Palladium-Catalyzed Enantioselective Cycloadditions of Aliphatic 1,4-Dipoles: Access to Chiral Cyclohexanes and Spiro [2.4] heptanes.

Design and exploration of new intermediates for chemo-, regio-, and stereoselective cycloadditions remain a formidable challenge in modern organic synthesis. Compared to the well-developed 1,3-dipolar cycloadditions, Pd-catalyzed1,4-dipolar cycloadditions are generally limited to specialized substrates due to the inherent nature of the thermodynamically driven intramolecular transformations and undesired isomerizations. Herein, we demonstrate the use of ligated palladium catalysts to control and modulate the intermolecular reactivity of aliphatic 1,4-dipoles, enabling two distinctive cycloaddition pathways with a broad scope of acceptors.

Direct Enantio- and Diastereoselective Zn-ProPhenol-Catalyzed Mannich Reactions of CF- and SCF-Substituted Ketones.

Enantioselective incorporation of trifluoromethyl (-CF) and trifuoromethylthio (-SCF) groups in small molecules is of high interest to modulate the potency and pharmacological properties of drug candidates. Herein, we report a Zn-ProPhenol catalyzed diastereo- and enantioselective Mannich addition of α-trifluoromethyl- and α-trifuoromethylthio-substituted ketones. This transformation uses cyclic and acyclic ketones and generates quaternary trifluoromethyl and tetrasubstituted trifuoromethylthio stereogenic centers in excellent yields and selectivities.

Use of α-trifluoromethyl carbanions for palladium-catalysed asymmetric cycloadditions.

The development of new methodologies that enable chemo- and stereoselective construction of fluorinated substituents, such as the trifluoromethyl (CF) group, plays an essential role in the synthesis of new pharmaceutical agents. The exceptional ability of the CF moiety to prevent in vivo metabolism as well as improve other pharmacological properties has led to numerous innovative strategies for installing this unique functional group. One potential yet underdeveloped approach to access these trifluoromethylated products is direct substitution of α-trifluoromethyl carbanions.

Acyclic Branched α-Fluoro Ketones for the Direct Asymmetric Mannich Reaction Leading to the Synthesis of β-Tetrasubstituted β-Fluoro Amines.

The preparation of acyclic β-fluoro amines bearing tetrasubstituted fluorine stereocenters is described via a direct Zn/ProPhenol-catalyzed Mannich reaction. The reaction utilizes branched vinyl or alkynyl α-fluoro ketones that can be coupled with a range of aryl, heteroaryl, vinyl, or cyclopropyl aldimines in high yield and with excellent diastereo- (up to >20:1) and enantioselectivity (up to 99 %). The use of readily cleaved tert-butoxycarbonyl (Boc) or carboxybenzyl (Cbz) imine protecting groups adds utility to the reaction by allowing for easy access to the free amine products under mild and chemoselective reaction conditions.

Enantioselective Divergent Syntheses of (+)-Bulleyanaline and Related Isoquinoline Alkaloids from the Genus .

The isoquinoline alkaloids isolated from the genus possess potent and diverse biological activities. Herein, a concise, divergent, and enantioselective route to access these natural products is disclosed. Key transformations of our approach include a challenging Zn-ProPhenol-catalyzed asymmetric Mannich reaction to build a quaternary stereogenic center and a rapid cationic Au-catalyzed cycloisomerization to the common structural skeleton of these natural products.

Elaborating Complex Heteroaryl-Containing Cycles via Enantioselective Palladium-Catalyzed Cycloadditions.

A general method for asymmetric synthesis of heteroaryl-containing cycles via palladium-catalyzed cyclization is reported. Most classes of nitrogen-containing aromatics, including pyridines, quinolines, pyrimidines, various azoles and the derivatives of nucleobases are compatible substrates, offering various heteroaryl-substituted cyclopentane, pyrrolidine, furanidine and bicyclo[4.3.

Dinuclear Metal-ProPhenol Catalysts: Development and Synthetic Applications.

The ProPhenol ligand is a member of the chiral aza-crown family that spontaneously forms a bimetallic complex upon treatment with alkyl metal reagents, such as Et Zn and Bu Mg. The resulting complex features Lewis acidic and Brønsted basic sites, enabling simultaneous activation of both nucleophile and electrophile in the same chiral environment. Since the initial report in 2000, metal-ProPhenol catalysts have been used to facilitate a broad range of asymmetric transformations, including aldol, Mannich, and Henry reactions, as well as alkynylations and conjugation additions.

Synthesis of Chiral, Densely Substituted Pyrrolidones via Phosphine-Catalyzed Cycloisomerization.

