Attractive noncovalent interactions in asymmetric catalysis: links between enzymes and small molecule catalysts

Abstract

Catalysis by neutral, organic, small molecules capable of binding and activating substrates solely via noncovalent interactions--particularly H-bonding--has emerged as an important approach in organocatalysis. The mechanisms by which such small molecule catalysts induce high enantioselectivity may be quite different from those used by catalysts that rely on covalent interactions with substrates. Attractive noncovalent interactions are weaker, less distance dependent, less directional, and more affected by entropy than covalent interactions. However, the conformational constraint required for high stereoinduction may be achieved, in principle, if multiple noncovalent attractive interactions are operating in concert. This perspective will outline some recent efforts to elucidate the cooperative mechanisms responsible for stereoinduction in highly enantioselective reactions promoted by noncovalent catalysts.

Fig. 1

Noncovalent interactions between a transition state analog and active site residues of chorismate mutase. These attractive interactions stabilize the electrostatic character of the pericyclic transition state converting chorismate to prephenate, resulting in rate accelerations of up to 10⁶.

Fig. 2

Stereochemical models for synthetically important enantioselective transformations wherein stereoselectivity is rationalized through steric destabilization of minor pathways.

Fig. 3

Examples of rate acceleration in Claisen rearrangements of polarized allyl vinyl ethers facilitated by hydrogen bonding interactions.

Fig. 4

Diastereomeric transition structures for the enantioselectve Claisen rearrangements of ester-substiuted allyl vinyl ether 1 catalyzed by guanidinium 3 calculated using density functional theory (B3LYP 6-31G). Hydrogen bonding interactions are indicated in black and the stereodifferentiating cation–π interaction is highlighted in red.

Fig. 5

Generalized reaction scheme for anion-binding thiourea catalysis.

Fig. 6

Effects of catalyst aromatic group on the efficiency and enantioselectivity of the polycyclization of hydroxylactam 6.

Fig. 7

(A) Differential activation parameters for the competing diastereomeric pathways in the polycyclization of hydroxylactam 6 catalyzed by 9, 10, and 11. These values were derived from an Eyring analysis of enantioselectivity over a temperature range of 70 °C. (B and C) Linear correlations between ln(er) and the polarizability and quadropole moment of the catalyst aromatic group obtained for the reaction of 6 with catalysts 8–11 under the reaction conditions described in Fig. 6.

Fig. 8

Effect of tertiary amide structure on enantioselectivity in the thiourea-catalyzed hydrocyanation of imine 12.

Fig. 9

Proposed mechanism for the thiourea-catalyzed Strecker reaction.

Fig. 10

Correlation of transition structure bond lengths with enantioselectivity for Strecker reactions of imine 12. Plots of the sum of the cyanide-(thio)urea H-bond lengths (d₁ + d₂, Left) and cyanide N-iminium H + amide O-iminium H bond lengths (d₃ + d₄, Right) in B3LYP 6-31G(d) transition structures for eight structurally distinct H-bond donor catalysts. This analysis points to differential iminium ion stabilization through hydrogen bonding interactions as a basis for enantioselectivity.

Fig. 11

Representative asymmetric Povarov reaction catalyzed by urea 21. Illustrated below are the hydrogen bonding interactions that lead to the strong binding observed between the 21 and the iminium sulfonate intermediate.

Fig. 12

Plots of initial rate and enantiomeric excess in the Povarov reaction versus [21] at three different concentrations of triflic acid. This graph was reproduced from reference 54.

Fig. 13

Calculated transition states structures for the Povarov reaction catalyzed by 21. A stabilizing, transition state π–π interaction is proposed as a basis for enantioselectivity and is highlighted in the structure leading to the (R) enantiomer of product.