Diastereo- and Enantioselective Construction of Stereochemical Arrays Exploiting Non-Classical Hydrogen Bonding in Enolborates.

We report a copper-catalyzed reductive aldol addition to aldehydes and ketones, with pinacolborane as stoichiometric reductant, that results in the generation of stereodefined syn-aldol products. Cyclic, acyclic, fused and spirocyclic aldols bearing contiguous stereocenters are obtained with excellent yields and diastereoselectivities. Moreover, enantioselective reactions could be carried out with cycloalkenones to deliver aldols bearing three contiguous stereocenters and with up to 98 % ee. Computations reveal that the enolborate intermediate undergoes the syn-aldol reaction via a twist-boat transition state that is stabilized by non-classical hydrogen bonding interactions.

Comment on the Definition and Labeling of pK50.

We propose a more rigorous definition for the recently introduced concept of pK50. The value of pK50 should be associated not with a "functional group", as originally postulated, but instead with an atom. The proposed clarification is meant to improve the interpretation and labeling of pK50.

Epik: pKa and Protonation State Prediction through Machine Learning.

Epik version 7 is a software program that uses machine learning for predicting the pKa values and protonation state distribution of complex, druglike molecules. Using an ensemble of atomic graph convolutional neural networks (GCNNs) trained on over 42,000 pKa values across broad chemical space from both experimental and computed origins, the model predicts pKa values with 0.42 and 0.72 pKa unit median absolute and root mean square errors, respectively, across seven test sets. Epik version 7 also generates protonation states and recovers 95% of the most populated protonation states compared to previous versions. Requiring on average only 47 ms per ligand, Epik version 7 is rapid and accurate enough to evaluate protonation states for crucial molecules and prepare ultra-large libraries of compounds to explore vast regions of chemical space. The simplicity and time required for the training allow for the generation of highly accurate models customized to a program's specific chemistry.

Mechanistic Investigation of Dimethylmercury Formation Mediated by a Sulfide Mineral Surface.

Mercury (Hg) pollution is a global environmental problem. The abiotic formation of dimethylmercury (DMeHg) from monomethylmercury (MMeHg) may account for a large portion of DMeHg in oceans. Previous experimental work has shown that abiotic formation of DMeHg from MMeHg can be facilitated by reduced sulfur groups on sulfide mineral surfaces. In that work, a mechanism was proposed in which neighboring MMeHg moieties bound to sulfide sites on a mineral surface react through an SN2-type mechanism to form DMeHg and incorporate the remaining Hg atoms into the mineral surface. Here, we perform density functional theory calculations to explore the mechanisms of DMeHg formation on the 110 surface of a CdS(s) (hawleyite) nanoparticle. We show that coordination of MMeHg substituents to adjacent reduced sulfur groups protruding from the surface indeed facilitates DMeHg formation and that the reaction proceeds through direct transmethylation from one MMeHg substituent to another. Coordination of Hg by multiple S atoms provides a transition-state stabilization and activates a C-Hg bond for methyl transfer. In addition, solvation effects play an important role in the surface reconstruction of the nanoparticle and in decreasing the energetic barrier for DMeHg formation relative to the corresponding reaction in vacuo.

Quantum Chemical Calculation of p Kas of Environmentally Relevant Functional Groups: Carboxylic Acids, Amines, and Thiols in Aqueous Solution.

