Chiral Atropisomeric-NHC Catechodithiolate Ruthenium Complexes for Z-Selective Asymmetric Ring-Opening Cross Metathesis of Exo-Norbornenes.

A set of 16 chiral ruthenium complexes containing atropisomerically stable N-Heterocyclic Carbene (NHC) ligands was synthesized from prochiral NHC precursors. After a rapid screening in asymmetric ring-opening-cross metathesis (AROCM), the most effective chiral atrop BIAN-NHC Ru-catalyst (up to 97 : 3 er) was then converted to a Z-selective catechodithiolate complex. The latter proved to be highly efficient in Z-selective AROCM of exo-norbornenes affording valuable trans-cyclopentanes with excellent Z-selectivity (>98 %) and high enantioselectivity (up to 96.5 : 3.5 er).

Continuous Flow Z-Stereoselective Olefin Metathesis: Development and Applications in the Synthesis of Pheromones and Macrocyclic Odorant Molecules*.

The first continuous flow Z-selective olefin metathesis process is reported. Key to realizing this process was the adequate choice of stereoselective catalysts combined with the design of an appropriate continuous reactor setup. The designed continuous process permits various self-, cross- and macro-ring-closing-metathesis reactions, delivering products in high selectivity and short residence times. This technique is exemplified by direct application to the preparation of a range of pheromones and macrocyclic odorant molecules and culminates in a telescoped Z-selective cross-metathesis/ Dieckmann cyclisation sequence to access (Z)-Civetone, incorporating a serial array of continually stirred tank reactors.

Hybrids of cationic [4]helicene and N-heterocyclic carbene as ligands for complexes exhibiting (chir)optical properties in the far red spectral window.

Synthesis, electronic and structural properties of a chiral NHC bearing a N-bonded cationic [4]helicene moiety are reported. This ligand is used to construct AuI, AuIII and RhI complexes exhibiting far-red (chir)optical properties regardless of the metal.

Optically Pure C1-Symmetric Cyclic(alkyl)(amino)carbene Ruthenium Complexes for Asymmetric Olefin Metathesis.

An expedient access to the first optically pure ruthenium complexes containing C1-symmetric cyclic (alkyl)(amino)carbene ligands is reported. They demonstrate excellent catalytic performances in asymmetric olefin metathesis with high enantioselectivities (up to 92% ee). Preliminary mechanistic insights provided by density functional theory models highlight the origin of the enantioselectivity.

Copper-catalyzed enantioselective conjugate addition of organometallic reagents to challenging Michael acceptors.

The copper-catalyzed enantioselective conjugate addition (ECA) of organometallic nucleophiles to electron-deficient alkenes (Michael acceptors) represents an efficient and attractive methodology for providing a wide range of relevant chiral molecules. In order to increase the attractiveness of this useful catalytic transformation, some Michael acceptors bearing challenging electron-deficient functions (i.e., aldehydes, thioesters, acylimidazoles, N-acyloxazolidinones, N-acylpyrrolidinones, amides, N-acylpyrroles) were recently investigated. Remarkably, only a few chiral copper-based catalytic systems have successfully achieved the conjugate addition of different organometallic reagents to these challenging Michael acceptors, with excellent regio- and enantioselectivity. Furthermore, thanks to their easy derivatization, the resulting chiral conjugated products could be converted into various natural products. The aim of this tutorial review is to summarize recent advances accomplished in this stimulating field.

From Prochiral N-Heterocyclic Carbenes to Optically Pure Metal Complexes: New Opportunities in Asymmetric Catalysis.

Well-defined optically pure transition metal (TM) complexes bearing C1- and C2-symmetric N-heterocyclic carbene (NHC) ligands were prepared from prochiral NHC precursors. As predicted by DFT calculations, our strategy capitalizes on the formation of a metal-carbene bond which induces an axis of chirality. Configurationally stable atropisomers of various NHC-containing TM complexes were isolated by preparative HPLC on a chiral stationary phase in good yields and excellent optical purities (up to 99.5% ee). The carbene transfer from an optically pure Cu complex to a gold or palladium center reveals, for the first time, a full stereoretentivity, supporting the hypothesis of an associative mechanism for the transmetalation. The potential of these new chiral TM complexes was illustrated in asymmetric catalysis with up to 98% ee.

The debut of chiral cyclic (alkyl)(amino)carbenes (CAACs) in enantioselective catalysis.

