Treatment of Organophosphorus Poisoning with 6-Alkoxypyridin-3-ol Quinone Methide Precursors: Resurrection of Methylphosphonate-Aged Acetylcholinesterase.

Organophosphorus (OP) nerve agents inhibit acetylcholinesterase (AChE), creating a cholinergic crisis in which death can occur. The phosphylated serine residue spontaneously dealkylates to the OP-aged form, which current therapeutics cannot reverse. Soman's aging half-life is 4.2 min, so immediate recovery (resurrection) of OP-aged AChE is needed. In 2018, we showed pyridin-3-ol-based quinone methide precursors (QMPs) can resurrect OP-aged electric eel AChE in vitro, achieving 2% resurrection after 24 h of incubation (pH 7, 4 mM). We prepared 50 unique 6-alkoxypyridin-3-ol QMPs with 10 alkoxy groups and five amine leaving groups to improve AChE resurrection. These compounds are predicted in silico to cross the blood-brain barrier and treat AChE in the central nervous system. This library resurrected 7.9% activity of OP-aged recombinant human AChE after 24 h at 250 µM, a 4-fold increase from our 2018 report. The best QMP (1b), with a 6-methoxypyridin-3-ol core and a diethylamine leaving group, recovered 20.8% (1 mM), 34% (4 mM), and 42.5% (predicted maximum) of methylphosphonate-aged AChE activity over 24 h. Seven QMPs recovered activity from AChE aged with Soman and a VX degradation product (EA-2192). We hypothesize that QMPs form the quinone methide (QM) to realkylate the phosphylated serine residue as the first step of resurrection. We calculated thermodynamic energetics for QM formation, but there was no trend with the experimental biochemical data. Molecular docking studies revealed that QMP binding to OP-aged AChE is not the determining factor for the observed biochemical trends; thus, QM formation may be enzyme-mediated.

4-Amidophenol Quinone Methide Precursors: Effective and Broad-Scope Nonoxime Reactivators of Organophosphorus-Inhibited Cholinesterases and Resurrectors of Organophosphorus-Aged Acetylcholinesterase.

Acetylcholinesterase (AChE) inhibition by organophosphorus (OP) compounds poses a serious health risk to humans. While many therapeutics have been tested for treatment after OP exposure, there is still a need for efficient reactivation against all kinds of OP compounds, and current oxime therapeutics have poor blood-brain barrier penetration into the central nervous system, while offering no recovery in activity from the OP-aged forms of AChE. Herein, we report a novel library of 4-amidophenol quinone methide precursors (QMP) that provide effective reactivation against multiple OP-inhibited forms of AChE in addition to resurrecting the aged form of AChE after exposure to a pesticide or some phosphoramidates. Furthermore, these QMP compounds also reactivate OP-inhibited butyrylcholinesterase (BChE) which is an in vivo, endogenous scavenger of OP compounds. The in vitro efficacies of these QMP compounds were tested for reactivation and resurrection of soluble forms of human AChE and BChE and for reactivation of cholinesterases within human blood as well as blood and brain samples from a humanized mouse model. We identify compound 10c as a lead candidate due to its broad-scope efficacy against multiple OP compounds as well as both cholinesterases. With methylphosphonates, compound 10c (250 µM, 1 h) shows >60% recovered activity from OEt-inhibited AChE in human blood as well as mouse blood and brain, thus highlighting its potential for future in vivo analysis. For 10c, the effective concentration (EC50) is less than 25 µM for reactivation of three different methylphosphonate-inhibited forms of AChE, with a maximum reactivation yield above 80%. Similarly, for OP-inhibited BChE, 10c has EC50 values that are less than 150 µM for two different methylphosphonate compounds. Furthermore, an in vitro kinetic analysis show that 10c has a 2.2- and 92.1-fold superior reactivation efficiency against OEt-inhibited and OiBu-inhibited AChE, respectively, when compared to an oxime control. In addition to 10c being a potent reactivator of AChE and BChE, we also show that 10c is capable of resurrecting (ethyl paraoxon)-aged AChE, which is another current limitation of oximes.

