Racemization transition

Top substrate-fixed middle racemization transition bot-surface-decoupling transition. 

Figure A2.5.30. Left-hand side Eight hypothetical phase diagrams (A through H) for ternary mixtures of d-and /-enantiomers with an optically inactive third component. Note the syimnetry about a line corresponding to a racemic mixture. Right-hand side Four T, x diagrams ((a) tlirough (d)) for pseudobinary mixtures of a racemic mixture of enantiomers with an optically inactive third component. Reproduced from [37] 1984 Phase Transitions and Critical Phenomena ed C Domb and J Lebowitz, vol 9, eh 2, Knobler C M and Scott R L Multicritical points in fluid mixtures. Experimental studies pp 213-14, (Copyright 1984) by pennission of the publisher Academic Press.

Whereas the barrier for pyramidal inversion is low for second-row elements, the heavier elements have much higher barriers to inversion. The preferred bonding angle at trivalent phosphorus and sulfur is about 100°, and thus a greater distortion is required to reach a planar transition state. Typical barriers for trisubstituted phosphines are BOSS kcal/mol, whereas for sulfoxides the barriers are about 35-45 kcal/mol. Many phosphines and sulfoxides have been isolated in enantiomerically enriched form, and they undergo racemization by pyramidal inversion only at high temperature. ... 

Among the J ,J -DBFOX/Ph-transition(II) metal complex catalysts examined in nitrone cydoadditions, the anhydrous J ,J -DBFOX/Ph complex catalyst prepared from Ni(C104)2 or Fe(C104)2 provided equally excellent results. For example, in the presence of 10 mol% of the anhydrous nickel(II) complex catalyst R,R-DBFOX/Ph-Ni(C104)2, which was prepared in-situ from J ,J -DBFOX/Ph ligand, NiBr2, and 2 equimolar amounts of AgC104 in dichloromethane, the reaction of 3-crotonoyl-2-oxazolidinone with N-benzylidenemethylamine N-oxide at room temperature produced the 3,4-trans-isoxazolidine (63% yield) in near perfect endo selectivity (endo/exo=99 l) and enantioselectivity in favor for the 3S,4J ,5S enantiomer (>99% ee for the endo isomer. Scheme 7.21). The copper(II) perchlorate complex showed no catalytic activity, however, whereas the ytterbium(III) triflate complex led to the formation of racemic cycloadducts. 

The enantiomers are obtained as a racemic mixture if no asymmetric induction becomes effective. The ratio of diastereomers depends on structural features of the reactants as well as the reaction conditions as outlined in the following. By using properly substituted preformed enolates, the diastereoselectivity of the aldol reaction can be controlled. Such enolates can show E-ot Z-configuration at the carbon-carbon double bond. With Z-enolates 9, the syn products are formed preferentially, while fi-enolates 12 lead mainly to anti products. This stereochemical outcome can be rationalized to arise from the more favored transition state 10 and 13 respectively ... 

To understand why a racemic product results from the reaction of T120 wjtl 1-butene, think about the reaction mechanism. 1-Butene is first protonaled tc yield an intermediate secondary (2°) carbocation. Since the trivalent carbon i sp2-hybridized and planar, the cation has no chirality centers, has a plane o symmetry, and is achiral. As a result, it can react with H20 equally well fron either the top or the bottom. Reaction from the top leads to (S)-2-butano through transition state 1 (TS 1) in Figure 9.15, and reaction from the bottorr leads to R product through TS 2. The two transition states are mirror images. The] therefore have identical energies, form at identical rates, and are equally likeb to occur. 

In a catalytic asymmetric reaction, a small amount of an enantio-merically pure catalyst, either an enzyme or a synthetic, soluble transition metal complex, is used to produce large quantities of an optically active compound from a precursor that may be chiral or achiral. In recent years, synthetic chemists have developed numerous catalytic asymmetric reaction processes that transform prochiral substrates into chiral products with impressive margins of enantio-selectivity, feats that were once the exclusive domain of enzymes.56 These developments have had an enormous impact on academic and industrial organic synthesis. In the pharmaceutical industry, where there is a great emphasis on the production of enantiomeri-cally pure compounds, effective catalytic asymmetric reactions are particularly valuable because one molecule of an enantiomerically pure catalyst can, in principle, direct the stereoselective formation of millions of chiral product molecules. Such reactions are thus highly productive and economical, and, when applicable, they make the wasteful practice of racemate resolution obsolete. 

