Enantioselective Hydrophosphination of Terminal Alkenyl Aza-Heteroarenes.

This paper presents a Mn(I)-catalysed methodology for the enantioselective hydrophosphination of terminal alkenyl aza-heteroarenes. The catalyst operates through H-P bond activation, enabling successful hydrophosphination of a diverse range of alkenyl-heteroarenes with high enantioselectivity. The presented protocol addresses the inherently low reactivity and the commonly encountered suboptimal enantioselectivities of these challenging substrates. As an important application we show that this method facilitates the synthesis of a non-symmetric tridentate P,N,P-containing ligand like structure in just two synthetic steps using a single catalytic system.

Manganese(I)-Catalyzed H-P Bond Activation via Metal-Ligand Cooperation.

Here we report that chiral Mn(I) complexes are capable of H-P bond activation. This activation mode enables a general method for the hydrophosphination of internal and terminal α,ß-unsaturated nitriles. Metal-ligand cooperation, a strategy previously not considered for catalytic H-P bond activation, is at the base of the mechanistic action of the Mn(I)-based catalyst. Our computational studies support a stepwise mechanism for the hydrophosphination and provide insight into the origin of the enantioselectivity.

Nucleophilic Dearomatization of N-Heteroaromatics Enabled by Lewis Acids and Copper Catalysis.

Dearomative functionalization of heteroaromatics, a readily available chemical feedstock, is one of the most straightforward approaches for the synthesis of three-dimensional, chiral heterocyclic systems, important synthetic building blocks for both synthetic chemistry and drug discovery. Despite significant efforts, direct nucleophilic additions to heteroaromatics have remained challenging because of the low reactivity of aromatic substrates associated with the loss of aromaticity, as well the regio- and stereoselectivities of the reaction. Here we present a catalytic system that leads to unprecedented, high-yielding dearomative C-4 functionalization of quinolines with organometallics with nearly absolute regio- and stereoselectivities and with a catalyst turnover number (TON) as high as 1000. The synergistic action of the chiral copper catalyst, Lewis acid, and Grignard reagents allows us to overcome the energetic barrier of the dearomatization process and leads to chiral products with selectivities reaching 99% in most cases. Molecular modeling provides important insights into the speciation and the origin of the regio- and enantioselectivity of the catalytic process. The results reveal that the role of the Lewis acid is not only to activate the substrate toward a potential nucleophilic addition but also to subtly control the regiochemistry by preventing the C-2 addition from happening.

Copper-Catalyzed Addition of Grignard Reagents to in situ Generated Indole-Derived Vinylogous Imines.

Chiral indole derivatives are ubiquitous motifs in pharmaceuticals and alkaloids. Herein, the first protocol for catalytic asymmetric conjugate addition of Grignard reagents to various sulfonyl indoles, offering a straightforward approach for the synthesis of chiral 3-sec-alkyl-substituted indoles in high yields and enantiomeric ratios is presented. This methodology makes use of a chiral catalyst based on copper phosphoramidite complexes and in situ formation of vinylogous imine intermediates.

Enantioselective Cascade Reaction for Synthesis of Quinolinones through Synergistic Catalysis Using Cu-Pybox and Chiral Benzotetramisole as Catalysts.

In contrast to the well-studied asymmetric catalyzed synthesis of tetrahydroquinolines, the asymmetric methodologies toward 3,4-dihydroquinolin-2-ones are quite rare. Herein, the first asymmetric cascade reaction is reported between ethynyl benzoxazinanones and mixed-anhydrides generated from aryl acetic acids and pivaloyl chloride, based on synergistic catalysis. This allowed the formation of attractive 3,4-dihydroquinolin-2-ones bearing two vicinal chiral centers at C3 and C4 in high yields with excellent diastereo- and enantioselectivities. A plausible chiral induction model for this reaction was proposed. The utility of this methodology was exemplified by further elaboration of the cyclization products by removal of the N-protecting groups.

Amide-Phosphonium Salt as Bifunctional Phase Transfer Catalyst for Asymmetric 1,6-Addition of Malonate Esters to para-Quinone Methides.

Asymmetric 1,6-addition of malonates to para-quinone methides has been developed by using amide-phosphonium salts derived from easily available chiral α-amino acids as bifunctional phase transfer catalysts. Stabilized para-quinone methides with various substituents on the phenyl ring were reacted with diphenyl malonates to give functionalized diaryl methines in excellent yields and high to excellent ee's. Furthermore, to show the utility of this methodology, a gram scale synthesis of an 1,6-addition adduct and its further elaboration into the key intermediate for synthesis of GPR40 agonists were also described.

Enantio- and Z-selective synthesis of functionalized alkenes bearing tertiary allylic stereogenic center.

