantiotopic faces or groups (asymmetric induction) to mediate formation of a chiral product. The substrate and reagent combine to form diastereomeric transition states. (3) Use a chiral catalyst to discriminate enantiotopic groups or faces in diastereomeric transition states but only using catalytic amounts of a chiral species. 

Another advantageous use of hydrolytic enzymes consists in the enantioselec-tive hydrolysis of prochiral substrates, making use of the ability of these biocatalysts to discriminate between enantiotopic groups. An elegant way to obtain both enantiomers (/ )-7 and (5)-7 from the prochiral diol 6 is the combination of porcine pancreatic lipase (PPL)-mediated hydrolysis and esterification as shown in Scheme 3 [26]. 

Aminocyclopropanecarboxylate (ACPC) provides an interesting problem, having a plane of symmetry through the a-carbon atom. Isotopic substitution on one of the )3-carbon atoms will immediately provide a chiral molecule, and so labeling will allow us to see how enzymes can discriminate between the enantiotopic groups in the various reactions undergone by this compound. 

The other important type of kinetic resolution is that in which the chiral reagent or catalyst discriminates between two enantiotopic groups in an achiral substrate. This may be thought of as a kinetic resolution within the same molecule and the substrate can be completely converted to a single enantiomeric product. Thus diester (46) is hydrolysed by pig liver esterase (PLE) to give exclusively the (5)-enantiomer of (47). A drawback of the internal kinetic resolution is that it may not be possible to find a catalyst to obtain the opposite... 

For a recent review on enzymatic asymmetrization of prochiral and meso compounds, see Schoffers et al. [113]. Enzymatic asymmetrization of prochiral compounds was discussed by Ogston in 1948 [114]. He then rationalized the enzyme s ability to discriminate between enantiotopic groups on a prostereogenic substrate molecule based on the three-point combination model. 

Hydrolytic enzymes such as esterases and Upases have proven particularly useful for asymmetric synthesis because of their abiUties to discriminate between enantiotopic ester and hydroxyl groups. A large number of esterases and Upases are commercially available in large quantities many are inexpensive and accept a broad range of substrates. 

The first strategy involves discrimination between enantiotopic leaving groups (Type A). In the second approach, two enantiomers of a racemic substrate converge into a meso-n-al y complex wherein preferential attack of the nucleophile at one of either allylic termini leads to asymmetric induction, a process that may be referred to as a dynamic kinetic enantioselective transformation (Type B). The third requires differentiation between two enantiotopic transition... 

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. 

The enantiotopic protons of the prochiral methyl groups in the iminium salt 36 exhibited distinct resonances in the presence of Eu(hfc)3 . As already discussed for achiral lanthanide S-drketonates, the system likely forms an ion pair between the organic cation and the species [Ln( S-dik)3X]. The spectrum of racemic 37, which as its bromide salt has been studied as an ionic liquid, exhibits nonequivalence in the presence of Eu(tfc)3 and Eu(hfc)3. No splitting of the resonance occurs in the presence of Eu(fod)3. In addition to the likely ion-pairing interaction of 37 with [Ln(/ -dik)3X] , rather substantial shifts of some of the OCH2 protons implied that the ether oxygen atoms also likely coordinated with the europium ion. A similar ion-paired system explains the enantiomeric discrimination observed in the spectrum of the tris(phenanthroline) complexes of Ru(II) ([Ru(phen)3]Cl2) in the presence of Eu(tfc)3 . 

Intramolecular cyclopropanations with unsaturated diazo ketones have also been reported. Furthermore, enantioselective cyclopropanation with diazomethane can be achieved in up to 75% ee. In detailed mechanistic discussions, a copper(I) species, complexed with only one semicorrin ligand, and formed by reduction and decomplcxation, is suggested as the catalytical-ly active species, cisjtrans Stereoselection and discrimination of enantiotopic alkene faces should take place within a copper-carbene-alkene complex25-54"56. According to these interpretations, cisjtrans selectivity is determined solely by the substituents of the alkene and of the diazo compound (especially the ester group in diazoacetates) and is independent of the chiral ligand structure (salicylaldimine or semicorrin)25. 

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