Enantioselective Silver and Amine Co-catalyzed Desymmetrizing Cycloisomerization of Alkyne-Linked Cyclohexanones.

A silver(I) and amine co-catalyzed desymmetrization of 4-propargylamino cyclohexanones for the direct enantioselective synthesis of 2-azabicyclo[3.3.1]nonanes is described. Exploiting reactivity arising from dual activation of the pendant terminal alkyne by silver(I) and the ketone moiety through transient enamine formation, this synthetically relevant transformation is easy to perform, efficient and broad in scope. High enantioselectivity (up to 96 % ee) was achieved by exploiting a significant matching effect between the chirality of a cinchona alkaloid-derived aminophosphine ligand for the silver(I) salt and the 2-bis(aryl)methylpyrrolidine catalyst which was rationalized by DFT calculations. This allowed for the preparation of both enantiomers of the bicyclic product with near-identical stereocontrol.

Enantioselective desymmetrization of prochiral cyclohexanones by organocatalytic intramolecular Michael additions to α,ß-unsaturated esters.

A new catalytic asymmetric desymmetrization reaction for the synthesis of enantioenriched derivatives of 2-azabicyclo[3.3.1]nonane, a key motif common to many alkaloids, has been developed. Employing a cyclohexanediamine-derived primary amine organocatalyst, a range of prochiral cyclohexanone derivatives possessing an α,ß-unsaturated ester moiety linked to the 4-position afforded the bicyclic products, which possess three stereogenic centers, as single diastereoisomers in high enantioselectivity (83-99% ee) and in good yields (60-90%). Calculations revealed that stepwise C-C bond formation and proton transfer via a chair-shaped transition state dictate the exclusive endo selectivity and enabled the development of a highly enantioselective primary amine catalyst.

Dual amine and palladium catalysis in diastereo- and enantioselective allene carbocyclization reactions.

A pyrrolidine and Pd catalyzed diastereoselective carbocyclization of aldehyde and ketone-linked allenes has been developed. The cooperative organo/metal-catalyzed cyclization reaction, which presumably proceeds via an enamine intermediate, is efficient and broad in scope. Also, it has been extended to a catalytic asymmetric variant using diarylprolinol-based organocatalysts to afford substituted cyclopentane and pyrrolidine reaction products in up to 82% ee.

Highly stereoselective modifications of peptides via Pd-catalyzed allylic alkylation of internal peptide amide enolates.

Pd-catalyzed allylations are excellent tools for stereoselective peptide modifications, showing several advantages compared to normal alkylations. Reactions of internal peptide amide enolates with Pd-allyl complexes proceed not only with high yields of up to 86%, they show also high regio- and diastereoselectivities (88-99%), giving rise to the trans-configured products. Therefore, this protocol is a powerful synthetic tool for the synthesis of natural product and drug molecules.

Stereoselective palladium-catalyzed allylic alkylations of peptide amide enolates.

Pd-catalyzed allylations are an excellent tool for stereoselective peptide modifications, being clearly superior to normal alkylations. The reactions proceed not only in high yield, but also high regio- and diastereoselectivities, and trans-products are formed exclusively. Therefore, this is a powerful synthetic tool for natural product and drug synthesis.

Gold-catalyzed hydrative carbocyclization of 1,5- and 1,7-allenynes mediated by pi-allene complex: mechanistic evidence supported by the chirality transfer of allenyne substrates.

We report PPh3AuCl/AgOTf-catalyzed hydrative carbocyclization of 1,5- and 1,7-allenynes to give cyclized ketones chemoselectively. In this transformation, hydration occurrs regioselectively at the C[triple bond]CPh carbon, accompanied by addition of the C[triple bond]CPh carbon to the two terminal allenyl carbons. This method is effective for the construction of a quaternary carbon center. On the basis of the chirality transfer of allenyne substrates, control experiments, and theoretic calculations, we propose that this hydrative carbocyclization proceeds through an initial pi-allene complex with a small energy barrier.

Gold-catalyzed [4+3]-annulation of oxabicyclic benzenes with 2-substituted allylsilanes through tandem allylation and cyclization.

This work reports new gold-catalyzed [4+3]-annulations of oxacyclic benzenes with 2-substituted allylsilanes through tandem allylation and cyclization; on the basis of experimental observations, we propose a mechanism involving the opening of the oxacyclic ring by a PPh3Au+-assisted SN2-attack of allylsilanes.

The skeletal rearrangement of gold- and platinum-catalyzed cycloisomerization of cis-4,6-dien-1-yn-3-ols: pinacol rearrangement and formation of bicyclo[4.1.0]heptenone and reorganized styrene derivatives.

With gold and platinum catalysts, cis-4,6-dien-1-yn-3-ols undergo cycloisomerizations that enable structural reorganization of cyclized products chemoselectively. The AuCl3-catalyzed cyclizations of 6-substituted cis-4,6-dien-1-yn-3-ols proceeded via a 6-exo-dig pathway to give allyl cations, which subsequently undergo a pinacol rearrangement to produce reorganized cyclopentenyl aldehyde products. Using chiral alcohol substrates, such cyclizations proceed with reasonable chirality transfer. In the PtCl2-catalyzed cyclization of 7,7-disubstituted cis-4,6-dien-1-yn-3-ols, we obtained exclusively either bicyclo[4.1.0]heptenones or reorganized styrene products with varied substrate structures. On the basis of the chemoselectivity/structure relationship, we propose that bicyclo[4.1.0]heptenone products result from 6-endo-dig cyclization, whereas reorganized styrene products are derived from the 5-exo-dig pathway. This proposed mechanism is supported by theoretic calculations.

Ruthenium-catalyzed cyclization of 2-alkyl-1-ethynylbenzenes via a 1,5-hydrogen shift of ruthenium-vinylidene intermediates.

Catalytic cyclization of 2-alkyl-1-ethynylbenzene derivatives was implemented by TpRuPPh3(CH3CN)2PF6 (10 mol %) in hot toluene (105 degrees C, 36-100 h) to form 1-substituted-1H-indene and 1-indanone products; such cyclizations proceeded more efficiently for substrates bearing electron-rich benzenes. We propose that the cyclization mechanism involves a 1,5-hydrogen shift of initial metal-vinylidene intermediate.

Ruthenium-catalyzed cycloisomerization of cis-3-en-1-ynes to cyclopentadiene and related derivatives through a 1,5-sigmatropic hydrogen shift of ruthenium-vinylidene intermediates.

We report a new ruthenium-catalyzed cycloisomerization of unactivated cis-3-en-1-ynes, which produces substituted cyclopentadiene and related derivatives. The mechanism of this cyclization is proposed to involve a [1,5]-sigmatropic hydrogen shift of ruthenium-vinylidene intermediates on the basis of deuterium-labeling experiments.

A new ruthenium-catalyzed cleavage of a carbon-carbon triple bond: efficient transformation of ethynyl alcohol into alkene and carbon monoxide.

We report a new and efficient ruthenium-catalyzed reaction that transforms ethynyl alcohol into alkene and carbon monoxide. The most efficient catalysts are TpRu(PPh3)(CH3CN)2PF6 (10 mol %) and lithium triflate (20 mol %). The mechanism of this reaction was elucidated using an isotope-labeling experiment.