Enantioselective thermodynamically controlled

Our hypothesis of steric factors dominating the stability of the emerging radical centers in the transition states readily explains the enantioselective epoxide opening of meso-epoxide 35 to 36 that is shown in Fig. 3 [59,60]. In the case of a reversible epoxide opening, a stability difference of at least 3 kcalmol 1 between the two radicals 37 and 38 is necessary to explain the observed selectivity. According to the calculations this seems highly unlikely. A thermodynamically controlled epoxide opening can therefore be ruled out. 

Section 5.4 describes the enantioselective deprotonation of a deuterated benzylamine derivative 431 to give a configurationally unstable organolithium 432.75 Over a period of minutes, in the presence of (-)-sparteine, the organolithium 432 gave products of increasing ee as the organolithiums equilibrated under thermodynamic control to the more stable 432-(-)-sparteine complex, a process that could be accelerated by the precipitation of the complex. 

The previously discus.sed thermodynamically controlled molecular recognition processes are the basis for a successful enantioseparation. However, from a separation methodological point of view, also the performance of the separation system has to be considered, which in addition to the thermodynamically controlled enantioselectivity determines the peak resolution () which is a measure for the quality of a separation. 

In order to account for the origin of the enantioselectivity and diastereoselectivity of benzylidene transfer, it is necessary know whether the sulfur ylide reactions are under kinetic or thermodynamic control. From cross-over experiments it was found that the addition of benzylsulfonium ylide to aldehydes was remarkably finely balanced (Scheme 9) [28]. The trans-epoxide was derived directly from irreversible formation of the anti-betaine 4 and the cis-epoxide was derived from partial reversible formation of the syn-betaine 5. The higher transselectivity observed in reactions with aromatic aldehydes compared to aliphatic aldehydes was due to greater reversibility in the formation of the syn-betaine. 

Two types of selectivity may used to establish new stereogenic units in a molecule diastereoselectivity and enantioselectivity. In diastereoselective reactions, either kinetic or thermodynamic control are possible, but in enantioselective reactions, the products are isoenergetic and only kinetic control is possible. ... 

Control of selectivity (chemo, regio, stereo, and enantioselectivity) is among the most important objective in organic synthesis. The efficient use of reaction conditions (temperature, time, solvent, etc.), kinetic or thermodynamic control, protecting or activating groups (for example chiral auxiliaries), and catalysts (including chiral catalysts) have all been used to obtain the desired isomer. 

Enantioselective cychzations have also been achieved using chiral auxiliaries. Al -Benzyl groups have been used. The a-phenylethyl [337] and a-naphthylethyl [338] groups achieved diastereoselectivity in the 60-80% range in acid-catalyzed reactions with aromatic aldehydes. The diastereomer with syn orientation of the phenyl and aryl substituents is preferred and this appears to be the result of thermodynamic control. 

Along with steric aspects, the kinetics of the enantioselective protonation plays a crucial role. Here it is important that proton exchange reactions between electronegative atoms are usuaUy very fasL since there is a threat that the reactions become diffusion-controUed. Thermodynamic control then leads to the racemic product. 

For catalysing thermodynamically controlled reactions, lyases and transferases provide clear opportunities. Their relatively narrow substrate specificity largely prevents the occurrence of side-reactions, although at the same time this limits their appUcabiUty to compounds that are fairly closely related to their natural products. However, in some cases these products are synthetically very valuable, for example when carbon-carbon bonds are formed in an enantioselective manner. 

The first chapter in this volume is a particularly timely one given the recent surge of activity in natural product synthesis based upon stereocontrolled Aldol Condensations. D. A. Evans, one of the principal protagonists in this effort, and his associates, J. V. Nelson and T. R. Taber, have surveyed the several modem variants of the Aldol Condensation and discuss models to rationalize the experimental results, particularly with respect to stereochemistry, in a chapter entitled Stereoselective Aldol Condensations. The authors examine Aldol diastereoselection under thermodynamic and kinetic control as well as enantioselection in Aldol Condensations involving chiral reactants. 

It has been demonstrated recently that directed evolution is ideally suited to control the enantioselectivity of partial oxidations of this kind. The results are all the more significant because no X-ray data or homology models were available at the time to serve as a possible guide (103). In a model study using whole E. coli cells containing the CHMO from Acinobacter sp. NCIMB 9871, 4-hydroxy-cyclohexanone (51) was used as the substrate. The WT leads to the preferential formation of the primary product (7 )-52 which spontaneously rearranges to the thermodynamically more stable lactone (R)-53. The ee of this desymmetrization is... 

The chiral separation of cis enantiomers was improved with a decrease in temperature, whereas that of trans enantiomers was improved with an increase in temperature. The temperature dependence of enantioselectivities was studied to determine the thermodynamic parameters H°, S°, and Tiso. The thermodynamic parameters revealed that the separation of trans enantiomers was controlled by entropy in the range of temperatures examined, whereas enthalpy-controlled separation was observed for cis enantiomers. The separations of both cis and trans enantiomers, however, were controlled by enthalpy in normal phase HPLC [150],... 

Enantioselective cycloadditions of nitrones with alkylidene malonates were catalyzed by the complex of Go(ll) with trisoxazoline 528. The cycloaddition was reversible and the diastereoselectivity could be controlled by reaction temperature. For example, A, C-diphenyl nitrone and diethyl 2-benzylidenemalonate reacted at —40°C under kinetic control, affording mainly the m-adduct 530, but at 0°C the thermodynamically more stable /ra r-isomer 529 was the major product (Equation 85) <20040L1677>. 

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