The phosphoric acid catalyzed reaction of 1,4-dihydropyridines with N-arylimines has been investigated by using density functional theory. We first considered the reaction of acetophenone PMP-imine (PMP=p-methoxyphenyl) with the dimethyl Hantzsch ester catalyzed by diphenyl phosphate. Our study showed that, in agreement with what has previously been postulated for other reactions, diphenyl phosphate acts as a Lewis base/Brønsted acid bifunctional catalyst in this transformation, simultaneously activating both reaction partners. The calculations also showed that the hydride transfer transition states for the E and Z isomers of the iminium ion have comparable energies. This observation turned out to be crucial to the understanding of the enantioselectivity of the process. Our results indicate that when using a chiral 3,3'-disubstituted biaryl phosphoric acid, hydride transfer to the Re face of the (Z)-iminium is energetically more favorable and is responsible for the enantioselectivity, whereas the corresponding transition states for nucleophilic attack on the two faces of the (E)-iminium are virtually degenerate. Moreover, model calculations predict the reversal in enantioselectivity observed in the hydrogenation of 2-arylquinolines, which during the catalytic cycle are converted into (E)-iminium ions that lack the flexibility of those derived from acyclic N-arylimines. In this respect, the conformational rigidity of the dihydroquinolinium cation imposes an unfavorable binding geometry on the transition state for hydride transfer on the Re face and is therefore responsible for the high enantioselectivity.

We report a density functional theory investigation of the enantioselective Cinchona thiourea-catalyzed Henry reaction of aromatic aldehydes with nitromethane. We show that two pathways (differing in the binding modes of the reactants to the catalyst) are possible for the formation of the C À C bond, and that they have comparable reaction barriers. The enantioselectivity is investigated, and our results are in agreement with the experimentally observed solvent dependence of the reaction.

Abstract:The reason for enantioselectivity in the reductive amination of a-branched aldehydes was investigated. The relative energies of all the diastereomeric transition states for hydride transfer of a suitable computational model were calculated at the B3LYP/6-311 + GA C H T U N G T R E N N U N G (2d,2p) level of theory. Our calculations successfully reproduce and rationalize the experimentally observed stereochemical outcome of the reaction.Keywords: density functional theory; dynamic kinetic resolution; Hantzsch esters; organocatalysis; reduction The enantioselective reduction of C=N double bonds using dihydropyridines as hydrogen donors [1] in combination with axially chiral phosphoric acid catalysts [2] is among the most remarkable achievements in organocatalysis (Figure 1). Initially optimized and developed for N-arylketimines, [3] this approach to metalfree hydrogenation has been successively applied to the reduction of imino esters [4] and heterocycles [5] as well as reductive tandem reactions.[6] In all these processes, the catalyst controls the stereochemistry of a chiral center which is formed in the hydride transfer step. We recently reported a density functional theory study on the mode of action of diarylphosphoric acid organocatalysts in the transfer hydrogenation of ketimines using Hantzsch esters as hydrogen donors. [7] Our results showed that diarylphosphoric acids act as bifunctional Lewis base/Brønsted acid (LBBA) catalysts.[8] Moreover, we showed that both E and Z iminium (presumably in equilibrium under the reaction conditions) species are competent substrates for the hydride transfer. Following imine protonation, the resulting phosphate engages in two hydrogen bonds, one with the iminium and one with the N À H group of the dihydropyridine. Hydride transfer and phosphate protonation releases the N-arylamine and the Hantzsch pyridine and regenerates the phosphoric acid, hence closing the catalytic cycle. We also investigated the origins of enantioselection for two substrates displaying a reversed sense of stereoinduction, namely the N-PMP imine derived from acetophenone and 2-phenylquinoline. In both cases, our model succesfully reproduced the sense of enantioselection and we could rationalize the results in terms of the geometry of the C=N double bond in the reacting iminium ion.List and co-workers recently reported a highly efficient dynamic kinetic resolution (DKR) of abranched aldehydes via reductive amination with panisidine, giving b-branched PMP-protected amines in mostly excellent yields and enantiomeric excesses (Scheme 1). [9] In this protocol, imines are prepared in situ by mixing an aldehyde with p-anisidine and molecular sieves. In the presence of a phosphoric acid catalyst, imines undergo fast tautomerization and, therefore, racemize. The efficiency of this process is based on selective hydride transfer to one of the enantiomers of the resulting iminium ion. Unlike all the other aforementioned cases, in the DKR of aldehydes via reduc-

The mechanism of the catalytic Kinugasa reaction is investigated by means of density functional theory calculations. Different possible mechanistic scenarios are presented using phenanthroline as a ligand, and it is shown that the most reasonable one in terms of energy barriers involves two copper ions. The reaction starts with the formation of a dicopper-acetylide that undergoes a stepwise cycloaddition with the nitrone, generating a five-membered ring intermediate. Protonation of the nitrogen of the metalated isoxazoline intermediate results in ring opening and the formation of a ketene intermediate. This then undergoes a copper-catalyzed cyclization by an intramolecular nucleophilic attack of the nitrogen on the ketene, affording a cyclic copper enolate. Catalyst release and tautomerization gives the final β-lactamic product. A comprehensive study of the enantioselective reaction was also performed with a chiral bis(azaferrocene) ligand. In this case, two different reaction mechanisms, involving either the scenario with the two copper ions or a direct cycloaddition of the parent alkyne using one copper ion, were found to have quite similar barriers. Both mechanisms reproduced the experimental enantioselectivity, and the current calculations can therefore not distinguish between the two possibilities.

The intramolecular aldol reaction of acyclic ketoaldehydes catalyzed by 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) is investigated using density functional theory calculations. Compared to the proline-catalyzed aldol reaction, the use of TBD provides a unique and unusual complete switch of product selectivity. Three mechanistic pathways are proposed and evaluated. The calculations provide new insights into the activation mode of bifunctional guanidine catalysts. In the favored mechanism, TBD first catalyzes the enolization of the substrate and then the C-C bond formation through two concerted proton transfers. In addition, the computationally predicted stereochemical outcome of the reaction is in agreement with the experimental findings.