In-silico guided design, screening, and molecular dynamic simulation studies for the identification of potential SARS-CoV-2 main protease inhibitors for the targeted treatment of COVID-19.

COVID-19, the disease responsible for the recent pandemic, is caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The main protease (Mpro) of SARS-CoV-2 is an essential proteolytic enzyme that plays a number of important roles in the replication of the virus in human host cells. Blocking the function of SARS-CoV-2 Mpro offers a promising and targeted, therapeutic option for the treatment of the COVID-19 infection. Such an inhibitory strategy is currently successful in treating COVID-19 under FDA's emergency use authorization, although with limited benefit to the immunocompromised along with an unfortunate number of side effects and drug-drug interactions. Current COVID vaccines protect against severe disease and death but are mostly ineffective toward long COVID which has been seen in 5-36% of patients. SARS-CoV-2 is a rapidly mutating virus and is here to stay endemically. Hence, alternate therapeutics to treat SARS-CoV-2 infections are still needed. Moreover, because of the high degree of conservation of Mpro among different coronaviruses, any newly developed antiviral agents should better prepare us for potential future epidemics or pandemics. In this paper, we first describe the design and computational docking of a library of novel 188 first-generation peptidomimetic protease inhibitors using various electrophilic warheads with aza-peptide epoxides, α-ketoesters, and ß-diketones identified as the most effective. Second-generation designs, 192 compounds in total, focused on aza-peptide epoxides with drug-like properties, incorporating dipeptidyl backbones and heterocyclic ring motifs such as proline, indole, and pyrrole groups, yielding 8 hit candidates. These novel and specific inhibitors for SARS-CoV-2 Mpro can ultimately serve as valuable alternate and broad-spectrum antivirals against COVID-19.Communicated by Ramaswamy H. Sarma.

Identification of Corrosive Volatile Compounds Found in the Headspace of Chicken Noodle Soup Retorted in Metal Cans.

This study investigated the development of volatile compounds in the headspace of canned chicken noodle soup (and sought to develop appropriate testing methods). The primary objective of this study was to identify compounds in the soup that were responsible for the initiation of the corrosion in the cans. The long-term goal of these studies is to develop an efficient method to investigate how headspace volatile compounds in foods could cause corrosion defects in metal cans and how these could be corrected without undermining the quality and safety of the food. To determine and to evaluate the volatile compounds in the canned soups, selected ion flow tube-mass spectrometry (SIFT-MS) was used. The coatings of the tested cans were carefully stripped off and analyzed using this SIFT-MS method. High levels of sulfur-containing volatile compounds and organic acids were detected in both the soups and the coatings. It was concluded that during the retorting of the sealed cans filled with chicken soup, sulfur-containing volatile compounds formed and entered the headspace of the tested cans and interacted with the coating, leading to the formation of blackened stains.

Highly Enantioselective Catalytic Alkynylation of Quinolones: Substrate Scope, Mechanistic Studies, and Applications in the Syntheses of Chiral N-Heterocyclic Alkaloids and Diamines.

The alkynylation of 4-siloxyquinolinium triflates has been achieved under the influence of copper bis(oxazoline) catalysis. The identification of the optimal bis(oxazoline) ligand was informed through a computational approach that enabled the dihydroquinoline products to be produced with up to 96% enantiomeric excess. The conversions of the dihydroquinoline products to biologically relevant and diverse targets are reported.

Ligand Control in Co-Catalyzed Regio- and Enantioselective Hydroboration: Homoallyl Secondary Boronates via Uncommon 4,3-Hydroboration of 1,3-Dienes.

