Enantioselective Transformations by "1 + x" Synergistic Catalysis with Chiral Primary Amines.

ConspectusSynergistic catalysis is a powerful tool that involves two or more distinctive catalytic systems to activate reaction partners simultaneously, thereby expanding the reactivity space of individual catalysis. As an established catalytic strategy, organocatalysis has found numerous applications in enantioselective transformations under rather mild conditions. Recently, the introduction of other catalytic systems has significantly expanded the reaction space of typical organocatalysis. In this regard, aminocatalysis is a prototypical example of synergistic catalysis. The combination of aminocatalyst and transition metal could be traced back to the early days of organocatalysis and has now been well explored as an enabling catalytic strategy. Particularly, the acid-base properties of aminocatalysis can be significantly expanded to include usually electrophiles generated in situ via metal-catalyzed cycles. Later on, aminocatalyst has also been exploited in synergistically combining with photochemical and electrochemical processes to facilitate redox transformations. However, synergistically combining one type of aminocatalyst with many different catalytic systems remains a great challenge. One of the most daunting challenges is the compatibility of aminocatalysts in coexistence with other catalytic species. As nucleophilic species, aminocatalysts may also bind with metal, which leads to mutual inhibition or even quenching of the individual catalytic activity. In addition, oxidative stability of aminocatalyst is also a non-neglectable issue, which causes difficulties in exploring oxidative enamine transformations.In 2007, we developed a vicinal diamine type of chiral primary aminocatalysts. This class of primary aminocatalysts was developed and evolved as functional and mechanistic mimics to the natural aldolase and has been widely applied in a number of enamine/iminium ion-based transformations. By following a "1 + x" synergistic strategy, the chiral primary amine catalysts were found to work synergistically or cooperatively with a number of transition metal catalysts, such as Pd, Rh, Ag, Co, and Cu, or other organocatalysts, such as B(C6F5)3, ketone, selenium, and iodide. Photocatalysis and electrochemical processes can also be incorporated to work together with the chiral primary amine catalysts. The 1 + x catalytic strategy enabled us to execute unexploited transformations by fine-tuning the acid-base and redox properties of the enamine intermediates and to achieve effective reaction and stereocontrol beyond the reach individually. During these efforts, an unprecedented excited-state chemistry of enamine was uncovered to make possible an effective deracemization process. In this Account, we describe our recent efforts since 2015 in exploring synergistic chiral primary amine catalysis, and the content is categorized according to the type of synergistic partner such that in each section the developed synergistic catalysis, reaction scopes, and mechanistic features are presented and discussed.

Aerobic Asymmetric Allylic C-H Alkylation by Synergistic Chiral Primary Amine-Palladium-Hydroquinone Catalysis.

A synergistic chiral primary amine/palladium /p-hydroquinone catalysis was developed to facilitate oxidative asymmetric allylic C-H alkylation under aerobic conditions. The ternary synergistic catalysis enables a facile allylic C-H activation and alkylation with oxygen so that stoichiometric utilization of benzoquinone can be avoided. The identified optimal catalytic system allows for terminal addition to allyl arenes with α-branched ß-ketocarbonyls to afford allylic adducts bearing all-carbon quaternary centers with high regio- and enantioselectivity. This work provides new insights for further studies on the aerobically oxidative C-H alkylation reaction.

Visible Light Promoted de Mayo Type Reaction of Bicyclo[1.1.0]butanes.

We reported herein a visible light mediated de Mayo-type reaction between 1,3-diketones and BCB. The reaction proceeds through a [2π+2σ] cycloaddition and retro-aldol sequence, producing cis-difunctionalized cyclobutanes in high yields with good regio- and diastereoselectivity.

Transition-Metal-Free Direct α-Arylation of Weinreb-type Amides with Arylboronic Acids through Aza-oxyallyl Cation Intermediates.

Here, we report an efficient transition-metal-free C(sp2)-C(sp3) Suzuki-Miyaura-type cross-coupling between α-halo Weinreb-type amides and arylboronic acids. The reaction is carried out by capturing active aza-oxyallyl cation (AOAC) with arylboronic acid to form a boron "ate" complex, followed by 1,4-migration to give α-aryl amides with good yields.

Accurate Protein pKa Prediction with Physical Organic Chemistry Guided 3D Protein Representation.

