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.

Development of Immobilized Carreira (Phosphoramidite, Olefin) Ligands and Application in Iridium-Catalyzed Asymmetric Allylic Amination.

A family of polystyrene-supported (phosphoramidite, olefin) ligands L1-L4, based on the original design by Defieber and Carreira, has been developed and applied in iridium-catalyzed asymmetric allylic amination of unmasked allylic alcohols (27 examples, up to 99% ee). Among them, functional resins L1 and L4 exhibit important advantages such as easy preparation, ligand recyclability, and easy handling for sequential use. As a distinctive advantage, the catalytic use of the iridium complexes of L1 and L4 allows the straightforward reuse of a high percentage of the expensive iridium metal involved in the complexes, which is not achievable under homogeneous conditions with the corresponding monomeric complexes.

Structure-based Design of Novel Hepatitis B Virus Capsid Assembly Modulators.

Small-molecule capsid assembly modulators (CAMs) have been recently recognized as promising antiviral agents for curing chronic hepatitis B virus (HBV) infection. A target-based in silico screening study is described, aimed towards the discovery of novel HBV CAMs. Initial optimization of four weakly active screening hits was performed via focused library synthesis. Lead compound 42 and close analogues 56 and 57 exhibited in vitro potency in the sub- and micromolar range along with good physico-chemical properties and were further evaluated in molecular docking and mechanism of action studies.

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.

An enantio- and diastereoselective approach to indoloquinolizidines in continuous flow.

Merging polymer-supported asymmetric organocatalysis with continuous flow in a packed bed reactor has been used as the key, enantiodetermining step in a short synthesis of indoloquinolizidines. Using this approach, a highly enantioselective, solvent-free and rapid conjugate addition of dimethyl malonate to a diverse family of cinnamaldehydes in continuous flow, allowing the preparation of relevant oxodiesters in multigram amounts has been developed. The obtained Michael adducts have been used to complete an expedient diastereoselective synthesis of indoloquinolizidine via cascade Pictet-Splengler cyclisation-lactamisation in continuous flow. The conversion of enantiopure Michael adducts into δ-lactones via telescoped reduction/cyclisation in continuous flow has also been explored.

Anion-π Interactions in Light-Induced Reactions: Role in the Amidation of (Hetero)aromatic Systems with Activated N-Aryloxyamides.

The importance of anion-π interactions as a driving force for chemical and biological processes is increasingly being recognized. In this communication, we describe for the first time its key participation in light-induced reactions. We show, in particular, how transient complexes formed through noncovalent anion-π interactions between electron-poor N-aryloxyamides and multiply-charged anions (such as carbonate or phosphate) can undergo facile light-promoted N-O cleavage, affording amidyl radicals that can subsequently be trapped by (hetero)aromatics.

Catalytic Enantioselective Flow Processes with Solid-Supported Chiral Catalysts.

Sustainability concerns are the wind in the sails for the development of novel, more selective catalytic processes. Hence, chiral catalysts play a crucial role in the green production of enantioenriched compounds. To further increase the green profile of this approach, the use of solid-supported catalytic species is appealing due to the reduced generation of waste, as well as the possibility of reusing the precious catalyst. Even more attractive is the implementation of flow processes based on these immobilized catalysts, a flexible strategy that allows to generate from milli- to multi-gram amounts of chiral product with a reduced footprint set-up. Herein, we will present the efforts devoted in our laboratory towards the immobilization of chiral catalysts and their use in single-pass, highly enantioselective, flow processes. Proline, diarylprolinols, other aminocatalysts, squaramides, thioureas, phosphoric acids and even chiral ligands and metal-based catalysts constitute our current toolkit of supported species for enantioselective catalysis.

Nickel-Catalyzed Reductive [2+2] Cycloaddition of Alkynes.

The nickel-catalyzed synthesis of tetrasubstituted cyclobutenes from alkynes is reported. This transformation is uniquely promoted by the use of a primary aminophosphine, an unusual ligand in nickel catalysis. Mechanistic insights for this new transformation are provided, and postreaction modifications of the cyclobutene products to stereodefined cyclic and acyclic compounds are reported, including the synthesis of epi-truxillic acid.

Catalytic Asymmetric [8+2] Annulation Reactions Promoted by a Recyclable Immobilized Isothiourea.

Higher-order cycloaddition reactions constitute an efficient approach towards the construction of medium to large ring systems. However, enantioselective versions of these transformations remain scarce, which hampers their deployment in medicinal chemistry, or any other discipline in which homochirality is deemed crucial. Herein, we report a novel method for the production of enantiomerically enriched cycloheptatrienes fused to a pyrrolidone ring on the basis of an isothiourea-catalyzed periselective [8+2] cycloaddition reaction between chiral ammonium enolates (generated in situ from carboxylic acids) and azaheptafulvenes. The resulting bicyclic compounds can be hydrogenated, but, most remarkably, they can also undergo completely regioselective [4+2] cycloaddition with active dienophiles to give architecturally complex polycyclic compounds in a straightforward manner.

Key Non-Metal Ingredients for Cu-catalyzed "Click" Reactions in Glycerol: Nanoparticles as Efficient Forwarders.

The effect of long-alkyl-chain amines in CuI-assisted azide-alkyne cycloadditions of terminal alkynes with organic azides in glycerol and other environmentally benign solvents (water, ethanol) has been examined. The presence of these additives favors the in situ formation of CuI -based nanoparticles and results in an increase of the catalytic reactivity. In glycerol, liquid-phase transmission electron microscopy (TEM) analyses, enabled by the negligible vapor pressure of this solvent, proved that CuI nanoparticles are responsible for the observed catalytic activity. The wide variety of alkynes and azides of which this effect has been investigated (14 combinations) confirms the role played by these additives in Cu-catalyzed Huisgen cycloadditions.

Metal-Free Intermolecular Azide-Alkyne Cycloaddition Promoted by Glycerol.

Metal-free intermolecular Huisgen cycloadditions using nonactivated internal alkynes have been successfully performed in neat glycerol, both under thermal and microwave dielectric heating. In sharp contrast, no reaction occurs in other protic solvents, such as water, ethanol, or diols. DFT calculations have shown that the BnN3/glycerol adduct promotes a more important stabilization of the corresponding LUMO than that produced in the analogous BnN3/alcohol adducts, favoring the reactivity with the alkyne in the first case. The presence of copper salts in the medium did not change the reaction pathway (Cu(I) acts as spectator), except for disubstituted silylalkynes, for which desilylation takes place in contrast to the metal-free system.

A polystyrene-supported 9-amino(9-deoxy)epi quinine derivative for continuous flow asymmetric Michael reactions.

A polystyrene (PS)-supported 9-amino(9-deoxy)epi quinine derivative catalyzes Michael reactions affording excellent levels of conversion and enantioselectivity using different nucleophiles and structurally diverse enones. The highly recyclable, immobilized catalyst has been used to implement a single-pass, continuous flow process (residence time: 40 min) that can be operated for 21 hours without significant decrease in conversion and with improved enantioselectivity with respect to batch operation. The flow process has also been used for the sequential preparation of a small library of enantioenriched Michael adducts.

Synthesis of triarylmethanols via tandem arylation/oxidation of diarylmethanes.

A tandem arylation/oxidation of diarylmethanes for the convenient synthesis of unsymmetrical triarylmethanols bearing different aryl and heteroaryl groups is described. A Pd(OAc)2-NiXantphos catalyst system efficiently catalyzed arylation of weakly acidic sp3-hybridized C-H bonds of diarylmethanes with aryl bromides, and the arylation products were then oxidized in situ to carbinols by simply opening the reaction flasks to air. The triarylmethanol products were obtained in 35-98% yield.

Air- and water-tolerant rare earth guanidinium BINOLate complexes as practical precatalysts in multifunctional asymmetric catalysis.

Shibasaki's REMB catalysts (REMB; RE = Sc, Y, La-Lu; M = Li, Na, K; B = 1,1'-bi-2-naphtholate; RE/M/B = 1/3/3) are among the most enantioselective asymmetric catalysts across a broad range of mechanistically diverse reactions. However, their widespread use has been hampered by the challenges associated with their synthesis and manipulation. We report here the self-assembly of novel hydrogen-bonded rare earth metal BINOLate complexes that serve as bench-stable precatalysts for Shibasaki's REMB catalysts. Incorporation of hydrogen-bonded guanidinium cations in the secondary coordination sphere leads to unique properties, most notably, improved stability toward moisture in solution and in the solid state. We have exploited these properties to develop straightforward, high-yielding, and scalable open-air syntheses that provide rapid access to crystalline, nonhygroscopic complexes from inexpensive hydrated RE starting materials. These compounds can be used as precatalysts for Shibasaki's REMB frameworks, where we have demonstrated that our system performs with comparable or improved levels of stereoselectivity in several mechanistically diverse reactions including Michael additions, aza-Michael additions, and direct Aldol reactions.

Enantioselective continuous-flow production of 3-indolylmethanamines mediated by an immobilized phosphoric acid catalyst.