In reactions in which separated ion pairs are involved, e.g., R4N+, K or Na +, and as a borderline case, Li +, the cation does not contribute to the adjustment of the reaction partners in a dense, well-ordered transition state poor selcctivities arc usually the result of these carbanionic carbonyl additions. Further, the high basicity of such carbanionic species may cause decomposition or racemization of sensitive reactions partners. 

The reactions of allylboronates 1 (R = H or CH3) may proceed either by way of transition state 3, in which the a-substituent X adopts an axial position, or 4 in which X occupies an equatorial position. These two pathways are easily distinguished since 3 provides 7 with a Z-olefin, whereas 4 provides 8 with an E-olefinic linkage. There is also a second fundamental stereochemical difference between these two transition states 7 and 8 are heterochirally related from reactions in which 1 is not racemic. That is, 7 and 8 arc enantiomers once the stereochemistry-associated with the double bond is destroyed. Thus, the selectivity for reaction by way of 3 in preference to 4, or via 6 in preference to 5 in reactions of a-subsliluted (Z)-2-butenylboronate 2, is an important factor that determines the suitability of these reagents for applications in enantioselective or acyclic diastereoselective synthesis. 

The stereochemical features of the reactions of racemic 1-substituted (Z)-2-butenyl-boronates 2 are considerably different from those of the 1-substituted 2-propenyl- and 1-substituted ( )-2-butenylboronates discussed above. Transition state 5 (see p 1470) is destabilized by allylic interactions between X and the (Z)-methyl substituent26, and consequently diastcrcomcr 10 is the major product via transition state 6 (sec the following table)4,15. 

Propenyl)-1,3-dithiane, after lithiation and addition of zinc chloride, reacts with ethyl 2-oxopropanoate to give preferentially the. vvn-adduct37, which is an intermediate in the synthesis of racemic /ra .s-tetrahydro-2,3-dimethyl-5-oxo-2-furancarboxylic acid. It is assumed, that the ethoxycarbonyl group is brought to a pseudoaxial position in the cyclic transition state by the chelating zinc cation. 

Following the general rules (Section 1.3.3.1.2.), the racemic ( )-2-butenyl derivative 1 exhibits good anti diastereoselectivity on reaction with benzaldehyde2. This is explained as passing through a six-membered chair-like transition state. 

The chiral auxiliary can be recovered without any racemization. A chelated transition state has been suggested in which the Grignard reagent is delivered to the 7t-face more distal from the sterically demanding toy-butyl group1 2. 

In some cases the yields were poor due to competing deprotonation of the substrate by the organolithium reagent. Deprotonation was the predominant reaction with methyllithium or when (Z)-2-(l-alkenyl)-4,5-dihydrooxazoles were employed. The stereochemical outcome has been rationalized as occurring from a chelated transition state. The starting chiral amino alcohol auxiliary can also be recovered without racemization for reuse. 

The fact that different proportions of cis- and frans-[Co(en)2Cl(H20)]2+ products are obtained shows that the two reactions do not proceed by the same intermediate. The complex D-m-[Co(en)2Cl2]+ yields only D-m-[Co(en)2Cl(H20)]2+, showing complete stereochemical retention in the intermediates and transition states.19 The achiral trans isomer, of course, forms the racemic mixture. 

The evidence presented so far excludes the formation of dissociated ions as the principal precursor to sulfone, since such a mechanism would yield a mixture of two isomeric sulfones. Similarly, in the case of optically active ester a racemic product should be formed. The observed data are consistent with either an ion-pair mechanism or a more concerted cyclic intramolecular mechanism involving little change between the polarity of the ground state and transition state. Support for the second alternative was found from measurements of the substituent and solvent effects on the rate of reaction. 

This type of procedure is referred to as a kinetic resolution since the enantiomers of the racemic substrate exhibit different rates of reaction with the optically active compound, i.e. the diastereomeric transition states that arise from differences in e.g. non-bonded interactions have different free energies. Horeau and Nouaille (1966) estimate that a rate difference corresponding to A AG of the order of 0 2 cal mol at 25°C could in principle be revealed by this method. 