Developing accurate quantum chemical approaches for calculating p Kas is of broad interest. Useful accuracy can be obtained by using density functional theory (DFT) in combination with a polarizable continuum solvent model. However, some classes of molecules present problems for this approach, yielding errors greater than 5 p K units. Various methods have been developed to improve the accuracy of the combined strategy. These methods perform well but either do not generalize or introduce additional degrees of freedom, increasing the computational cost. The Solvation Model based on Density (SMD) has emerged as one of the most commonly used continuum solvent models. Nevertheless, for some classes of organic compounds, e.g., thiols, the p Kas calculated with the original SMD model show errors of 6-10 p K units, and we traced these errors to inaccuracies in the solvation free energies of the anions. To improve the accuracy of p Kas calculated with DFT and the SMD model, we developed a scaled solvent-accessible surface approach for constructing the solute-solvent boundary. By using a "direct" approach, in which all quantities are computed in the presence of the continuum solvent, the use of thermodynamic cycles is avoided. Furthermore, no explicit water molecules are required. Three benchmark data sets of experimentally measured p Ka values, including 28 carboxylic acids, 10 aliphatic amines, and 45 thiols, were used to assess the optimized SMD model, which we call SMD with a scaled solvent-accessible surface (SMDsSAS). Of the methods tested, the M06-2X density functional approximation, 6-31+G(d,p) basis set, and SMDsSAS solvent model provided the most accurate p Kas for each set, yielding mean unsigned errors of 0.9, 0.4, and 0.5 p K units, respectively, for carboxylic acids, aliphatic amines, and thiols. This approach is therefore useful for efficiently calculating the p Kas of environmentally relevant functional groups.

Synthesis of spirocyclic orthoesters by 'anomalous' rhodium(ii)-catalysed intramolecular C-H insertions.

A tetrahydropyranyl acetal bearing a proximal phenyl diazoketone substituent underwent Rh(ii)-catalysed C-H insertion via an 'anomalous' C-O bond-forming, rather than C-C bond-forming, transformation, giving spirocyclic orthoesters. Density functional theory calculations with M06 show that the formation of these anomalous products involves hydride transfer to the rhodium carbene, giving an intermediate zwitterion which undergoes C-O bond formation in preference to C-C bond formation.

Direct visualization of critical hydrogen atoms in a pyridoxal 5'-phosphate enzyme.

Enzymes dependent on pyridoxal 5'-phosphate (PLP, the active form of vitamin B6) perform a myriad of diverse chemical transformations. They promote various reactions by modulating the electronic states of PLP through weak interactions in the active site. Neutron crystallography has the unique ability of visualizing the nuclear positions of hydrogen atoms in macromolecules. Here we present a room-temperature neutron structure of a homodimeric PLP-dependent enzyme, aspartate aminotransferase, which was reacted in situ with α-methylaspartate. In one monomer, the PLP remained as an internal aldimine with a deprotonated Schiff base. In the second monomer, the external aldimine formed with the substrate analog. We observe a deuterium equidistant between the Schiff base and the C-terminal carboxylate of the substrate, a position indicative of a low-barrier hydrogen bond. Quantum chemical calculations and a low-pH room-temperature X-ray structure provide insight into the physical phenomena that control the electronic modulation in aspartate aminotransferase.Pyridoxal 5'-phosphate (PLP) is a ubiquitous co factor for diverse enzymes, among them aspartate aminotransferase. Here the authors use neutron crystallography, which allows the visualization of the positions of hydrogen atoms, and computation to characterize the catalytic mechanism of the enzyme.

Formation of Aza-ortho-quinone Methides Under Room Temperature Conditions: Cs2CO3 Effect.

Since the first report of a facile, room temperature process to access aza-ortho-quinone methides (aoQMs) by Corey in 1999, this chemistry has remained dormant until our report of an enantioselective catalytic example in 2014. We report a theoretical and experimental study of the key to success behind these successful examples to enable broader exploitation of this useful intermediate. We have discovered that transformations involving the aoQM are remarkably facile with barriers <17 kcal/mol. The main difficulty of exploiting aoQM in synthesis is that they are unstable (ΔG > 30 kcal/mol), precluding their formation under mild conditions. The use of Cs2CO3 as base is critical. It provides a thermodynamically and kinetically favorable means to form aoQMs, independent of the salt solubility and base strength. The exothermic formation of salt byproducts provides a driving force (average ΔG = -30.8 kcal/mol) compensating for the majority of the inherent unfavorable thermodynamics of aoQM formation.

