Jonathan M Goodman

• PhD
• University of Cambridge at University of Cambridge

Humans are exposed to many chemicals, yet limited toxicity data hinder effectively managing their impact on human health. High-performing machine learning models hold potential for addressing this gap, but their uncharacterized prediction performance across the wider chemical space undermines confidence in their results. We developed uncertainty-aw...

How much chemistry can be described by looking only at each atom, its neighbours and its next-nearest neighbours? We present a method for predicting reaction sites based only on a simple, two-bond model. Machine learning classification models were trained and evaluated using atom-level labels and descriptors, including bond strength and connectivit...

C–H borylation is a high-value transformation in the synthesis of lead candidates for the pharmaceutical industry because a wide array of downstream coupling reactions is available. However, predicting its regioselectivity, especially in drug-like molecules that may contain multiple heterocycles, is not a trivial task. Using a data set of borylatio...

Owing to its high natural abundance compared to the commonly used transition (precious) metals, as well as its high Lewis acidity and ability to change oxidation state, aluminium has recently been explored as the basis for a range of single‐site catalysts. This paper aims to establish the ground rules for the development of a new type of cationic a...

Machine Learning (ML) is increasingly applied to fill data gaps in assessments to quantify impacts associated with chemical emissions and chemicals in products. However, the systematic application of ML-based approaches to fill chemical data gaps is still limited, and their potential for addressing a wide range of chemicals is unknown. We prioritiz...

The selectivity in a group of oxazaborolidinium ion-catalysed reactions between aldehyde and diazo compounds cannot be explained using transition state theory. VRAI-selectivity, developed to predict the outcome of dynamically controlled reactions, can account for both the chemo- and the stereo-selectivity in these reactions, which are controlled by...

In the pursuit of improved compound identification and database search tasks, this study explores Heteronuclear Single Quantum Coherence (HSQC) spectra simulation and matching methodologies. HSQC spectra serve as unique molecular fingerprints, enabling a valuable balance of data collection time and information richness. We conducted a comprehensive...

CONFPASS (Conformer Prioritizations and Analysis for DFT re-optimizations) has been developed to extract dihedral angle descriptors from conformational searching outputs, perform clustering, and return a priority list for density functional theory (DFT) re-optimizations. Evaluations were conducted with DFT data of the conformers for 150 structurall...

The selectivity in a group of oxazaborolidinium ion-catalysed reactions between aldehyde and diazo compounds cannot be explained using transition state theory. VRAI-selectivity, developed to predict the outcome of dynamically controlled reactions, can account for both the chemo- and the stereo-selectivity in these reactions, which are controlled by...

CONFPASS (Conformer Prioritizations & Analysis for DFT re-optimisations) has been developed to extract dihedral angle descriptors from conformational searching outputs, perform clustering and return a priority list for DFT re-optimisations. Evaluations were conducted with DFT data of the conformers for 150 structurally diverse molecules, most of wh...

CONFPASS (Conformer Prioritizations & Analysis for DFT re-optimisations) has been developed to extract dihedral angle descriptors from conformational searching outputs, perform clustering and return a priority list for DFT re-optimisations. Evaluations were conducted with DFT data of the conformers for 150 structurally diverse molecules, most of wh...

The epigenetic modification 5‐methylcytosine plays a vital role in development, cell specific gene expression and disease states. The selective chemical modification of the 5‐methylcytosine methyl group is challenging. Currently, no such chemistry exists. Direct functionalisation of 5‐methylcytosine would improve the detection and study of this epi...

The epigenetic modification 5‐methylcytosine plays a vital role in development, cell specific gene expression and disease states. The selective chemical modification of the 5‐methylcytosine methyl group is challenging. Currently, no such chemistry exists. Direct functionalisation of 5‐methylcytosine would improve the detection and study of this epi...

Vibrational circular dichroism (VCD) spectroscopy can generate the data required for the assignment of absolute configuration, but the spectra are hard to interpret. We have recorded VCD data for thirty pairs of small organic compounds and we use this database to validate a method for the automated analysis of VCD spectra and the assignment of abso...

Computational reaction prediction has become a ubiquitous task in chemistry due to the potential value accurate predictions can bring to chemists. Boronic acids are widely used in industry; however, understanding how to avoid the protodeboronation side reaction remains a challenge. We have developed an algorithm for in silico prediction of the rate...