Densely substituted chiral pyrrolidones are synthesized via phosphine-catalyzed cycloisomerization of enantioenriched β-amino ynones, which are prepared in a single step using a highly enantioselective Zn-ProPhenol-catalyzed Mannich reaction. The exocyclic alkenes in the cyclization products provide versatile handles for further transformations and typically form with good E/ Z selectivity. This cycloisomerization method can be performed in streamlined fashion, without purification of the intermediate Mannich adduct, and extends to anthranilic acid based scaffolds in addition to ProPhenol-derived Mannich adducts.

Direct Enantio- and Diastereoselective Vinylogous Addition of Butenolides to Chromones Catalyzed by Zn-ProPhenol.

We report the first enantio- and diastereoselective 1,4-addition of butenolides to chromones. Both α,β- and β,γ-butenolide nucleophiles are compatible with the Zn-ProPhenol catalyst, and preactivation as the siloxyfurans is not required. The scope of electrophiles includes a variety of substituted chromones, as well as a thiochromone and a quinolone, and the resulting vinylogous addition products are generated in good yield (31 to 98%), diastereo- (3:1 to >30:1), and enantioselectivity (90:10 to 99:1 er).

Direct Catalytic Asymmetric Vinylogous Additions of α,β- and β,γ-Butenolides to Polyfluorinated Alkynyl Ketimines.

We report a Zn-ProPhenol catalyzed asymmetric Mannich reaction between butenolides and polyfluorinated alkynyl ketimines to obtain vinylogous products featuring two contiguous tetrasubstituted stereogenic centers. Notably, this is the first successful use of ketimines in the ProPhenol Mannich process, and the reaction offers a new approach for the preparation of pharmaceutically relevant products possessing trifluoromethylated tetrasubstituted alkylamines. The reaction can be performed on large scale with reduced catalyst loading without impacting its efficiency.

Controlling Regioselectivity in the Enantioselective N-Alkylation of Indole Analogues Catalyzed by Dinuclear Zinc-ProPhenol.

The enantioselective N-alkylation of indole and its derivatives with aldimines is efficiently catalyzed by a zinc-ProPhenol dinuclear complex under mild conditions to afford N-alkylated indole derivatives in good yield (up to 86 %) and excellent enantiomeric ratio (up to 99.5:0.5 e.

Efficient Access to Chiral Trisubstituted Aziridines via Catalytic Enantioselective Aza-Darzens Reactions.

Herein, we report a Zn-ProPhenol catalyzed aza-Darzens reaction using chlorinated aromatic ketones as nucleophilic partners for the efficient and enantioselective construction of complex trisubstituted aziridines. The α-chloro-β-aminoketone intermediates featuring a chlorinated tetrasubstituted stereocenter can be isolated in high yields and selectivities for further derivatization. Alternatively, they can be directly transformed to the corresponding aziridines in a one-pot fashion.

Direct Catalytic Asymmetric Mannich Reactions for the Construction of Quaternary Carbon Stereocenters.

Herein, we report a Zn-ProPhenol catalyzed Mannich reaction using α-branched ketones as nucleophilic partners for the direct enantio- and diastereoselective construction of quaternary carbon stereocenters. The reaction can be run on a gram-scale with a low catalyst loading without impacting its efficiency. Moreover, the Mannich adducts can be further elaborated with complete diastereocontrol to access molecules possessing complex stereotriads.

Broad Spectrum Enolate Equivalent for Catalytic Chemo-, Diastereo-, and Enantioselective Addition to N-Boc Imines.

Alkynyl ketones are attractive but challenging nucleophiles in enolate chemistry. Their susceptibility to other reactions such as Michael additions and the difficulty of controlling the enolate geometry make them difficult substrates. Mannich-type reactions, which previously have not been reported using N-carbamoyl-imines with simple ketone enolates, became our objective.

Catalytic Asymmetric Mannich Reactions with Fluorinated Aromatic Ketones: Efficient Access to Chiral β-Fluoroamines.

Reported herein is a Zn/Prophenol-catalyzed Mannich reaction using fluorinated aromatic ketones as nucleophilic partners for the direct enantio- and diastereoselective construction of β-fluoroamine motifs featuring a fluorinated tetrasubstituted carbon. The reaction can be run on a gram scale with a low catalyst loading without impacting its efficiency. Moreover, a related aldol reaction was also developed.

Development of Non-C2-symmetric ProPhenol Ligands. The Asymmetric Vinylation of N-Boc Imines.

The development and application of a new generation of non-C2-symmetric ProPhenol ligands is reported herein. Rational design of the ProPhenol ligand paved the way to the first catalytic and asymmetric vinylation of N-Boc imines via hydrozirconation giving rise to valuable allylic amines in excellent yields and enantioselectivities. The utility of this method was demonstrated by developing the shortest reported asymmetric synthesis of the selective serotonine reuptake inhibitor (SSRI) (-)-dapoxetine.