Theory and Modeling of Asymmetric Catalytic Reactions

Abstract

Modern density functional theory and powerful contemporary computers have made it possible to explore complex reactions of value in organic synthesis. We describe recent explorations of mechanisms and origins of stereoselectivities with density functional theory calculations. The specific functionals and basis sets that are routinely used in computational studies of stereoselectivities of organic and organometallic reactions in our group are described, followed by our recent studies that uncovered the origins of stereocontrol in reactions catalyzed by (1) vicinal diamines, including cinchona alkaloid-derived primary amines, (2) vicinal amidophosphines, and (3) organo-transition-metal complexes. Two common cyclic models account for the stereoselectivity of aldol reactions of metal enolates (Zimmerman-Traxler) or those catalyzed by the organocatalyst proline (Houk-List). Three other models were derived from computational studies described in this Account. Cinchona alkaloid-derived primary amines and other vicinal diamines are venerable asymmetric organocatalysts. For α-fluorinations and a variety of aldol reactions, vicinal diamines form enamines at one terminal amine and activate electrophilically with NH(+) or NF(+) at the other. We found that the stereocontrolling transition states are cyclic and that their conformational preferences are responsible for the observed stereoselectivity. In fluorinations, the chair seven-membered cyclic transition states is highly favored, just as the Zimmerman-Traxler chair six-membered aldol transition state controls stereoselectivity. In aldol reactions with vicinal diamine catalysts, the crown transition states are favored, both in the prototype and in an experimental example, shown in the graphic. We found that low-energy conformations of cyclic transition states occur and control stereoselectivities in these reactions. Another class of bifunctional organocatalysts, the vicinal amidophosphines, catalyzes the (3 + 2) annulation reaction of allenes with activated olefins. Stereocontrol here is due to an intermolecular hydrogen bond that activates the electrophilic partner in this reaction. We have also studied complex organometallic catalysts. Krische's ruthenium-catalyzed asymmetric hydrohydroxyalkylation of butadiene involves two chiral ligands at Ru, a chiral diphosphine and a chiral phosphate. The size of this combination strains the limits of modern computations with over 160 atoms, multiple significant steps, and a variety of ligand coordinations and conformations possible. We found that carbon-carbon bond formation occurs via a chair Zimmerman-Traxler-type transition structure and that a formyl CH···O hydrogen bond from aldehyde CH to phosphate oxygen, as well as steric interactions of the two chiral ligands, control the stereoselectivity.

Solvent selection for chemical reactions: automated computational screening of solvents using the SMD model

“…54,55 In special, organocatalyzed controlled enantioselectivity is a very active research field in the present time. [56][57][58][59][60][61] In the same direction, the thermodynamic of the reaction can be an important issue in the selectivity when the reaction ∆G is close to zero. 15 These properties may have a significative solvent effect, and the present approach is a viable method to test a high number of solvents (179 available in SMD) using modern workstations.…”

Enantioselective S−H Insertion Reactions of α‐Carbonyl Sulfoxonium Ylides

“…Subsequent DFT investigations (Gaussian16 (Revision A.03), [41] see SI) allowed modelling of the selectivitydetermining protonation step from 4 b:1 a to 10 in order to determine the origins of selectivity. [42] These calculations were performed on the optimised conditions in Table 2 (entry 6, 85 % ee), however the trifluoromethyl and pyrene groups of the catalyst were truncated to fluorines and phenyl, respectively, to reduce computational expense. Superimposition of the lowest energy conformations of catalyst 4 b and the model catalyst (RMSD = 0.095 over core atoms, see SI) indicates that these truncations do not significantly impact the conformation of the catalyst, and hence allow reasonable approximation of the full transition structures (TSs).…”

John D. Roberts, his beginnings at UCLA, his transformation of physical organic chemistry, and his impact on science

“…Jack Roberts pushed organic chemists in this direction in 1961, and now, we cannot only calculate Hückel MOs but even locate TSs of complex reactions and develop intimate understanding of them. Figure shows one of these TSs, for an aldol reaction catalyzed by a cinchona alkaloid derivative …”