Vibrational circular dichroism (VCD) spectroscopy can generate the data required for the assignment of absolute configuration, but the spectra are hard to interpret. We have recorded VCD data for thirty pairs of small organic compounds and we use this database to validate a method for the automated analysis of VCD spectra and the assignment of abso...

The use of machine learning techniques in computational chemistry has gained significant momentum since large molecular databases are now readily available. Predictions of molecular properties using machine learning have advantages over the traditional quantum mechanics calculations because they can be cheaper computationally without losing the acc...

The RInChI is a canonical identifier for reactions which is widely used in reaction databases. It can be used to handle large collections of reactions and to link information from diverse data sources. How much information can it handle? Studies of the SAVI database, which contains more than a billion reactions, demonstrate that the RInChI is usefu...

In November 2020 the Royal Society of Chemistry Chemical Information and Computer Applications interest group (RSC CICAG) ran a five-day meeting entitled Open Chemical Science (https://www.rsc.org/events/detail/42090/open-chemical-science). This event had three intertwined themes, Open Data, Open Access publishing and a series of workshops highligh...

Next-generation risk assessment (NGRA) involves the combination of in vitro and in silico models for more human-relevant, ethical, and sustainable human chemical safety assessment. NGRA requires a quantitative mechanistic understanding of the effects of chemicals across human biology (be they molecular, cellular, organ-level or higher) coupled with...

Whenever a new molecule is made, a chemist will justify the proposed structure by analysing the NMR spectra. The widely-used DP4 algorithm will choose the best match from a series of possibilities, but draws no conclusions from a single candidate structure. Here we present the DP5 probability, a step-change in the quantification of molecular uncert...

Whenever a new molecule is made, a chemist will justify the proposed structure by analysing the NMR spectra. The widely-used DP4 algorithm will choose the best match from a series of possibilities, but draws no conclusions from a single candidate structure. Here we present the DP5 probability, a step-change in the quantification of molecular uncert...

Research in chemistry increasingly requires interdisciplinary work prompted by, among other things, advances in computing, machine learning, and artificial intelligence. Everyone working with molecules, whether chemist or not, needs an understanding of the representation of molecules in a machine‐readable format, as this is central to computational...

The stereoselective reaction of 1,4-dicarbonyls with diarylprolinol silyl ether catalysts was studied with force field and density functional theory calculations. A robust procedure has been developed for computational investigations of...

Correction for ‘Computational insights on the origin of enantioselectivity in reactions with diarylprolinol silyl ether catalysts via a radical pathway’ by Ching Ching Lam et al. , Org. Chem. Front. , 2022, https://doi.org/10.1039/d2qo00354f.

Whenever a new molecule is made, a chemist will justify the proposed structure by analysing the NMR spectra. The widely-used DP4 algorithm will choose the best match from a series of possibilities, but draws no conclusions from a single candidate structure. Here we present the DP5 probability, a step-change in the quantification of molecular uncert...

Whenever a new molecule is made, a chemist will justify the proposed structure by analysing the NMR spectra. The widely-used DP4 algorithm will choose the best match from a series of possibilities, but draws no conclusions from a single candidate structure. Here we present the DP5 probability, a step-change in the quantification of molecular uncert...

N-Triflylphosphoramides (NTPA), have become increasingly popular catalysts in the development of enantioselective transformations as they are stronger Brønsted acids than the corresponding phosphoric acids (PA). Their highly acidic, asymmetric active site can activate difficult, unreactive substrates. In this review, we present an account of asymme...

Whenever a new molecule is made, a chemist will justify the proposed structure by analysing the NMR spectra. The widely-used DP4 algorithm will choose the best match from a series of possibilities, but draws no conclusions from a single candidate structure. Here we present the DP5 probability, a step-change in the quantification of molecular uncert...

Whenever a new molecule is made, a chemist will justify the proposed structure by analysing the NMR spectra. The widely-used DP4 algorithm will choose the best match from a series of possibilities, but draws no conclusions from a single candidate structure. Here we present the DP5 probability, a step-change in the quantification of molecular uncert...

