Data-Efficient, Chemistry-Aware Machine Learning Predictions of Diels-Alder Reaction Outcomes.

The application of machine learning models to the prediction of reaction outcomes currently needs large and/or highly featurized data sets. We show that a chemistry-aware model, NERF, which mimics the bonding changes that occur during reactions, allows for highly accurate predictions of the outcomes of Diels-Alder reactions using a relatively small training set, with no pretraining and no additional features. We establish a diverse data set of 9537 intramolecular, hetero-, aromatic, and inverse electron demand Diels-Alder reactions. This data set is used to train a NERF model, and the performance is compared against state-of-the-art classification and generative machine learning models across low- and high-data regimes, with and without pretraining. The predictive accuracy (regio- and site selectivity in the major product) achieved by NERF exceeds 90% when as little as 40% of the data set is used for training. Another high-performing model, Chemformer, requires a larger training data set (>45%) and pretraining to reach 90% Top-1 accuracy. Accurate predictions of less-represented reaction subclasses, such as those involving heteroatomic or aromatic substrates, require higher percentages of training data. We also show how NERF can use small amounts of additional training data to quickly learn new systems and improve its overall understanding of reactivity. Synthetic chemists stand to benefit as this model can be rapidly expanded and tailored to areas of chemistry corresponding to the low-data regime.

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.

Origins of Temperature-Dependent Anomeric Selectivity in Glycosylations with an L-Idose Thioglycoside.

L-Idose thioglycosides are useful glycosyl donors for the construction of glycosaminoglycan oligosaccharides. When activated with NIS and catalytic TMSOTf in the presence of methanol, the stereoselectivity of O-glycosylation displays an intriguing dependence on the reaction temperature, with an increased preference for formation of the α-glycoside at higher temperatures. Using a combination of vt-NMR spectroscopy and DFT calculations, we show how a simple mechanistic model, based on competing reactions of the iodinated thioglycoside, can explain the main features of the temperature dependence. In this model, the increased selectivity at high temperature is attributed to differences among the entropy and energy terms of the competing reaction pathways. Neighbouring-group participation (giving an intermediate acyloxonium ion) plays an increasingly dominant role as temperature is raised. The general features of this kinetic regime may also apply more broadly to other glycosylations that likewise favour α-glycoside formation at high temperature.

Reassignment of the Structure of a Tryptophan-Containing Cyclic Tripeptide Produced by the Biarylitide Crosslinking Cytochrome P450blt.

The structure of the sidechain crosslinked Tyr-Leu-Trp peptide produced by the biarylitide crosslinking cytochrome P450Blt from Micromonospora sp. MW-13 has been reanalysed by a series of NMR, computational and isotope labelling experiments and shown to contain a C-N rather than a C-O bond. Additional in vivo experiments using such a modified peptide show there is a general tolerance of biarylitide crosslinking P450 enzymes for histidine to tryptophan mutations within their minimal peptide substrate sequences despite the lack of such residues noted in natural biarylitide gene clusters. This work further highlights the impressive ability of P450s from biarylitide biosynthesis pathways to act as biocatalysts for the formation of a range of sidechain crosslinked tripeptides.

Binding of the plant-derived toxin simplexin to bovine protein kinase C: insights from molecular dynamics.

Pimelea poisoning of cattle is toxicologically linked to the activation of bovine protein kinase C (PKC) by the plant-derived toxin simplexin. To understand the affinity of PKC for simplexin, we performed molecular dynamics (MD) studies of simplexin, simplexin analogues, and several other activators of PKC. Binding enthalpy calculations indicated that simplexin had the strongest affinity for PKCα-C1B among the activators studied. Key to simplexin's affinity is its ability to form more hydrogen bonds to PKC, compared to the other activators. The C-3 carbonyl group and C-20 hydroxyl group of simplexin were identified as especially important for stabilizing the PKC binding interaction. The hydrophobic alkyl chain of simplexin induces deep membrane embedding of the PKC-simplexin complex, enhancing the protein-ligand hydrogen bonding. Our findings align with previous experiments on structure-activity relationships (SAR) for simplexin analogues, and provide insights that may guide the development of interventions or treatments for Pimelea poisoning.

Dearomative Intramolecular (4+3) Cycloadditions of Thiophenes.

