Chiral Primary Amine Research Articles

Primary Amine-Functionalized Chiral Covalent Organic Framework Enables High-Efficiency Asymmetric Catalysis in Water.

Aqueous asymmetric catalysis using chiral covalent organic frameworks (COFs) represents a significant advancement but remains to be explored. Herein, we present the first example of aqueous asymmetric catalysis catalyzed by a primary amine-tagged chiral D-ADP-TAPB COF. The D-ADP-TAPB COF was synthesized by the postsynthetic deprotection of D-ADP-TAPB-Boc bearing a protective tert-butoxycarbonyl (Boc) group, which was constructed by a Schiff-base reaction between an alanine-derived chiral building block (D-ADP-Boc) and 1,3,5-tris(4-aminophenyl)benzene (TAPB). The crystalline D-ADP-TAPB COF exhibits a uniform, spherical morphology with abundant, well-distributed chiral primary amines, rendering it highly active in the asymmetric aldol reaction between cyclohexanone and 4-nitrobenzaldehyde. Notably, this reaction is conducted entirely in water, achieving impressive yields and enantiomeric excess (ee) values of up to 90 and 85%, respectively. To the best of our knowledge, D-ADP-TAPB COF represents the first chiral COF catalyst with high reactivity and enantioselectivity for an asymmetric aldol reaction solely in water, eliminating the need for conventional organic solvents. Moreover, a plausible mechanism for D-ADP-TAPB COF-mediated aqueous asymmetric aldol reactions is elucidated. This work not only expands the toolbox for designing rare primary amine-functionalized chiral COFs for asymmetric catalysis but also opens exciting avenues for developing green and water-based enantioselective catalysis.

Transaminase-Catalyzed Synthesis of β-Branched Noncanonical Amino Acids Driven by a Lysine Amine Donor.

Transaminases are choice biocatalysts for the synthesis of chiral primary amines, including amino acids bearing contiguous stereocenters. In this study, we employ lysine as a "smart" amine donor in transaminase-catalyzed dynamic kinetic resolution reactions to access β-branched noncanonical arylalanines. Our mechanistic investigation demonstrates that, upon transamination, the lysine-derived ketone byproduct readily cyclizes to a six-membered imine, driving the equilibrium in the desired direction and thus alleviating the need to load superstoichiometric quantities of the amine donor or deploy a multienzyme cascade. Lysine also shows good overall compatibility with a panel of wild-type transaminases, a promising hint of its application as a smart donor more broadly. Indeed, by this approach, we furnished a broad scope of β-branched arylalanines, including some bearing hitherto intractable cyclopropyl and isopropyl substituents, with high yields and excellent selectivities.

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.

Biocatalytic, Enantioenriched Primary Amination of Tertiary C-H Bonds.

Intermolecular functionalization of tertiary C-H bonds to construct fully substituted stereogenic carbon centers represents a formidable challenge: without the assistance of directing groups, state-of-the-art catalysts struggle to introduce chirality to racemic tertiary sp 3 -carbon centers. Direct asymmetric functionalization of such centers is a worthy reactivity and selectivity goal for modern biocatalysis. Here we present an engineered nitrene transferase (P411-TEA-5274), derived from a bacterial cytochrome P450, that is capable of aminating tertiary C-H bonds to provide chiral α-tertiary primary amines with high efficiency (up to 2300 total turnovers) and selectivity (up to >99% enantiomeric excess (e.e.)). The construction of fully substituted stereocenters with methyl and ethyl groups underscores the enzyme's remarkable selectivity. A comprehensive substrate scope study demonstrates the biocatalyst's compatibility with diverse functional groups and tertiary C-H bonds. Mechanistic studies elucidate how active-site residues distinguish between the enantiomers and enable the enzyme to perform this transformation with excellent enantioselectivity.