Enantiopure homoallylic boronate esters are versatile intermediates because the C-B bond in these compounds can be stereospecifically transformed into C-C, C-O, and C-N bonds. Regio- and enantioselective synthesis of these precursors from 1,3-dienes has few precedents in the literature. We have identified reaction conditions and ligands for the synthesis of nearly enantiopure (er >97:3 to >99:1) homoallylic boronate esters via a rarely seen cobalt-catalyzed [4,3]-hydroboration of 1,3-dienes. Monosubstituted or 2,4-disubstituted linear dienes undergo highly efficient regio- and enantioselective hydroboration with HBPin catalyzed by [(L*)Co]+[BARF]-, where L* is typically a chiral bis-phosphine ligand with a narrow bite angle. Several such ligands (e.g., i-PrDuPhos, QuinoxP*, Duanphos, and BenzP*) that give high enantioselectivities for the [4,3]-hydroboration product have been identified. In addition, the equally challenging problem of regioselectivity is uniquely solved with a dibenzooxaphosphole ligand, (R,R)-MeO-BIBOP. A cationic cobalt(I) complex of this ligand is a very efficient (TON >960) catalyst while also providing excellent regioselectivities (rr >98:2) and enantioselectivities (er >98:2) for a broad range of substrates. A detailed computational investigation of the reactions using Co complexes from two widely different ligands (BenzP* and MeO-BIBOP) employing the B3LYP-D3 density functional theory provides key insights into the mechanism and the origins of selectivities. The computational results are in full agreement with the experiments. For the complexes we have examined thus far, the relative stabilities of the diastereomeric diene-bound complexes [(L*)Co(η4-diene)]+ lead to the initial diastereofacial selectivity, which in turn is retained in the subsequent steps, providing exceptional enantioselectivity for the reactions.

Mass Spectrometry Approach for Differentiation of Positional Isomers of Saccharides: Toward Direct Analysis of Rare Sugars.

Rare sugars have gained popularity in recent years due to their use in antiaging treatments, their ability to sweeten with few calories, and their ability to heal infections. Rare sugars are found in small quantities in nature, and they exist typically as isomeric forms of traditional sugars, rendering some challenges in their isolation, synthesis, and characterization. In this work, we present the first direct mass spectrometric approach for differentiating structural isomers of sucrose that differ only by their glycosidic linkages. The method employed a noncontact nanoelectrospray (nESI) platform capable of analyzing minuscule volumes (5 µL) of saccharides via the formation of halide adducts ([M+X]-; X = Cl and Br). Tandem mass spectrometry analysis of the five structural isomers of sucrose afforded diagnostic fragment ions that can be used to distinguish each isomer. Detailed mechanisms showcasing the distinct fragmentation pattern for each isomer are discussed. The method was applied to characterize and confirm the presence of all five selected rare sugars in raw honey complex samples. Aside from the five natural α isomers of sucrose, the method was also suitable for differentiating some ß isomers of the same glycosidic linkages, provided the monomeric sugar units are different. The halide adduct formation via the noncontact nESI source was also proven to be effective for oligosaccharides such as raffinose, ß-cyclodextrin, and maltoheptaose. The results from this study encourage the future development of methods that function with simple operation to enable straightforward characterization of small quantities of rare sugars.

Vibrational relaxation by methylated xanthines in solution: Insights from 2D IR spectroscopy and calculations.