Protein pKa is a fundamental physicochemical parameter that dictates protein structure and function. However, accurately determining protein site-pKa values remains a substantial challenge, both experimentally and theoretically. In this study, we introduce a physical organic approach, leveraging a protein structural and physical-organic-parameter-based representation (P-SPOC), to develop a rapid and intuitive model for protein pKa prediction. Our P-SPOC model achieves state-of-the-art predictive accuracy, with a mean absolute error (MAE) of 0.33 pKa units. Furthermore, we have incorporated advanced protein structure prediction models, like AlphaFold2, to approximate structures for proteins lacking three-dimensional representations, which enhances the applicability of our model in the context of structure-undetermined protein research. To promote broader accessibility within the research community, an online prediction interface was also established at isyn.luoszgroup.com.

Phase-Transfer Catalysis for Electrochemical Chlorination and Nitration of Arenes.

A biphasic anodic oxidation method for aromatic halogenation process was developed, where aqueous metal salts were directly used as halogen source. Ammonium salts serve as both electrolytes and phase transfer catalysis to facilitate anion transport and oxidative transformation. This design allows for chlorination or nitration of multiple types of arenes using NaCl or KNO2.

Catalytic Asymmetric Visible-Light de Mayo Reaction by ZrCl4-Chiral Phosphoric Acid Complex.

Catalytic asymmetric de Mayo reaction was achieved for the first time under visible light using asymmetric binary acid catalysis (ABC) involving zirconium chloride and chiral phosphoric acid (CPA). The chiral zirconium catalysis enables effective reactions over a broad range of 1,3-diketones and alkenes with up to >99% yield and 98% ee. The key chiral zirconium enolate was isolated and characterized to account for the observed catalysis and stereoselectivity.

Catalytic Deracemization Reactions.

Deracemization, which converts a racemate into its single enantiomer without separation of the intermediate, has gained renewed interest in asymmetric synthesis with its inherent atomic economy and high efficiency. However, this ideal process requires selective energy input and delicate reaction design to surmount the thermodynamical and kinetical constraints. With the rapid development of asymmetric catalysis, many catalytic strategies in concert with exogenous energy input have been exploited to facilitate this nonspontaneous enantioenrichment. In this perspective, we will discuss the basic ideas to accomplish catalytic deracemization, categorized by the three major exogenous energy sources including chemical (redox)-, photo- and mechanical energy from attrition. Emphasis will be given to the catalytic features and the underlying deracemization mechanism together with perspectives on future development.

Electrophotochemical Metal-Catalyzed Enantioselective Decarboxylative Cyanation.

In contrast to the rapid growth of electrophotocatalysis in recent years, enantioselective catalytic reactions powered by this unique methodology remain rare. In this work, we report an electrophotochemical metal-catalyzed protocol for direct asymmetric decarboxylative cyanation of aliphatic carboxylic acids. The synergistic merging of electrophotochemical cerium catalysis and asymmetric electrochemical copper catalysis permits mild reaction conditions for the formation and utilization of the key carbon centered radicals by combining the power of light and electrical energy. Electrophotochemical cerium catalysis enables radical decarboxylation to produce alkyl radicals, which could be effectively intercepted by asymmetric electrochemical copper catalysis for the construction of C-CN bonds in a highly stereoselective fashion. This environmentally benign method smoothly converts a diverse array of arylacetic acids into the corresponding alkyl nitriles in good yields and enantioselectivities without using chemical oxidants or pre-functionalization of the acid substrates and can be readily scaled up.

Prediction of Nucleophilicity and Electrophilicity Based on a Machine-Learning Approach.

Nucleophilicity and electrophilicity dictate the reactivity of polar organic reactions. In the past decades, Mayr et al. established a quantitative scale for nucleophilicity (N) and electrophilicity (E), which proved to be a useful tool for the rationalization of chemical reactivity. In this study, a holistic prediction model was developed through a machine-learning approach. rSPOC, an ensemble molecular representation with structural, physicochemical and solvent features, was developed for this purpose. With 1115 nucleophiles, 285 electrophiles, and 22 solvents, the dataset is currently the largest one for reactivity prediction. The rSPOC model trained with the Extra Trees algorithm showed high accuracy in predicting Mayr's N and E parameters with R2 of 0.92 and 0.93, MAE of 1.45 and 1.45, respectively. Furthermore, the practical applications of the model, for instance, nucleophilicity prediction of NADH, NADPH and a series of enamines showed potential in predicting molecules with unknown reactivity within seconds. An online prediction platform (http://isyn.luoszgroup.com/) was constructed based on the current model, which is available free to the scientific community.