Engineering the substrate acceptance of l-amine dehydrogenase enables the collective biocatalytic synthesis of N-heterocyclic primary amines

Chiral N-heterocyclic primary amines are highly attractive synthons in the pharmaceutical industry. Amine dehydrogenases (AmDHs)-catalyzed direct asymmetric reductive amination of the readily available N-heterocyclic ketones represents a promising approach for synthesizing N-heterocyclic primary amines. However, the limited substrate acceptance of AmDHs restricts their application in biocatalytic synthesis. Here, we engineered the substrate acceptance of L-EsAmDH from Exiguobacterium sibiricum to access a panel of structurally diverse N-heterocyclic ketones. Through reverse substrate design and combining with substrate walking strategy, two active mutants with extended substrate specificity toward N-Boc-4-acetylpiperidine were identified, and two additional rounds of iterative site mutagenesis further increased the activity by 116.3-fold. The optimal mutant M4-2 (L49G/V303A/L307A/T143A) exhibited significantly expanded N-Boc, N-Bn, and N-Cbz-substituted heterocyclic ketones scope, and its practical biocatalytic synthesis performance was verified in the gram-scale synthesis of (R)-4-aminoethyl-1-Boc-piperidine, achieving 95 % conversion, >99 % ee, and an overall isolated yield of 86 % (9.8 g). Our study lays the foundation for the collective biocatalytic synthesis of structurally diverse N-heterocyclic primary amines and gives referable guidance for engineering AmDH family members into versatile biocatalysts.

DFT study on the Stereoselectivity of Asymmetric Synthesis of C, N‐Cyclic Azomethine Imines with Allyl Alkyl Ketones

AbstractBased on the density functional theory, the stereoselectivity of the asymmetric synthesis of tetrahydroisoquinolinopyrazole derivatives by the cycloaddition reaction of C, N‐cyclic azomethine imines with allyl alkyl ketones which was catalyzed using a chiral primary amine is studied theoretically. The results demonstrate that the four chiral transition states (TS‐1R2R, TS‐1R2S, TS‐1S2R and TS‐1S2S) are formed by the reaction of dienamine intermediate with C, N‐cyclic azomethine imine, and the reaction barrier of TS‐1R2S is in the lowest level (ΔG=6.98 kcal/mol). The consequence reveal that the 1R2S configuration product is formed by TS‐1R2S transition state. Non‐covalent interaction and electron density topology analysis show that the stereoselectivity of the chiral product is determined through van der Waals forces and hydrogen bond interaction of the transition state molecules.

Stereoselective mechanochemical synthesis of thiomalonate Michael adducts via iminium catalysis by chiral primary amines.

The study presents a novel approach utilizing iminium salt activation and mild enolization of thioesters, offering an efficient and rapid synthesis of Michael adducts with promising stereoselectivity and marking a significant advancement in mechanocatalysis. The stereoselective addition of bisthiomalonates 1-4 to cyclic enones and 4-chlorobenzylideneacetone proceeds stereoselectively under iminium activation conditions secured by chiral primary amines, in contrast to oxo-esters as observed in dibenzyl malonate addition. Mild enolization of thioesters allows for the generation of Michael adducts with good yields and stereoselectivities. Reactions in a ball mill afford product formation with similar efficacy to solution-phase reactions but with slightly reduced enantioselectivity, yet they yield products in just one hour compared to 24 or even 168 hours in solution-based reactions. It is noteworthy that this represents one of the early reports on the application of iminium catalysis using first-generation chiral amines under mechanochemical conditions, along with the utilization of easily enolizable thioesters as nucleophiles in this transformation.

Efficient synthesis of (R)-4-methoxyamphetamine and its analogues under low ammonium concentration using engineered amine dehydrogenase

Amphetamine and its analogues are widely used in various drugs because of its powerful and diverse effects on the nervous system of the brain, e.g., (R)-4-methoxyamphetamine is the key intermediate in formoterol for the treatment of asthma. Biocatalytic reductive amination of ketone by amine dehydrogenase (AmDH) is a potential method for the synthesis of chiral primary amines, but usually requires a high ammonium concentration to drive the amination reaction. In this study, iterative evolution was performed to generate a LsAmDH mutant W5–5 (T123G/S157T/S275G), which was able to catalyze the reductive amination of 200 mM 4-methoxypropiophenone at 500 mM ammonium concentration to afford (R)-4-methoxyamphetamine with >99% ee and 90% isolated yield. This variant also catalyzed the reductive amination of other phenylacetone analogues with high yields and excellent enantioselectivity at low ammonium concentration. This would greatly reduce the generation of ammonium-containing wastes and make the reaction more economic and greener, laying a foundation for the industrial application of AmDHs.

