Toward a computational tool predicting the stereochemical outcome of asymmetric reactions: development and application of a rapid and accurate program based on organic principles.

Department of Chemistry, McGill University, 801 Sherbrooke Street W., Montréal, Québec H3A 2K6, Canada.
Angewandte Chemie International Edition (Impact Factor: 11.34). 02/2008; 47(14):2635-8. DOI: 10.1002/anie.200704774
Source: PubMed
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    ABSTRACT: A review. Reaction of 2-phenylacetaldehyde with the Me3Si ether of diphenyl-prolinol, with removal of H2O, gives a cryst. enamine (I). The HBF4 salts of the MePh2Si ether of diphenyl-prolinol and of 2-(tert-butyl)-3-methyl- and 5-benzyl-2,2,3-trimethyl-1,3-imidazolidin-4-one react with cinnamaldehyde to give cryst. iminium salts II, III, and IV. Single crystals of the enamine and of two iminium salts, II and III, were subjected to x-ray structure anal., and a 2-dimensional-NMR spectrum of the third iminium salt was recorded. The crystal and NMR structures confirm the commonly accepted, general structures of the two types of reactive intermediates in organocatalysis with the five-membered heterocycles, i.e., V, VI. Fine details of the crystal structures are discussed in view of the obsd. stereoselectivities of the corresponding reactions with electrophiles and nucleophiles. The structures I and II are compared with those of other diphenyl-prolinol derivs. (from the Cambridge File CSD) and discussed in connection with other reagents and ligands, contg. geminal diaryl groups and being used in enantioselective synthesis. The iminium ions III and IV are compared with N-acylated imidazolidinones VII and VIII, and common structural aspects such as minimization of 1,5-repulsion (the A1,3-effect), are discussed. The crystal structures of the simple diphenyl-prolinol.HBF4 salt and of Boc- and benzoyl-(tert-butyl)methyl-imidazolidinone (Boc-BMI and Bz-BMI, resp.) are also reported. Finally, the crystal structures are compared with previously published theor. structures, which were obtained from high-level-of-theory DFT calcns. Delicate details including pyramidalization of trigonal N-atoms, distortions around iminium C=N bonds, shielding of diastereotopic faces, and the pi-interaction between a benzene ring and a Me group match so well with, and were actually predicting the exptl. results that the question may seem appropriate, whether one will soon start considering to carry out such calcns. before going to the lab. for exptl. optimizations.
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    ABSTRACT: A support vector machine (SVM)-based virtual screening method is demonstrated as a rapid computational tool for the prediction of potential asymmetric organocatalysts for the direct aldol reaction. Our models show good accuracy at cross-validation and independent testing. Structure analyses of screening hits from the PubChem database revealed several new classes of compounds, including �-amino acids, diamines and hydrazides, as potential chiral organocatalysts
    Journal of Molecular Catalysis A Chemical 12/2009; 319:114-118. · 3.68 Impact Factor