The popularity of NHCs in transition metal catalysis has prompted the development of chiral versions as electron-rich neutral stereodirecting ancillary ligands for enantioselective transformations. Herein we demonstrate that cyclic (alkyl)(amino)carbene (CAAC) ligands can also engage in asymmetric transformations, thereby expanding the toolbox of available chiral carbenes.

A kinetic resolution strategy for the synthesis of chiral octahedral NHC-iridium(iii) catalysts.

The transmetalation reaction of a chiral-bidentate NHC-silver complex to racemic [Ir(µ-Cl)(ppy)2]2 operates with kinetic resolution leading to chiral octahedral NHC-iridium(iii) complexes and enantio-enriched bis-cyclometalated iridium(iii) complexes. The iridium(iii) complexes demonstrated efficient catalytic activities in intermolecular [2+2] photocycloaddition reactions and in asymmetric Friedel-Crafts alkylations, respectively.

Copper-Catalyzed Asymmetric Conjugate Additions of Bis(pinacolato)diboron and Dimethylzinc to Acyl- N-methylimidazole Michael Acceptors: A Highly Stereoselective Unified Strategy for 1,3,5,... n (OH, Me) Motif Synthesis.

A unified strategy for the construction of prevalent 1,3,5,... n (OH, Me) motifs based on consecutive copper-catalyzed asymmetric conjugate borylation (ACB) and methylation (ACA) reactions involving α,ß-unsaturated 2-acyl- N-methylimidazoles is described. Good yields and high diastereoselectivities have been obtained in ACA and ACB reactions for both matched and mismatched pairs as illustrated in the synthesis of syn/ anti and anti/ anti (Me, OTBS, Me) and (OH, OTBS, Me) motifs.

Bleaching Earths as Powerful Additives for Ru-Catalyzed Self-Metathesis of Non-Refined Methyl Oleate at Pilot Scale.

A practical and cost-effective ruthenium-catalyzed self-metathesis of non-refined methyl oleate (85 %) derived from very high oleic sunflower oils was demonstrated at pilot scale using a robust and kg-scale commercially available SIPr-M71 pre-catalyst. The simple addition of 1 wt % bleaching earths (Tonsil 110FF) to a thermally pretreated oil could efficiently prevent catalyst deactivation. Remarkably, without the need for filtration, the catalytic system was able to achieve a turnover number (TON) of more than 744 000 at a catalyst loading of only 1 ppm. At large scale (up to 200 kg), the equilibrium of the self-metathesis reaction was reached within 1 hour at 50 °C under neat conditions at a very low 5 ppm catalyst loading to produce the expected primary metathesis products (PMP), that is, 9-octadecene and dimethyl-9-octadecenoate, with a productive TON of 94900.

Asymmetric Sequential Cu-Catalyzed 1,6/1,4-Conjugate Additions of Hard Nucleophiles to Cyclic Dienones: Determination of Absolute Configurations and Origins of Enantioselectivity.

The first stereocontrolled Cu-catalyzed sequential 1,6/1,4-asymmetric conjugate addition (ACA) of C-metalated hard nucleophiles to cyclic dienones is reported. The use of DiPPAM (diphenylphosphinoazomethinylate) followed by a phosphoramidite as the stereoinducing ligands facilitated both high ee values for the 1,6-ACA and high de values for the 1,4-ACA reaction components, which thus gave enantioenriched 1,3-dialkylated moieties. The absolute configurations were determined by using vibrational circular dichroism (VCD) and optical rotatory dispersion (ORD) spectroscopy, in combination with DFT calculations and X-ray analysis. Interestingly, DFT calculations for the mechanism of enantioselective 1,6-addition by using an unprecedented Cu-Zn bimetallic catalytic system confirmed this attribution. Lastly, exploring intramolecular cyclization avenues for enantioenriched 1,3-dialkylated products provided access to the challenging drimane skeleton.

Readily Accessible Unsymmetrical Unsaturated 2,6-Diisopropylphenyl N-Heterocyclic Carbene Ligands. Applications in Enantioselective Catalysis.

A new multicomponent procedure was applied to the synthesis of (a)chiral bulky unsymmetrical unsaturated 2,6-diisopropylphenyl N-heterocyclic carbene (NHC) precursors with excellent selectivity (up to 95%) and good yields. This approach offers access to new chiral NHC ligands, which have found successful applications in both copper-catalyzed asymmetric allylic alkylation and copper-catalyzed asymmetric borylation.

Copper-Catalyzed Asymmetric Conjugate Addition of Dimethylzinc to Acyl-N-methylimidazole Michael Acceptors: a Powerful Synthetic Platform.