Understanding how charge-charge interaction affects the stereochemistry of enamine fluorination by chiral primary amine catalysis

Understanding how charge-charge interaction affects the stereochemistry of enamine fluorination by chiral primary amine catalysis

Application of methyl itaconate–anthracene adducts (MIAs) in configuration assignment of chiral primary amines by means of 1H NMR

Methyl itaconate–anthracene adducts (MIAs) were previously introduced as chiral derivatizing agents (CDAs) for the determination of chiral secondary alcohols. In this study, they were further employed with chiral primary amines to assign their absolute configuration. Each chiral amine compound was linked to the (R)- and (S)-MIAs through amidation to obtain diastereomeric amides in moderate yield. The modified Mosher's method was applied, where the difference in chemical shift (ΔδSR = δHS−MIA-amide – δHR−MIA-amide) values of each substituent of the chiral amine adducts was utilized to validate the capability of MIAs as CDAs. Finally, the proposed model was successfully achieved, and the MIAs were proven effective for the determination of the absolute configuration of chiral amines.

Visible Light-Promoted Enantioselective Aerobic Hydroxylation of β-Ketocarbonyls by Chiral Primary Amine Catalysis

Highly effective and stereoselective enamine-singlet oxygen coupling was achieved by synergistic chiral primary amine and photocatalysis in hexafluoroisopropanol. The current enamine catalysis enables α-hydroxylation of β-ketocarbonyls with good yields and high enantioselectivity across a broad range of substrates. Mechanistic studies revealed a direct participation of solvents in the critical enamine coupling step, and a solvent-1O2 H-bonding mode was invoked to account for the dramatic solvent effect.

Experimental spectroscopic investigation and electrochemical sensor studies of facile and controllable synthesis of ferrocene-based chiral Schiff base compounds

BackgroundThis work aims at preparing a novel series of low-cost, easily-synthesizable, and modifiable ferrocene-based chiral Schiff base compounds designed to use different application areas of the electrochemical sensor properties. MethodsFerrocene-based chiral Schiff bases (1–4) have been synthesized by the reactions of ferrocene carboxaldehyde and different chiral primary amines in the presence of CH3COOH as a catalyst under mild conditions. After that, the reaction of ferrocene-based chiral Schiff bases (1–4) and NaBH4 in methanol gave the ferrocene-based chiral Schiff base (1a-4a) compounds, respectively. The target ferrocene-based chiral Schiff base compounds were characterized by various spectroscopic techniques and the obtained experimental and spectroscopic findings show that they were synthesized successfully and fairly consistent with the proposed molecular structures. Significant findingsThe electrochemical properties of ferrocene-based chiral Schiff base compounds were investigated by cyclic voltammetry techniques (CV) at GCE. This work provides a new idea that ferrocene-based chiral Schiff base compounds in reduced form (1a-4a) are more suitable for the fabrication of a ganciclovir-sensitive as an electrochemical sensor. The electrochemical sensor was fabricated for ganciclovir using compound (2a), which exhibited the best electroactivity among these compounds due to the increase of electrocatalytic activity in the electrooxidation process of ganciclovir.

