Lewis-Base-Catalyzed Reductive Aldol Reaction To Access Quaternary Carbons.

A synthetic method for the efficient construction of ß-hydroxylactones and lactams bearing α-quaternary carbon centers is described. This transformation relies on an electronically differentiated Lewis base catalyst, which is uniquely capable of promoting a reductive aldol reaction of α,α-disubstituted and α,α,ß-trisubstituted enones. This approach provides a valuable synthetic alternative for carbon-carbon bond formation in complex molecular settings due to its orthogonal reactivity compared to that of traditional aldol reactions. Based on this method described herein, lactones, lactams, and morpholine amides bearing α-quaternary carbon centers are accessible in yields up to 85% and 50:1 dr.

Mechanistic Studies of ε-Caprolactone Polymerization by (salen)AlOR Complexes and a Predictive Model for Cyclic Ester Polymerizations.

Aluminum alkoxide complexes (2) of salen ligands with a three-carbon linker and para substituents having variable electron-withdrawing capabilities (X = NO2, Br, OMe) were prepared, and the kinetics of their ring-opening polymerization (ROP) of ε-caprolactone (CL) were investigated as a function of temperature, with the aim of drawing comparisons to similar systems with two-carbon linkers investigated previously (1). While 1 and 2 exhibit saturation kinetics and similar dependences of their ROP rates on substituents X (invariant Keq, similar Hammett ρ = +1.4(1) and 1.2(1) for k2, respectively), ROP by 2 was significantly faster than for 1. Theoretical calculations confirm that, while the reactant structures differ, the transition state geometries are quite similar, and by analyzing the energetics of the involved distortions accompanying the structural changes, a significant contribution to the basis for the rate differences was identified. Using this knowledge, a simplified computational method for evaluating ligand structural influences on cyclic ester ROP rates is proposed that may have utility for future catalyst design.

Effective donor abilities of E-t-Bu and EPh (E = O, S, Se, Te) to a high valent transition metal.

Amido rotation in the chromium(vi), d(0)-system NCr(NPr(i)2)2X is under investigation as a method for the parameterization of ligands for their donor properties toward high valent metals. In this study, two new series were prepared and studied based on chalcogenide ligands, X = EBu(t) and EPh and where E = O, S, Se, Te; the OPh and SPh compounds were previously reported. The ligand donor parameters for these ligands correlate with the Cr-E-C angles in these chalcogenide series. In addition, it was found that NBO calculated overlaps and DFT calculated bond dissociation enthalpies correlate within X = halide-, EBu(t)- and EPh-series. All of the new complexes were characterized by X-ray diffraction.

Understanding the mechanism of polymerization of ε-caprolactone catalyzed by aluminum salen complexes.

Studies of the kinetics of polymerization of ε-caprolactone (CL) by salen-aluminum catalysts comprising ligands with similar steric profiles but different electron donating characteristics (R = OMe, Br, or NO2) were performed using high initial monomer concentrations (2 M < [CL]0 < 2.6 M) in toluene-d8 at temperatures ranging from 20 to 90 °C. Saturation behavior was observed, enabling determination of monomer equilibrium constants (Keq) and catalytic rate constants (k2) as a function of R and temperature. While Keq varied only slightly with the electron donating properties of R (Hammett ρ = +0.16(8)), k2 showed a more significant dependence reflected by ρ = +1.4(1). Thermodynamic parameters ΔG° (associated with Keq) and ΔG(‡) (associated with k2) were determined, with the former being ∼0 kcal/mol for all catalysts and the latter exhibiting the trend R = OMe > Br > NO2. Density functional theory (DFT) calculations were performed to characterize mechanistic pathways at a microscopic level of detail. Lowest energy transition-state structures feature incipient bonding of the nucleophile to the lactone carbonyl that is approaching the metal ion, but a distinct CL adduct is not an energy minimum on the reaction pathway, arguing against Keq being associated with coordination of monomer according to the typical coordination-insertion mechanism. An alternative hypothesis is presented associating Keq with "nonproductive" coordination of substrate in a manner that inhibits the polymerization reaction at high substrate concentrations.

(S)-Styryl-α-alanine used to probe the intermolecular mechanism of an intramolecular MIO-aminomutase.

A Taxus canadensis phenylalanine aminomutase (TcPAM) catalyzes the isomerization of (S)-α- to (R)-ß-phenylalanine, making (E)-cinnamate (~10%) as a byproduct at steady state. A currently accepted mechanism for TcPAM suggests that the amino group is transferred from the substrate to a prosthetic group comprised of an amino acid triad in the active site and then principally rebinds to the carbon skeleton of the cinnamate intermediate to complete the α-ß isomerization. In contrast, when (S)-styryl-α-alanine is used as a substrate, TcPAM produces (2E,4E)-styrylacrylate as the major product (>99%) and (R)-styryl-ß-alanine (<1%). Comparison of the rates of conversion of the natural substrate (S)-α-phenylalanine and (S)-styryl-α-alanine to their corresponding products (k(cat) values of 0.053 ± 0.001 and 0.082 ± 0.002 s(-1), respectively) catalyzed by TcPAM suggests that the amino group resides in the active site longer than styrylacrylate. To demonstrate this principle, inhibition constants (K(I)) for selected acrylates ranging from 0.6 to 106 µM were obtained, and each had a lower K(I) compared to that of (2E,4E)-styrylacrylate (337 ± 12 µM). Evaluation of the inhibition constants and the rates at which both the α/ß-amino acids (between 7 and 80% yield) and styrylacrylate were made from a corresponding arylacrylate and styryl-α-alanine, respectively, by TcPAM catalysis revealed that the reaction progress was largely dependent on the K(I) of the acrylate. Bicyclic amino donor substrates also transferred their amino groups to an arylacrylate, demonstrating for the first time that ring-fused amino acids are productive substrates in the TcPAM-catalyzed reaction.