Improving the Accuracy of Computed ¹³C NMR Shift Predictions by Specific Environment Error Correction: Fragment Referencing

The accuracy of both Gauge-including atomic orbital (GIAO) and continuous set of gauge transformations (CSGT) ¹³C NMR spectra prediction by Density Functional Theory (DFT) at the B3LYP/6-31G** level is shown to be usefully enhanced by employing a ‘fragment referencing’ method for predicting chemical shifts without recourse to empirical scaling. Fragment referencing refers to a process of reducing the error in calculating a particular NMR shift by consulting a similar molecule for which the error in the calculation is easily deduced. The absolute accuracy of the chemical shifts predicted when employing fragment referencing relative to conventional techniques (e.g., using TMS or MeOH/benzene dual referencing) is demonstrated to be improved significantly for a range of substrates, which illustrates the superiority of the technique particularly for systems with similar chemical shifts arising from different chemical environments. The technique is particularly suited to molecules of relatively low molecular weight containing ‘non-standard’ magnetic environments, e.g., α to halogen atoms, which are poorly predicted by other methods. The simplicity and speed of the technique mean that it can be employed to resolve routine structural assignment problems that require a degree of accuracy not provided by standard incremental or hierarchically ordered spherical description of environment (HOSE) algorithms. The approach is also demonstrated to be applicable when employing the MP2 method at 6-31G**, cc-pVDZ, aug-cc-pVDZ, and cc-pVTZ levels, although none of these offer advantage in terms of accuracy of prediction over the B3LYP/6-31G** DFT method

Diels–Alder Reactions of α‑Amido Acrylates with <i>N</i>‑Cbz-1,2-dihydropyridine and Cyclopentadiene

Thermal Diels–Alder reactions of α-amido acrylates with <i>N</i>-Cbz-1,2-dihydropyridine and cyclopentadiene have been explored to investigate the factors influencing the <i>endo/exo</i> selectivity. For the dihydropyridine, steric factors allowed the diastereoselectivity to be modulated to favor either <i>endo-</i> or <i>exo-</i>ester adducts. For cyclopentadiene, the <i>endo</i>-ester adducts were favored regardless of steric perturbation, although catalysis by bulky Lewis acids increased the proportion of <i>exo</i>-ester adducts in some cases. These Lewis acids were incompatible with the dihydropyridine diene as they induced its decomposition

Theoretical Prediction of Selectivity in Kinetic Resolution of Secondary Alcohols Catalyzed by Chiral DMAP Derivatives

The mechanism of esterification of the secondary alcohol 1-(1-naphthyl)­ethanol <b>9</b> by isobutyric anhydride catalyzed by 4-pyrrolidinopyridine (PPY, <b>11</b>) and a series of single enantiomer atropisomeric 4-dialkylaminopyridines <b>8a</b>–<b>g</b> has been studied computationally at the B3LYP/6-311+G­(d,p)//B3LYP/6-31G­(d) level. Comparison of the levels of enantioselectivity predicted computationally with the results obtained experimentally allowed the method to be validated. The value of the approach is demonstrated by the successful prediction that a structural modification of an aryl group within the catalyst from phenyl to 3,5-dimethylphenyl would lead to improved levels of selectivity in this type of kinetic resolution (KR) reaction, as was subsequently verified following synthesis and evaluation of this catalyst (<b>8d</b>). Experimentally, the selectivity of this type of KR is found to exhibit a significant deuterium isotope effect (for <b>9</b> vs <b><i>d</i>₁</b>-<b>9</b>)

Total Synthesis of (+)-Lophirone H and Its Pentamethyl Ether Utilizing an Oxonium–Prins Cyclization

The first total synthesis of (+)-lophirone H (<b>1</b>) and its pentamethyl ether <b>29</b>, featuring an oxonium–Prins cyclization/benzylic cation trapping reaction, is described

3d/4f Coordination Clusters as Cooperative Catalysts for Highly Diastereoselective Michael Addition Reactions

Michael addition (MA) is one of the most well studied chemical transformation in synthetic chemistry. Here, we report the synthesis and crystal structures of a library of 3d/4f coordination clusters (CCs) formulated as [Zn^II₂Y^III₂L₄­(solv)_X(Z)_Y] and study their catalytic properties toward the MA of nitrostyrenes with barbituric acid derivatives. Each CC presents two borderline hard/soft Lewis acidic Zn^II centers and two hard Lewis acidic Y^III centers in a defect dicubane topology that brings the two different metals into a proximity of ∼3.3 Å. Density functional theory computational studies suggest that these tetrametallic CCs dissociate in solution to give two catalytically active dimers, each containing one 3d and one 4f metal that act cooperatively. The mechanism of catalysis has been corroborated via NMR, electron paramagnetic resonance, and UV–vis. The present work demonstrates for the first time the successful use of 3d/4f CCs as efficient and high diastereoselective catalysts in MA reactions

Synthesis and Incorporation into Cyclic Peptides of Tolan Amino Acids and Their Hydrogenated Congeners: Construction of an Array of A–B-loop Mimetics of the Cε3 Domain of Human IgE

The disruption of the human immunolobulin E–high affinity receptor I (IgE–FcεRI) protein–protein interaction (PPI) is a validated strategy for the development of anti asthma therapeutics. Here, we describe the synthesis of an array of conformationally constrained cyclic peptides based on an epitope of the A–B loop within the Cε3 domain of IgE. The peptides contain various tolan (i.e., 1,2-biarylethyne) amino acids and their fully and partially hydrogenated congeners as conformational constraints. Modest antagonist activity (IC₅₀ ∼660 μM) is displayed by the peptide containing a 2,2′-tolan, which is the one predicted by molecular modeling to best mimic the conformation of the native A–B loop epitope in IgE