Unlocking the Asymmetric Hydrogenation of Tetrasubstituted Acyclic Enones.

Asymmetric hydrogenation (AH) of tetrasubstituted olefins generating two stereocenters is still an open topic. There are only a few reports on the AH of tetrasubstituted olefins with conjugated functional groups, while this process can create useful intermediates for the subsequent elaboration of relevant end products. Most of the tetrasubstituted olefins successfully submitted to AH belong to a small number of functional classes; remarkably, the AH of tetrasubstituted acyclic enones still represents an unsolved challenge. Herein, we disclose a class of air-stable Ir-P,N catalysts, prepared in three steps from commercially available amino alcohols, that can hydrogenate, in minutes, a wide range of electronically and sterically diverse acyclic tetrasubstituted enones (including exocyclic ones) with high yields and high enantioselectivities. The factors responsible for the excellent selectivities were elucidated by combining deuterogenation experiments and theoretical calculations. The calculations indicated that the reduction follows an IrI /IrIII mechanism, in which enantioselectivity is controlled in the first migratory insertion of the hydride to the most electrophilic olefinic Cß and the formation of the hydrogenated product via reductive elimination takes place prior to the coordination of dihydrogen and the subsequent oxidative addition. The potential of the new catalytic systems is demonstrated by the derivatization of hydrogenation products.

A Unified Determinant-Preserving Formulation for Compressible/Incompressible Finite Viscoelasticity.

This paper presents a formulation alongside a numerical solution algorithm to describe the mechanical response of bodies made of a large class of viscoelastic materials undergoing arbitrary quasistatic finite deformations. With the objective of having a unified formulation that applies to a wide range of highly compressible, nearly incompressible, and fully incompressible soft organic materials in a numerically tractable manner, the viscoelasticity is described within a Lagrangian setting by a two-potential mixed formulation. In this formulation, the deformation field, a pressure field that ensues from a Legendre transform, and an internal variable of state Fv that describes the viscous part of the deformation are the independent fields. Consistent with the experimental evidence that viscous deformation is a volume-preserving process, the internal variable Fv is required to satisfy the constraint det Fv=1. To solve the resulting initial-boundary-value problem, a numerical solution algorithm is proposed that is based on a finite-element (FE) discretization of space and a finite-difference discretization of time. Specifically, a Variational Multiscale FE method is employed that allows for an arbitrary combination of shape functions for the deformation and pressure fields. To deal with the challenging non-convex constraint det Fv=1, a new time integration scheme is introduced that allows to convert any explicit or implicit scheme of choice into a stable scheme that preserves the constraint det Fv=1 identically. A series of test cases is presented that showcase the capabilities of the proposed formulation.

P-Stereogenic Ir-MaxPHOX: A Step toward Privileged Catalysts for Asymmetric Hydrogenation of Nonchelating Olefins.

The Ir-MaxPHOX-type catalysts demonstrated high catalytic performance in the hydrogenation of a wide range of nonchelating olefins with different geometries, substitution patterns, and degrees of functionalization. These air-stable and readily available catalysts have been successfully applied in the asymmetric hydrogenation of di-, tri-, and tetrasubstituted olefins (ee's up to 99%). The combination of theoretical calculations and deuterium labeling experiments led to the uncovering of the factors responsible for the enantioselectivity observed in the reaction, allowing the rationalization of the most suitable substrates for these Ir-catalysts.

The effective shear modulus of a random isotropic suspension of monodisperse liquid n-spheres: from the dilute limit to the percolation threshold.

A numerical and analytical study is made of the macroscopic or homogenized mechanical response of a random isotropic suspension of liquid n-spherical inclusions (n = 2, 3), each having identical initial radius A, in an elastomer subjected to small quasistatic deformations. Attention is restricted to the basic case when the elastomer is an isotropic incompressible linear elastic solid, the liquid making up the inclusions is an incompressible linear elastic fluid, and the interfaces separating the solid elastomer from the liquid inclusions feature a constant initial surface tension γ. For such a class of suspensions, it has been recently established that the homogenized mechanical response is that of a standard linear elastic solid and hence, for the specific type of isotropic incompressible suspension of interest here, one that can be characterized solely by an effective shear modulus n in terms of the shear modulus µ of the elastomer, the initial elasto-capillary number eCa = γ/2µA, the volume fraction c of inclusions, and the space dimension n. This paper presents numerical solutions-generated by means of a recently introduced finite-element scheme-for n over a wide range of elasto-capillary numbers eCa and volume fractions of inclusions c. Complementary to these, a formula is also introduced for n that is in quantitative agreement with all the numerical solutions, as well as with the asymptotic results for n in the limit of dilute volume fraction of inclusions and at percolation . The proposed formula has the added theoretical merit of being an iterated-homogenization solution.