Olefins are ubiquitous in biologically active molecules and frequently used as building blocks in chemical transformations. However, although many strategies exist for the synthesis of stereodefined E-olefines, their thermodynamically less stable Z counterparts are substantially more demanding, while access to those bearing an allylic stereocenter with an adjacent reactive functionality remains unsolved altogether. Even the classic Wittig reaction, arguably the most versatile and widely used approach to construct Z-alkenes, falls short for the synthesis of these particularly challenging yet highly useful structural motives. Here, we report a general methodology for Z-selective synthesis of functionalized chiral alkenes that establishes readily available alkene-derived phosphines as an alternative to alkylating reagents in Wittig olefination, thus offering previously unidentified retrosynthetic disconnections for the formation of functionalized disubstituted alkenes. We demonstrate the potential of this method by structural diversification of several bioactive molecules.

Manganese(I)-Catalyzed Asymmetric Hydrophosphination of α,ß-Unsaturated Carbonyl Derivatives.

Here we report catalytic asymmetric hydrophosphination of α,ß-unsaturated carbonyl derivatives using a chiral Mn(I) complex as a catalyst. Through H-P bond activation, various phosphine-containing chiral products can be accessed via hydrophosphination of various ketone-, ester-, and carboxamide-based Michael acceptors.

Manganese(i)-catalyzed access to 1,2-bisphosphine ligands.

Chiral bisphosphine ligands are of key importance in transition-metal-catalyzed asymmetric synthesis of optically active products. However, the transition metals typically used are scarce and expensive noble metals, while the synthetic routes to access chiral phosphine ligands are cumbersome and lengthy. To make homogeneous catalysis more sustainable, progress must be made on both fronts. Herein, we present the first catalytic asymmetric hydrophosphination of α,ß-unsaturated phosphine oxides in the presence of a chiral complex of earth-abundant manganese(i). This catalytic system offers a short two-step, one-pot synthetic sequence to easily accessible and structurally tunable chiral 1,2-bisphosphines in high yields and enantiomeric excess. The resulting bidentate phosphine ligands were successfully used in asymmetric catalysis as part of earth-abundant metal based organometallic catalysts.

Catalytic Access to 4-(sec-Alkyl)Anilines via 1,6-Conjugate Addition of Grignard Reagents to in Situ Generated aza-p-Quinone Methides.

The synthesis of aniline derivatives, common building blocks in many pharmaceuticals, agrochemicals, dyes or polymers, has been limited to reactions based on benzene-toluene-xylene derivatives (BTX) due to their ample availability. Despite the large number of existing methodologies, the synthesis of chiral 4-(sec-alkyl)anilines has not been accomplished so far. In this work, a tandem strategy based on the generation of a reactive aza-p-quinone methide (aza-p-QM) intermediate followed by Cu(I)-catalyzed addition of Grignard reagents has been developed.

Trialkyl Methanetricarboxylate as Dialkyl Malonate Surrogate in Copper-Catalyzed Enantioselective Propargylic Substitution.

The first copper-catalyzed enantioselective propargylation of trialkyl methantricarboxylate with propargylic alcohol derivatives was developed. The tricarboxylate unit in the obtained adducts could be easily transformed into a malonate moiety by treating with in situ generated NaOEt in excellent yield without racemization.

[Changes of lens capsule after phacoemulsification].

OBJECTIVE: To observe the changes in the lens capsule after phacoemulsification and its effects on the position of intraocular lens (IOL) and to demonstrate the best position of IOL in relation to the anterior capsule. METHODS: The present series comprised 141 eyes in 127 patients underwent phacoemulsification and foldable lens implantation with 5 mm continuous curvilinear capsulorhexis. The changes in the lens capsule and the position of IOL with dilated pupil were observed using slit lamp microscope 3 months after the operation. RESULTS: Capsular bag shrinkage and white Soemmering ring along the margin of capsulorhexis were observed in all cases. Three different kinds of relationship between anterior capsule opening and the IOL optic surface were found, including the non-capture (68 eyes), partial-capture (52 eyes) and total-capture (21 eyes) relationships. The incidence of central posterior capsule opacification (PCO) was significantly higher in the total-capture group (47.6%) than that in the non-capture (11.7%) and partial-capture (21.2%) groups (P < 0.01). IOL in well centered position was significantly higher in the non-capture (91.2%) and total-capture (81.0%) groups than that in the partial-capture group (42.3%) (P < 0.01). CONCLUSION: In the present study, various changes in the lens capsule were observed after phacoemulsification and foldable lens implantation. It is suggested that keeping the IOL in a non-capture position is a key point to avoid the occurrence of PCO and IOL decentration.