Protonation of enolates

Figure 3.3 Antibody 14D9 catalyzes the enantioselective protonation of enol ethers.

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. 

Chiral a-sulfinyl alcohols have proved useful in enantioselective protonation of enolates.Addition of lithium bromide enhances the ee in a number of cases, apparently via simultaneous coordination of lithium to the enolate and to the sulflnyl alcohol. 

For a short review on asymmetric protonation of enol derivatives, see Yanagisawa, A. Ishihara, K. Yamamoto, H. Synlett 1997, 411 20. 

Recent developments in enantioselective protonation of enolates and enols have been reviewed, illustrating the reactions utility in asymmetric synthesis of carbonyl compounds with pharmaceutical or other industrial applications.150 Enolate protonation may require use of an auxiliary in stoichiometric amount, but it is typically readily recoverable. In contrast, the chiral reagent is not consumed in protonation of enols, so a catalytic quantity may suffice. Another variant is the protonation of a complex of the enolate and the auxiliary by an achiral proton source. Differentiation of these three possibilities may be difficult, due to reversible proton exchange reactions. 

The diastereoselectivity of protonation of enolate anions has been studied by H/D exchange.156 /i-Substituted ethyl butanoates were chosen as substrates, with conditions that rigorously excluded ion-pairing and aggregation effects. Stereoelectronic effects were found typically to produce higher stereoselection than purely steric effects, hi the specific case of H/D exchange in 3-ethoxybutanoate in ethanol-4 protonation of the enolate of 3-fluorobutanoate was chosen as a computational model.157 Similar... 

Reviews have featured asymmetric protonations of enol derivatives133 and of enolates and enols.134 Highly enantiofacial protonation of prochiral lithium enolates has been achieved using chiral /J-hydroxy sulfoxides.135... 

Fig. 9 Variation of the Bronsted parameter a for general acid catalysis of enol ketonization with the free energy change AG° for carbon protonation of enols (o) and enolates ( ). The data are taken from Table 2.

The modest amount of scatter in Fig. 10 is remarkable, considering that it includes four different reaction types (carbon protonation of enols or enolates by hydronium ions or by water) and a wide range of substrates. The standard deviation between the 62 observed values of log kK and those calculated by Equation (19) is 0.95. 

The acidity constants of protonated ketones, pA %, are needed to determine the free energy of reaction associated with the rate constants ArG° = 2.3RT(pKe + pK ). Most ketones are very weak bases, pAT < 0, so that the acidity constant K b cannot be determined from the pi I rate profile in the range 1 < PH <13 (see Equation (11) and Fig. 3). The acidity constants of a few simple ketones were determined in highly concentrated acid solutions.19 Also, carbon protonation of the enols of carboxylates listed in Table 1 (entries cyclopentadienyl 1-carboxylate to phenylcyanoacetate) give the neutral carboxylic acids, the carbon acidities of which are known and are listed in the column headed pA . As can be seen from Fig. 10, the observed rate constants k, k for carbon protonation of these enols (8 data points marked by the symbol in Fig. 10) accurately follow the overall relationship that is defined mostly by the data points for k, and k f. We can thus reverse the process by assuming that the Marcus relationship determined above holds for the protonation of enols and use the experimental rate constants to estimate the acidity constants A e of ketones via the fitted Marcus relation, Equation (19). This procedure indicates, for example, that protonated 2,4-cyclohexadienone is less acidic than simple oxygen-protonated ketones, pA = —1.3. 

In principle, reaction of enolate ions with electrophiles should be influenced by stereoelectronic effects. For instance, protonation of enolate ions in acidic medium could provide information about the stereochemistry of the forming of a C —H bond. 

Enantioselective Protonation of Enolates formed in situ from Enolate Precursors... 

Enantioselective Protonation of Enolates Generated in situ from Conjugated Unsaturated Carboxylates... 

C. Fehr, Enantioselective Protonation of Enolates and Ends , Angew. Chem. Int. Ed. Engl. 1996, 35, 2566-2587. 

The chemistry of asymmetric protonation of enols or enolates has further developed since the original review in Comprehensive Asymmetric Catalysis [1], Numbers of literature reports of new chiral proton sources have emerged and several reviews [2-6] cover the topics up to early 2001. This chapter concentrates on new examples of catalytic enantioselective protonation of prochiral metal enolates (Scheme 1). Compounds 1-41 [7-45] shown in Fig. 1 are the chiral proton sources or chiral catalysts reported since 1998 which have been employed for the asymmetric protonation of metal enolates. Some of these have been successfully utilized in the catalytic version. 

Think about reversible formation and protonation of enolate anions, and about the symmetry of the resulting isomers. The bicyclic ring structure is unchanged in all the products. 

TABLE 6. Selected rate and equilibrium constants for protonation of enolates according to... 

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