Whenever a new molecule is made, a chemist will justify the proposed structure by analysing the NMR spectra. The widely-used DP4 algorithm will choose the best match from a series of possibilities, but draws no conclusions from a single candidate structure. Here we present the DP5 probability, a step-change in the quantification of molecular uncert...

Whenever a new molecule is made, a chemist will justify the proposed structure by analysing the NMR spectra. The widely-used DP4 algorithm will choose the best match from a series of possibilities, but draws no conclusions from a single candidate structure. Here we present the DP5 probability, a step-change in the quantification of molecular uncert...

Whenever a new molecule is made, a chemist will justify the proposed structure by analysing the NMR spectra. The widely-used DP4 algorithm will choose the best match from a series of possibilities, but draws no conclusions from a single candidate structure. Here we present the DP5 probability, a step-change in the quantification of molecular uncert...

Whenever a new molecule is made, a chemist will justify the proposed structure by analysing the NMR spectra. The widely-used DP4 algorithm will choose the best match from a series of possibilities, but draws no conclusions from a single candidate structure. Here we present the DP5 probability, a step-change in the quantification of molecular uncert...

Whenever a new molecule is made, a chemist will justify the proposed structure by analysing the NMR spectra. The widely-used DP4 algorithm will choose the best match from a series of possibilities, but draws no conclusions from a single candidate structure. Here we present the DP5 probability, a step-change in the quantification of molecular uncert...

Whenever a new molecule is made, a chemist will justify the proposed structure by analysing the NMR spectra. The widely-used DP4 algorithm will choose the best match from a series of possibilities, but draws no conclusions from a single candidate structure. Here we present the DP5 probability, a step-change in the quantification of molecular uncert...

Whenever a new molecule is made, a chemist will justify the proposed structure by analysing the NMR spectra. The widely-used DP4 algorithm will choose the best match from a series of possibilities, but draws no conclusions from a single candidate structure. Here we present the DP5 probability, a step-change in the quantification of molecular uncert...

Whenever a new molecule is made, a chemist will justify the proposed structure by analysing the NMR spectra. The widely-used DP4 algorithm will choose the best match from a series of possibilities, but draws no conclusions from a single candidate structure. Here we present the DP5 probability, a step-change in the quantification of molecular uncert...

Mitochondrial toxicity is a problem of growing concern in modern society, resulting in several serious adverse health effects including cardiac failure, hepatotoxicity, and neurodegenerative disorders. Adverse outcome pathways provide models for structuring a mechanistic understanding of toxicology, but most existing in silico models for prediction...

The software for the IUPAC Chemical Identifier, InChI, is extraordinarily reliable. It has been tested on large databases around the world, and has proved itself to be an essential tool in the handling and integration of large chemical databases. InChI version 1.05 was released in January 2017 and version 1.06 in December 2020. In this paper, we re...

In recent years, a growing number of organic reactions in the literature have shown selectivity controlled by reaction dynamics rather than by transition state theory. Such reactions are difficult to analyse because the transition state theory approach often does not capture the subtlety of the energy landscapes the compounds traverse and, therefor...

Background: Humans are exposed to tens of thousands of chemical substances that need to be assessed for their potential toxicity. Acute systemic toxicity testing serves as the basis for regulatory hazard classification, labeling, and risk management. However, it is cost- and time-prohibitive to evaluate all new and existing chemicals using traditi...

The software for the IUPAC Chemical Identifier, InChI, is extraordinarily reliable. It has been tested on large databases around the world, and has proved itself to be an essential tool in the handling and integration of large chemical databases. InChI version 1.05 was released in January 2017 and v. 1.06 in December 2020. In this paper, we report...

In recent times, machine learning has become increasingly prominent in predictive toxicology as it has shifted from in vivo studies toward in silico studies. Currently, in vitro methods together with other computational methods such as quantitative structure-activity relationship modeling and absorption, distribution, metabolism, and excretion calc...

Having a measure of confidence in computational predictions of biological activity from in silico tools is vital when making predictions for new chemicals, for example, in chemical risk assessment. Where predictions of biological activity are used as an indicator of a potential hazard, false-negative predictions are the most concerning prediction;...

