The palladium-catalyzed aerobic kinetic resolution of secondary alcohols: reaction development, scope, and applications.

The first palladium-catalyzed enantioselective oxidation of secondary alcohols has been developed, utilizing the readily available diamine (-)-sparteine as a chiral ligand and molecular oxygen as the stoichiometric oxidant. Mechanistic insights regarding the role of the base and hydrogen-bond donors have resulted in several improvements to the original system. Namely, addition of cesium carbonate and tert-butyl alcohol greatly enhances reaction rates, promoting rapid resolutions. The use of chloroform as solvent allows the use of ambient air as the terminal oxidant at 23 degrees C, resulting in enhanced catalyst selectivity. These improved reaction conditions have permitted the successful kinetic resolution of benzylic, allylic, and cyclopropyl secondary alcohols to high enantiomeric excess with good-to-excellent selectivity factors. This catalyst system has also been applied to the desymmetrization of meso-diols, providing high yields of enantioenriched hydroxyketones.

Structural features and reactivity of (sparteine)PdCl2: a model for selectivity in the oxidative kinetic resolution of secondary alcohols.

The chiral ligand (-)-sparteine and PdCl(2) catalyze the enantioselective oxidation of secondary alcohols to ketones and thus effect a kinetic resolution. The structural features of sparteine that led to the selectivity observed in the reaction were not clear. Substitution experiments with pyridine derivatives and structural studies of the complexes generated were carried out on (sparteine)PdCl(2) and indicated that the C(1) symmetry of (-)-sparteine is essential to the location of substitution at the metal center. Palladium alkoxides were synthesized from secondary alcohols that are relevant steric models for the kinetic resolution. The solid-state structures of the alkoxides also confirmed the results from the pyridine derivative substitution studies. A model for enantioinduction was developed with C(1) symmetry and Cl(-) as key features. Further studies of the diastereomers of (-)-sparteine, (-)-alpha-iso- and (+)-beta-isosparteine, in the kinetic resolution showed that these C(2)-symmetric counterparts are inferior ligands in this stereoablative reaction [Mohr, J. T., Ebner, D. C., and Stoltz, B. M. Org. Biomol. Chem. 2007, 5, 3571-3576].

Oxidative cyclizations in a nonpolar solvent using molecular oxygen and studies on the stereochemistry of oxypalladation.

Oxidative cyclizations of a variety of heteroatom nucleophiles onto unactivated olefins are catalyzed by palladium(II) and pyridine in the presence of molecular oxygen as the sole stoichiometric oxidant in a nonpolar solvent (toluene). Reactivity studies of a number of N-ligated palladium complexes show that chelating ligands slow the reaction. Nearly identical conditions are applicable to five different types of nucleophiles: phenols, primary alcohols, carboxylic acids, a vinylogous acid, and amides. Electron-rich phenols are excellent substrates, and multiple olefin substitution patterns are tolerated. Primary alcohols undergo oxidative cyclization without significant oxidation to the aldehyde, a fact that illustrates the range of reactivity available from various Pd(II) salts under differing conditions. Alcohols can form both fused and spirocyclic ring systems, depending on the position of the olefin relative to the tethered alcohol; the same is true of the acid derivatives. The racemic conditions served as a platform for the development of an enantioselective reaction. Experiments with stereospecifically deuterated primary alcohol substrates rule out a "Wacker-type" mechanism involving anti oxypalladation and suggest that the reaction proceeds by syn oxypalladation for both mono- and bidentate ligands. In contrast, cyclizations of deuterium-labeled carboxylic acid substrates undergo anti oxypalladation.

An experimentally derived model for stereoselectivity in the aerobic oxidative kinetic resolution of secondary alcohols by (sparteine)PdCl2.

A model for asymmetric induction in palladium-catalyzed aerobic oxidative kinetic resolution is described. The model is based on coordination complexes and general reactivity trends of the parent (sp)PdCl2 catalyst. The first example of a nonracemic chiral palladium alkoxide complex is presented, and exhibits the subtle steric influences of the C1 symmetric ligand sparteine.