Catalytic Enantioselective [2,3]-Rearrangements of Allylic Ammonium Ylides: A Mechanistic and Computational Study.

A mechanistic study of the isothiourea-catalyzed enantioselective [2,3]-rearrangement of allylic ammonium ylides is described. Reaction kinetic analyses using 19F NMR and density functional theory computations have elucidated a reaction profile and allowed identification of the catalyst resting state and turnover-rate limiting step. A catalytically relevant catalyst-substrate adduct has been observed, and its constitution elucidated unambiguously by 13C and 15N isotopic labeling. Isotopic entrainment has shown the observed catalyst-substrate adduct to be a genuine intermediate on the productive cycle toward catalysis. The influence of HOBt as an additive upon the reaction, catalyst resting state, and turnover-rate limiting step has been examined. Crossover experiments have probed the reversibility of each of the proposed steps of the catalytic cycle. Computations were also used to elucidate the origins of stereocontrol, with a 1,5-S···O interaction and the catalyst stereodirecting group providing transition structure rigidification and enantioselectivity, while preference for cation-π interactions over C-H···π is responsible for diastereoselectivity.

Toward Quantitatively Accurate Calculation of the Redox-Associated Acid-Base and Ligand Binding Equilibria of Aquacobalamin.

Redox processes in complex transition metal-containing species are often intimately associated with changes in ligand protonation states and metal coordination number. A major challenge is therefore to develop consistent computational approaches for computing pH-dependent redox and ligand dissociation properties of organometallic species. Reduction of the Co center in the vitamin B12 derivative aquacobalamin can be accompanied by ligand dissociation, protonation, or both, making these properties difficult to compute accurately. We examine this challenge here by using density functional theory and continuum solvation to compute Co-ligand binding equilibrium constants (Kon/off), pKas, and reduction potentials for models of aquacobalamin in aqueous solution. We consider two models for cobalamin ligand coordination: the first follows the hexa, penta, tetra coordination scheme for Co(III), Co(II), and Co(I) species, respectively, and the second model features saturation of each vacant axial coordination site on Co(II) and Co(I) species with a single, explicit water molecule to maintain six directly interacting ligands or water molecules in each oxidation state. Comparing these two coordination schemes in combination with five dispersion-corrected density functionals, we find that the accuracy of the computed properties is largely independent of the scheme used, but including only a continuum representation of the solvent yields marginally better results than saturating the first solvation shell around Co throughout. PBE performs best, displaying balanced accuracy and superior performance overall, with RMS errors of 80 mV for seven reduction potentials, 2.0 log units for five pKas and 2.3 log units for two log Kon/off values for the aquacobalamin system. Furthermore, we find that the BP86 functional commonly used in corrinoid studies suffers from erratic behavior and inaccurate descriptions of Co-axial ligand binding, leading to substantial errors in predicted pKas and Kon/off values. These findings demonstrate the effectiveness of the present approach for computing electrochemical and thermodynamic properties of a complex transition metal-containing cofactor.

Computational Insights into the Central Role of Nonbonding Interactions in Modern Covalent Organocatalysis.