Unexpectedly facile dearomative intramolecular (4+3) cycloadditions of thiophenes with epoxy enolsilanes, providing sulfur-bridged cycloadducts, are reported. A total of fifteen thiophene substrates have been found to undergo (4+3) cycloaddition smoothly to produce endo and exo (4+3) adducts in yields of up to 83 % with moderate to good diastereoselectivity. Complete conservation of enantiomeric purity was observed when the optically enriched epoxide was used. The desulfurizing transformations of the sulfur-bridged skeleton of the cycloadducts provide functionalized 6,7-fused bicyclic frameworks consisting of 1,3-cycloheptadiene subunits. Density functional theory calculations reveal the origins of the facile dearomatization of thiophenes in these (4+3) cycloadditions.

The Oxidation of Oxygen and Sulfur-Containing Heterocycles by Cytochrome P450 Enzymes.

The cytochrome P450 (CYP) superfamily of monooxygenase enzymes play important roles in the metabolism of molecules which contain heterocyclic, aromatic functional groups. Here we study how oxygen- and sulfur-containing heterocyclic groups interact with and are oxidized using the bacterial enzyme CYP199A4. This enzyme oxidized both 4-(thiophen-2-yl)benzoic acid and 4-(thiophen-3-yl)benzoic acid almost exclusively via sulfoxidation. The thiophene oxides produced were activated towards Diels-Alder dimerization after sulfoxidation, forming dimeric metabolites. Despite X-ray crystal structures demonstrating that the aromatic carbon atoms of the thiophene ring were located closer to the heme than the sulfur, sulfoxidation was still favoured with 4-(thiophen-3-yl)benzoic acid. These results highlight a preference of this cytochrome P450 enzyme for sulfoxidation over aromatic hydroxylation. Calculations predict a strong preference for homodimerization of the enantiomers of the thiophene oxides and the formation of a single major product, in broad agreement with the experimental data. 4-(Furan-2-yl)benzoic acid was oxidized to 4-(4'-hydroxybutanoyl)benzoic acid using a whole-cell system. This reaction proceeded via a γ-keto-α,ß-unsaturated aldehyde species which could be trapped in vitro using semicarbazide to generate a pyridazine species. The combination of the enzyme structures, the biochemical data and theoretical calculations provides detailed insight into the formation of the metabolites formed from these heterocyclic compounds.

Enabling Aromatic Hydroxylation in a Cytochrome P450 Monooxygenase Enzyme through Protein Engineering.

The cytochrome P450 (CYP) family of heme monooxygenases catalyse the selective oxidation of C-H bonds under ambient conditions. The CYP199A4 enzyme from Rhodopseudomonas palustris catalyses aliphatic oxidation of 4-cyclohexylbenzoic acid but not the aromatic oxidation of 4-phenylbenzoic acid, due to the distinct mechanisms of aliphatic and aromatic oxidation. The aromatic substrates 4-benzyl-, 4-phenoxy- and 4-benzoyl-benzoic acid and methoxy-substituted phenylbenzoic acids were assessed to see if they could achieve an orientation more amenable to aromatic oxidation. CYP199A4 could catalyse the efficient benzylic oxidation of 4-benzylbenzoic acid. The methoxy-substituted phenylbenzoic acids were oxidatively demethylated with low activity. However, no aromatic oxidation was observed with any of these substrates. Crystal structures of CYP199A4 with 4-(3'-methoxyphenyl)benzoic acid demonstrated that the substrate binding mode was like that of 4-phenylbenzoic acid. 4-Phenoxy- and 4-benzoyl-benzoic acid bound with the ether or ketone oxygen atom hydrogen-bonded to the heme aqua ligand. We also investigated whether the substitution of phenylalanine residues in the active site could permit aromatic hydroxylation. Mutagenesis of the F298 residue to a valine did not significantly alter the substrate binding position or enable the aromatic oxidation of 4-phenylbenzoic acid; however the F182L mutant was able to catalyse 4-phenylbenzoic acid oxidation generating 2'-hydroxy-, 3'-hydroxy- and 4'-hydroxy metabolites in a 83 : 9 : 8 ratio, respectively. Molecular dynamics simulations, in which the distance and angle of attack were considered, demonstrated that in the F182L variant, in contrast to the wild-type enzyme, the phenyl ring of 4-phenylbenzoic acid attained a productive geometry for aromatic oxidation to occur.

Examining the Role of Aryldiazonium Salts in Surface Electroinitiated Polymerization.