Asymmetric C-H Dehydrogenative Allylic Alkylation by Ternary Photoredox-Cobalt-Chiral Primary Amine Catalysis under Visible Light.

We report herein an asymmetric C-H dehydrogenative allylic alkylation by a synergistic catalytic system involving a chiral primary amine, a photoredox catalyst, and a cobaloxime cocatalyst. The ternary catalytic system enables the coupling of ß-ketocarbonyls and olefins with good yields and high enantioselectivities. Mechanism studies disclosed a cooperative radical addition process with a chiral α-imino radical and Co(II)-metalloradical wherein the chiral primary aminocatalyst and the cobaloxime catalyst work in concert to control the stereoinduction.

Chiral Primary Amine Catalyzed α-Arylation of Simple Ketones via Asymmetric Retro-Claisen Cleavage.

Highly enantioselective α-arylation of simple ketones has been achieved by chiral primary amine catalyzed asymmetric retro-Claisen cleavage of ß-diketones. This mild organocatalytic strategy enables the construction of α-aryl tertiary carbon stereocenters in good yields and excellent enantioselectivities (up to 98 % ee) with the para-quinone monoimines as aryl sources. Furthermore, oxidative catalytic asymmetric α-arylation has also been realized with free p-aminophenols.

Electrophotochemical Metal-Catalyzed Decarboxylative Coupling of Aliphatic Carboxylic Acids.

An electrophotochemical dual metal-catalyzed protocol for decarboxylative arylation of simple aliphatic carboxylic acids with aryl halides is reported. The relative stabilities of catalytically active metal complexes simultaneously generated at anode and cathode are the key design elements for the success of this convergent paired electrolysis. This new electrophotocatalytic method is mild, robust, and most importantly, capable of accommodating simple primary aliphatic acids including acetic acid - ubiquitous and variegated structural motifs yet remain oddly challenging substrates - directly as native functional groups for decarboxylative C(sp2 )-C(sp3 ) bond formation.

An Ensemble Structure and Physicochemical (SPOC) Descriptor for Machine-Learning Prediction of Chemical Reaction and Molecular Properties.

Feature representations, or descriptors, are machines' chemical language that largely shapes the prediction capability, generalizability and interpretability of machine learning models. To develop a generally applicable descriptor is highly warranted for chemists to deal with conventional prediction tasks in the context of sparsely distributed and small datasets. Inspired by the chemist's vision on molecules, we presented herein an ensemble descriptor, SPOC, curated on the principles of physical organic chemistry that integrates Structure and Physicochemical property (SPOC) of a molecule. SPOC could be readily constructed by combining molecular fingerprints, representing the structure of a given molecule, and molecular physicochemical properties extracted from RDKit or Mordred molecular descriptors. The applicability of SPOC was fully surveyed in a range of well-structured chemical databases with machine learning tasks varying from regression to classifications.

Catalytic Asymmetric α-Alkylsulfenylation with a Disulfide Reagent.

The use of alkylthio electrophiles in synthesis has remained elusive because of the lack of a suitable reagent that is practical and of excellent enantioselectivity and appropriate reactivity. In this work we introduce a novel alkylthio reagent based on the 2-mercapto-5-methyl-1,3,4-thiadiazole (MMTD) fragment for direct alkylsulfenylation of ketones and aldehydes. It can be readily prepared by the oxidative coupling between thiadiazole and other alkylthio reagents and be combined with chiral primary aminocatalysis. This protocol provides facile access to diverse α-alkylthio quaternary carbon centers with good stereoselectivities.

Chiral Primary Amine/Ketone Cooperative Catalysis for Asymmetric α-Hydroxylation with Hydrogen Peroxide.