Two-dimensional infrared (2D IR) spectroscopy, infrared pump-infrared probe spectroscopy, and density functional theory calculations were used to study vibrational relaxation by ring and carbonyl stretching modes in a series of methylated xanthine derivatives in acetonitrile and deuterium oxide (heavy water). Isotropic signals from the excited symmetric and asymmetric carbonyl stretch modes decay biexponentially in both solvents. Coherent energy transfer between the symmetric and asymmetric carbonyl stretching modes gives rise to a quantum beat in the time-dependent anisotropy signals. The damping time of the coherent oscillation agrees with the fast decay component of the carbonyl bleach recovery signals, indicating that this time constant reflects intramolecular vibrational redistribution (IVR) to other solute modes. Despite their similar frequencies, the excited ring modes decay monoexponentially with a time constant that matches the slow decay component of the carbonyl modes. The slow decay times, which are faster in heavy water than in acetonitrile, approximately match the ones observed in previous UV pump-IR probe measurements on the same compounds. The slow component is assigned to intermolecular energy transfer to solvent bath modes from low-frequency solute modes, which are populated by IVR and are anharmonically coupled to the carbonyl and ring stretch modes. 2D IR measurements indicate that the carbonyl stretching modes are weakly coupled to the delocalized ring modes, resulting in slow exchange that cannot explain the common solvent-dependence. IVR is suggested to occur at different rates for the carbonyl vs ring modes due to differences in mode-specific couplings and not to differences in the density of accessible states.

[3 + 2]-Cycloadditions with Porphyrin ß,ß'-Bonds: Theoretical Basis of the Counterintuitive meso-Aryl Group Influence on the Rates of Reaction.

Removal of a ß,ß'-bond from meso-tetraarylporphyrin using [3 + 2]-cycloadditions generates meso-tetraarylhydroporphyrins. Literature evidence indicates that meso-tetraphenylporphyrins react more sluggishly with 1,3-dipoles such as ylides and OsO4 (in the presence of pyridine) than meso-tetrakis(pentafluorophenyl)porphyrin. The trend is counterintuitive for the reaction with OsO4, as this formal oxidation reaction is expected to proceed more readily with more electron-rich substrates. This work presents a density functional theory-based computational study of the frontier molecular orbital (FMO) interactions and reaction profile thermodynamics involved in the reaction of archetypical cycloaddition reactions (a simple ylide, OsO4, OsO4·py, OsO4·(py)2, and ozone) with the ß,ß'-double bonds of variously fluorinated meso-arylporphyrins. The trend observed for the Type I cycloaddition of an ylide is straightforward, as lowering the LUMO of the porphyrin with increasing meso-phenyl-fluorination also lowers the reaction barrier. The corresponding simple FMO analyses of Type III cycloadditions do not correctly model the reaction energetics. This is because increasing fluorination leads to lowering of the porphyrin HOMO-2, thus increasing the reaction barrier. However, coordination of pyridine to OsO4 preorganizes the transition state complex; lowering of the energy barrier by the preorganization exceeds the increase in repulsive orbital interactions, overall accelerating the cycloaddition and rationalizing the counterintuitive experimental findings.

Capturing Fleeting Intermediates in a Claisen Rearrangement Using Nonequilibrium Droplet Imbibition Reaction Conditions.

The Claisen rearrangement of aromatic allyl phenyl ether to 2-allyl phenol is known to be induced by heat, acid, and air-water interfacial (on-water) effects. In this work, we show that the combination of acid and interfacial effects in an "on-droplet" experiment accelerates this reaction even further (by a factor >10×). The reaction acceleration was achieved through a droplet imbibition mass spectrometry (MS) experiment that allows reactants to be deposited on rapidly moving (100 m/s), charged microdroplets while avoiding turbulent mixing. In this case, reactants are concentrated mainly at the surface of the short-lived microdroplets (microseconds), enabling enhanced interfacial effects. By doping n-butylamine in the spray solvent and subsequently exposing the resultant electrosprayed microdroplets to formic acid vapor, the ketone intermediate, 6-allylcyclohexa-2,4-dien-1-one, involved in this Claisen rearrangement was captured and characterized by tandem MS, successfully differentiating it from the corresponding isobaric reactant (allyl phenyl ether) and product (2-allyl phenol). Similar results showing rate acceleration and subsequent capture of the ketone intermediate via an instantaneous reaction with n-butylamine were demonstrated for p-methyl and p-nitro substituted allyl phenyl ether. Density functional theory calculations confirmed that the on-droplet reaction condition, with a high abundance of proton sources, is different from the neutral rearrangement. With a calculated free energy of activation of 5.2 kcal mol-1 for the protonated reactant, the on-droplet experimental condition provides a unique mechanism for catalyzing the Claisen rearrangement on the microsecond lifetime of the droplets. This experiment marks the first direct capture and detection of a short-lived ketone intermediate in the Claisen rearrangement, a task that is challenged by a thermodynamically favorable tautomerization step to give a more stabilized product (by 20 kcal/mol).

Molecular Docking as a Tool to Examine Organic Cation Sorption to Organic Matter.

Molecular docking simulations were performed to examine the structural effects of organic cations on their sorption to organic matter. A set of benzylamine compounds was used to assess the sorption trends arising from the systematic structural differences between ring or nitrogen substituents. Binding simulations were performed using AutoDock 4.2 with Schulten's proposed soil organic matter as a representative organic matter structure. The calculated binding energies for the sorbate compounds correlated strongly with the measured sorption energies for Pahokee peat, indicating that the simulated binding energies and their associated sorbate orientations were representative of the experimental conditions. Graphical docking orientations showed primary, secondary, and tertiary aminium compounds to form hydrogen-bond interactions with deprotonated carboxylic acid groups in a pocket of the organic matter structure. Quaternary ammonium compounds formed pi-pi or cation-pi interactions with the aromatic groups elsewhere in the same organic matter pocket. Ring substituents showed no clear trends in sorption energies with the substituent group type for primary aminium compounds. Rather, substituent groups altered the simulated van der Waals, electrostatic, hydrogen-bond, and desolvation energy contributions to the overall sorption energies, in part because of the variations in docking orientations between compounds. Increasing methyl substitution of the aminium nitrogen group was associated with an increase in van der Waals energy contributions and a decrease in electrostatic energy contributions to the overall compound sorption energies because of aminium charge delocalization into methyl substituents and steric hindrance from methyl substituents to form specific interactions. The findings illustrate how molecular docking can be used to explore the effects of organic cation structure on sorption interactions with organic matter.

A computational study of competing conformational selection and induced fit in an abiotic system.

Host-guest complexations can be described by two competing mechanisms, conformational selection (CS) and induced fit (IF). In this work, we used a combination of nudged elastic band (NEB), adaptive steered molecular dynamics (ASMD), and density functional theory (DFT, with a correction for dispersion) to study the dynamics of the pathways (IF/CS) by which two conformers of basket B(+) and B(-) interconvert and trap CX4 guests (X = Cl and Br). While the results from NEB/DFT studies disclosed host-guest noncovalent contacts reducing the basket's conformational dynamics, ASMD methodology suggested an associative mechanism for the guest complexation. With theory in excellent agreement with experiments, NEB and ASMD emerge as the methods of choice for studying dynamics of supramolecular systems.

Cationic Co(I) Catalysts for Regiodivergent Hydroalkenylation of 1,6-Enynes. An Uncommon cis-ß-C-H Activation Leads to Z-Selective Coupling of Acrylates.

Two intermolecular hydroalkenylation reactions of 1,6-enynes are presented which yield substituted 5-membered carbo- and -heterocycles. This reactivity is enabled by a cationic bis-diphenylphosphinopropane (DPPP)CoI species which forms a cobaltacyclopentene intermediate by oxidative cyclization of the enyne. This key species interacts with alkenes in distinct fashion, depending on the identity of the coupling partner to give regiodivergent products. Simple alkenes undergo insertion reactions to furnish 1,3-dienes whereby one of the alkenes is tetrasubstituted. When acrylates are employed as coupling partners, the site of intermolecular C-C formation shifts from the alkyne to the alkene motif of the enyne, yielding Z-substituted-acrylate derivatives. Computational studies provide support for our experimental observations and show that the turnover-limiting steps in both reactions are the interactions of the alkenes with the cobaltacyclopentene intermediate via either a 1,2-insertion in the case of ethylene, or an unexpected ß-C-H activation in the case of most acrylates. Thus, the H syn to the ester is activated through the coordination of the acrylate carbonyl to the cobaltacycle intermediate, which explains the uncommon Z-selectivity and regiodivergence. Variable time normalization analysis (VTNA) of the kinetic data reveals a dependance upon the concentration of cobalt, acrylate, and activator. A KIE of 2.1 was observed with methyl methacrylate in separate flask experiments, indicating that C-H cleavage is the turnover-limiting step in the catalytic cycle. Lastly, a Hammett study of aryl-substituted enynes yields a ρ value of -0.4, indicating that more electron-rich substituents accelerate the rate of the reaction.

Heat-induced compounds development in processed tomato and their influence on corrosion initiation in metal food cans.

Selected ion flow tube mass spectrometry (SIFT-MS) and ion chromatography (IC) were used to investigate the presence of volatile and nonvolatile compounds in canned tomatoes and in the polymeric lining before and after retorting the cans. This allowed us to observe if these compounds contributed to corrosion and the migration of iron and tin compounds from the cans to the tomatoes. Diced Roma tomatoes and other simulant treatment groups were sealed in two-piece tinplated cans (controls in glass jars), retorted at 121℃ for 30 min, then stored at 49℃ for 50 days. Results showed that thermal degradation of amino acids in the tomatoes gave rise to volatile methyl sulfides and nonvolatile nitrogenous compounds which were subsequently sorbed by the can lining. SIFT-MS showed a 20-fold increase in dimethyl sulfide concentration. Inductively coupled plasma (ICP-MS) results showed fourfold and 16-fold increases in iron and tin compounds, respectively, that migrated from the metal to the tomatoes as a result of acid and electrolyte interactions.

Alkynyl-Based Covalent Organic Frameworks as High-Performance Anode Materials for Potassium-Ion Batteries.

The development of high-performance organic electrodes for potassium-ion batteries (KIBs) is attracting interest due to their sustainability and low costs. However, the electrolyte systems and moieties that generally proved to be successful in high-performance Li-ion batteries have found relatively little success in KIBs. Herein, two alkynyl-based covalent organic frameworks (COFs) containing 1,3,5-tris(arylethynyl)benzene (TAEB) and dehydrobenzoannulene (DBA) units are utilized as bulk anode materials for KIBs in a localized high-concentration electrolyte. TAEB-COF provides a high capacity value of 254.0 mAh g-1 at ∼100% efficiency after 300 cycles, and DBA-COF 3 provides a capacity of 76.3 mAh g-1 with 98.7% efficiency after 300 cycles. DFT calculations suggest that the alkynyl units of TAEB-COF facilitate the binding of K-ions through both enthalpic and geometric driving forces, leading to high reversible capacities.

From Selection to Instruction and Back: Competing Conformational Selection and Induced Fit Pathways in Abiotic Hosts.

Two limiting cases of molecular recognition, induced fit (IF) and conformational selection (CS), play a central role in allosteric regulation of natural systems. The IF paradigm states that a substrate "instructs" the host to change its shape after complexation, while CS asserts that a guest "selects" the optimal fit from an ensemble of preexisting host conformations. With no studies that quantitatively address the interplay of two limiting pathways in abiotic systems, we herein and for the first time describe the way by which twisted capsule M-1, encompassing two conformers M-1(+) and M-1(-), trap CX4 (X=Cl, Br) to give CX4 ⊂M-1(+) and CX4 ⊂M-1(-), with all four states being in thermal equilibrium. With the assistance of 2D EXSY, we found that CBr4 would, at its lower concentrations, bind M-1 via a M-1(+)→M-1(-)→CBr4 ⊂M-1(-) pathway corresponding to conformational selection. For M-1 complexing CCl4 though, data from 2D EXSY measurements and 1D NMR line-shape analysis suggested that lower CCl4 concentrations would favor CS while the IF pathway prevailed at higher proportions of the guest. Since CS and IF are not mutually exclusive, we reason that our work sets the stage for characterizing the dynamics of a wide range of already existing hosts to broaden our fundamental understanding of their action. The objective is to master the way in which encapsulation takes place for designing novel and allosteric sequestering agents, catalysts and chemosensors akin to those found in nature.