Historically, the irreversible reduction of aryldiazonium salts has provided a reliable method to modify surfaces, demonstrating a catalogue of suitable diazonium salts for targeted applications. This work expands the knowledge of diazonium salt chemistry to participate in surface electroinitiated emulsion polymerization (SEEP). The influence of concentration, electronic effects, and steric hindrance/regiochemistry of the diazonium salt initiator on the production of polymeric films is examined. The objective of this work is to determine if a polymer film can be tailored, controlling the thickness, density, and surface homogeneity using specific diazonium chemistry. The data presented herein demonstrate a significant difference in polymer films that can be achieved when selecting a variety of diazonium salts and vinylic monomers. A clear trend aligns with the electron-rich diazonium salt substitution providing the thickest films (up to 70.9 ± 17.8 nm) with increasing diazonium concentration and electron-withdrawing substitution achieving optimal homogeneity for the surface of the film at a 5 mM diazonium concentration.

Nazarov Cyclizations Catalyzed by BINOL Phosphoric Acid Derivatives: Quantum Chemistry Struggles To Predict the Enantioselectivity.

Quantum chemical calculations have successfully predicted the stereoselectivities of many BINOL phosphoric acid catalyzed reactions over the past 10-15 years. Herein we report a contrasting example: a reaction for which standard quantum chemistry techniques have proven unexpectedly ineffective at explaining the stereoselectivity. The Nazarov cyclizations of a divinyl ketone catalyzed by a BINOL phosphoric acid or H8-BINOL dithiophosphoric acid were studied with a conventional contemporary quantum chemical approach, consisting of transition state optimizations with B3LYP-D3(BJ) and single-point calculations with several functionals in implicit solvent. Unexpectedly, different functionals gave widely different predictions of the level of enantioselectivity and were unable even to agree on which enantiomer of the product would predominate. Molecular dynamics simulations with the OPLS-AA force field provided evidence that the transition state geometries optimized with DFT in the gas phase or in implicit solvent are not good representations of the true transition states of these reactions in solution. One possible reason for this, which may also explain the failure of quantum chemical techniques to reliably predict the enantioselectivity, is the fact that the transition states contain ion pairs which are not highly organized and do not contain any strongly directional noncovalent interactions between the substrate and the catalyst.

Mechanistic Studies on the Base-Promoted Ring Opening of Glycal-Derived gem-Dibromocyclopropanes.

In the presence of a nucleophilic base, ring-fused gem-dibromocyclopropanes derived from d-glycals undergo ring opening to give 2-deoxy-2-(E-bromomethylene)glycosides. Such cleavage of an exocyclic cyclopropane bond contrasts with the more usual silver-promoted ring-expansion reactions in which endocyclic bond cleavage occurs. Experimental and theoretical studies are reported which provide insights into the reaction mechanism and the origin of its kinetic selectivity for E-configured bromoalkene products. Density functional theory computations (M06-2X) predict that the reaction commences with alkoxide-induced HBr elimination from the dibromocyclopropane to form a bromocyclopropene. Ring opening then gives a configurationally stable zwitterionic (oxocarbenium cation/vinyl carbanion) intermediate, which undergoes nucleophilic addition and protonation to give the bromoalkene. There are two competing sources of the proton in the final step: One is the alcohol (co)solvent, and the other is the molecule of alcohol produced during the initial deprotonation step. The roles of the formed alcohol molecule and the bulk (co)solvent are demonstrated by isotope-labeling studies performed with deuterated solvents. The acid-promoted isomerization of the E-bromoalkene product into the corresponding Z-bromoalkene is also described. The mechanistic knowledge gained in this investigation sheds light on the unusual chemistry of this system and facilitates its future application in new settings.

Computational discoveries of reaction mechanisms: recent highlights and emerging challenges.

This review examines some of the notable advances and trends that have shaped the field of computational elucidation of organic reaction mechanisms over the last 10-15 years. It highlights the types of mechanistic problems that have recently become possible to study and summarizes the methodological developments that have permitted these new advances. Case studies are taken from three representative areas of organic chemistry-asymmetric catalysis, glycosylation reactions, and single electron transfer reactions-which illustrate themes common to the broader field. These include the trend towards modelling systems that are increasingly complex (both structurally and mechanistically), the growing appreciation of the mechanistic roles of non-covalent interactions, and the increasing ability to explore dynamical features of reaction mechanisms. Some interesting new challenges that have emerged in the field are identified.

