Mechanistically Guided One Pot Synthesis of Phosphine‐Phosphite and Its Implication in Asymmetric Hydrogenation

Seo C.S., Morris R.H.

This is an overview of successes in the realm of catalytic homogeneous asymmetric hydrogenation of substrates primarily of interest in the synthesis of pharmaceuticals in order to identify importan...

Mote N.R., Chikkali S.H.

The process of catalyst screening and discovery still largely relies on traditional ligand-design approaches, which suffer from complex synthetic requirements and offer limited structural diversity. On the contrary, supramolecular chemistry offers the potential to harness multiple weak secondary interactions to deliver self-assembled catalysts with diverse structures or to orient substrates to achieve enzyme-like activity and selectivity. Herein, the application of hydrogen-bonding (H-bonding) interactions as a construction element and directing group in "supramolecular transition-metal catalysis" is critically reviewed and the current state-of-the-art in the field is presented. H-bonding interactions empower structurally simple ligands to deliver complex self-assembled catalysts, which have been found to catalyze a gamut of organic transformations, including hydroformylation, hydrogenation, and allylation reactions. As we will discuss, on many occasions, these supramolecular catalysts outperform their analogous covalently linked catalytic systems. The potential of H-bonding interactions as directing groups has recently been recognized by the scientific community and this Focus Review presents the role of hydrogen-bonding interactions in directing substrates to obtain excellent selectivities and activities in a range of catalytic transformations.

Renom-Carrasco M., Lefort L.

To accelerate the discovery of new or improved homogeneous catalysts, research groups in industry and academia have embraced high throughput experimentation (HTE). Such methodologies consist of preparing and testing large numbers of catalysts in parallel. Homogeneous metal catalysts are very well-suited for HTE, since in many cases, they can be prepared by simply mixing a metal precursor and a ligand. However, an HTE program requires a large set of chemically diverse ligands, i.e. a ligand library. In this review, we describe five different approaches for assembling ligand libraries based on an extensive survey of the literature. These approaches are based on commercial ligands, modular ligands, mixtures of ligands, supramolecular ligands or ligands prepared via the tools of biochemistry.

Xie X., Lu B., Li W., Zhang Z.

Chiral secondary alcohols are ubiquitous motifs in numerous natural products, pharmaceuticals, and biological active compounds. Catalytic asymmetric hydrogenation of multi-functionalized ketones provides an effective and powerful synthesis method to construct chiral secondary alcohols. In the asymmetric hydrogenation of multi-functionalized ketones, the simultaneous coordination of the carbonyl oxygen of ketones and adjacent functional groups to central metal of the catalyst is the key factor for the asymmetric induction. However, for ketones with two adjacent coordinating groups, the competitive ligation of the adjacent coordinating groups to central metal tends to decrease the enantioselectivities. In this review, we summarized the know how in achieving high chemo-, enantio-, and diastereoselectivities in asymmetric hydrogenation of multi-functionalized ketones, i.e. to change the bulkiness and/or electronic properties of the coordinating groups in substrates and in ligands, or to introduce a third coordinating ligand (solvent) to make one coordination much more stronger than the other.

Adams G.M., Weller A.S.

Hemilabile ligands – ligands containing two or more potential donors to a metal centre, of which one or more can dissociate – have the ability to provide a transition metal complex with open coordination sites at which reactivity can occur, or stabilise low coordinate intermediates along reaction pathways. POP-type ligands and in particular POP, Xantphos, DBFphos and DPEphos-based ligands contain three possible binding sites: two phosphines and an ether linker, thus have the potential to show κ1-, κ2- or κ3-binding modes. This review summarises the examples where POP-type ligands display hemilabile, or closely related variable coordination, characteristics in either synthesis or catalysis.

Meemken F., Baiker A.