The Minisci reaction is one of the most valuable methods for directly functionalizing basic heteroarenes to form carbon–carbon bonds. Use of prochiral, heteroatom-substituted radicals results in stereocenters being formed adjacent to the heteroaromatic system, generating motifs which are valuable in medicinal chemistry and chiral ligand design. Rec...

The IUPAC international chemical identifier, InChI, provides a way to name molecules. It is defined by an open algorithm that transforms molecular structures into unique strings of text. Each molecule should have exactly one InChI, and each InChI should correspond to exactly one molecule. This property makes it a useful tool in the management of ch...

Deep learning neural networks, constructed for the prediction of chemical binding at 79 pharmacologically important human biological targets, show extremely high performance on test data (accuracy 92.2 ± 4.2%, MCC 0.814 ± 0.093 and ROC-AUC 0.96 ± 0.04). A new molecular similarity measure, Neural Network Activation Similarity, has been developed, ba...

Characterization of the complex molecular scafold of the marine polyketide natural product phormidolide A represents a challenge that has persisted for nearly two decades. In light of discordant results arising from recent synthetic and biosynthetic reports, a rigorous study of the configuration of phormidolide A was necessary. This report outlines...

Molecular initiating events (MIEs) are key events in adverse outcome pathways (AOPs) that link molecular chemistry to target biology. As they are based in chemistry, these interactions are excellent targets for computational chemistry approaches to in silico modelling. In this work, we aim to link ligand chemical structure to MIEs for androgen rece...

A large number of reported organic reactions feature post transition state bifurcating reaction pathways. The selectivity in such reactions is difficult to analyze because it cannot be determined by comparing the energies of competing transition states. Molecular dynamics approaches can provide an answer but are computationally very expensive. We p...

A robust system for automatic processing and assignment of raw 13C and 1H NMR data DP4-AI has been developed and integrated into our computational organic molecule structure elucidation workflow. Starting from a molecular structure with undefined stereochemistry or other structural uncertainty, this system allows for completely automated structure...

Coordination of Cu(I) or Pd(II) to seleno-cyclodiphosph(V)azanes of the type [RNH(Se)P(-NtBu)]2 results in positively charged anion receptor units which have increased anion affinity over the neutral seleno-phosph(V)azanes, due to the...

div> A robust system for automatic processing and assignment of raw 13C and 1H NMR data DP4-AI has been developed and integrated into our computational organic molecule structure elucidation workflow. Starting from a molecular structure with undefined stereochemistry or other structural uncertainty, this system allows for completely automated stru...

A molecular initiating event (MIE) is the gateway to an adverse outcome pathway (AOP), a sequence of events ending in an adverse effect. In silico predictions of MIEs are a vital tool in a modern, mechanism-focused approach to chemical risk assessment. For 90 biological targets representing important human MIEs, structural alert-based models have b...

The aim of human toxicity risk assessment is to determine a safe dose or exposure to a chemical for humans. This requires an understanding of the exposure of a person to a chemical, and how much of the chemical is required to cause an adverse effect. To do this computationally we need to understand how much of a chemical is required to perturb norm...

Modern supramolecular chemistry is overwhelmingly based on non‐covalent interactions involving organic architectures. However, the question of what happens when you depart from this area to the supramolecular chemistry of structures based on non‐carbon frameworks remains largely unanswered, and is an area that potentially provides new directions in...

Modern coordination chemistry is overwhelmingly based on supramolecular interactions involving organic architectures. However, the question of what happens when you depart from this ‘natural’ world to the supramolecular chemistry of ‘unnatural’ structures based on non‐carbon frameworks remains largely unanswered, and is an area that potentially pro...

What computational methods should be used to achieve the most reliable result in computational structure elucidation? A study on the effect of quality and quantity of geometries on computational NMR structure elucidation performance is reported. Semi-empirical, HF and DFT methods were explored, and B3LYP optimized geometries in combination with mPW...

A catalyst selection program, BINOPtimal, has been developed. This interactive web tool selects the best performing chiral phosphoric acid catalysts from analysis of the starting materials, imine and nucleophile, on...

Molecular Initiating Events (MIEs) are important concepts for in silico predictions. They can be used to link chemical characteristics to biological activity through an adverse outcome pathway (AOP). In this work, we capture chemical characteristics in 2D structural alerts, which are then used as models to predict MIEs. An automated procedure has b...

