Enantioselectivity proton transfer

Mechanistically, the Brpnsted acid-catalyzed cascade hydrogenation of quinolines presumably proceeds via the formation of quinolinium ion 56 and subsequent 1,4-hydride addition (step 1) to afford enamine 57. Protonation (step 2) of the latter (57) followed by 1,2-hydride addition (step 3) to the intermediate iminium ion 58 yields tetrahydroquinolines 59 (Scheme 21). In the case of 2-substituted precursors enantioselectivity is induced by an asymmetric hydride transfer (step 3), whereas for 3-substituted ones asymmetric induction is achieved by an enantioselective proton transfer (step 2). 

Enantioselective Proton Transfer in Enols and Enol Derivatives... 

The protonation must take place irreversibly at the prochiral C-atom O-protonation likewise leads to the racemic product. Unfortunately, many enantioselective proton transfers are often strongly influenced by solvation, aggregation and complexation, which are less weU understood. [45]... 

Sibi and co-workers explored the power of the radical chemistry through a terminal proton abstraction to achieve the enantioselective proton transfer (Scheme 31.31). Indeed, the formation of a bidentate complex by coordination of a chiral Mg complex to a Michael acceptor bearing an achiral template can promote the 1,4-radical addition followed by an enantioselective hydrogen transfer. This strategy is believed to form a bidentade complex aimed to control the enolate geometry, which is a key point of the enantiodetermining step of the reaction. 

SCHEME 31.31. Sibi and co-workers strategy for the enantioselective proton transfer. 

SCHEME 31.34. Radical addition of fluoro alkyl chain followed by enantioselective proton transfer chiral fluoro amino acid derivative synthesis. 

SCHEME 3U6. Enantioselective formation of 1,3-stereogenic centers involving an enantioselective proton transfer. 

SCHEME 31.40. Enantioselective proton transfer promoted by NHC and its application to the synthesis of FCE28833. 

SCHEME 31.41. Dehalogenation/enantioselective protonation transfer and a-fluoro carboxylic acid synthesis by Rovis and co-workers. 

Independently, Liang and Trauner and Rueping and leawsuwan took advantage of the chiral enolate formation during the electrocyclization process to perform an enantioselective proton transfer (Scheme 31.44). 

On the other hand, this lack of synthetic application clearly points out that further improvements are required to achieve enantioselective proton transfer with a broad substrate scope and high enantiomeric excess. The development of such kinds of catalytic system remains as a holy grail, and the synthetic chemist will probably continue to pay attention and focus his or her creativity. Indeed, in flie future, to address these main issues, organic chemists are expected to develop new creative and innovative processes to transform enantioselective protonation from an emerging tool into a major method toward the formation of tertiary chiral carbon centers. 

Proton transfer processes are involved in many biochemical events and often play a key role in the catalytic activity of enzymes. Of particular interest, are enantioselective proton transfer processes frequently encountered in a number of biosynthetic sequences. Over the last few years, esterase and decarboxylase enzymes have appeared as appealing biocatalysts to achieve enantioselective protonation of enol acetates [1] and enantioselective decarboxylation of malonate derivatives [2] respectively. Conceptually, enantioselective protonation provides a simple... 

The detailed mechanism of this enantioselective transformation remains under investigation.178 It is known that the acidic carboxylic group is crucial, and the cyclization is believed to occur via the enamine derived from the catalyst and the exocyclic ketone. A computational study suggested that the proton transfer occurs through a TS very similar to that described for the proline-catalyzed aldol reaction (see page 132).179... 

The optically active Schiff bases containing intramolecular hydrogen bonds are of major interest because of their use as ligands for complexes employed as catalysts in enantioselective reactions or model compounds in studies of enzymatic reactions. In the studies of intramolecularly hydrogen bonded Schiff bases, the NMR spectroscopy is widely used and allows detection of the presence of proton transfer equilibrium and determination of the mole fraction of tautomers [21]. Literature gives a few names of tautomers in equilibrium. The OH-tautomer has been also known as OH-, enol- or imine-form, while NH tautomer as NH-, keto-, enamine-, or proton-transferred form. More detail information concerning the application of NMR spectroscopy for investigation of proton transfer equilibrium in Schiff bases is presented in reviews.42-44... 

The proton transfer from multiply charged [cytochrome c] " (n = 7-9) to (/ )- and (5)-2-butylamine show a significant enantioselectivity." " Ions [cytochrome n = l-9) were produced by ESI and introduced into the analyzer cell of a FT-ICR containing an alkylamine, i.e., (/ )- and (5)-2-butyIamine, 1-propylamine, or tert-butylamine. Rate constants for the proton transfer are listed in Table 18. 

The favourable effect of lithium bromide on facial enantioselective protonation of methyl tetralone enolate by a-sulfinyl alcohols has been attributed to coordination of lithium to both enolate and sulfinyl alcohol followed by competition between diastere-omeric paths involving intramolecular proton transfer the proposed transition-state model is supported by results of PM3 semiempirical calculations. ... 

Propynyl bromides can be enantioselectively converted to chiral allenes by stoichiometric conversion into a propynylchromium(III) complex followed by stereoselective proton transfer from a chiral auxiliary, e.g., (-)-borneol or (-)-menthol120, l2 . Formally, substitution of bromide takes place. 

When the alkylation was performed with ethyl allyl carbonate as the precursor of the it-allyl intermediate, only 32% ee was obtained, indicative of a subtle proton-transfer process involved in the catalytic process such as in Scheme 8E.39. The chiral rhodium catalyst was shown to be the primary source of the asymmetric induction because the same reaction in the absence of the rhodium catalyst generated a racemic product in 91% yield. It is interesting that the use of only half an equivalent of the chiral ligand together with half an equivalent of achiral ligand (dppb) with respect to [Pd + Rh] was sufficient to give a high enantioselectivity (93% ee). 

An NMR kinetic study of a phosphine-catalysed aza-Baylis-Hillman reaction of but-3-enone with arylidene-tosylamides showed rate-limiting proton transfer in the absence of added protic species, but no autocatalysis.175 Brpnsted acids accelerate the elimination step. Study of the effects of BINOL-phosphinoyl catalysts sheds light not only on the potential for enantioselection with such bifunctional catalysis, but also on their scope for catalysing racemization. 

Quantum chemical DFT calculations at the B3LYP/6-31G(d) level have been used to study the enantioselective lithiation/deprotonation of O -alkyl and O-alk-2-enyl carbamates in the presence of (—)-sparteine and (—)-(f )-isosparteine.7 Complete geometry optimization of the precomplexes consisting of the carbamate, the chiral ligand, and the base (/-PrLi), for the transition states of the proton-transfer reaction, and for the resulting lithio carbamates have been performed in order to quantify activation barriers and reaction energies. 

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. 

---