PPM Ir-f-phamidol-Catalyzed Asymmetric Hydrogenation of γ-Amino Ketones Followed by Stereoselective Cyclization for Construction of Chiral 2-Aryl-pyrrolidine Pharmacophores.

Transition metal catalysts with a million turnovers and excellent selectivity are rarely reported but are crucial for the industrial manufacture of optical pure pharmaceuticals, natural products, and fine chemicals. In this paper, we report an unprecedented aninoic Ir-f-phamidol catalyst for asymmetric hydrogenation of γ-amino ketones followed by stereoselective cyclization for construction of valuable chiral 2-aryl-pyrrolidine pharmacophores. The Ir-f-phamidol catalyst showed up to 1,000,000 TON and >99% ee, as well as excellent tolerance of substrates and protecting groups, providing various chiral amino alcohol intermediates. Upon optimization of the conditions, the stereoselective cyclization reaction was highly smooth and efficient (quantitative conversions, 92 to >99% ee). Finally, this solution was applied in the preparation of high-value chiral entities containing such chiral 2-aryl-pyrrolidine pharmacophores.

Ru-Catalyzed Asymmetric Reductive Amination of Aryl-Trifluoromethyl Ketones for Synthesis of Primary α-(Trifluoromethyl)arylmethylamines.

The ruthenium-catalyzed asymmetric reductive amination of aryl-trifluoromethyl ketones affording high value primary α-(trifluoromethyl)arylmethylamines using cheap NH4OAc as the nitrogen source and H2 as the reductant is reported. This user-friendly and simple catalytic method tolerates various aromatic functions with electron-withdrawing or -donating substituents at the para- or meta-positions and as well challenging heteroaromatic functions, yielding primary α-(trifluoromethyl)arylmethylamines with excellent chemoselectivities, enantioselectivities, and useful yields (80-97% ee, 51-92% isolated yields). Finally, scalable and concise synthesis of key drug intermediates using this methodology is presented.

A 13-million turnover-number anionic Ir-catalyst for a selective industrial route to chiral nicotine.

Developing catalysts with both useful enantioselectivities and million turnover numbers (TONs) for asymmetric hydrogenation of ketones is attractive for industrial production of high-value bioactive chiral entities but remains a challenging. Herein, we report an ultra-efficient anionic Ir-catalyst integrated with the concept of multidentate ligation for asymmetric hydrogenation of ketones. Biocatalysis-like efficacy of up to 99% ee (enantiomeric excess), 13,425,000 TON (turnover number) and 224 s-1 TOF (turnover frequency) were documented for benchmark acetophenone. Up to 1,000,000 TON and 99% ee were achieved for challenging pyridyl alkyl ketone where at most 10,000 TONs are previously reported. The anionic Ir-catalyst showed a novel preferred ONa/MH instead of NNa/MH bifunctional mechanism. A selective industrial route to enantiopure nicotine has been established using this anionic Ir-catalyst for the key asymmetric hydrogenation step at 500 kg batch scale, providing 40 tons scale of product.

Concise Synthesis of Chiral Tricyclic Lactams by Tandem Dynamic Kinetic Asymmetric Reductive Amination/Lactamization Using Ammonium Salts.

The atom- and step-efficient synthesis of chiral fused tricyclic lactams from readily available ketoesters using cheap ammonium salts as the nitrogen source is reported. This ruthenium-catalyzed system operates through an efficient tandem dynamic kinetic asymmetric reductive amination (ARA)/lactamization and produces chiral fused tricyclic lactams in high yields with excellent diastereo- and enantioselectivity (up to >99 % ee, >20 : 1 dr and 98 % yield). The robust method was also applied to the concise synthesis of key intermediates in the synthesis of rivastigmine analogues and chiral N-heterocyclic carbene catalysts.

Integration of Milstein Ru-PNN and Rh-Tribi/Tetrabi for Isomerization Linear Selective Hydroformylation of Far Internal Alkenes.

Converting cheap and abundant internal alkenes to value-added linear aldehydes is of great importance but not an addressed issue. In this paper, an integration of a Milstein-type Ru-PNN catalyst and our Rh-Tribi/Tetrabi catalyst was first demonstrated in highly improved isomerization linear selective hydroformylation of 2-, 3-, and 4-alkenes, yielding excellent linear selectivities and activities (linear selectivity improvements of 2.2-58%, up to 94.2-98.6%, and turnover numbers improvements of 61-335 TON, up to 385-851) compared to the Ru-PNN/Rh-Bisbi system.

Rhodium-Catalyzed Chemo-, Regio- and Enantioselective Hydroformylation of Cyclopropyl-Functionalized Trisubstituted Alkenes.

The first rhodium-catalyzed highly chemo-, regio- and enantioselective hydroformylation of cyclopropyl-functionalized trisubstituted alkenes affording useful chiral cyclopropyl entities is reported. Compared to generally used diphosphine ligands for asymmetric catalysis, the modified hybrid phosphorus ligand, named (R,S)-DTBM-Yanphos, can convert a series of readily available cyclopropyl-functionalized trisubstituted alkenes into high-value chiral cyclopropyl-functionalized aldehydes with high selectivities (81-98 % ee). Gram-scale reactions (TON up to 1500) and follow-up transformations to the corresponding alcohol, acid, esters and nitrile are also presented. Finally, a possible hydroformylation mechanism involving ring-open-hydroformylation pathways is proposed based on control and deuteroformylation reactions.

