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.

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.

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.

Assessing Methodologies to Synthesize α-Sulfenylated Carbonyl Compounds by Green Chemistry Metrics.

α-Sulfenylated carbonyl compounds are important both as active pharmaceutical ingredients and as intermediates in organic synthesis. Owing to their relevance in synthetic organic chemistry, this Minireview focuses on assessing the most relevant synthetic procedures based on green chemistry metrics. The Minireview starts with the traditional routes and then focuses on more recently developed methodologies. These routes include sulfenylating reagents using organocatalysis, cross-dehydrogenative couplings using in situ halogenations to prevent reactive intermediates in high concentrations, oxidative couplings using terminal oxidants such as DDQ or TEMPO, and redox-neutral couplings using transition metal catalysis. These methodologies have been evaluated on the basis of atom economy, E factor, and the safety and toxicity of the transformations and the solvents used. Besides using green metrics to evaluate these novel methodologies, the synthetic utility is also assessed with regard to the availability of starting materials and the generality of the reactions. This Minireview aims to inspire researchers to apply green assessments to other methodologies and also for them to take measures to increase the greenness of their developed transformations.

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.

High-Atom Economic Approach To Prepare Chiral α-Sulfenylated Ketones.

Chiral α-sulfenylated ketones are versatile building blocks, although there are still several limitations with their preparation. Here we report a new two-step procedure, consisting of Pd-catalyzed hydrothiolation of propargylic alcohols followed by an enantioselective Rh isomerization of allylic alcohols. The isomerization reaction is the key step for obtaining the ketones in their enantioenriched form. The new methodology has a high atom economy and induces good to high levels of enantioselectivity; no waste is produced. A mechanism involving a Rh-hydride-enone intermediate is proposed for the isomerization reaction.

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.

Intramolecular substitutions of secondary and tertiary alcohols with chirality transfer by an iron(III) catalyst.

Optically pure alcohols are abundant in nature and attractive as feedstock for organic synthesis but challenging for further transformation using atom efficient and sustainable methodologies, particularly when there is a desire to conserve the chirality. Usually, substitution of the OH group of stereogenic alcohols with conservation of chirality requires derivatization as part of a complex, stoichiometric procedure. We herein demonstrate that a simple, inexpensive, and environmentally benign iron(III) catalyst promotes the direct intramolecular substitution of enantiomerically enriched secondary and tertiary alcohols with O-, N-, and S-centered nucleophiles to generate valuable 5-membered, 6-membered and aryl-fused 6-membered heterocyclic compounds with chirality transfer and water as the only byproduct. The power of the methodology is demonstrated in the total synthesis of (+)-lentiginosine from D-glucose where iron-catalysis is used in a key step. Adoption of this methodology will contribute towards the transition to sustainable and bio-based processes in the pharmaceutical and agrochemical industries.

Nickel-Catalyzed Suzuki-Miyaura Cross-Coupling Reaction of Naphthyl and Quinolyl Alcohols with Boronic Acids.

A nickel-catalyzed C(sp3)-C(sp2) Suzuki cross-coupling of arylboronic acids and (hetero)naphthyl alcohols has been developed. A Ni(dppp)Cl2 complex showed the highest efficiency and broadest substrate scope. High functional group tolerance has been achieved where 35  compounds could be generated in good to excellent yields, including both primary and secondary benzylic alcohols. Mechanistic studies using multiple NMR techniques as well as ESI-HRMS showed that the C-O cleavage is facilitated by an activation of the benzylic alcohol through formation of a boronic ester intermediate.

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.

A theoretically-guided optimization of a new family of modular P,S-ligands for iridium-catalyzed hydrogenation of minimally functionalized olefins.

A library of modular iridium complexes derived from thioether-phosphite/phosphinite ligands has been evaluated in the asymmetric iridium-catalyzed hydrogenation of minimally functionalized olefins. The modular ligand design has been shown to be crucial in finding highly selective catalysts for each substrate. A DFT study of the transition state responsible for the enantiocontrol in the Ir-catalyzed hydrogenation is also described and used for further optimization of the crucial stereodefining moieties. Excellent enantioselectivities (enantiomeric excess (ee) values up to 99 %) have been obtained for a range of substrates, including E- and Z-trisubstituted and disubstituted olefins, α,ß-unsaturated enones, tri- and disubstituted alkenylboronic esters, and olefins with trifluoromethyl substituents.