Ruthenium-Catalyzed Asymmetric Reduction of Isoxazolium Salts: Access to Optically Active Δ4-Isoxazolines.

A tethered MsDPEN-ruthenium catalyst reduces a series of isoxazolium salts, affording optically active Δ4-isoxazolines in moderate to good yields and enantioenrichment. The redundancy of heating or high pressures allowed for chemoselective reduction with no subsequent heterocyclic ring opening. Our results reinforce our understanding of the workings of these Noyori-class catalysts.

Our Odyssey with Functionalized Chiral Phosphines: From Optical Resolution to Asymmetric Synthesis to Catalysis.

Our journey in organophosphorus research over the past 26 years is compiled in this Personal Account. Advances in palladacycle design have engendered a shift in our focus from template-mediated transformations to catalysis for the direct preparation of chiral phosphines containing a wide variety of functional groups. Novel approaches to access previously inaccessible phosphines and their applications in cancer research are summarized herein.

Highly selective anti-cancer properties of ester functionalized enantiopure dinuclear gold(I)-diphosphine.

Two chiral (-)-diphosphine-digold(I) complexes containing mono- and di-methylester substituted diphosphine ligands have been prepared and structurally characterized. Both complexes are highly potent against breast cancer cell line MDA-MB-231 but showed much lower cytotoxicity against the normal human breast epithelial cells MCF10A. When compared with its mono-substituted analogue, the di-methylester substituted complex caused markedly lower and relatively insignificant damage to the normal breast cells. The analogous mono- and di-ethylester substituted complexes with the same stereochemistry exhibited similar anti-cancer properties but with noticeably higher cytotoxicity against the MCF10A cells. The enantiomeric complex (+)-diphosphine-digold(I) complexes containing the di-methylester substituted diphosphine ligand exhibited clearly different biological properties from its (-)-enantiomer. Furthermore, a structurally similar diphosphine-digold(I) complex but in the absence of an ester substituent, killed both the cancerous and the healthy cells indiscriminately. The current study thus revealed that the introduction of multi-esters, particularly methylesters, is an efficient approach to suppress the side-effects and to improve the efficiency of potential gold-based anti-cancer reagents. When combined with the biological observations, the chirality of gold complexes may serve as a sensitive probe for the future mechanistic studies.

Pd-catalyzed enantiodivergent and regiospecific phospha-Michael addition of diphenylphosphine to 4-oxo-enamides: efficient access to chiral phosphinocarboxamides and their analogues.

The palladacycle-catalyzed asymmetric P-H addition of 4-oxo-enamides has been developed, which provides efficient access to phosphinocarboxamides and their analogues. Solvent-mediated reversal of stereoselectivity (ee from +96% to -92%) was observed, and the underlying mechanism that allows facile access to both enantiomers of the product by judicious choice of solvents is revealed.

Palladacycle catalyzed asymmetric P-H addition of diarylphosphines to N-enoyl phthalimides.

The first asymmetric phospha-Michael addition of diarylphosphines to N-enoyl phthalimides has been developed in the presence of a chiral palladacycle catalyst. A library of free chiral tertiary phosphine adducts were directly obtained with excellent yields and enantioselectivities. Products can be subsequently functionalized to afford ß-phosphinoamides, the direct preparation of which from cinnamides has been notoriously challenging.

Enantioselective phospha-Michael addition of diarylphosphines to ß,γ-unsaturated α-ketoesters and amides.

An enantioselective hydrophosphination of ß,γ-unsaturated α-ketoesters and amides has been developed using a chiral palladacycle catalyst. Adducts can be obtained in excellent yields and enantioselectivities, providing direct access to chiral tertiary phosphines which are synthetically useful intermediates in the preparation of bidentate ligands.

Asymmetric synthesis of enaminophosphines via palladacycle-catalyzed addition of Ph2PH to α,ß-unsaturated imines.

A highly reactive, chemo- and enantioselective addition of diphenylphosphine to α,ß-unsaturated imines catalyzed by a palladacycle has been developed, thus providing the access to a series of chiral tertiary enaminophosphines in high yields. A putative catalytic cycle has also been proposed.

Direct synthesis of chiral tertiary diphosphines via Pd(II)-catalyzed asymmetric hydrophosphination of dienones.

A highly diastereo- and enantioselective Pd(II)-catalyzed hydrophosphination of dienones with Ph(2)PH involving formation of double C*-P bonds has been developed, providing a series of chiral tertiary diphosphines (chiral PCP pincer ligands) in high yields. A catalytic cycle for the reaction was proposed.