Lignin-First Monomers to Catechol: Rational Cleavage of C-O and C-C Bonds over Zeolites.

A catalytic route is developed to synthesize bio-renewable catechol from softwood-derived lignin-first monomers. This process concept consists of two steps: 1) O-demethylation of 4-n-propylguaiacol (4-PG) over acidic beta zeolites in hot pressurized liquid water delivering 4-n-propylcatechol (4-PC); 2) gas-phase C-dealkylation of 4-PC providing catechol and propylene over acidic ZSM-5 zeolites in the presence of water. With large pore sized beta-19 zeolite as catalyst, 4-PC is formed with more than 93 % selectivity at nearly full conversion of 4-PG. The acid-catalyzed C-dealkylation over ZSM-5 zeolite with medium pore size gives a catechol yield of 75 %. Overall, around 70 % catechol yield is obtained from pure 4-PG, or 56 % when starting from crude 4-PG monomers obtained from softwood by lignin-first RCF biorefinery. The selective cleavage of functional groups from biobased platform molecules through a green and sustainable process highlights the potential to shift feedstock from fossil oil to biomass, providing drop ins for the chemicals industry.

Homogeneous and heterogeneous catalysts for hydrogenation of CO2 to methanol under mild conditions.

In the context of a carbon neutral economy, catalytic CO2 hydrogenation to methanol is one crucial technology for CO2 mitigation providing solutions for manufacturing future fuels, chemicals, and materials. However, most of the presently known catalyst systems are used at temperatures over 220 °C, which limits the theoretical yield of methanol production due to the exothermic nature of this transformation. In this review, we summarize state-of-the-art catalysts, focusing on the rationales behind, for CO2 hydrogenation to methanol at temperatures lower than 170 °C. Both hydrogenation with homogeneous and heterogeneous catalysts is covered. Typically, additives (alcohols, amines or aminoalcohols) are used to transform CO2 into intermediates, which can further be reduced into methanol. In the first part, molecular catalysts are discussed, organized into: (1) monofunctional, (2) M/NH bifunctional, and (3) aromatization-dearomatization bifunctional molecular catalysts. In the second part, heterogeneous catalysts are elaborated, organized into: (1) metal/metal or metal/support, (2) active-site/N or active-site/OH bifunctional heterogeneous catalysts, and (3) cooperation of catalysts and additives in a tandem process via crucial intermediates. Although many insights have been gained in this transformation, in particular for molecular catalysts, the mechanisms in the presence of heterogeneous catalysts remain descriptive and insights unclear.

Effector enhanced enantioselective hydroformylation.

In this communication, we report rhodium DIMPhos complexes with an integrated DIM-receptor that can bind carboxylate containing effectors and their application in the rhodium catalyzed hydroformylation reaction. The binding of chiral effectors in non-chiral [Rh(DIMPhos)] catalysts does not lead to enantioselective hydroformylation, but the binding of either achiral or chiral effectors can significantly enhance the enantioselectivity induced by the chiral Rh-metal complexes. For example, the supramolecular complex [Rh]/[1S⊂L3] displays high regio- and enantioselectivity in the hydroformylation of vinyl acetate (72% ee, and b/l >99), whereas in absence of this effector the ee is around 17%.

Effector responsive hydroformylation catalysis.

Herein, we report a supramolecular rhodium complex that can form dimeric or monomeric Rh-species catalytically active in hydroformylation, depending on the binding of effectors within the integrated DIM-receptor. X-ray crystal structures, in situ (high-pressure (HP)) spectroscopy studies, and molecular modelling studies show that in the absence of effectors, the preferred Rh-species formed is the dimer, of which two ligands coordinate to two rhodium metals. Importantly, upon binding guest molecules, -effectors-, to the DIM-receptor under hydroformylation conditions, the monomeric Rh-active species is formed, as evidenced by a combination of in situ HP NMR and IR spectroscopy studies and molecular modelling. As the monomeric complex has different catalytic properties from the dimeric complex, we effectively generate a catalytic system of which the properties respond to the presence of effectors, reminiscent of how the properties of proteins are regulated in nature. Indeed, catalytic and kinetic experiments show that both the selectivity and activity of this supramolecular catalytic system can be influenced in the hydroformylation of 1-octene using acetate as an effector that shift the equilibrium from the dimeric to monomeric species.

Hydrogen Bond Directed ortho-Selective C-H Borylation of Secondary Aromatic Amides.

Reported is an iridium catalyst for ortho-selective C-H borylation of challenging secondary aromatic amide substrates, and the regioselectivity is controlled by hydrogen-bond interactions. The BAIPy-Ir catalyst forms three hydrogen bonds with the substrate during the crucial activation step, and allows ortho-C-H borylation with high selectivity. The catalyst displays unprecedented ortho selectivities for a wide variety of substrates that differ in electronic and steric properties, and the catalyst tolerates various functional groups. The regioselective C-H borylation catalyst is readily accessible and converts substrates on gram scale with high selectivity and conversion.