Enantioconvergent reaction

In prindple, KR is possible in this approach, which remains unusual and stiU unknown for non-enzymatic reactions. However, sometimes the enantiomericaUy enriched recovered substrate of a KR can be recycled to the chiral product, or the chiral product can be transformed into the resolved substrate. In both cases, the additional transformation must involve an inversion of stereochemistry. 

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In the steroid series, an enantioconvergent reaction sequence has been used for the synthesis of model steroids 7 and 8 in order to elucidate the absolute C-24 configuration of naturally occurring ooginols 14391. 

This chapter focuses on stoichiometric KR reactions. In Section 2.2, the main kinetic treatments are discussed. In Section 2.3, some examples of the use of chiral reagents in KR are presented. In Sections 2.4 and 2.5, the cases of enantiodivergent and enantioconvergent reactions are discussed. The KR of diastereomers is kineti-caUy similar to KR of enantiomers and is briefly presented in Section 2.6. Finally, some examples of apphcations of KR are collected in Section 2.7. 

There is the possibility to combine several KR reactions and to approach the theoretical maximum values of 50% recovery and 100% ee for one of the enantiomers. This can be achieved after isolation of the components of a first KR [30]. Consecutive KRs will also enhance the enantiomeric excess [31]. The amount of recovered material will decrease. KR has been used to increase the enantiomeric excess of an aheady enantioenriched material (obtained by KR or asymmetric synthesis). The conversion extent needed for going from 90% to 95% ee, for example, for a given s value, has been calculated for pseudo-first-order reactions [23]. Enantioconvergent reactions (see below. Section 2.5) is a rare but convenient way to optimize a KR from a racemic mixture where the enantiomers are susceptible to interconversion. 

The full transformation of a racemic mixture into a chiral product is possible by the combination of formation of a chiral product and a fast racemization of the residual substrate. Dynamic KR is detailed in Chapter 5. There is another strategy for transforming the two enantiomers of a racemic substrate into the same enantiomer of the product (enantioconvergent reactions). Two different types of reactions must concern the two enantiomers. For example, hydrolysis of rac-l-phenyloxirane fuUy converted it into (R)-l-phenyl-l,2-dihydroxyethane in the presence of a biocatalyst [87,88]. The regioselectivity of the reaction is not the same for both enantiomers moreover, hydrolysis at the asymmetric centre occurs with inversion (Scheme 2.8). 

As outlined above, enantioconvergent processes require two separate reaction pathways in order to transform a racemic substrate into a single product enantiomer. This is accomplished by employing a catalyst, which transforms one of the substrate enantiomers to the product with retention of configuration. Concurrently, another catalyst, with opposite enantioselectivity and opposite regioselectivity, transforms the other substrate enantiomer with inversion of configuration (Figure 5.24). 

Figure 6.69 An enantioconvergent enzyme-triggered cascade reaction.

A novel system for the enantioconvergent decarboxylative protonation of racemic /3-kclo esters has been developed.48 The reaction tolerates a variety of substitution and functionality and delivers products of high enantiopurity in excellent yield. The enan-tioinduction in the observed protonated products is consistent with the intermediacy of an enolate that is intimately associated with a chiral Pd complex. 

Importantly, mixtures of E- and Z-olefin substrates could be hydrogenated with comparable enantioselectivities, providing an enantioconvergent process a highly desirable yet rare feature of a catalytic asymmetric reaction. In addition, this transformation effectively differentiates between />,/>-olefin substituents of similar steric demand (e.g., Me/Et, Ar/c-hex), furnishing hydrogenated products with very high enantioselectivity. 

The Baeyer-Villiger reaction occurs with retention of stereochemistry at die migrating center. This stereoselectivity has been utilized in a practical method for the preparation of isotopically chiral metiiyl acetic acid (5) ftom [2- H]cyclohexanone (4) prepared by enzyme-catalyzed stereoselective exchange of the pro-R a -proton and enantioconvergent exchange of the a-proton with deuterium (Scheme 2). As a cautionary note, prior epimerization of an acyl group prior to oxidation has been observed. ... 

Kellogg, R. M. Enantioconvergent synthesis by sequential asymmetric Horner-Wadsworth-Emmons and palladium-catalyzed allylic substitution reactions. Chemtracts 2002, 15, 69-73. 

An alternative conceptual approach to enantioconvergent synthesis involves intermediates whose enantiomers may be readily interconverted by simple chemical reactions. Compound 2 potentially represents such a species since it can be reasoned that a... 

Stereoconvergent A reaction or reaction sequence is stereoconvergent if stereo-isomerically different starting materials yield the same stereoisomeric product. The sequence may be more specifically labeled either enantioconvergent or diastereoconvergent. 

The losses in material normally associated with a resolution scheme can be avoided when one succeds in coupling the resolution to another reaction, rendering the overall process enantioconvergent (Scheme 10.8) [12]. 

Concerning reaction mechanism, the enantioconvergent character of the reduction makes unnecessary to work with geometrically pure enals (Scheme 2.1). This is due to the rapid interconversion of the two initially formed iminium ions 5 and 6 prior to the rate determining hydride attack from the dihydropyridine (Scheme 2.2). 

An exceptional case for an enantioconvergent biocatalytic hydrolysis of a ( )-c -2,3-epoxyalkane is shown in Scheme 2.97 [617]. Based on O-labeling experiments, the stereochemical pathway of this reaction was elucidated to proceed via attack of the (formal) hydroxyl ion at the (S)-configured oxirane carbon atom with concomitant inversion of configuration at both enantiomers with opposite regioselectivity. As a result, the (/ ,/ )-diol was formed as the sole product in up to 97% e.e. in almost quantitative yield. 

While enantioconvergent as well as divergent sequences at any rate need chiral starting materials, the very useful and highly efficient differentiation of enantiotopic groups asks only for prochiral compounds, as for instance 325. To arrive at pure enantiomers, one of the two structurally identical side chains of the starting material 325 has to be attacked enantioselectively, as is demonstrated with the Sharpless oxidation, which in this case leads to epoxide 326 as the main reaction product [115]. 

Asymmetric Reduction of Enals by Transfer Hydrogenation. The metal-free reduction of olefins relies on the use of Hantzsch-type dihydropyridines, as hydrogen donors. The asymmetric variant of this reaction can be mediated by catalyst 1. The reduction is enantioconvergent both stereoisomers of... 

One important feature of this reaction is the enantioconvergence of the reaction. The reaction allowed the use of (E/Z) mixtures of the starting enal to furnish equally high enantioselectivities. 

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