Robust, Enantioselective Construction of Challenging, Biologically Relevant Tertiary Ether Stereocenters.

A robust, catalytic enantioselective method to construct challenging, biologically relevant, tertiary ether stereocenters has been developed. The process capitalizes on readily accessible bis(oxazoline) ligands to control the facial selectivity of the addition of copper acetylides to benzopyrylium triflates, reactive species generated in situ. Up to 99% enantiomeric excesses are achieved with a broad substrate scope. Using density functional theory (DFT) calculations, the origin of the experimentally observed enantiocontrol was attributed to additional non-covalent interactions observed in the transition state leading to the major enantiomer, such as π-stacking. The resultant substrates have direct applications in the synthesis of naturally occurring bioactive chromanones and tetrahydroxanthones.

Design, synthesis, and in vitro evaluation of aza-peptide aldehydes and ketones as novel and selective protease inhibitors.

Aza-peptide aldehydes and ketones are a new class of reversible protease inhibitors that are specific for the proteasome and clan CD cysteine proteases. We designed and synthesised aza-Leu derivatives that were specific for the chymotrypsin-like active site of the proteasome, aza-Asp derivatives that were effective inhibitors of caspases-3 and -6, and aza-Asn derivatives that inhibited S. mansoni and I. ricinus legumains. The crystal structure of caspase-3 in complex with our caspase-specific aza-peptide methyl ketone inhibitor with an aza-Asp residue at P1 revealed a covalent linkage between the inhibitor carbonyl carbon and the active site cysteinyl sulphur. Aza-peptide aldehydes and ketones showed no cross-reactivity towards cathepsin B or chymotrypsin. The initial in vitro selectivity of these inhibitors makes them suitable candidates for further development into therapeutic agents to potentially treat multiple myeloma, neurodegenerative diseases, and parasitic infections.

Insights on Absolute and Relative Stereocontrol in Stereodivergent Cooperative Catalysis.

An increasing number of examples demonstrate that the use of two mutually compatible chiral catalysts in one-pot conditions can help realize the long-cherished goal of simultaneous control of absolute and relative configurations in asymmetric catalysis. Engaging two transition metal catalysts for this goal presents a considerable degree of mechanistic challenge to control the mode of substrate activation as well as origin of enantio- and diastereoselectivities, both of which are central to the burgeoning domain of stereodivergent catalysis. We have employed density functional theory (B3LYP-D3) computations to investigate an important stereodivergent reaction between azaaryl acetamide and cinnamyl methyl carbonate. These compounds participate in the stereocontrolling C-C bond formation in the form of activated substrates, respectively, when bound to chiral Cu-Walphos and Ir-phosphoramidite catalysts. Herein, we provide the molecular origin of how all four stereoisomers of the product bearing two contiguous stereogenic centers could be accessed by changing the combinations of chiral catalysts (C1(R,Rp) or C2(S,Sp) of Cu-Walphos in conjunction with P1(R,R,R) or P2(S,S,S) of Ir-phosphoramidite catalysts). The origin of stereodivergence is identified to depend on the differences in the number and nature of noncovalent interactions (NCIs) in the stereocontrolling transition states. In particular, NCIs between the chiral catalysts (C-H···π in C1-P1 catalyst dyad and C-H···π, C-H···F, and π···π in C2-P1) in stereocontrolling transition states are found to be the differentiating factors rendering one of the four stereochemically distinct transition states to be the lowest energy one for a given catalyst combination. These molecular insights suggest that subtle modifications to the catalyst framework could be further exploited in stereodivergent catalysis.