Synthesis, structure and stereodynamics of atropisomeric N-chloroamides.

Atropisomeric N-chloroamides were efficiently accessed by electrophilic halogenation of ortho-substituted secondary anilides. The stereodynamics of atropisomerism in these novel scaffolds was interrogated by detailed experimental and computational studies, revealing that racemization is correlated with amide isomerization. The stereoelectronic nature of the amide was shown to significantly influence racemization rates, with potentially important implications for other C-N atropisomeric scaffolds.

Interrogating the Crucial Interactions at Play in the Chiral Cation-Directed Enantioselective Borylation of Arenes.

Rendering a common ligand scaffold anionic and then pairing it with a chiral cation represents an alternative strategy for developing enantioselective versions of challenging transformations, as has been recently demonstrated in the enantioselective borylation of arenes using a quinine-derived chiral cation. A significant barrier to the further generalization of this approach is the lack of understanding of the specific interactions involved between the cation, ligand, and substrate, given the complexity of the system. We have embarked on a detailed computational study probing the mechanism, the key noncovalent interactions involved, and potential origin of selectivity for the desymmetrizing borylation of two distinct classes of substrate. We describe a deconstructive, stepwise approach to tackling this complex challenge, which involves building up a detailed understanding of the pairwise components of the nominally three component system before combining together into the full 263-atom reactive complex. This approach has revealed substantial differences in the noncovalent interactions occurring at the stereodetermining transition state for C-H oxidative addition to iridium for the two substrate classes. Each substrate engages in a unique mixture of diverse interactions, a testament to the rich and privileged structure of the cinchona alkaloid-derived chiral cations. Throughout the study, experimental support is provided, and this culminates in the discovery that prochiral phosphine oxide substrates, lacking hydrogen bond donor functionality, can also give very encouraging levels of enantioselectivity, potentially through direct interactions with the chiral cation. We envisage that the findings in this study will spur further developments in using chiral cations as controllers in asymmetric transition-metal catalysis.

MolE8: finding DFT potential energy surface minima values from force-field optimised organic molecules with new machine learning representations.

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 accuracy. We present a new extrapolatable and explainable molecular representation based on bonds, angles and dihedrals that can be used to train machine learning models. The trained models can accurately predict the electronic energy and the free energy of small organic molecules with atom types C, H N and O, with a mean absolute error of 1.2 kcal mol-1. The models can be extrapolated to larger organic molecules with an average error of less than 3.7 kcal mol-1 for 10 or fewer heavy atoms, which represent a chemical space two orders of magnitude larger. The rapid energy predictions of multiple molecules, up to 7 times faster than previous ML models of similar accuracy, has been achieved by sampling geometries around the potential energy surface minima. Therefore, the input geometries do not have to be located precisely on the minima and we show that accurate density functional theory energy predictions can be made from force-field optimised geometries with a mean absolute error 2.5 kcal mol-1.

Hydrogen Atom Transfer Driven Enantioselective Minisci Reaction of Alcohols.

Catalytic enantioselective Minisci reactions have recently been developed but all instances so far utilize α-amino radical coupling partners. We report a substantial evolution of the enantioselective Minisci reaction that enables α-hydroxy radicals to be used, providing valuable enantioenriched secondary alcohol products. This is achieved through the direct oxidative coupling of two C-H bonds on simple alcohol and pyridine partners through a hydrogen atom transfer (HAT)-driven approach: a challenging process to achieve due to the numerous side reactions that can occur. Our approach is highly regioselective as well as highly enantioselective. Dicumyl peroxide, upon irradiation with 390 nm light, serves as both HAT reagent and oxidant whilst selectivity is controlled by use of a chiral phosphoric acid catalyst. Computational and experimental evidence provide mechanistic insight as to the origin of selectivity, revealing a stereodetermining deprotonation step distinct from the analogous reaction of amide-containing substrates.

Gold(I)-Catalyzed Nucleophilic Allylation of Azinium Ions with Allylboronates.

Gold(I)-catalyzed nucleophilic allylations of pyridinium and quinolinium ions with various allyl pinacolboronates are reported. The reactions are completely selective with respect to the site of the azinium ion that is attacked, to give various functionalized 1,4-dihydropyridines and 1,4-dihydroquinolines. Evidence suggests that the reactions proceed through nucleophilic allylgold(I) intermediates formed by transmetalation from allylboronates. Density functional theory (DFT) calculations provided mechanistic insight.

Enantioselective "clip-cycle" synthesis of di-, tri- and spiro-substituted tetrahydropyrans.

ω-Unsaturated alcohols were "clipped" via alkene metathesis to a thioester activating group, which was followed by a chiral phosphoric acid catalyzed intramolecular oxa-Michael cyclization to yield tetrahydropyrans and spiro-tetrahydropyrans with excellent enantioselectivity. The mechanism and origin of the enantioselectivity was probed by DFT calculations and kinetic isotope studies, where there was excellent correlation between the computational and synthetic investigations.