The ease of separation, simple regeneration, and the usually high stability of solid catalysts facilitating continuous production processes have stimulated the development of heterogeneous asymmetric hydrogenation catalysis. The simplest and so far most promising strategy to induce enantioselectivity to solid metal catalysts is their modification by chiral organic compounds, as most prominently represented by the cinchona-modified Pt and Pd catalysts for the asymmetric hydrogenation of activated C═O and C═C bonds. In this Review, we provide a systematic account of the research accomplished in the past decade on noble metal-based heterogeneous asymmetric hydrogenation of prochiral C═O and C═C bonds, including all important facets of these catalytic systems. The advances made are critically analyzed, and future research challenges are identified.

Kraft S., Ryan K., Kargbo R.B.

The asymmetric hydrogenation of tetrasubstituted olefins provides direct access to very useful biological molecules and intermediates. The development of the technology has been slow, due in part to the synthetic challenges involved in developing chiral catalysts for a successful asymmetric induction. We briefly recount the breakthroughs in functionalized and unfunctionalized tetrasubstituted olefins, from the reports of Zhou and Buchwald for functionalized and unfunctionalized substrates, respectively, to the advent of chiral phosphoramidite ligands. The main emphasis of this Perspective lies in bringing into focus the complexity and challenges of inducing an asymmetric reduction for these substrates, which includes a brief discussion of the mechanism, the latest developed chiral catalysts, and the enormous scientific opportunities that still exist in developing "go to" catalyst systems for the various substrate types.

Margarita C., Andersson P.G.

The catalytic enantioselective hydrogenation of prochiral olefins is a key reaction in asymmetric synthesis. Its relevance applies to both industry and academia as an inherently direct and sustainable strategy to induce chirality. Here we briefly recount the early breakthroughs concerning the asymmetric hydrogenation of largely unfunctionalized olefins, from the first reports to the advent of chiral Crabtree-like catalysts. The mechanism and its implications on the enantioselectivity are shortly discussed. The main focus of this Perspective lies on the more recent advances in the field, such as the latest developed classes of ligands and the opportunity to employ more Earth-abundant metals. Therefore, separate sections consider iridium N,P-, NHC-, P,S-, and O,P-catalysts, and rhodium, palladium, cobalt, and iron catalysts. Finally, the remaining unsolved challenges are examined, and the potential directions of forthcoming research are outlined.

Pàmies O., Magre M., Diéguez M.

Asymmetric hydrogenation is one of the most efficient and atom-economical tools to prepare chiral molecules. However, the enantiodiscrimination of simple, minimally functionalized olefins is still challenging and requires more sophisticated ligand design. Herein, we discuss our progress in the successful development of ligand design for the iridium-catalyzed asymmetric hydrogenation of minimally functionalized olefins.

Beliaev A.

The asymmetric hydrogenation of methyl (6,8-difluoro-2H-chromen-3-yl)carbamate is a key step in the manufacturing route to etamicastat. A development of this step including the ruthenium or rhodium catalyst screening and the influence of the catalyst preparation (isolated, preformed in solution or in situ), solvent, temperature, pressure, additive, and concentration on the performance of the given ligand was discussed. Scale-up experiments for the best catalysts under optimized conditions were described.

Chirik P.J.

