Proline-derived organocatalysis and synergism between theory and experiments

The ability of proline and its derivatives toward catalyzing asymmetric organic reactions is highlighted. Illustration of the impact of interdisciplinary efforts between computational and experimental research is provided through a number of interesting examples. (C) 2011 John Wiley & Sons, Ltd. WIREs Comput Mol Sci 2011 1 920-931 DOI: 10.1002/wcms.3

Rational design of catalysts for asymmetric diamination reaction using transition state modeling

The stereoselective synthesis of 1,2-diamines has remained a formidable challenge. A recent palladium-catalyzed asymmetric diamination of conjugated double bonds using di-tert-butyldiaziridinone appears promising. The axially chiral binol phosphoramidite ligands are successful in offering high enantioselectivity. The density functional theory investigations revealed that the energies of the stereo-controlling transition states for the C-N bond formation depend on a number of weak non-covalent interactions such as C-H center dot center dot center dot pi, C-H center dot center dot center dot O and anagostic interactions. We envisaged that the modulation in these interactions in the transition states, through subtle changes in chiral phosphoramidite substituents, could be exploited toward steering the stereoselectivity. The effect of systematic modifications on both 3,3' positions of the binol as well as on the amido nitrogen on the stereochemical outcome is predicted. It is identified that high enantioselectivity requires a balance between the nature of the substituents on binol and amido groups. The reduced size of the amido substituents demands increased bulk on the binol whereas lowering the size on the binol demands increased bulk on the amido for higher stereoselectivity. The substituent at the alpha-position of the amido group is found to be vital and appears to be a hot spot for modifications. These insights derived from studies on the stereocontrolling transition states could help improve the catalytic efficacies in palladium-catalyzed asymmetric diamination reactions

Intramolecular nonbonding interactions in organoseleniums: quantification using a computational thermochemical approach

Intramolecular Se···O nonbonding interactions in a series of ortho-formylarylselenides (O···Se–Y, with Y = –Me, –Ph, –CN, –Cl, and –F) are quantified using density functional theory. Two methods based on the relative stabilities of various conformers are employed in evaluating the strength of intramolecular interactions. These methods, namely, cis–trans (CT) and thermodynamic cycle (TDC), depends on the energy changes associated with conformational interconversion, where the nonbonding interaction is turned on or off (respectively, in cis and trans conformer). The strength of interactions are found to be dependent on the nature of Se–Y acceptor orbitals and follows the order Me ~ Ph < CN < Cl < F. Natural Bond Orbital (NBO) analysis using DFT methods points to nO→σSe–Y* electron delocalization as the key contributing factor towards Se···O nonbonding interaction. Examination of the topological properties of the electron density with the Atoms-in-Molecule (AIM) method reveals that the electron density at the Se···O bond critical point exhibits a fairly good correlation with the nonbonding interaction energies estimated using the CT and TDC methods.© Elsevie

On the Relative Preference of Enamine/Iminium Pathways in an Organocatalytic Michael Addition Reaction

The mechanism of the organocatalyzed Michael addition between propanal and methyl vinyl ketone is investigated using the density functional and ab intio methods. Different modes of substrate activation offered by a secondary amine (pyrrolidine) organocatalyst are reported. The electrophilic activation of enone (P-I) through the formation of an iminium ion, and nucleophilic activation of propanal (P-II) in the form of enamine have been examined by identifying the corresponding transition states. The kinetic preference for the formation of key intermediates is established in an effort to identify the competing pathways associated with the title reaction. A comparison of barriers associated with different pathways as well as intermediate formation allows us to provide a suitable mechanistic rationale for Michael addition reactions catalyzed by a secondary amine. The overall barriers for the C-C bond formation pathways involving enol or iminium intermediates are identified as hi-her than the enamine pathway. Additionally, the generation of iminium is found to be less favored as compared to enamine formation. The effect of co-catalyst/protic solvent on the energetics of the overall reaction is also studied using the cluster continuum approach. Significant reduction in the activation energies for each step of the reaction is predicted for the solvent-assisted models. The co-catalyst assisted addition of propanal-enamine to methyl vinyl ketone is identified as the most preferred pathway (P-IV) for the Michael addition reaction. The results are in concurrence with the available experimental reports on the rate acceleration by the use of a co-catalyst in this reaction