An efficient copper-catalyzed enantioselective conjugate addition of dimethylzinc to α,ß- and α,ß,γ,δ-unsaturated 2-acyl-N-methylimidazoles has been achieved using a chiral bidentate hydroxyalkyl-NHC ligand. The reactions proceeded with both excellent regio- and enantioselectivity (14 examples, 87-95 % ee) to afford the desired 1,4-adducts, which were easily transformed to the corresponding aldehydes, esters, and ketones. Subsequently, this powerful methodology was therefore successfully applied in the synthesis of natural products. Furthermore, an iterative process was also disclosed leading to highly desirable 1,3-desoxypropionate skeletons (up to 94 % d.e.).

Multicomponent synthesis of chiral bidentate unsymmetrical unsaturated N-heterocyclic carbenes: copper-catalyzed asymmetric C-C bond formation.

A multicomponent strategy was applied to the synthesis of chiral bidentate unsaturated hydroxyalkyl- and carboxyalkyl-N-heterocyclic carbene (NHC) precursors. The newly developed low-cost chiral ligands derived from amino alcohols and amino acids were evaluated in copper-catalyzed asymmetric conjugated addition and asymmetric allylic alkylation, which afforded the desired tertiary and quaternary carbon stereocenters with excellent regio- and enantioselectivities (up to 99:1 e.r.).

Copper-catalyzed asymmetric conjugate addition of organometallic reagents to extended Michael acceptors.

The copper-catalyzed asymmetric conjugate addition (ACA) of nucleophiles onto polyenic Michael acceptors represents an attractive and powerful methodology for the synthesis of relevant chiral molecules, as it enables in a straightforward manner the sequential generation of two or more stereogenic centers. In the last decade, various chiral copper-based catalysts were evaluated in combination with different nucleophiles and Michael acceptors, and have unambiguously demonstrated their usefulness in the control of the regio- and enantioselectivity of the addition. The aim of this review is to report recent breakthroughs achieved in this challenging field.

Cationic bis-N-heterocyclic carbene (NHC) ruthenium complex: structure and application as latent catalyst in olefin metathesis.

An unexpected cationic bis-N-heterocyclic carbene (NHC) benzylidene ether based ruthenium complex (2 a) was prepared through the double incorporation of an unsymmetrical unsaturated N-heterocyclic carbene (U2 -NHC) ligand that bore an N-substituted cyclododecyl side chain. The isolation and full characterization (including X-ray diffraction studies) of key synthetic intermediates along with theoretical calculations allowed us to understand the mechanism of the overall cationization process. Finally, the newly developed complex 2 a displayed interesting latent behavior during ring-closing metathesis, which could be "switched on" under acidic conditions.

Biopolymer-supported ionic-liquid-phase ruthenium catalysts for olefin metathesis.

Original ruthenium supported ionic liquid phase (SILP) catalysts based on alginates as supports were developed for olefin metathesis reactions. The marine biopolymer, which fulfills most of the requisite properties for a support such as widespread abundance, insolubility in the majority of organic solvents, a high affinity for ionic liquids, high chemical stability, biodegradability, low cost, and easy processing, was impregnated by [bmim][PF6 ] containing an ionically tagged ruthenium catalyst. These biosourced catalysts show promising performances in ring-closing metathesis (RCM) and cross-metathesis (CM) reactions, with a high level of recyclability and reusability combined with a good reactivity.

Multicomponent synthesis of unsymmetrical unsaturated N-heterocyclic carbene precursors and their related transition-metal complexes.

A low-cost, modular, and easily scalable multicomponent procedure affording access in good yields and excellent selectivity (up to 93%) to a wide range of (a)chiral unsymmetrical 1-aryl-3-cycloalkyl-imidazolium salts is disclosed. Electronic and steric properties of the corresponding unsymmetrical unsaturated N-heterocyclic carbene (U2-NHC) ligands were evaluated and evidenced strong electron donor ability, high steric discrimination, and modular steric demand.

Enantioselective 1,6-conjugate addition of dialkylzinc reagents to acyclic dienones catalyzed by Cu-DiPPAM complex-extension to asymmetric sequential 1,6/1,4-conjugate addition.

CC coupling: DiPPAM 1 and BINAP 2 ligands led to divergent behaviors in the asymmetric conjugate addition (ACA) of dialkylzinc reagents to linear aryldienones, which were applied to the development of a highly selective sequential asymmetric 1,6/1,4-ACA process (see scheme; Tf = triflate, DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene).