Chiral Phosphoric Acid Catalyst Research Articles

General, Modular Access toward Immobilized Chiral Phosphoric Acid Catalysts and Their Application in Flow Chemistry.

Chiral phosphoric acids (CPAs) are among the most frequently used organocatalysts, with an ever-increasing number of applications. However, these catalysts are only obtained in a multistep synthesis and are poorly recyclable, which significantly deteriorates their environmental and economic performance. We herein report a conceptually different, general strategy for the direct immobilization of CPAs on a broad scope of solid supports including silica, polystyrene, and aluminum oxide. Solid-state catalysts were obtained in high yields and thoroughly characterized with elemental analysis by inductively coupled plasma-optical emission spectrometry (ICP-OES), nitrogen sorption measurements, thermogravimetric analysis, scanning transmission electron microscopy/energy-dispersive X-ray spectroscopy (STEM/EDX) images, and solid-state NMR spectroscopy. Further, the immobilized catalysts were applied to a variety of synthetically valuable, highly stereoselective transformations under batch and flow conditions including transfer hydrogenations, a Friedländer condensation/transfer hydrogenation sequence, and Mannich reactions under cryogenic flow conditions. Generally, high yields and stereoselectivities were observed along with robust catalyst stability and reusability. After being used for 10 runs under batch conditions, no loss of selectivity or catalytic activity was observed. Under continuous-flow conditions, the heterogeneous system was in operation for 19 h and the high enantioselectivity remained unchanged throughout the entire process. We expect our approach to extend the applicability of CPAs to a higher level, with a focus on flow chemistry and a more environmentally friendly and resource-efficient use of these powerful catalysts.

MATEO: intermolecular α-amidoalkylation theoretical enantioselectivity optimization. Online tool for selection and design of chiral catalysts and products.

The enantioselective Brønsted acid-catalyzed α-amidoalkylation reaction is a useful procedure is for the production of new drugs and natural products. In this context, Chiral Phosphoric Acid (CPA) catalysts are versatile catalysts for this type of reactions. The selection and design of new CPA catalysts for different enantioselective reactions has a dual interest because new CPA catalysts (tools) and chiral drugs or materials (products) can be obtained. However, this process is difficult and time consuming if approached from an experimental trial and error perspective. In this work, an Heuristic Perturbation-Theory and Machine Learning (HPTML) algorithm was used to seek a predictive model for CPA catalysts performance in terms of enantioselectivity in α-amidoalkylation reactions with R2 = 0.96 overall for training and validation series. It involved a Monte Carlo sampling of > 100,000 pairs of query and reference reactions. In addition, the computational and experimental investigation of a new set of intermolecular α-amidoalkylation reactions using BINOL-derived N-triflylphosphoramides as CPA catalysts is reported as a case of study. The model was implemented in a web server called MATEO: InterMolecular Amidoalkylation Theoretical Enantioselectivity Optimization, available online at: https://cptmltool.rnasa-imedir.com/CPTMLTools-Web/mateo . This new user-friendly online computational tool would enable sustainable optimization of reaction conditions that could lead to the design of new CPA catalysts along with new organic synthesis products.

Radical Cross Coupling and Enantioselective Protonation through Asymmetric Photoredox Catalysis.

An unprecedented enantioselective protonation reaction enabled by photoredox catalytic radical coupling is developed. Under cooperative dicynopyrazine-derived chromophore (DPZ) as a photosensitizer and a chiral phosphoric acid catalyst, and Hantzsch ester as a sacrificial reductant, the transformations between α-substituted enones and cyanoazaarenes or 2-(chloromethyl)azaaren-1-iums can proceed a tandem reduction, radical coupling, and enantioselective protonation process efficiently. Two classes of pharmaceutically important enantioenriched azaarene variants, which contain a synthetically versatile ketone-substituted tertiary carbon stereocenter at the β- or γ-position of the azaarenes, are synthesized with high yields and ees.

Organocatalytic regio- and enantioselective C1-arylation of β,γ-alkynyl-α-imino esters with pyrrolo[2,1-a]isoquinolines.

We herein report regio- and enantioselective arylation of β,γ-alkynyl-α-imino esters with pyrroloisoquinolines. Using chiral phosphoric acid catalysts, a wide range of novel axially chiral tetrasubstituted α-amino allenoates were accessed in good yields with excellent enantioselectivities. Notably, this transformation occurred preferentially at the sterically more hindered C1-position of pyrroloisoquinolines. The potential scalability and late-stage functionalization demonstrated the utility of the current protocol.

Recent Advances in Asymmetric Catalysis Using p-Block Elements.

The development of new methods for enantioselective reactions that generate stereogenic centres within molecules are a cornerstone of organic synthesis. Typically, metal catalysts bearing chiral ligands as well as chiral organocatalysts have been employed for the enantioselective synthesis of organic compounds. In this review, we highlight the recent advances in main group catalysis for enantioselective reactions using the p-block elements (boron, aluminium, phosphorus, bismuth) as a complementary and sustainable approach to generate chiral molecules. Several of these catalysts benefit in terms of high abundance, low toxicity, high selectivity, and excellent reactivity. This minireview summarises the utilisation of chiral p-block element catalysts for asymmetric reactions to generate value-added compounds.

Asymmetric Synthesis of Axially Chiral Arylpyrazole via an Organocatalytic Arylation Reaction.

Herein, a highly enantioselective arylation reaction of 3-aryl-5-aminopyrazoles and quinone derivatives was realized using a chiral phosphoric acid catalyst under mild conditions. The reaction has a broad scope with respect to both arylation reaction partners and hence offers rapid access to an array of axially chiral arylpyrazoles with pretty outcomes (up to 95% yield and 99% ee). Notably, the reaction is very efficient, as the catalyst loadings for the model reaction can be reduced to 1 mol % and the enantioselectivity is still maintained. Besides, the synthetic utility of the protocol was proven by a gram-scale reaction and the transformation of the product.

A Telescoped Continuous Flow Enantioselective Process for Accessing Intermediates of 1-Aryl-1,3-diols as Chiral Building Blocks.

A telescoped continuous flow process is reported for the enantioselective synthesis of chiral precursors of 1-aryl-1,3-diols, intermediates in the synthesis of ezetimibe, dapoxetine, duloxetine, and atomoxetine. The two-step sequence consists of an asymmetric allylboration of readily available aldehydes using a polymer-supported chiral phosphoric acid catalyst to introduce asymmetry, followed by selective epoxidation of the resulting alkene. The process is highly stable for at least 7 h and represents a transition-metal free enantioselective approach to valuable 1-aryl-1,3-diols.

Activation Model and Origins of Selectivity for Chiral Phosphoric Acid Catalyzed Diradical Reactions.

To develop new radical synthesis strategies, a profound understanding of the electronic transfer mechanism is critical. An activation model called relayed proton-coupled electron transfer (relayed-PCET) was developed and investigated for chiral phosphoric acid-catalyzed diradical reactions by density functional theory (DFT). The driving force of electron transfer from the nucleophile to the electrophile is the proton transfer that occurs via the chiral phosphoric acid (CPA) catalyst to the electrophile. Moreover, the origins of the selectivity can be explained by distortion of the catalyst, favorable hydrogen bonding, and strong interactions of the substrates with substituents of the CPAs.

Highly enantioselective [3+2] annulation of 4-amino-isoxazoles with quinone monoimines to access structurally diverse isoxazoline fused dihydrobenzofurans and antifungal evaluation

The first catalytic enantioselective [3+2] cyclization between 4-amino-isoxazoles and quinone monoimines was achieved by using a chiral phosphoric acid catalyst. This transformation afforded a series of isoxazoline fused dihydrobenzofuran derivatives with two sequential chiral centers in high yields and outstanding enantioselectivities. The absolute configuration of the title compounds was determined by X-ray crystal structure analysis. The subsequent application of the obtained products displayed good antifungal activity against five plant pathogenic fungi further demonstrates the versatility of this transformation.This approach provided an excellent alternative strategy for the synthesis of corresponding bioactive molecules containing an isoxazoline fused dihydrobenzofurans skeleton.

Chiral Phosphoric Acid Catalyzed Asymmetric Hydrolysis of Biaryl Oxazepines for the Synthesis of Axially Chiral Biaryl Amino Phenol Derivatives

AbstractThe development of catalytic asymmetric reaction with water as the reactant is challenging due to the reactivity‐ and stereoselectivity‐control issues resulted from the low nucleophilicity and the small size of water. We disclose herein a chiral phosphoric acid (CPA) catalyzed atroposelective ring‐opening reaction of biaryl oxazepines with water. A series of biaryl oxazepines undergo the CPA catalyzed asymmetric hydrolysis in a highly enantioselective manner. The key for the success of this reaction is the use of a new SPINOL‐derived CPA catalyst and the high reactivity of biaryl oxazepine substrates towards water under acidic conditions. Density functional theory calculations suggest that the reaction proceeds via a dynamic kinetic resolution pathway and the CPA catalyzed addition of water to the imine group is both enantio‐ and rate‐determining.

Chiral Phosphoric Acid Catalyzed Asymmetric Hydrolysis of Biaryl Oxazepines for the Synthesis of Axially Chiral Biaryl Amino Phenol Derivatives.

The development of catalytic asymmetric reaction with water as the reactant is challenging due to the reactivity- and stereoselectivity-control issues resulted from the low nucleophilicity and the small size of water. We disclose herein a chiral phosphoric acid (CPA) catalyzed atroposelective ring-opening reaction of biaryl oxazepines with water. A series of biaryl oxazepines undergo the CPA catalyzed asymmetric hydrolysis in a highly enantioselective manner. The key for the success of this reaction is the use of a new SPINOL-derived CPA catalyst and the high reactivity of biaryl oxazepine substrates towards water under acidic conditions. Density functional theory calculations suggest that the reaction proceeds via a dynamic kinetic resolution pathway and the CPA catalyzed addition of water to the imine group is both enantio- and rate-determining.

Chiral Phosphoric Acid-Catalyzed Enantioselective Synthesis of Axially Chiral Compounds Involving Indole Derivatives.

Indoles are one of the most ubiquitous subclass of N-heterocycles and are increasingly incorporated to design new axially chiral scaffolds. The rich profile of reactivity and N-H functionality allow chemical derivatization for enhanced medicinal, material and catalytic properties. Although asymmetric C-C coupling of two arenes gives the most direct access of axially chiral biaryl scaffolds, this chemistry has been the remit of metal catalysis and works efficiently on limited substrates. Our group has devoted special interest in devising novel organocatalytic arylation reactions to fabricate biaryl atropisomers. In this realm, indoles and derivatives have been reliably used as the arylation partners in combination with azoarenes, nitrosonapthalenes and quinone derivatives. Their efficient interaction with chiral phosphoric acid catalyst as well as the tunability of electronics and sterics have enabled excellent control of stereo-, chemo- and regioselectivity to furnish diverse scaffolds. In addition, indoles could act as nucleophiles in desymmetrization of 1,2,4-triazole-3,5-diones. This account provides a succinct illustration of these developments.

Organocatalytic Enantioselective 1,8-Addition for the Synthesis of Chiral Tetraarylmethanes from 2-Naphthol/Naphthalen-2-amine-Based Tertiary Alcohols.

Catalytic enantioselective construction of optically active tetraarylmethanes remains a challenging issue in the field of asymmetric synthesis because of the overwhelming steric hindrance and formidable stereocontrol that existed in construction of the all-aryl-substituted quaternary carbon stereocenter. Here, we reported an organocatalytic asymmetric synthesis of chiral tetraarylmethanes from racemic tertiary alcohols. With the aid of a chiral phosphoric acid catalyst, 6-methylenenaphthalen-2(6H)-ones were generated in situ from 6-(hydroxydiarylmethyl)naphthalen-2-ols, followed by stereoselective 1,8-conjugate addition to afford the corresponding tetraarylmethanes in high to excellent yields with high enantioselectivities. Furthermore, the scope of tertiary alcohols has been successfully enlarged to 6-(hydroxydiphenylmethyl)naphthalen-2-amines. Notably, it is the first time to use 2-naphthol/naphthalen-2-amine unit as the auxiliary group to in situ generate α,β,γ,δ,ε,ζ-conjugate systems, which have been successfully involved in organocatalytic remote stereocontrolled 1,8-conjugate addition reactions. Particularly, organocatalytic stereoconvergent formal nucleophilic substitution reaction of triarylmethanols has been achieved for the asymmetric construction of chiral tetraarylmethanes. In addition, DFT calculations have been applied to provide guidance for the design of additional tertiary alcohols and understand the origin of stereoselectivity.

Copper‐Catalyzed Intramolecular Radical Amination of Tertiary C(sp3)−H Bonds to Access α‐Quaternary Pyrrolidines

AbstractHerein, we describe a Cu(I)/phosphoric acid catalyzed intramolecular radical tertiary C(sp3)−H amination of N‐chlorosulfonamide, providing an applicable route to the pyrrolidine structural motifs bearing an α‐quaternary stereocenter (>20 examples with up to 94 % yield). Mechanistic studies indicate that the reaction involves an intramolecular 1,5‐hydrogen atom transfer process to form the key tertiary C‐centered radical followed by a C−N bond formation. The corresponding enantioselective amination is accordingly disclosed by Cu(I)/chiral phosphoric acid catalyst to afford the chiral products with up to 81 % enantiomeric excess (ee). This strategy is anticipated to facilitate the development of tertiary C(sp3)−H functionalization.

A Data-Driven Workflow for Assigning and Predicting Generality in Asymmetric Catalysis.

The development of chiral catalysts that can provide high enantioselectivities across a wide assortment of substrates or reaction range is a priority for many catalyst design efforts. While several approaches are available to aid in the identification of general catalyst systems, there is currently no simple procedure for directly measuring how general a given catalyst could be. Herein, we present a catalyst-agnostic workflow centered on unsupervised machine learning that enables the rapid assessment and quantification of catalyst generality. The workflow uses curated literature data sets and reaction descriptors to visualize and cluster chemical space coverage. This reaction network can then be applied to derive a catalyst generality metric through designer equations and interfaced with other regression techniques for general catalyst prediction. As validating case studies, we have successfully applied this method to identify-through-quantification the most general catalyst chemotype for an organocatalytic asymmetric Mannich reaction and predicted the most general chiral phosphoric acid catalyst for the addition of nucleophiles to imines. The mechanistic basis for catalyst generality can then be gleaned from the calculated values by deconstructing the contributions of chemical space and enantiomeric excess to the overall result. Finally, our generality techniques permitted the development of mechanistically informative catalyst screening sets that allow experimentalists to rationally select catalysts that have the highest probability of achieving a good result in the first round of reaction development. Overall, our findings represent a framework for interrogating catalyst generality, and this strategy should be relevant to other catalytic systems widely applied in asymmetric synthesis.

Catalyst Control over Threefold Stereogenicity: Selective Synthesis of Atropisomeric Sulfones with Stereogenic C-S Axes.

Catalyst control over higher-order stereogenicity addresses significantly extended stereochemical space, but selective methods to govern threefold stereogenic units remained elusive. Herein, we report the stereoselective synthesis of threefold stereogenic triptycyl sulfones with atropisomerism arising from a C(sp3 )-S bond. An oxidation of a stereodynamic thioether controlled by a chiral phosphoric acid catalyst allowed selective access to enantioenriched triptycyl sulfoxides. The ensuing enantiospecific and diastereoselective catalytic oxidation to a threefold stereogenic sulfone provided overall control over the stereogenic C-S axis. All three stereoisomers were addressable with enantio- and diastereodivergence and a stereoselectivity of up to (-sc): (+sc) : (ap)=94 : 6 :<1.

Switchable Brønsted Acid‐Catalyzed Ring Contraction of Cyclooctatetraene Oxide Towards the Enantioselective Synthesis of Cycloheptatrienyl‐Substituted Homoallylic Alcohols and Oxaborinanes

AbstractThe ability of cyclooctatetraene oxide to undergo two sequential ring contraction events under mild conditions, using Brønsted acid catalysis, has been studied in detail. We have found that the selectivity can be controlled by the acidity of the catalyst and by the temperature, being able to obtain selectively either the cycloheptatriene carbaldehyde product, arising from a single ring‐contraction event, or phenylacetaldehyde that is formed after a second ring contraction process. A complete mechanistic picture of the reaction and a rationale behind the influence of the catalyst is provided based on both experimental and computational data. Finally, this acid‐catalyzed ring contraction has been coupled with an in situ enantioselective allylation reaction, delivering enantioenriched cycloheptatrienyl‐substituted homoallylic alcohols when it is carried out in the presence of a chiral phosphoric acid catalyst. These homoallylic alcohols have also been converted into enantioenriched oxaborinanes through copper‐catalyzed nucleophilic borylation/cyclization protocol.magnified image

Data science enables the development of a new class of chiral phosphoric acid catalysts

The widespread success of BINOL-chiral phosphoric acids (CPAs) has led to the development of several high molecular weight, sterically encumbered variants. Herein, we disclose an alternative, minimalistic chiral phosphoric acid backbone incorporating only a single instance of point chirality. Data science techniques were used to select a diverse training set of catalysts, which were benchmarked against the transfer hydrogenation of an 8-aminoquinoline. Using a univariate classification algorithm and multivariate linear regression, key catalyst features necessary for high levels of selectivity were deconvoluted, revealing a simple catalyst model capable of predicting selectivity for out-of-set catalysts. This workflow enabled extrapolation to a catalyst providing higher selectivity than both reported peptide-type and BINOL-type catalysts (up to 95:5 er). These techniques were then successfully applied towards two additional transforms. Taken together, these examples illustrate the power of combining rational design with data science (ab initio) to efficiently explore reactivity during catalyst development.

Brønsted Acid Catalyzed Friedel-Crafts Alkylation of Naphthols with In Situ Generated Naphthol-Derived ortho-Quinone Methides: Synthesis of Chiral and Achiral Xanthene Derivatives.

We disclose herein an enantioselective protocol for the Brønsted acid catalyzed addition of naphthols to in situ generated naphthol-derived ortho-quinone methides (o-QMs) followed by intramolecular cyclization, which delivers substituted chiral xanthene derivatives, in a one-pot reaction sequence under mild conditions. This process serves to convert naphthol-derived ortho-hydroxyl benzylic alcohols into reactive naphthol-derived o-QMs using a chiral phosphoric acid (CPA) catalyst. Moreover, it is helpful in controlling the enantioselectivity of the carbon-carbon bond-forming event via hydrogen-bonding followed by intramolecular cyclization. Additionally, for the first time, we observe a Brønsted acid catalyzed C(sp2)-C(sp3) bond cleavage of naphthol-derived ortho-hydroxyl benzylic alcohols for the synthesis of achiral xanthene (sigma plane containing) derivatives in good to excellent yields.

Catalytic Asymmetric Synthesis of Atropisomeric N-Aryl 1,2,4-Triazoles.

The atroposelective synthesis of N-aryl 1,2,4-triazoles was developed. A cyclodehydration reaction was rendered asymmetric with the use of a chiral phosphoric acid catalyst to afford atropisomeric N-aryl 1,2,4-triazoles in up to 91:9 er. Recrystallization of the isolated heterocycle further enriched the atropisomeric ratio of several analogs to 99:1 er or greater. A divergent and substrate-dependent reaction pathway yielding a different heterocyclic product is also disclosed.