Carbonyls and amines are yin and yang in organocatalysis as they mutually activate and transform each other. These intrinsically reacting partners tend to condense with each other, thus depleting their individual activity when used together as cocatalysts. Though widely established in many prominent catalytic strategies, aminocatalysis and carbonyl catalysis do not coexist well, and, as such, a cooperative amine/carbonyl dual catalysis remains essentially unknown. Here we report a cooperative primary amine and ketone dual catalytic approach for the asymmetric α-hydroxylation of ß-ketocarbonyls with H2O2. Besides participating in the typical enamine catalytic cycle, the chiral primary amine catalyst was found to work cooperatively with a ketone catalyst to activate H2O2 via an oxaziridine intermediate derived from an in-situ-generated ketimine. Ultimately, this enamine-oxaziridine coupling facilitated the highly controlled α-hydroxylation of several ß-ketocarbonyls in excellent yield and enantioselectivity. Notably, late-stage hydroxylation for peptidyl amide or chiral esters can also be achieved with high stereoselectivity. In addition to its operational simplicity and mild conditions, this cooperative amine/ketone catalytic approach also provides a new strategy for the catalytic activation of H2O2 and expands the domain of typical amine and carbonyl catalysis to include this challenging transformation.

Catalytic Asymmetric Disulfuration by a Chiral Bulky Three-Component Lewis Acid-Base.

A three-component Lewis acid-base (Lewis trio) involving a bulky chiral primary amine, B(C6 F5 )3 and a bulky tertiary amine has been developed as an effective enamine catalyst for enantioselective disulfuration reactions. The bulky tertiary amine was found to activate a bulky primary-tertiary diamine-borane Lewis pair for enamine catalysis via frustrated interaction. The resulted chiral bulky Lewis trio (BLT) allows for the construction of chiral disulfides via direct disulfuration with ß-ketocarbonyls or α-branched aldehydes in a practical and highly stereocontrolled manner.

π-Coordinating Chiral Primary Amine/Palladium Synergistic Catalysis for Asymmetric Allylic Alkylation.

We report an arene-containing chiral primary amine as a dual aminocatalyst and ligand: the π-coordinating aminocatalyst/palladium synergistic catalysis for asymmetric allylic alkylation of α-branched ß-ketocarbonyls. The use of arene-containing chiral primary amine catalyst led to not only enhanced reaction rate but also reversed chiral induction compared with its sterically bulky derivative. Both enantiomers of the allylic adducts bearing acyclic all-carbon quaternary stereocenters could be obtained from the same configured chiral aminocatalysts with high efficiency and excellent regio-, stereo-, and enantioselectivity. Mechanistic studies revealed a distinctive Pd-arene π-coordination mode for effective catalysis. The π-coordinating chiral primary amine catalyst could be successfully applied in the asymmetric allylation reactions of vinylethylene carbonates, vinyl epoxides, or simple allylic alcohols.

Catalytic Asymmetric Electrochemical α-Arylation of Cyclic ß-Ketocarbonyls with Anodic Benzyne Intermediates.

Asymmetric catalysis with benzyne remains elusive because of the highly fleeting and nonpolar nature of benzyne intermediates. Reported herein is an electrochemical approach for the oxidative generation of benzynes (cyclohexyne) and its successful merging with chiral primary aminocatalysis, formulating the first catalytic asymmetric enamine-benzyne (cyclohexyne) coupling reaction. Cobalt acetate was identified to stabilize the in situ generated arynes and facilitate its coupling with an enamine. This catalytic enamine-benzyne protocol provides a concise method for the construction of diverse α-aryl (α-cyclohexenyl) quaternary carbon stereogenic centers with good stereoselectivities.

Holistic Prediction of the pKa in Diverse Solvents Based on a Machine-Learning Approach.

While many approaches to predict aqueous pKa values exist, the fast and accurate prediction of non-aqueous pKa values is still challenging. Based on the iBonD experimental pKa database (39 solvents), a holistic pKa prediction model was established using machine learning. Structural and physical-organic-parameter-based descriptors (SPOC) were introduced to represent the electronic and structural features of the molecules. The models trained with a neural network or the XGBoost algorithm showed the best prediction performance with a low MAE value of 0.87 pKa units. The approach allows a comprehensive mapping of all possible pKa correlations between different solvents and it was validated by predicting the aqueous pKa and micro-pKa of pharmaceutical molecules and pKa values of organocatalysts in DMSO and MeCN with high accuracy. An online prediction platform was constructed based on the current model, which can provide pKa prediction for different types of X-H acidity in the most commonly used solvents.