The Ames mutagenicity assay is a long established in vitro test to measure the mutagenicity potential of a new chemical used in regulatory testing globally. One of the key computational approaches to modelling the Ames assay relies on the formation of chemical categories based on the different electrophilic compounds that are able to react directly...

The Reaction InChI (RInChI) extends the idea of the InChI, which provides a unique descriptor of molecular structures, towards reactions. Prototype versions of the RInChI have been available since 2011. The first official release (RInChI-V1.00), funded by the InChI Trust, is now available for download ( http://www.inchi-trust.org/downloads/ ). This...

Through synthesising both candidate diastereomers of a model C1–C28 fragment of the potent cytotoxic marine polyketide hemicalide, an assignment of the relative configuration between the C1–C15 and C16–C26 regions has been achieved. By detailed NMR comparisons with the natural product, the relative stereochemistry between these two 1,6-related ster...

Through synthesising both candidate diastereomers of a model C1-C28 fragment of the potent cytotoxic marine polyketide hemicalide, an assignment of the relative configuration between the C1-C15 and C16-C26 regions has been achieved. By detailed NMR comparisons with the natural product, the relative stereochemistry between these two stereoclusters i...

A large-scale optimisation of density functional theory (DFT) conditions for computational NMR structure elucidation has been conducted by systematically screening the DFT functionals and statistical models. The extended PyDP4 workflow was tested on a diverse and challenging set of 42 biologically active and stereochemically rich compounds, includi...

Choosing the optimal catalyst for a new transformation is challenging because the ideal molecular requirements of the catalyst for one reaction do not always simply translate to another. Large groups at the 3,3' positions of the binaphthol rings are important for efficient stereoinduction but if they are too large this can lead to unusual or poor r...

Choosing the optimal catalyst for a new transformation is challenging because the ideal molecular requirements of the catalyst for one reaction do not always simply translate to another. Large groups at the 3,3' positions of the binaphthol rings are important for efficient stereoinduction but if they are too large this can lead to unusual or poor r...

Chiral BINOL-derived phosphoric acids catalyse the transfer hydrogenation of ketimines using Hantszch esters. In many cases the nitrogen on the imine binds to the catalyst through the catalyst hydroxyl group and the nucleophile forms a second hydrogen bond to the phosphoryl oxygen. DFT and ONIOM calculations show that the introduction of an ortho-...

Chiral BINOL-derived phosphoric acids catalyse the transfer hydrogenation of ketimines using Hantszch esters. In many cases the nitrogen on the imine binds to the catalyst through the catalyst hydroxyl group and the nucleophile forms a second hydrogen bond to the phosphoryl oxygen. DFT and ONIOM calculations show that the introduction of an ortho-...

The algorithmic, large-scale use and analysis of reaction databases such as Reaxys is currently hindered by the absence of widely adopted standards for publishing reaction data in machine readable formats. Crucial data such as yields of all products or stoichiometry are frequently not explicitly stated in the published papers and, hence, not report...

The Takai olefination (or Takai reaction) is a method for the conversion of aldehydes to vinyl iodides, and has seen widespread implementation in organic synthesis. The reaction is usually noted for its high (E)-selectivity; however, herein we report the highly (Z)-selective Takai olefination of salicylaldehyde derivatives. Systematic screening of...

Experimental procedures and analytical data.

The Takai olefination (or Takai reaction) is a method for the conversion of aldehydes to vinyl iodides, and has seen widespread implementation in organic synthesis. The reaction is usually noted for its high (E)-selectivity; however, herein we report the highly (Z)-selective Takai olefination of salicylaldehyde derivatives. Systematic screening of...

The adverse outcome pathway (AOP) framework provides an alternative to traditional $\textit{in vivo}$ experiments for the risk assessment of chemicals. AOPs consist of a number of key events (KEs) linked by key event relationships across a range of biological organization backed by scientific evidence. The first KE in the pathway is the molecular i...

The adverse outcome pathway (AOP) framework provides an alternative to traditional in vivo experiments for the risk assessment of chemicals. AOPs consist of a number of key events (KEs) linked by key event relationships (KERs) across a range of biological organization backed by scientific evidence. The first KE in the pathway is the molecular initi...