The flexibility, complexity, and size of contemporary organocatalytic transformations pose interesting and powerful opportunities to computational and experimental chemists alike. In this Account, we disclose our recent computational investigations of three branches of organocatalysis in which nonbonding interactions, such as C-H···O/N interactions, play a crucial role in the organization of transition states, catalysis, and selectivity. We begin with two examples of N-heterocyclic carbene (NHC) catalysis, both collaborations with the Scheidt laboratory at Northwestern. In the first example, we discuss the discovery of an unusual diverging mechanism in a catalytic kinetic resolution of a dynamic racemate that depends on the stereochemistry of the product being formed. Specifically, the major product is formed through a concerted asynchronous [2 + 2] aldol-lactonization, while the minor products come from a stepwise spiro-lactonization pathway. Stereoselectivity and catalysis are the results of electrophilic activation from C-H···O interactions between the catalyst and the substrate and conjugative stabilization of the electrophile. In the second example, we show how knowledge and understanding of the computed transition states led to the development of a more enantioselective NHC catalyst for the butyrolactonization of acyl phosphonates. The identification of mutually exclusive C-H···O interactions in the computed major and minor TSs directly resulted in structural hypotheses that would lead to targeted destabilization of the minor TS, leading to enhanced stereoinduction. Synthesis and evaluation of the newly designed NHC catalyst validated our hypotheses. Next, we discuss two works related to Lewis base catalysis involving 4-dimethylaminopyridine (DMAP) and its derivatives. In the first, we discuss our collaboration with the Smith laboratory at St Andrews, in which we discovered the origins of the regioselectivity in carboxyl transfer reactions. We disclose how different Lewis base catalysts (NHC or DMAP) can lead to different regiomeric products as a result of differing magnitudes of aromatic and C-H···O interactions present in the respective transition states. In the second example, we discuss the mechanism and origins of the stereoselectivity of a reaction catalyzed by a planar-chiral 4-(pyrrolidino)pyridine derivative, namely, the coupling of ketenes with cyanopyrrole. We discovered that the chiral base mechanism is operative, in contrast to the originally proposed Brønsted acid mechanism. The selectivity is determined by the ease with which the major and minor TSs can realize strong stabilizing C-H···N interactions between the pyrrole cyano group and the catalyst. These interactions induce increased catalyst distortion in the minor TS, thereby leading to enantioselectivity. Finally, we discuss our computations related to amine-based organocatalysis in collaboration with the Carter laboratory at Oregon State. We probed the mechanism and stereoselectivity of a bifunctional amine thiourea-catalyzed Michael reaction. Our computations led to the design of an improved catalyst. However, synthesis and tests revealed that this catalyst was prone to degradation to side products that also catalyze the reaction, ultimately reducing the observed enantioselectivity. Lastly, we discuss our study of the mechanism and stereoselectivity of a proline sulfonamide-catalyzed Robinson annulation, in which we discovered that the enantioselectivity is controlled by the first Michael step but the diastereoselectivity is controlled by the following Mannich step.

Construction of Stereogenic α,α-Disubstituted Cycloalkanones via 1° Amine Thiourea Dual Catalysis: Experimental Scope and Computational Analyses.

The mechanistic exploration and an expanded experimental discussion of the organocatalyzed, asymmetric Pfau-d'Angelo reaction by exploiting a bifunctional 1° amine thiourea catalyst system is disclosed. Notable breadth in substrate scope has been demonstrated on both the cyclic ketone moiety and the α,ß-unsaturated electrophile. Exploration into the matched and mismatched selectivity of this process with a ketone containing pre-existing stereocenters has been demonstrated. Computational analyses of the reaction mechanism are reported. In concert with kinetic isotope effect (KIE) experiments, these computational results provide a detailed understanding of the likely mechanism, including the aspects of the organocatalyst scaffold that are critical for stereoselectivity.

AlCl3-Catalyzed Ring Expansion Cascades of Bicyclic Cyclobutenamides Involving Highly Strained Cis,Trans-Cycloheptadienone Intermediates.

We report the first experimental evidence for the generation of highly strained cis,trans-cycloheptadienones by electrocyclic ring opening of 4,5-fused cyclobutenamides. In the presence of AlCl3, the cyclobutenamides rearrange to [2.2.1]-bicyclic ketones; DFT calculations provide evidence for a mechanism involving torquoselective 4π-electrocyclic ring opening to a cis,trans-cycloheptadienone followed by a Nazarov-like recyclization and a 1,2-alkyl shift. Similarly, 4,6-fused cyclobutenamides undergo AlCl3-catalyzed rearrangements to [3.2.1]-bicyclic ketones through cis,trans-cyclooctadienone intermediates. The products can be further elaborated via facile cascade reactions to give complex tri- and tetracyclic molecules.

Functionalized cyclopentenes through a tandem NHC-catalyzed dynamic kinetic resolution and ambient temperature decarboxylation: mechanistic insight and synthetic application.