The hydrogenation of alkenes is one of the most impactful reactions catalyzed by homogeneous transition metal complexes finding application in the pharmaceutical, agrochemical, and commodity chemical industries. For decades, catalyst technology has relied on precious metal catalysts supported by strong field ligands to enable highly predictable two-electron redox chemistry that constitutes key bond breaking and forming steps during turnover. Alternative catalysts based on earth abundant transition metals such as iron and cobalt not only offer potential environmental and economic advantages but also provide an opportunity to explore catalysis in a new chemical space. The kinetically and thermodynamically accessible oxidation and spin states may enable new mechanistic pathways, unique substrate scope, or altogether new reactivity. This Account describes my group's efforts over the past decade to develop iron and cobalt catalysts for alkene hydrogenation. Particular emphasis is devoted to the interplay of the electronic structure of the base metal compounds and their catalytic performance. First generation, aryl-substituted pyridine(diimine) iron dinitrogen catalysts exhibited high turnover frequencies at low catalyst loadings and hydrogen pressures for the hydrogenation of unactivated terminal and disubstituted alkenes. Exploration of structure-reactivity relationships established smaller aryl substituents and more electron donating ligands resulted in improved performance. Second generation iron and cobalt catalysts where the imine donors were replaced by N-heterocyclic carbenes resulted in dramatically improved activity and enabled hydrogenation of more challenging unactivated, tri- and tetrasubstituted alkenes. Optimized cobalt catalysts have been discovered that are among the most active homogeneous hydrogenation catalysts known. Synthesis of enantiopure, C1 symmetric pyridine(diimine) cobalt complexes have enabled rare examples of highly enantioselective hydrogenation of a family of substituted styrene derivatives. Because improved hydrogenation performance was observed with more electron rich supporting ligands, phosphine cobalt(II) dialkyl complexes were synthesized and found to be active for the diastereoselective hydrogenation of various substituted alkenes. Notably, this class of catalysts was activated by hydroxyl functionality, representing a significant advance in the functional group tolerance of base metal hydrogenation catalysts. Through collaboration with Merck, enantioselective variants of these catalysts were discovered by high throughput experimentation. Catalysts for the hydrogenation of functionalized and essentially unfunctionalized alkenes have been discovered using this approach. Development of reliable, readily accessible cobalt precursors facilitated catalyst discovery and may, along with lessons learned from electronic structure studies, provide fundamental design principles for catalysis with earth abundant transition metals beyond alkene hydrogenation.

Louise Hazeland E., Chapman A.M., Pringle P.G., Sparkes H.A.

A chlorosilane elimination reaction has been developed that allows the efficient synthesis of optically pure C1-symmetric, C1-backboned diphosphines with a wide variety of stereoelectronic characteristics.

de Vries J.G.

A personal account is given of a selection of the research projects the author has been involved in over the past 25 years, aimed at developing production processes for fine chemicals and bulk chemicals using homogeneous catalysis. The focus in fine chemicals has been on asymmetric hydrogenation using monodentate phosphoramidites (MonoPhos), palladium-catalysed C–C bond formation (“homeopathic palladium”), copper-catalysed amination, nanocatalysis and combinations of enzymes and homogeneous catalysis. Rhodium-catalysed isomerising hydroformylation was developed for a new process for caprolactam based on butadiene and palladium-catalysed methoxycarbonylation was used in a new adipic acid process based on levulinic acid. The use of high throughput experimentation has been crucial in a large part of this research. Collaborations with universities, in particular with the University of Groningen has also played a major role.

Lao J.R., Benet-Buchholz J., Vidal-Ferran A.

A new series of narrow-bite-angle phosphine–phosphite (1,1-P–OP) ligands (3a–d) has been efficiently prepared from the enantiopure (SP)-tert-butyl(hydroxymethyl)methylphosphino borane complex 1, a crucial intermediate. The catalytic performance of the ligands in Rh-mediated asymmetric hydrogenations and hydroformylations is described. The corresponding rhodium complexes provided excellent efficiencies (full conversion in all cases) and high enantioselectivities (up to 98% ee) for the asymmetric hydrogenation of structurally diverse functionalized alkenes. Furthermore, rhodium catalysts derived from these 1,1-P–OP ligands were highly active and gave excellent regioselectivities (branched/linear product ratios of up to 97/3) and moderate enantioselectivities in the hydroformylation of different terminal olefins.

Fernández I., Bickelhaupt F.M.

In this Tutorial Review, we make the point that a true understanding of trends in reactivity (as opposed to measuring or simply computing them) requires a causal reactivity model.

Gavrilov K.N., Chuchelkin I.V., Gavrilov V.K., Firsin I.D., Trunina V.M., Shiryaev A.A., Shkirdova A.O., Bermesheva E.V., Tafeenko V.A., Chernyshev V.V., Zimarev V.S., Goulioukina N.S.

Diamidophosphite-thioethers with terpenoid bridging moieties have been prepared and used in asymmetric transition-metal catalysis for the first time.

Kumar R., Sen A., Chikkali S.H.