Molecular initiating events (MIEs) can be boiled down to chemical interactions. Chemicals that interact must have intrinsic properties that allow them to do this, be these stereochemical, electronic or otherwise. In an attempt to discover some of these chemical characteristics we have utilized chemical informatics approaches, searching the ChEMBL d...

BINOL-derived phosphoric acids provide effective asymmetric catalysis for many organic reactions. Catalysts based on this scaffold show a large structural diversity, especially in the 3, 3' substituents, and little is known about the molecular requirements for high selectivity. As a result, selection of the best catalyst for a particular transforma...

Chiral phosphoric acids have become powerful catalysts for the stereocontrolled synthesis of a diverse array of organic compounds. Since the initial report, the development of phosphoric acids as catalysts has been rapid, demonstrating the tremendous generality of this catalyst system and advancing the use of phosphoric acids to catalyze a broad ra...

The DP4 parameter, which provides a confidence level for NMR assignment, has been widely used to help assign the structures of many stereochemically-rich molecules. We present an improved version of the procedure, which can be downloaded as Python script instead of running within a web-browser, and which analyses output from open-source molecular m...

Using the DP4f GIAO-NMR method, the stereochemistry of hemicalide was computationally analysed, resulting in a reassignment at C18 as supported by improved NMR shift correlations with a model C13-C25 fragment 23. An advanced C16-C28 subunit 6 of this potent anticancer agent was then synthesised with the revised 18,19-syn relationship.

BINOL-derived phosphoric acids provide effective asymmetric catalysis for many organic reactions. Catalysts based on this scaffold show a large structural diversity, especially in the 3,3′ substituents, and little is known about the molecular requirements for high selectivity. As a result, selection of the best catalyst for a particular transformat...

Molecular initiating events (MIEs) can be boiled down to chemical interactions. Chemicals that interact must have intrinsic properties that allow them to exhibit this behavior, be these properties stereochemical, electronic, or otherwise. In an attempt to discover some of these chemical characteristics, we have constructed structural alert-style st...

Computational prediction of reaction outcomes and optimum synthetic routes was a two-day meeting and workshop organised by the EPSRC Dial-a-molecule grand challenge network. Forty delegates discussed computer predictions of synthetic routes and reactions, and considered their relevance to contemporary chemistry.Graphical abstract:Dial-a-molecule wo...

The reaction of tryptamine and (2-oxo-cyclohexyl)-acetic acid can be catalyzed by 3,3'-Bis(triphenylsilyl)-1,1'-bi-2-naphthol phosphoric acid to give an asymmetric beta-carboline. This reaction was first studied by Holloway et al. but their mechanistic work did not explain the high stereoselectivity achieved. This study uses density functional theo...

Density functional theory calculations suggest that asymmetric boronate addition to o-quinone methides proceeds via a Lewis-acid catalyzed process through a closed six-membered transition structure. The BINOL-derived catalyst undergoes an exchange process with the original ethoxide boronate ligands. This activation mode successfully accounts for th...

1-Azatricyclo[3.3.1.13,7]decan-2-one (3), the parent compound of a rare class of 90° twisted amides, has finally been synthesized, using an unprecedented transformation. These compounds are of special interest as transition state mimics for the enzyme-catalysed cis-trans rotamer interconversion of amides involved in peptide and protein folding and...

Two base mediated cascade rearrangement reactions of diallyl ethers were developed leading to selective [2,3]-Wittig-oxy-Cope and isomerization-Claisen rearrangements. Both diaryl and aryl-silyl substituted 1,3-substituted propenyl substrates were examined and each exhibits unique reactivity and different reaction pathways. Detailed mechanistic and...

The preparation and NMR analysis of 2,3-di-O-benzyl d-ribose and 2,3-di-O-d-xylose are described. In DMSO-d6 the sugars adopt a conformation in which the hydroxyl groups are in an equatorial position. In CDCl3 and CD2Cl2 the sugars adopts a conformation in which intramolecular hydrogen bonding plays an important role in determining the equilibrium...

Consumer and environmental safety decisions are based on exposure and hazard data, interpreted using risk assessment approaches. The adverse outcome pathway (AOP) conceptual framework has been presented as a logical sequence of events or processes within biological systems which can be used to understand adverse effects and refine current risk asse...