Proofreading experimentally assigned stereochemistry through Q2MM predictions in Pd-catalyzed allylic aminations.

The palladium-catalyzed enantioselective allylic substitution by carbon or nitrogen nucleophiles is a key transformation that is particularly useful for the synthesis of bioactive compounds. Unfortunately, the selection of a suitable ligand/substrate combination often requires significant screening effort. Here, we show that a transition state force field (TSFF) derived by the quantum-guided molecular mechanics (Q2MM) method can be used to rapidly screen ligand/substrate combinations. Testing of this method on 77 literature reactions revealed several cases where the computationally predicted major enantiomer differed from the one reported. Interestingly, experimental follow-up led to a reassignment of the experimentally observed configuration. This result demonstrates the power of mechanistically based methods to predict and, where necessary, correct the stereochemical outcome.

Self-Adaptable Tropos Catalysts.

Biological systems have often served as inspiration for the design of synthetic catalysts. The lock and key analogy put forward by Emil Fischer in 1894 to explain the high substrate specificity of enzymes has been used as a general guiding principle aimed at enhancing the selectivity of chemical processes by optimizing attractive and repulsive interactions in molecular recognition events. However, although a perfect fit of a substrate to a catalytic site may enhance the selectivity of a specific catalytic reaction, it inevitably leads to a narrow substrate scope, excluding substrates with different sizes and shapes from efficient binding. An ideal catalyst should instead be able to accommodate a wide range of substrates-it has indeed been recognized that enzymes also are often highly promiscuous as a result of their ability to change their conformation and shape in response to a substrate-and preferentially be useful in various types of processes. In biological adaptation, the process by which species become fitted to new environments is crucial for their ability to cope with changing environmental conditions. With this in mind, we have been exploring catalytic systems that can adapt their size and shape to the environment with the goal of developing synthetic catalysts with wide scope.In this Account, we describe our studies aimed at elucidating how metal catalysts with flexible structural units adapt their binding pockets to the reacting substrate. Throughout our studies, ligands equipped with tropos biaryl units have been explored, and the palladium-catalyzed allylic alkylation reaction has been used as a suitable probe to study the adaptability of the catalytic systems. The conformations of catalytically active metal complexes under different conditions have been studied by both experimental and theoretical methods. By the design of ligands incorporating two flexible units, the symmetry properties of metal complexes could be used to facilitate conformational analysis and thereby provide valuable insight into the structures of complexes involved in the catalytic cycle. The importance of flexibility was convincingly demonstrated when a phosphine group in a privileged ligand that is well-known for its versatility in a number of processes was exchanged for a tropos biaryl phosphite unit: the result was a truly self-adaptive ligand with dramatically increased scope.

Recent Advances in Enantioselective Pd-Catalyzed Allylic Substitution: From Design to Applications.

This Review compiles the evolution, mechanistic understanding, and more recent advances in enantioselective Pd-catalyzed allylic substitution and decarboxylative and oxidative allylic substitutions. For each reaction, the catalytic data, as well as examples of their application to the synthesis of more complex molecules, are collected. Sections in which we discuss key mechanistic aspects for high selectivity and a comparison with other metals (with advantages and disadvantages) are also included. For Pd-catalyzed asymmetric allylic substitution, the catalytic data are grouped according to the type of nucleophile employed. Because of the prominent position of the use of stabilized carbon nucleophiles and heteronucleophiles, many chiral ligands have been developed. To better compare the results, they are presented grouped by ligand types. Pd-catalyzed asymmetric decarboxylative reactions are mainly promoted by PHOX or Trost ligands, which justifies organizing this section in chronological order. For asymmetric oxidative allylic substitution the results are grouped according to the type of nucleophile used.

Rh-Catalyzed Asymmetric Hydroaminomethylation of α-Substituted Acrylamides: Application in the Synthesis of RWAY.

The successful rhodium-catalyzed asymmetric hydroformylation and hydroaminomethylation of α-substituted acrylamides is described using 1,3-phosphite-phosphoramidite ligands based on a sugar backbone. A broad scope of chiral aldehydes and amines were afforded in high yields and excellent enantioselectivities (up to 99%). Furthermore, the synthetic potential of this method is demonstrated by the single-step synthesis of the brain imaging molecule RWAY.

Evolution of phosphorus-thioether ligands for asymmetric catalysis.

