Stereochemical Stability of Planar-Chiral Benzazepine Tricyclics: Inversion Energies of P- and S-Alkene Ligands.

Inversion barriers ΔG‡ for planar chiral phosphine-alkene and sulfonamide-alkene hybrid ligands based on phenyl-dibenz[b,f]azepine have been determined by density-functional theory calculations. Analysis of the structural and electronic characteristics of the minima and transition states explains the magnitudes of ΔG‡ and the geometrical changes during the inversion process. The steric repulsion caused by bulky substituents attached to the azepine nitrogen atom has a pronounced effect on the ΔG‡ value, explaining, inter alia, the stereochemical stability of the P- and S-alkene ligands when compared to the fluxional parent compound where X = H.

Evolution of a 'privileged' P-alkene ligand: added planar chirality beats BINOL axial chirality in catalytic asymmetric C-C bond formation.

Alkene planar chirality is introduced in the 'privileged' P-alkene phosphoramidite ligand 1. The resulting diastereomeric ligands (pR,R)-5 and (pS,R)-5 form optically pure complexes of Rh(I) and Pd(II), which catalyze conjugate additions of boron C-nucleophiles to enones and allylic alkylations, respectively. In the Rh-catalyzed reaction, the planar chirality of the alkene exerts absolute enantiocontrol over the potent BINOL auxiliary.

Enantioselective synthesis of 4-amino-3,4-dihydrocoumarins and their non-cyclic hydroxyester precursors: Biological evaluation for the treatment of glioblastoma multiforme.

The stereoselective addition of ethyl acetate enolate to the C═N bond of N-tert-butylsulfinylimines has been investigated in depth. A significant effect of the LHMDS amount and the N-sulfinylimine nature on the stereoselectivity of the process was observed. Conditions were found where sulfinylimines of differently substituted salicylaldehydes derivatives, ethyl acetate, and LHMDS afforded the corresponding addition products as a single diastereomer in good yields. The developed protocol was successfully applied to the first stereoselective synthesis of differently substituted 4-amino-3,4-dihydrocoumarin derivatives. Computational models confirmed the prominent role of the ortho aryl substituent in the stereoselectivity of the process. A significant and selective cytotoxic activity against Glioblastoma Multiforme (GBM) cancer line has been determined for the noncyclic hydroxy ester derivative.

Sulfinamide Phosphinates as Chiral Catalysts for the Enantioselective Organocatalytic Reduction of Imines.

A new type of chiral sulfinamide phosphinate catalysts with up to three stereogenic centers, readily accessible from commercially available starting materials, is reported. The naphthyl derivative SulPhos proved to be highly efficient in the organocatalytic asymmetric imine reduction, leading to a wide range of arylmethylamines in high yields with up to 99% ee under 10% catalyst loading. The synthetic utility of this method was demonstrated by the expeditious enantioselective synthesis of the calcimimetic NPS-R568.

Flexible C2-symmetric bis-sulfoxides as ligands in enantioselective 1,4-addition of boronic acids to electron-deficient alkenes.

The application of acyclic C2-symmetric chelating bis-sulfoxide ligands in the Rh(I)-catalyzed enantioselective 1,4-addition of boronic acids to electron-deficient alkenes is reported. Among the acyclic ethane-bridged bis-sulfoxides tested, the ligand Ferbisox (11), bearing ferrocenyl moieties as substituents at the sulfinyl sulfurs, has exhibited the best results in terms of chemical yield (up to 96%) and enantioselectivity (up to 97% ee). The conjugate addition takes place smoothly in toluene at room temperature in short reaction times (typically 2 h). The reaction scope, including the use of different boronic acids, five-, six-, and seven-membered cyclic enones, an unsaturated lactone, and the most challenging acyclic ketones, is reported. An X-ray diffraction study of the [Ferbisox·RhCl]2 precatalyst clearly exhibits a dimeric structure with an S coordination of the sulfoxide to rhodium. On the basis of the X-ray data and on structural studies conducted in solution by (1)H NMR, a model explaining the high enantioselection observed is proposed.

"Sulfolefin": highly modular mixed S/olefin ligands for enantioselective Rh-catalyzed 1,4-addition.

Reported is a single high yielding step approximation to mixed olefin/sulfinamide ligands enclosing a chiral sulfur atom as the sole chiral center. The synthetic design is validated by a rapid optimization of the substituent at the sulfinyl sulfur, and by the synthesis of an efficient, highly enantioselective catalyst for the Rh-catalyzed 1,4-addition of boronic acids to both, cyclic and acyclic olefins.