Ruthenium-Catalyzed Direct Asymmetric Reductive Amination for the Synthesis of a Chiral Primary Amine Intermediate En Route to a PDE2A Inhibitor, TAK-915

Ruthenium-Catalyzed Direct Asymmetric Reductive Amination for the Synthesis of a Chiral Primary Amine Intermediate En Route to a PDE2A Inhibitor, TAK-915

Synthesis of Chiral Primary Amines via Enantioselective Reductive Amination: From Academia to Industry

AbstractChiral primary amines widely exist in drugs and are exceptionally important subunits or synthons in the syntheses of chiral secondary and tertiary amines of medicinal interest. Metal-catalyzed enantioselective reductive amination (ERA) of ketones with ammonium salts or ammonia provides a direct method for their synthesis. Although very useful, progress in this field has been very slow and important advances have only been achieved in the last few years. Several major challenges exist in this reaction, including (1) the reversible formation of unstable NH-imine intermediates; (2) the strong coordination property of N-containing reagents toward metal species; and (3) the lack of efficient catalytic systems that enable high enantiocontrol. Generally, the efficiency and enantiocontrol of this reaction is dependent on the substrate type, for instance, the use of α-keto esters/amides or aryl alkyl ketones is well established and they have even been used in the industrial production of chiral amine drugs. However, highly enantioselective control in dialkyl ketones, cyclic ketones, and α-keto acids remains unsolved. Herein, the historical development of ERA reactions with ammonium salts or ammonia gas is summarized, and novel synthetic applications toward useful synthons or drugs are presented. In addition, the factors restricting the growth of this method are also discussed.1 Introduction2 Enantioselective Reductive Amination via Hydrogenation2.1 Enantioselective Reductive Amination of β-Keto Esters/Amides2.2 Enantioselective Reductive Amination of Simple Ketones2.3 Enantioselective Reductive Amination of α-Functionalized Ketones2.4 Enantioselective Reductive Amination/Cyclization Cascade Reactions2.5 Others3 Enantioselective Reductive Amination via Transfer Hydrogenation4 Synthetic Applications5 Conclusions and Outlook

Subtilisin integrated artificial plant cell walls as heterogeneous catalysts for asymmetric synthesis of (S)-amides.

Subtilisin integrated artificial plant-cell walls (APCWs) were fabricated by self-assembly using cellulose or nanocellulose as the main component. The resulting APCW catalysts are excellent heterogeneous catalysts for the asymmetric synthesis of (S)-amides. This was demonstrated by the APCW-catalyzed kinetic resolution of several racemic primary amines to give the corresponding (S)-amides in high yields with excellent enantioselectivity. The APCW catalyst can be recycled for multiple reaction cycles without loss of enantioselectivity. The assembled APCW catalyst was also able to cooperate with a homogeneous organoruthenium complex, which allowed for the co-catalytic dynamic kinetic resolution (DKR) of a racemic primary amine to give the corresponding (S)-amide in high yield. The APCW/Ru co-catalysis constitutes the first examples of DKR of chiral primary amines when subtilisin is used as a co-catalyst.

Bio‐inspired Small Molecular Catalysis

Comprehensive SummaryNature is an inspiring resource for chemists to exploit uncharted chemical spaces. Enzymes in nature are characteristic of high efficiency and exquisite stereocontrol under rather mild conditions. Not surprisingly, chemists have a long history in developing new catalysts by learning from and imitating the natural enzymes. This review summarizes our long‐standing efforts in developing bio‐inspired small molecular catalysis. These were categorized according to the employed strategies: 1) bi‐/multi‐functional strategy for the bio‐inspired chiral primary amine catalyst; 2) cofactor strategy for bio‐inspiredortho‐quinone catalyst; 3) intermediate strategy for chiral latent carbocation catalysis based on natural carbocation process. Each section includes brief introduction of the biological origin, design of catalyst, development of methodology as well as the underlying mechanistic insights.What is the most favorite and original chemistry developed in your research group?I hope it's always the next one.How do you get into this specific field? Could you please share some experiences with our readers?Nature provides many astonishing catalytic machineries for building up molecular complexity and harnessing energy in the most efficient ways. Nature's recipe for catalysis serves as a starting point to develop new catalyst for synthetic and energy chemistry. I was trained as a synthetic chemist in a physical organic group in Nankai and ICCAS, and spent part of my graduate studies doing enzymatic synthesis of oligosaccharide and its related biological applications in Ohio State University. This gave me a mixed view on organocatalysis, then under its golden stage of renaissance, not only for its synthetic potentials as a new catalytic concept, but also with an eye on its biological origin and possible impact beyondsynthesis. I also benefit a lot from the physical organic chemistry training which helps to shape my research path in width and depth, in a way I never imagined and expected at the beginning of my career.How do you supervise your students?Try to inspire beyond instruct. I learned and am still learning. “因材施教” is easy to say than to do. In reality, I become bossy the way I dislike and have to instruct heavily.What is the most important personality for scientific research?Curiosity, broad reading and sufficient “free time” for daydreaming. In order to have enough time to waste, you have to work really hard at first.Who influences you mostly in your life?My Ph.D. supervisor, Prof. Jin‐Pei Cheng who teaches me a rational and quantitative view for chemistry and inspires me all the time to pursue a rational approach in research.