Density functional theory investigations on sulfur ylide promoted cyclopropanation reactions: insights on mechanism and diastereoselection issues

[graphics] The mechanism and diastereoselectivity of synthetically useful sulfur ylide promoted cyclopropanation reactions have been studied using the density functional theory method. Addition of different substituted ylides (Me2S+CH-R) to enone ((E)-pent-3-en-2-one, MeHCCH-COMe) has been investigated. The nature of the substituent on the ylidic carbon brings about subtle changes in the reaction profile. The stabilized (R = COMe) and semistabilized (R = Ph) ylides follow a cisoid addition mode, leading to 1,2-trans and 1,2-cis cyclopropanes, respectively, via syn and anti betaine intermediates. The simplest and highly reactive model ylide (R = H) prefers a transoid addition mode. Diastereoselectivity is controlled by the barrier for cisoid-transoid rotation in the case of stabilized ylides, whereas the initial electrophilic addition is found to be the diastereoselectivity-determining step for semistabilized ylides. High selectivity toward trans cyclopropanes with stabilized ylides are predicted on the basis of the relative activation energies of diastereomeric torsional transition states. The energy differences between these transition states could be rationalized with the help of weak intramolecular as well as other stereoelectronic interactions

On the Origins of Kinetic Resolution of Cyclohexane-1,2-diols Through Stereoselective Acylation by Chiral Tetrapeptides

The relative energies of cyclohexane-1,2-diols and chiral tetrapeptide (2 (Boc) or 3 (Moc)) complexes calculated using DFT indicate a thermodynamic preference for chiral recognition toward (1R,2R)(e,e)-alpha isomer. The barrier for stereoselective acyl transfer is identified as lower for trans-(1R,2R)-cyclohexane-1,2-diol, leading to the kinetic resolution (KR) of trans-(1S,2S)-cyclohexane-1,2-diol. The prediction is in concert with the reported experiments for trans-diols, while that for hitherto unknown cis-diol demands experimental verification. It is proposed that desymmetrization would enable the resolution of cis-(1R,2S)-2-hydroxycyclohexyl acetate

Mechanistic Insights on Cooperative Asymmetric Multicatalysis Using Chiral Counterions

Cooperative multicatalytic methods are steadily gaining popularity in asymmetric catalysis. The use of chiral Bronsted acids such as phosphoric acids in conjunction with a range of transition metals has been proven to be effective in asymmetric synthesis. However, the lack of molecular-level understanding and the accompanying ambiguity on the role of the chiral species in stereoinduction continues to remain an unresolved puzzle. Herein, we intend to disclose some novel transition state models obtained through DFT(B3LYP and M06) computations for a quintessential reaction in this family, namely, palladium-catalyzed asymmetric Tsuji-Trost allylation of aldehydes. The aldehyde is activated as an enamine by the action of a secondary amine (organocatalysis), which then adds to an activated Pd-allylic species (transition metal catalysis) generated through the protonation of allyic alcohol by chiral BINOL-phosphoric acid (Bronsted acid catalysis). We aim to decipher the nature of chiral BINOL-phosphates and their role in creating a quaternary chiral carbon atom in this triple catalytic system. The study reports the first transition state model capable of rationalizing chiral counterion-induced enantioselectivity. It is found that the chiral phosphate acts as a counterion in the stereocontrolling event rather than the conventional ligand mode

Stereocontrol in proline-catalyzed asymmetric amination: a comparative assessment of the role of enamine carboxylic acid and enamine carboxylate

The transition state models in two mechanistically distinct pathways, involving (i) an enamine carboxylic acid (path-A, 4) and (ii) an enamine carboxylate (path-B, 8), in the proline-catalyzed asymmetric alpha-amination have been examined using DFT methods. The path-A predicts the correct product stereochemistry under base-free conditions while path-B accounts for reversal of configuration in the presence of a base