Cibalackrot Dendrimers for Hyperfluorescent Organic Light-Emitting Diodes.

Hyperfluorescent organic light-emitting diodes (HF-OLEDs) enable a cascading Förster resonance energy transfer (FRET) from a suitable thermally activated delayed fluorescent (TADF) assistant host to a fluorescent end-emitter to give efficient OLEDs with relatively narrowed electroluminescence compared to TADF-OLEDs. Efficient HF-OLEDs require optimal FRET with minimum triplet diffusion via Dexter-type energy transfer (DET) from the TADF assistant host to the fluorescent end-emitter. To hinder DET, steric protection of the end-emitters has been proposed to disrupt triplet energy transfer. In this work, the first HF-OLEDs based on structurally well-defined macromolecules, dendrimers is reported. The dendrimers contain new highly twisted dendrons attached to a Cibalackrot core, resulting in high solubility in organic solvents. HF-OLEDs based on dendrimer blend films are fabricated to show external quantum efficiencies of >10% at 100 cd m-2 . Importantly, dendronization with the bulky dendrons is found to have no negative impact to the FRET efficiency, indicating the excellent potential of the dendritic macromolecular motifs for HF-OLEDs. To fully prevent the undesired triplet diffusion, Cibalackrot dendrimers HF-OLEDs are expected to be further improved by adding additional dendrons to the Cibalackrot core and/or increasing dendrimer generations.

Chemoselective and Diastereoselective Intramolecular (3+2) Cycloadditions of Epoxy and Aziridinyl Enolsilanes.

Epoxy and aziridinyl enolsilanes react as oxyallylic cation equivalents in highly chemo- and diastereoselective intramolecular (3+2) cycloadditions with a range of dienes and olefins. With acyclic dienes, the (3+2) cycloaddition outcompetes the (4+3) pathway traditionally observed in this kind of system almost exclusively. With both conjugated dienes and isolated olefins, excellent diastereoselectivities are observed, and cycloadducts can be obtained in optically-enriched forms. Computational studies indicate that the stepwise (3+2) cycloaddition involves an activated epoxy/aziridinyl intermediate and the conformational flexibility of the intermediate determines the preference for (3+2) cycloadduct formation. Further transformations of the (3+2) cycloadducts produce densely functionalized trans-hydrindane scaffolds.

Does H3O+ Really Act as a Ligand in the Solid State?

The evidence for the existence of metal complexes containing H3O+ as a ligand in the solid state is examined. Each of the 68 examples in the Cambridge Structural Database in which H3O+ is bound to a transition metal, lanthanoid, actinoid, or main group metal ion is detailed and critically appraised. It is concluded that none of the reported examples of complexes containing coordinated H3O+ have been unequivocally characterized and that they result from either curation errors or misinterpretations of the crystallographic data. These conclusions are supported by computational techniques, which show that three purported H3O+ complexes based on the 1,4,7,10,13,16,21,24-octa-azabicyclo(8.8.8)hexacosane azacryptand skeleton are better described as aqua complexes, with protonation occurring at the amine ligand.

EBC-232 and 323: A Structural Conundrum Necessitating Unification of Five In Silico Prediction and Elucidation Methods.

Structurally unique halimanes EBC-232 and EBC-323, isolated from the Australian rainforest plant Croton insularis, proved considerably difficult to elucidate. The two diastereomers, which consist an unusual oxo-6,7-spiro ring system fused to a dihydrofuran, were solved by unification and consultation of five in silico NMR elucidation and prediction methods [i.e., ACDLabs, olefin strain energy (OSE), DP4, DU8+ and TD DFT CD]. Structure elucidation challenges of this nature are prime test case examples for empowering future AI learning in structure elucidation.

How does cross-conjugation influence thiol additions to enones? A computational study of thiol trapping by the naturally occurring divinyl ketones zerumbone and α-santonin.