Easily accessible BINOL-based monodentate phosphite ligand L1 and hybrid ligand L2 have been synthesized in good yield by following a one-pot, two-step protocol. A single 31P resonance at 146.6 ppm confirmed the formation of L1. Subsequent 1-2D NMR and mass spectrometric analysis authenticated the existence of L1. These ligands afforded excellent activity and regio-selectivity in the Rh-catalyzed AHF of styrenic substrates. L1 showed excellent regioselectivity but did not discriminate between the two enantiomers, while L2 displayed an enantiomeric excess (ee) of up to 20%. In our attempts to understand the reasons for low ee, the coordination behavior of L2 was investigated. The coordination study revealed that L2 coordinates with the Rh as a monodentate ligand, although there are two P-sites. It was found that only the phosphine arm was coordinated to the Rh and the phosphite arm stayed away from the Rh core at the ambient temperature, leading to moderate ee. One-step synthesis of a phosphite (L1) and a phosphine-phosphite (L2) ligand and their implication in the asymmetric hydroformylation of olefins with excellent regioselectivity (>95%) and moderate enantioselectivity (up to 20%) is reported.

Gavrilov K.N., Chuchelkin I.V., Gavrilov V.K., Zheglov S.V., Firsin I.D., Trunina V.M., Borisova N.E., Bityak Y.P., Maloshitskaya O.A., Tafeenko V.A., Zimarev V.S., Goulioukina N.S.

A series of structurally diverse diamidophosphite-sulfides were synthesized from 1,2-thioether alcohols. With respect to Pd(II), these hemilabile ligands showed the ability to form both P,S-chelates and complexes with two ligands connected to the metal P-monodentately. The structures of the ligands and complexes were confirmed by two-dimensional (2D) NMR spectroscopy and single-crystal X-ray diffraction. These stereoselectors provided up to 98% ee in the Pd-catalyzed asymmetric allylic substitution of (E)-1,3-diphenylallyl acetate with C- and N-nucleophiles and up to 78% ee in the Pd-mediated allylic alkylation of cinnamyl acetate with β-ketoesters. Furthermore, up to 71% ee was achieved in the rare reaction between 2-(diethoxyphosphoryl)-1-phenylallyl acetate and aniline. The effects of the structural parameters, reaction conditions, and ligand-to-metal ratio on the catalytic results are discussed. Due to the ability of the ligands to form structurally different catalytic species, a pronounced dependence of the asymmetric induction on the ligand-to-metal ratio is shown.

Li J., Li J., Cui Y., Wang M., Feng J., Yao P., Wu Q., Zhu D.

Chiral dimethyl 2-methylsuccinate (1) is a very important building block for the manufacturing of many active pharmaceutical ingredients and fine chemicals. The asymmetric reduction of C=C double bond of dimethyl citraconate (2), dimethyl mesaconate (3) or dimethyl itaconate (4) by ene-reductases (ERs) represents an attractive straightforward approach, but lack of high-performance ERs, especially (S)-selective ones, has limited implementing this method to prepare the optically pure dimethyl 2-methylsuccinate. Herein, three ERs (Bac-OYE1 from Bacillus sp., SeER from Saccharomyces eubayanus and AfER from Aspergillus flavus) with high substrate tolerance and stereoselectivity towards 2, 3 and 4 have been identified. Up to 500 mM of 3 was converted to (S)-dimethyl 2-methylsuccinate ((S)-1) by SeER in high yields (80%) and enantioselectivity (98% ee), and 700 mM of 2 and 400 mM of 4 were converted to (R)-1 by Bac-OYE1 and AfER, respectively, in high yields (86% and 77%) with excellent enantioselectivity (99% ee). The reductions of diethyl citraconate (5), diethyl mesaconate (6) and diethyl itaconate (7) were also tested with the three ERs. Although up to 500 mM of 5 was completely converted to (R)-diethyl 2-methylsuccinate ((R)-8) by Bac-OYE1 with excellent enantioselectivity (99% ee), the alcohol moiety of the esters had a great effect on the activity and enantioselectivity of ERs. This work provides an efficient methodology for the enantiocomplementary production of optically pure dimethyl 2-methylsuccinate from dimethyl itaconate and its isomers at high titer.