Sulfonation of pyrene-based metal–organic framework for the encapsulation of chiral organocatalyst and application in asymmetric aldol addition

Encapsulation of bulky chiral chiral organocatalysts into metal-organic frameworks (MOFs) is a challenge because of difficult control on the crystallinity of MOFs. Herein, Zr6(μ3-OH)8(OH)8TBAPy)2 (NU-1000) with is sulfonated at − 30 °C by ClSO3H at low concentration, and then bulky cinchona alkaloid-derived chiral primary amines, 9-amino (9-deoxy)epi-quinine (QNNH2) and 9-amino(9-deoxy) epi-cinchonidine (CDNH2), are anchored to NU-1000 via acid-base reaction. At a molar ratio of QNNH2/-SO3H = 0.96, NU-1000-supported QNNH2 with high surface area (677 m2 g−1), large pore volume (0.48 cc g−1), and most probable pore size of 3.0 nm shows high yields (86–95 %) with good to excellent diasteroselectivities (anti/syn = 81/19–93/3) and enantioselectivies (89–96 %ee) in the asymmetric aldol reaction of cyclohexanone with benzaldehydes bearing electron-withdrawing groups (-NO2 and -CN) at o, m, p-positions. This work develops an effective strategy for anchoring bulky chiral organocatalyst into the porous framework of MOFs, broadening the application of MOFs in heterogeneous asymmetric organocatalysis.

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 β-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.

Inducing Propeller Chirality in Triaryl Boranes with Chiral Amines.

Stabilization of chiral propeller conformations in triaryl compounds is challenging due to generally low racemization barriers. Nonetheless, it was recently found that chiral conformational preferences can be induced to triaryl boranes by incorporating point-chiral alkylether chains to the aryl blades and subsequently locking the structure with ammonia. A four-point interaction, meaning that the cooperative effects of Lewis-adduct formation and three hydrogen bonds, was proposed as stabilizing mechanism. Herein, it was shown that three such strong interactions suffice to introduce a preferential propeller handedness. Although DFT calculations predict no noteworthy preferences for either P- or M-chiral propellers for some of the investigated triarylborane-amine adducts that were prepared with chiral primary amines, vibrational circular dichroism (VCD) spectroscopic characterizations revealed that there is indeed a measurable excess of one propeller handedness. Furthermore, the steric demand of the amine was found to play a key role in the induction process and especially in preventing blade rotations.

Chiral Cyclic Alkyl Amino Carbene (CAAC) Transition-Metal Complexes: Synthesis, Structural Analysis, and Evaluation in Asymmetric Catalysis

Despite recent advances in the field of cyclic alkyl amino carbenes (CAACs) including a few complementary synthetic strategies affording CAACs with various substitution patterns, the application potential of chiral CAACs to efficiently catalyze asymmetric organometallic transformations remains largely underdeveloped. Herein, we describe a convenient and robust route that incorporates common chiral primary amine allowing access of a broad range of chiral CAACs precursors. The corresponding transition-metal complexes with Cu, Au, Ru, Rh, Ir, and Pd were obtained in a straightforward manner. The steric parameters of the complexes were comprehensively collected by X-ray single-crystal analysis to serve as a source of information for further ligand design. The preliminary application potential of the copper CAAC complexes was tested in asymmetric conjugate borylation of an α,β-unsaturated ester providing 89:11 er, thus illustrating the potential of chiral CAACs in asymmetric catalysis.