Protonation, enantioselective enolate anions

The general reaction mechanism of the Michael reaction is given below (Scheme 4). First, deprotonation of the Michael donor occurs to form a reactive nucleophile (A, C). This adds enantioselectively to the electron-deficient olefin under the action of the chiral catalyst. In the final step, proton transfer to the developed enolate (B, D) occurs from either a Michael donor or the conjugate acid of a catalyst or a base, affording the desired Michael adduct. It is noteworthy that the large difference of stability between the two enolate anions (A/B, C/D) is the driving force for the completion of the catalytic cycle. 

When a ketone reacts with a suitable base (secs. 9.1, 9.2) an enolate anion is formed by removal of the a-proton. In the case of an unsymmetrical ketone such as 30, a mixture of (Z)-enolate (31) and ( )-enolate (32) usually results (secs. 9.2.E, 9.5.A). This mixture influences the diastereoselectivity and enantioselectivity of enolate condensation reactions (sec. 9.5). Such a mixture of geometrical isomers generates both syn- and antiproducts upon reaction with aldehydes so it is important to control or at least identify the geometry of the enolate. Several solutions to this problem have been developed, including formation of stable and separable enolate isomers and controlling reaction conditions to maximize production of one isomer. 

Catalysts 1 and 4 are reported to give the best results for the conjugate addition of thiophenol to 2-phenylacrylates (Scheme 6.2) [17]. The products were obtained with opposite enantioselectivity in the reaction with 1 and 4, respectively, as the catalyst. Based upon a computational analysis, it was proposed that the transition state for the reaction involves hydrogen bonding between the hydroxy group of the catalyst and the carbonyl group of the ester and asymmetric proton transfer from the thiol to enolate anion (Scheme 6.2). 

A preliminary approach to understand the mechanism of the enantioselective protonation and the role of lithium bromide, based on TSs containing one hthium atom, failed to explain the selectivity enhancement by hthium bromide, and the calculated energies of the TSs did not account for the experimentally observed selectivity. Asensio, Domingo and coworkers studied the molecular process associated with the proton transfer at the semiempirical PM3 level . Based on hterature data , they defined the structure of a mixed dimer enolate 234 consisting of a four-membered ring where the bromide anion and the oxygen atom of the enolate were connected by two hthium cations. These bridging... 

In 2008, we reported the use of chiral IV-trifyl thiophosphoimide to catalyze enantioselective protmiation of silyl enol ethers with various achiral proton sources (Fig. 13) [56]. It was found that neither the achiral acids nor stoichiometric amount of chiral catalyst alone can protonate the silyl enol ether substrate under such reaction conditions. We believe the combined BBA catalyst, which is an oxonium cation with chiral thiophosphoimide counteranion, is the reactive species for this protonation reaction. On the other hand, since the extremely bulky chiral counter anion cannot accomplish the desilylation step, presence of achiral proton source for catalyst regeneration turns out to be essential. 

Based upon the results of kinetic studies that revealed a zero-order decay of the P-keto ester, a catalytic cycle was proposed that is shown in a simplified manner in Scheme 5.122. In an oxidative addition, the palladium complex of ligand (S )-42b reacts with P-keto ester rac-489 to give palladium carboxylate 492, the decarboxylation of which generates palladium enolate 493. Next, Meldrum s acid 490 transfers a proton to the enolate in an enantioselective manner, so that the nomacemic ketone 491 results. Concomitantly, an ion pair consisting of allylpal-ladium cation 494 and the anion 495 of Meldrum s acid is formed. This anion then plays the role of a nucleophile for an allylic alkylation by accepting the allyl residue under formation of the stoichiometric by-product 496. This last step closes the cycle by releasing the chiral palladium catalyst [241b]. 

To account for the catalytic activity of catalyst 45d, several experimental data led the authors to privilege a Brpnsted acid/base catalysis over a nucleophilic catalysis. In particular, the full protonation of catalyst 45d observed by simply adding HN3 lends strong support to this point of view. The protonated catalyst 45d would promote the nucleophilic addition of azide counter anion to ketene followed by an enantioselective protonation of the resulting enolate 57 (Scheme 3.27). 

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