Carboxylates, which are chiral in the a-position totally lose their optical activity in mixed Kolbe electrolyses [93, 94]. This racemization supports either a free radical or its fast dynamic desorption-adsorption at the electrode. A clearer distinction can be made by looking at the diastereoselectivity of the coupling reaction. Adsorbed radicals should be stabilized and thus react via a more product like transition state... 

The second group of studies tries to explain the solvent effects on enantioselectivity by means of the contribution of substrate solvation to the energetics of the reaction [38], For instance, a theoretical model based on the thermodynamics of substrate solvation was developed [39]. However, this model, based on the determination of the desolvated portion of the substrate transition state by molecular modeling and on the calculation of the activity coefficient by UNIFAC, gave contradictory results. In fact, it was successful in predicting solvent effects on the enantio- and prochiral selectivity of y-chymotrypsin with racemic 3-hydroxy-2-phenylpropionate and 2-substituted 1,3-propanediols [39], whereas it failed in the case of subtilisin and racemic sec-phenetyl alcohol and traws-sobrerol [40]. That substrate solvation by the solvent can contribute to enzyme enantioselectivity was also claimed in the case of subtilisin-catalyzed resolution of secondary alcohols [41]. 

Figure 4.5 Simplified mechanism of the racemization of sec-alcohols catalyzed by transition metal complexes.

The racemization mechanism of sec-alcohols has been widely studied [16,17]. Metal complexes of the main groups of the periodic table react through a direct transfer of hydrogen (concerted process), such as aluminum complexes in Meerwein-Ponn-dorf-Verley-Oppenauer reaction. However, racemization catalyzed by transition metal complexes occurs via hydrogen transfer processes through metal hydrides or metal dihydrides intermediates (Figure 4.5) [18]. 

Williams and coworkers have reported a DKR of ot-bromo [56a] and a-chloro esters [56b]. In the latter case, the KR is catalyzed by commerdally available cross-linked enzyme crystals derived from Candida cylindracea lipase. The racemization takes place through halide 5 2 displacement. The DKR is possible because the racemization of the substrate is faster than that of the produd (carboxylate). For the ester, the empty ii (C=0) orbital is able to stabilize the Sn2 transition state by accepting... 

Chiral epoxides and their corresponding vicinal diols are very important intermediates in asymmetric synthesis [163]. Chiral nonracemic epoxides can be obtained through asymmetric epoxidation using either chemical catalysts [164] or enzymes [165-167]. Biocatalytic epoxidations require sophisticated techniques and have thus far found limited application. An alternative approach is the asymmetric hydrolysis of racemic or meso-epoxides using transition-metal catalysts [168] or biocatalysts [169-174]. Epoxide hydrolases (EHs) (EC 3.3.2.3) catalyze the conversion of epoxides to their corresponding vicinal diols. EHs are cofactor-independent enzymes that are almost ubiquitous in nature. They are usually employed as whole cells or crude... 

Reaction temperature is one of the parameters affecting the enantioselectivity of a reaction [16]. For the oxidation of an alcohol, the values of kcat/fQn were determined for the (R)- and (S)-stereodefining enantiomers E is the ratio between them. From the transition state theory, the free energy difference at the transition state between (R) and (S) enantiomers can be calculated from E (Equation 2), and AAG is in turn the function of temperature (Equation 3). The racemic temperature (% ) can be calculated as shown in (Equation 4). Using these equations, % for 2-butanol and 2-pentanol of the Thermoanaerobacter ethanolicus alcohol dehydrogenase were determined to be 26 and 77 °C, respectively. 

The a carbon of mandelic acid is sp hybridized. The corresponding carbons of both a-phenylglycidic acid, 49, and the carbanion intermediate 48 are neither sp hybridized nor sp hybridized, but presumably between these two extremes. It is therefore possible that the a-phenylglycidic acid is restricted to a conformation which resembles a transition state in the racemization process, a transition state which would have much of the character of the intermediate 48, and for which the enzyme would presumably have a high affinity (1). 

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