In the early 1990s chiral P-thiother ligands emerged as promising ligands in the field of asymmetric catalysis, with the development of many P-thioether ligand families. However, only a few of them have shown a broad reaction and substrate scope. So, compared with other heterodonor ligands such as the widely studied P-N ligands, their impact in asymmetric catalysis was not realised until recently. This has been mainly attributed to the difficulty of controlling the configuration at the sulfur atom when coordinated to the metal. More recently, it has been found that this problem could be solved by a rigorous choice of the ligand scaffold, a process usually aided by mechanistic studies. This allowed the recent discovery of new P-thioether ligand families with a broader versatility, both in reactions and in substrate/reagent scope. This feature article aims to highlight those new P-thioether ligand libraries and the relationship between the structure and catalytic performance.

Effect of Ligand Chelation and Sacrificial Oxidant on the Integrity of Triazole-Based Carbene Iridium Water Oxidation Catalysts.

We report the effect of replacing the pyridine group in the chelating trz Ir-water oxidation catalysts by a benzoxazole and a thiazole moiety. We have also evaluated if the presence of bidentate ligands is crucial for high activities and to avoid the decomposition into undesired heterogeneous layers. The catalytic performance of these benzoxazole/thiazole-triazolidene Ir-complexes in water oxidation was studied at variable pH using either CAN (pH = 1) or NaIO4 (pH = 5.6 and 7). Electrocatalytic experiments indicated that while CAN-mediated water oxidation led to catalyst heterogeneization irrespective of the triazolylidene substituent, periodate as sacrificial oxidant preserved a homogeneously active species. Repetitive additions of sacrificial oxidant indicates higher integrity of the Ir-complex with a thiazole-substituted triazolylidene compared to ligands featuring a benzoxazole as chelating donor or no chelating group at all. Rigid chelation of the thiazole group was also established from stability measurements under highly acidic, oxidizing, and high ionic strength conditions.

P-Stereogenic N-Phosphine-Phosphite Ligands for the Rh-Catalyzed Hydrogenation of Olefins.

We have identified a successful family of simple P-stereogenic N-phosphine-phosphite ligands for the Rh-catalyzed asymmetric hydrogenation of olefins. These catalysts show excellent enantiocontrol for α-dehydroamino acid derivatives and α-enamides (ee's up to >99%) and promising results for the more challenging ß-analogues (ee's up to 80%). The usefulness of these catalytic systems was further demonstrated with the synthesis of several valuable precursors for pharmacologically active compounds, with ee's at least as high as the best ones reported previously (up to >99%).

A readily accessible and modular carbohydrate-derived thioether/selenoether-phosphite ligand library for Pd-catalyzed asymmetric allylic substitutions.

A large library of thioether/selenoether-phosphite ligands have been tested in the Pd-catalyzed asymmetric allylic substitution reaction. The presented ligands are derived from cheap and available carbohydrates and they are air-stable solids and easy to handle. Their highly modular nature has made it possible to achieve excellent enantioselectivities in the substitution of a range of hindered and unhindered substrates (ees up to 99% and 91%, respectively). In addition, twelve C-, N- and O-nucleophiles can be efficiently introduced, independently of their nature. Among the whole library, ligands that contain an additional chiral centre in the alkyl backbone chain next to the phosphite group and an enantiopure biaryl phosphite group provided the best enantioselectivities. In general, there is a cooperative effect between these two chiral elements, and therefore, a matched combination between them is necessary to achieve the highest enantioselectivities. However, in the case of cyclic substrates, this cooperative effect is less pronounced and advantageously, both enantiomers of the product can be obtained by setting up the desired configuration of the biaryl phosphite group. Studies of the key Pd-π-allyl intermediates allowed us to better understand the enantioselectivities obtained experimentally.

Giving a Second Chance to Ir/Sulfoximine-Based Catalysts for the Asymmetric Hydrogenation of Olefins Containing Poorly Coordinative Groups.

This work identifies a family of Ir/phosphite-sulfoximine catalysts that has been successfully used in the asymmetric hydrogenation of olefins with poorly coordinative or noncoordinative groups. In comparison with analogue Ir/phosphine-sulfoximine catalysts previously reported, the presence of a phosphite group extended the range of olefins than can be efficiently hydrogenated. High enantioselectivities, comparable to the best ones reported, have been achieved for a wide range of olefins containing relevant poorly coordinative groups such as α,ß-unsaturated enones, esters, lactones, and lactams as well as alkenylboronic esters.

Extending the Substrate Scope in the Hydrogenation of Unfunctionalized Tetrasubstituted Olefins with Ir-P Stereogenic Aminophosphine-Oxazoline Catalysts.

Air-stable and readily available Ir-catalyst precursors modified with MaxPHOX-type ligands have been successfully applied in the challenging asymmetric hydrogenation of tetrasubstituted olefins under mild reaction conditions. Gratifyingly, these catalyst precursors are able to efficiently hydrogenate not only a range of indene derivatives (ee's up to 96%) but also 1,2-dihydronapthalene derivatives and acyclic olefins (ee's up to 99%), which both constitute the most challenging substrates for this transformation.