Density functional theory calculations are reported which explore how the kinetics and thermodynamics of thiol additions to enones are affected by the incorporation of the enone into a cross-conjugated divinyl ketone moiety. Computations with ωB97X-D//M06-2X indicate that in the parent acyclic system (1,4-pentadien-3-one), cross-conjugation has a small stabilizing effect on the thiol adduct, making the ΔG for the addition slightly more negative, and a larger stabilizing effect on the transition state, lowering ΔG‡. By contrast, in the parent six-membered cyclic system (2,5-cyclohexadien-1-one), cross-conjugation makes ΔG significantly less negative while causing only a small increase in ΔG‡. Both scenarios correspond to a more reversible addition. Thiol additions to two naturally occurring divinyl ketones, zerumbone and α-santonin, are examined. Previous NMR-based assays had shown that zerumbone forms mono- and bis-thiol adducts while α-santonin showed no detectable adduct formation. Computations reveal that the eleven-membered ring structure of zerumbone accelerates thiol trapping, relative to an analogous acyclic model. For α-santonin, the computations reveal that thiol addition is actually also rather facile, and it likely does occur, but the adduct is unstable and rapidly eliminates the thiol. These results illustrate that the inability to detect a thiol adduct in an experimental assay does not necessarily imply that the adduct does not form; instead it may simply be a manifestation of a rapid addition/elimination equilibrium in which the adduct concentration is below the limits of detectability.

Catalytic Asymmetric Staudinger-aza-Wittig Reaction for the Synthesis of Heterocyclic Amines.

Many natural products and medicinal drugs are heterocyclic amines possessing a chiral quaternary carbon atom in their heterocyclic ring. Herein, we report the first catalytic and asymmetric Staudinger-aza-Wittig reaction for the desymmetrization of ketones. This highly enantioselective transformation proceeds at room temperature to provide high yields-even on multigram scales-of nitrogen heterocycles featuring a chiral quaternary center. The products of this reaction are potential precursors for the synthesis of pharmaceuticals. A commercially available small P-chiral phosphine catalyst, HypPhos, induces the asymmetry and is recycled through in situ reduction of its oxide, mediated by phenylsilane in the presence of a carboxylic acid. The efficiency, selectivity, scalability, mild reaction conditions, and broad substrate scope portend that this process will expedite the syntheses of chiral heterocyclic amines of significance to chemistry, biology, and medicine.

Rearrangement-Free Hydroxylation of Methylcubanes by a Cytochrome P450: The Case for Dynamical Coupling of C-H Abstraction and Rebound.

The highly strained cubylmethyl radical undergoes one of the fastest radical rearrangements known (reported k = 2.9 × 1010 s-1 at 25 °C) through scission of two bonds of the cube. The rearrangement has previously been used as a mechanistic probe to detect radical-based pathways in enzyme-catalyzed C-H oxidations. This paper reports the discovery of highly selective cytochrome P450-catalyzed methylcubane oxidations which notionally proceed via cubylmethyl radical intermediates yet are remarkably free of rearrangement. The bacterial cytochrome P450 CYP101B1 from Novosphingobium aromaticivorans DSM 12444 is found to hydroxylate the methyl group of a range of methylcubane substrates containing a regio-directing carbonyl functionality at C-4. Unlike other reported P450-catalyzed methylcubane oxidations, the designed methylcubanes are hydroxylated with high efficiency and selectivity, giving cubylmethanols in yields of up to 93%. The lack of cubane core ring-opening implies that the cubylmethyl radicals formed during these CYP101B1-catalyzed hydroxylations must have very short lifetimes, of just a few picoseconds, which are too short for them to manifest the side reactivity characteristic of a fully equilibrated P450 intermediate. We propose that the apparent ultrafast radical rebound can be explained by a mechanism in which C-H abstraction and C-O bond formation are merged into a dynamically coupled process, effectively bypassing a discrete radical intermediate. Related dynamical phenomena can be proposed to predict how P450s may achieve various other modes of reactivity by controlling the formation and fate of radical intermediates. In principle, dynamical ideas and two-state reactivity are each individually able to explain apparent ultrashort radical lifetimes in P450 catalysis, but they are best considered together.

Origins of stereoselectivity in uncatalyzed and ZnBr2-catalyzed Diels-Alder reactions of a chiral sulfinylquinone.

Density functional theory calculations are reported which explore how a chiral sulfinyl substituent controls the stereoselectivities of the Diels-Alder reactions of a 2-p-tolylsulfinylbenzoquinone. The π-facial stereoselectivities vary depending on the diene (cyclopentadiene or trans-piperylene) and on the presence or absence of a ZnBr2 catalyst. The stereoselectivities are shown to be controlled by steric effects and non-covalent (CH-π) interactions. The calculations reveal that the active dienophile in the ZnBr2-catalyzed reactions is likely to be a 1 : 2 complex of the dienophile and catalyst, not a 1 : 1 complex as commonly assumed.