An unusual room temperature ß-lactone decarboxylation facilitated a five-step enantioselective formal synthesis of the cyclopentane core of an estrogen receptor ß-agonist. A computational study probed the underlying factors facilitating unprecedented, rapid decarboxylation. Aryl substitution promotes faster reaction in the retro-[2+2] as a result of conjugative stabilization with the forming olefin. Additionally, the configuration of the α-ester in these fused ß-lactones leads to differential decarboxylation rates.

Biosynthetic insights provided by unusual sesterterpenes from the medicinal herb Aletris farinosa.

A series of novel sesterterpenes (2-6) have been isolated from the roots of Aletris farinosa and structurally characterized by MS, NMR, and X-ray crystallography in conjunction with computational modeling. Their structures provide new insights into the mechanisms of sesterterpene biosynthesis. Specifically, we propose with support from density functional theory computations that the configuration at a single stereocenter determines the fate of a key tetracyclic carbocationic intermediate, derived from an oxidogeranylfarnesol precursor. Whereas one epimer of the carbocation undergoes H+ elimination to give 6, the other undergoes a spectacular cascade of seven 1,2-methyl and hydride migrations leading to the previously unreported carbon skeleton of 5. Theoretical calculations suggest that the cascade is triggered by substrate preorganization in the enzyme active site.

Catalytic Kinetic Resolution of a Dynamic Racemate: Highly Stereoselective ß-Lactone Formation by N-Heterocyclic Carbene Catalysis.

This study describes the combined experimental and computational elucidation of the mechanism and origins of stereoselectivities in the NHC-catalyzed dynamic kinetic resolution (DKR) of α-substituted-ß-ketoesters. Density functional theory computations reveal that the NHC-catalyzed DKR proceeds by two mechanisms, depending on the stereochemistry around the forming bond: 1) a concerted, asynchronous formal (2+2) aldol-lactonization process, or 2) a stepwise spiro-lactonization mechanism where the alkoxide is trapped by the NHC-catalyst. These mechanisms contrast significantly from mechanisms found and postulated in other related transformations. Conjugative stabilization of the electrophile and non-classical hydrogen bonds are key in controlling the stereoselectivity. This reaction constitutes an interesting class of DKRs in which the catalyst is responsible for the kinetic resolution to selectively and irreversibly capture an enantiomer of a substrate undergoing rapid racemization with the help of an exogenous base.

Torquoselective ring opening of fused cyclobutenamides: evidence for a cis,trans-cyclooctadienone intermediate.

Electrocyclic ring opening of 4,6-fused cyclobutenamides 1 under thermal conditions leads to cis,trans-cyclooctadienones 2-E,E as transient intermediates, en route to 5,5-bicyclic products 3. Theoretical calculations predict that 4,5-fused cyclobutenamides should likewise undergo thermal ring opening, giving cis,trans-cycloheptadienones, but in this case conversion to 5,4-bicyclic products is thermodynamically disfavored, and these cyclobutenamides instead rearrange to vinyl cyclopentenones.

Asymmetric homoenolate additions to acyl phosphonates through rational design of a tailored N-heterocyclic carbene catalyst.

A highly selective NHC-catalyzed synthesis of γ-butyrolactones from the fusion of enals and α-ketophosphonates has been developed. Computational modeling of competing transition states guided a rational design strategy to achieve enhanced levels of enantioselectivity with a new tailored C1-symmetric biaryl-saturated imidazolium-derived NHC catalyst.

C-H···O non-classical hydrogen bonding in the stereomechanics of organic transformations: theory and recognition.

This manuscript describes the role of non-classical hydrogen bonds (NCHBs), specifically C-HO interactions, in modern synthetic organic transformations. Our goal is to point out the seminal examples where C-H···O interactions have been invoked as a key stereocontrolling element and to provide predictive value in recognizing future and/or potential C-H···O interactions in modern transformations.