Damage in elastomers: healing of internally nucleated cavities and micro-cracks.

Following on the work of Poulain et al. (Damage in elastomers: Nucleation and growth of cavities, micro-cracks, and macro-cracks, Int. J. Fract., 2017, 205, 1-21), this paper presents an investigation of the response of cavities/cracks internally nucleated within a transparent PDMS elastomer that is confined between two firmly embedded stiff beads and subjected to quasistatic cyclic loading-unloading. Specifically, it is observed that cracks that nucleate and propagate to reach tens of microns in length during the loading can heal completely upon unloading. They do so autonomously within a time scale of seconds. Furthermore, the regions of the elastomer that experience healing appear to acquire higher strength or toughness.

Enantioselective Synthesis of 6,6-Disubstituted Pentafulvenes Containing a Chiral Pendant Hydroxy Group.

Simple enantioselective synthesis of 6,6-disubstituted pentafulvenes bearing chiral pendant hydroxy groups are attained by cascade reactivity using commercially available proline-based organocatalysts. Condensation of cyclopentadiene with the acetyl function of a 1,2-formylacetophenone, followed by cyclization of a resulting fulvene-stabilized carbanion with the formyl group, generates bicyclic chiral alcohols with initial er values up to 94:6. Exceptional enantio-enrichment of the resultant alcohols results upon crystallization-even near racemic samples spontaneously de-racemize. This enables new families of substituted cyclopentadienes that are both enantiomerically and diastereomerically pure to be rapidly attained.

Triazolylidene Iridium Complexes for Highly Efficient and Versatile Transfer Hydrogenation of C═O, C═N, and C═C Bonds and for Acceptorless Alcohol Oxidation.

A set of iridium(I) and iridium(III) complexes is reported with triazolylidene ligands that contain pendant benzoxazole, thiazole, and methyl ether groups as potentially chelating donor sites. The bonding mode of these groups was identified by NMR spectroscopy and X-ray structure analysis. The complexes were evaluated as catalyst precursors in transfer hydrogenation and in acceptorless alcohol oxidation. High-valent iridium(III) complexes were identified as the most active precursors for the oxidative alcohol dehydrogenation, while a low-valent iridium(I) complex with a methyl ether functionality was most active in reductive transfer hydrogenation. This catalyst precursor is highly versatile and efficiently hydrogenates ketones, aldehydes, imines, allylic alcohols, and most notably also unpolarized olefins, a notoriously difficult substrate for transfer hydrogenation. Turnover frequencies up to 260 h-1 were recorded for olefin hydrogenation, whereas hydrogen transfer to ketones and aldehydes reached maximum turnover frequencies greater than 2000 h-1. Mechanistic investigations using a combination of isotope labeling experiments, kinetic isotope effect measurements, and Hammett parameter correlations indicate that the turnover-limiting step is hydride transfer from the metal to the substrate in transfer hydrogenation, while in alcohol dehydrogenation, the limiting step is substrate coordination to the metal center.

Phosphite-Thiother Ligands Derived from Carbohydrates allow the Enantioswitchable Hydrogenation of Cyclic ß-Enamides by using either Rh or Ir Catalysts.

Phosphite-thioether ligands with a simple modular architecture, derived from inexpensive l-(+)-tartaric acid and d-mannitol, have been for the first time successfully applied (ee values up to 99 %) in the synthesis of 2-aminotetralines and 3-aminochromanes by metal-catalyzed asymmetric hydrogenation of cyclic ß-enamides. The ligands have the advantages of the robustness of the thioether/phosphite moieties and the extra control provided by the flexibility of the chiral pocket through the presence of a biaryl phosphite group and a modular carbohydrate-derived backbone. Moreover, they are solid and stable to air and they are therefore easy to handle, manipulate, and store. Usefully, both enantiomers of the hydrogenated products were obtained by simply switching from Rh to Ir. Low hydrogen pressure and environmentally friendly propylene carbonate can be used, with no loss of selectivity.

Adaptable P-X Biaryl Phosphite/Phosphoroamidite-Containing Ligands for Asymmetric Hydrogenation and C-X Bond-Forming Reactions: Ligand Libraries with Exceptionally Wide Substrate Scope.

In this personal review, we present our efforts in the design of ligand libraries for the discovery of suitable metal catalysts for asymmetric hydrogenation and C-X bond-forming reactions.

Extending the Substrate Scope for the Asymmetric Iridium-Catalyzed Hydrogenation of Minimally Functionalized Olefins by Using Biaryl Phosphite-Based Modular Ligand Libraries.

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.