A polystyrene-supported 1,1'-bi-2-naphthol derived phosphoric acid has been synthesized and applied in the enantioselective Friedel-Crafts reaction of indoles and sulfonylimines. The immobilized catalyst was highly active and selective, and gave rise to a broad range of 3-indolylmethanamines (19 examples) in high yields and excellent enantioselectivities (up to 98 % enantiomeric excess) after short reaction times under very convenient reaction conditions (RT in dichloromethane). Moreover, repeated recycling (14 cycles) was possible with no substantial loss in catalytic performance and the system could be adapted to a continuous-flow operation (6 h). Finally, the applicability of the system was further confirmed by rapid access to a library of compounds with three points of diversity in a single continuous-flow experiment that involved sequential pumping of different substrate combinations.

Highly enantioselective cross-aldol reactions of acetaldehyde mediated by a dual catalytic system operating under site isolation.

Polystyrene-supported (PS) diarylprolinol catalysts 1 a (Ar = phenyl) and 1 b (Ar = 3,5-bis(trifluoromethyl)phenyl) have been developed. Operating under site-isolation conditions, PS-1 a/1 b worked compatibly with PS-bound sulfonic acid catalyst 2 to promote deoligomerization of paraldehyde and subsequent cross-aldol reactions of the resulting acetaldehyde in one pot, affording aldol products in high yields with excellent enantioselectivities. The effect of water on the performance of the catalytic system has been studied and its optimal amount (0.5 equiv) has been determined. The dual catalytic system (1/2) allows repeated recycling and reuse (10 cycles). The potential of this methodology is demonstrated by a two-step synthesis of a phenoperidine analogue (68% overall yield; 98% ee) and by the preparation of highly enantioenriched 1,3-diols 4 and 3-methylamino-1-arylpropanols 5, key intermediates in the synthesis of a variety of druglike structures.

Reaction of alkynes and azides: not triazoles through copper-acetylides but oxazoles through copper-nitrene intermediates.

Well-defined copper(I) complexes of composition [Tpm*(,Br) Cu(NCMe)]BF4 (Tpm*(,Br) =tris(3,5-dimethyl-4-bromo-pyrazolyl)methane) or [Tpa(*) Cu]PF6 (Tpa(*) =tris(3,5-dimethyl-pyrazolylmethyl)amine) catalyze the formation of 2,5-disubstituted oxazoles from carbonyl azides and terminal alkynes in a direct manner. This process represents a novel procedure for the synthesis of this valuable heterocycle from readily available starting materials, leading exclusively to the 2,5-isomer, attesting to a completely regioselective transformation. Experimental evidence and computational studies have allowed the proposal of a reaction mechanism based on the initial formation of a copper-acyl nitrene species, in contrast to the well-known mechanism for the copper-catalyzed alkyne and azide cycloaddition reactions (CuAAC) that is triggered by the formation of a copper-acetylide complex.

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.

Asymmetric allylation of ketones and subsequent tandem reactions catalyzed by a novel polymer-supported titanium-BINOLate complex.

By using a novel, simple, and convenient synthetic route, enantiopure 6-ethynyl-BINOL (BINOL = 1,1-binaphthol) was synthesized and anchored to an azidomethylpolystyrene resin through a copper-catalyzed alkyne-azide cycloaddition (CuAAC) reaction. The polystyrene (PS)-supported BINOL ligand was converted into its diisopropoxytitanium derivative in situ and used as a heterogeneous catalyst in the asymmetric allylation of ketones. The catalyst showed good activity and excellent enantioselectivity, typically matching the results obtained in the corresponding homogeneous reaction. The allylation reaction mixture could be submitted to epoxidation by simple treatment with tert-butyl hydroperoxide (TBHP), and the tandem asymmetric allylation epoxidation process led to a highly enantioenriched epoxy alcohol with two adjacent quaternary centers as a single diastereomer. A tandem asymmetric allylation/Pauson-Khand reaction was also performed, involving simple treatment of the allylation reaction mixture with Co2(CO)8/N-methyl morpholine N-oxide. This cascade process resulted in the formation of two diastereomeric tricyclic enones in high yields and enantioselectivities.

Light-driven organocatalysis using inexpensive, nontoxic Bi2O3 as the photocatalyst.

The development of enantioselective catalytic processes that make use of sunlight as the energy source and nontoxic, affordable materials as catalysts represents one of the new and rapidly evolving areas in chemical research. The direct asymmetric α-alkylation of aldehydes with α-bromocarbonyl compounds can be successfully achieved by combining bismuth-based materials as low-band-gap photocatalysts with the second-generation MacMillan imidazolidinone as the chiral catalyst and simulated sunlight as a low-cost and clean energy source. This reaction also proceeded with high efficiency when the reaction vial was exposed to the morning sunlight on a clear September day in Tarragona, Spain.