Enantiofaces

Hydrolysis of Enol Esters. Enzyme-mediated enantioface-differentiating hydrolysis of enol esters is an original method for generating optically active a-substituted ketones (84—86). If the protonation of a double bond occurs from one side with the simultaneous elimination of the acyl group (Fig. 3), then the optically active ketone should be produced. Indeed, the incubation of l-acetoxy-2-methylcyclohexene [1196-73-2] (68) with Pichia... 

C, 92% ee at -20 °C, 88% ee at 0°C in the reaction of acrolein and cyclopen-tadiene). This is unusual for metal-catalyzed asymmetric reactions, with only few similar examples. The titanium catalyst 10 acts as a suitable chiral template for the conformational fixing of a,/ -unsaturated aldehydes, thereby enabling efficient enantioface recognition, irrespective of temperature. 

Ni(C104)2 6H2O showed a litde better enantioselectivity than the anhydrous complex. Although the uncatalyzed reaction was highly exo selective (cis/trans=i 97), the catalyzed reactions were very poor in diastereoselectivity, a mixture of endo and exo cycloadducts being formed. We expected that this poor diastereoselectivity would not be a serious problem since the same enantioface should be involved at the 2-position of the diastereomeric cycloadducts (Scheme 7.27). The best enantioselectivity (cis > 99% ee, trans 94% ee) was observed when the reaction was catalyzed by l ,J -DBFOX/Ph-Ni(SbF6)2 (50 mol%). With the decreased amount of catalyst (10 mol%) still a satisfactory level of enantioselectivity was observed for the cis cycloadduct (94% ee). 

The stannanes (-)-ent-12 and ( + )-ent- 3 (R = CH3) are obtained with >80% ee from the alkenyllithium (-)-sparteine complex105,107a (Section 1.3.3.3.1.1.). Hence, their titanium(IV) chloride mediated carbonyl additions are accompanied by chirality transfer and enantioface selection of opposite sense. This was demonstrated for the reaction with (5)-2-benzyloxy-propanal107b the d.r. (88 12) roughly reflects the enantiomeric composition of the stannanes. 

The stereochemical course of the enantioface differentiation on the aldehyde is dictated by the configuration of the sulfoxide group sulfinyl-subsdtuted dihydroisoxazoles epimeric at C-5 (e.g., 18) provide aldol adducts 19 with the same configuration at the hydroxy-substituted carbon (C-2 ) independent of the absolute configuration at C-5, however, with different degrees of stereoselectivity23. 

Various chiral auxiliaries and catalysts have been developed that allow diastereoface-and enantioface-selective Michael additions. 

Four different orientations are possible when the enantiofaces of (E)- and (Z)-enolates and an ( )-enone combine via a closed transition state, in which the olefinic moieties of the donor and the acceptor are in a syn arrangement. It should be emphasized that, a further four enan-tiomorphous orientations of A-D are possible leading to the enantiomers 2 and 3. On the basis of extensive studies of Michael additions of the lithium enolates of esters (X = OR) and ketones (X = R) to enones (Y = R) it has been concluded ... 

The major difference, when compared with simple diastereoselection in aldol-type additions, is the E- and Z-geometrical isomers of the Michael acceptor. Model transition state G shows one of the orientations of the enantiofaces of an (A)-enolate with a (Z)-enone. These additions, again, result in the same. vyn/an/i-adducts, as in the case of an (A)-enone, but the substituent interactions will be different. 

The high enantioselectivity again can be rationalized by enantioface-selective alkene coordination in 63 (Fig. 35). The olefin moiety is expected to bind trans to the upper imidazoline moiety [70,73] thereby releasing the catalyst strain. Coordination at this position may, in principal, afford four different isomers assuming the stereoelectronically preferred perpendicular orientation of the alkene and the Pt(II) square plane. In the coordination mode shown, steric repulsion between both olefin substituents and the ferrocene moiety is minimized. Outer-sphere attack of the indole core results in the formation of the product s stereocenter. 

The low-temperature method is effective not only in the kinetic resolution of alcohols but also in the enantioface-selective asymmetric protonation of enol acetate of 2-methylcyclohexanone (15) giving (f )-2-methylcyclohexanone (16). The reaction in H2O at 30°C gave 28% ee (98% conv.), which was improved up to 77% ee (82% conv.) by the reaction using hpase PS-C 11 in /-Pt20 and ethanol at 0°C. Acceleration of the reaction with lipase PS-C 11 made this reaction possible because this reaction required a long reaction time. The temperature effect is shown in Fig. 14. The regular temperature effect was not observed. The protons may be supplied from H2O, methanol, or ethanol, whose bulkiness is important. 

Figure 14 Lipase-catalyzed enantioface-selective asymmetric protonation.

The result of enzymatic decarboxylation was extremely clear. While (S)-compound resulted in C-containing product, (/ )-compound gave the product with C no more than natural abundance. Apparently, the enzyme decarboxylated pro-(/ ) carboxyl group selectively and the reaction proceeds with net inversion of configuration. Thus, the presence of a planar intermediate can be reasonably postulated. Enantioface-differentiating protonation to the intermediate will give the optically active final product (Eig. 12). 

Figure I Possible precursor states to the selective enantioface adsorption of tiglic acid...

Table 1. Enantioface-Differentiating Hydrogenation of Various Keto Esters and 2-Octanone...

Asymmetric conjugate addition of dialkyl or diaryl zincs for the formation of all carbon quaternary chiral centres was demonstrated by the combination of the chiral 123 and Cu(OTf)2-C H (2.5 mol% each component). Yields of 94-98% and ee of up to 93% were observed in some cases. Interestingly, the reactions with dialkyl zincs proceed in the opposite enantioselective sense to the ones with diaryl zincs, which has been rationalised by coordination of the opposite enantiofaces of the prochiral enone in the alkyl- and aryl-cuprate intermediates, which precedes the C-C bond formation, and determines the configuration of the product. The copper enolate intermediates can also be trapped by TMS triflate or triflic anhydride giving directly the versatile chiral enolsilanes or enoltriflates that can be used in further transformations (Scheme 2.30) [110],... 

In 2000, Woodward et al. reported that LiGaH4, in combination with the S/ 0-chelate, 2-hydroxy-2 -mercapto-1,1 -binaphthyl (MTBH2), formed an active catalyst for the asymmetric reduction of prochiral ketones with catecholborane as the hydride source (Scheme 10.65). The enantioface differentiation was on the basis of the steric requirements of the ketone substituents. Aryl w-alkyl ketones were reduced in enantioselectivities of 90-93% ee, whereas alkyl methyl ketones e.g. i-Pr, Cy, t-Bu) gave lower enantioselectivities of 60-72% ee. 

The heterobimetallic asymmetric catalyst, Sm-Li-(/ )-BINOL, catalyzes the nitro-aldol reaction of ot,ot-difluoroaldehydes with nitromethane in a good enantioselective manner, as shown in Eq. 3.78. In general, catalytic asymmetric syntheses of fluorine containing compounds have been rather difficult. The S configuration of the nitro-aldol adduct of Eq. 3.78 shows that the nitronate reacts preferentially on the Si face of aldehydes in the presence of (R)-LLB. In general, (R)-LLB causes attack on the Re face. Thus, enantiotopic face selection for a,a-difluoroaldehydes is opposite to that for nonfluorinated aldehydes. The stereoselectivity for a,a-difluoroaldehydes is identical to that of (3-alkoxyaldehydes, as shown in Scheme 3.19, suggesting that the fluorine atoms at the a-position have a great influence on enantioface selection. 

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