A Computational and Experimental Investigation of the Origin of Selectivity in the Chiral Phosphoric Acid Catalyzed Enantioselective Minisci Reaction.

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. Recently a highly enantioselective and regioselective protocol for the Minisci reaction was developed, using chiral phosphoric acid catalysis. However, the precise mechanism by which this process operated and the origin of selectivity remained unclear, making it challenging to develop the reaction more generally. Herein we report further experimental mechanistic studies which feed into detailed DFT calculations that probe the precise nature of the stereochemistry-determining step. Computational and experimental evidence together support Curtin-Hammett control in this reaction, with initial radical addition being quick and reversible, and enantioselectivity being achieved in the subsequent slower, irreversible deprotonation. A detailed survey via DFT calculations assessed a number of different possibilities for selectivity-determining deprotonation of the radical cation intermediate. Computations point to a clear preference for an initially unexpected mode of internal deprotonation enacted by the amide group, which is a crucial structural feature of the radical precursor, with the assistance of the associated chiral phosphate. This unconventional stereodetermining step underpins the high enantioselectivities and regioselectivities observed. The mechanistic model was further validated by applying it to a test set of substrates possessing varied structural features.

Asymmetric "Clip-Cycle" Synthesis of Pyrrolidines and Spiropyrrolidines.

The development of an asymmetric "clip-cycle" synthesis of 2,2- and 3,3-disubstituted pyrrolidines and spiropyrrolidines, which are increasingly important scaffolds in drug discovery programs, is reported. Cbz-protected bis-homoallylic amines were activated by "clipping" them to thioacrylate via an alkene metathesis reaction. Enantioselective intramolecular aza-Michael cyclization onto the activated alkene, catalyzed by a chiral phosphoric acid, formed a pyrrolidine. The reaction accommodated a range of substitutions to form 2,2- and 3,3-disubstituted pyrrolidines and spiropyrrolidines with high enantioselectivities. The importance of the thioester activating group was demonstrated by comparison to ketone and oxoester-containing substrates. DFT studies supported the aza-Michael cyclization as the rate- and stereochemistry-determining step and correctly predicted the formation of the major enantiomer. The catalytic asymmetric syntheses of N-methylpyrrolidine alkaloids (R)-irnidine and (R)-bgugaine, which possess DNA binding and antibacterial properties, were achieved using the "clip-cycle" methodology.

Synergism of anisotropic and computational NMR methods reveals the likely configuration of phormidolide A.

Characterization of the complex molecular scaffold 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 a synergistic effort employing computational and anisotropic NMR investigation, that provided orthogonal confirmation of the reassigned side chain, as well as supporting a further correction of the C7 stereocenter.

DP4-AI automated NMR data analysis: straight from spectrometer to structure.

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 elucidation. Methods for NMR peak picking using objective model selection and algorithms for matching the calculated 13C and 1H NMR shifts to peaks in noisy experimental NMR data were developed. DP4-AI achieved a 60-fold increase in processing speed, and near-elimination of the need for scientist time, when rigorously evaluated using a challenging test set of molecules. DP4-AI represents a leap forward in NMR structure elucidation and a step-change in the functionality of DP4. It enables high-throughput analyses of databases and large sets of molecules, which were previously impossible, and paves the way for the discovery of new structural information through machine learning. This new functionality has been coupled with an intuitive GUI and is available as open-source software at https://github.com/KristapsE/DP4-AI.

The optimal DFT approach in DP4 NMR structure analysis - pushing the limits of relative configuration elucidation.

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 mPW1PW91 shifts and M06-2X conformer energies was found to be best. The required number of conformers considered has also been investigated, as well as several methods for the reduction of this number. Clear guidelines for the best computational NMR structure elucidation methods for different levels of available computing power are provided.

BINOPtimal: a web tool for optimal chiral phosphoric acid catalyst selection.

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 the basis of rules derived from the transformations within its database. This procedure has been applied to an example transformation demonstrating the potential to assist reaction design. The tool is available at www-mmm.ch.cam.ac.uk.

Conversion of Alcohols to Phosphorothiolates Using a Thioiminium Salt as Coupling Agent.

We report a method for the direct and rapid conversion of primary and secondary alcohols to the corresponding phosphorothiolates in yields ranging from 64% to 97%, using as a coupling agent the iminium salt prepared from N,N-dimethylthioformamide and Meerwein's salt. Selective reaction of primary alcohols in the presence of secondary alcohols is possible. The reaction of secondary alcohols proceeds stereospecifically with inversion of configuration.

The stereodivergent formation of 2,6-cis and 2,6-trans-tetrahydropyrans: experimental and computational investigation of the mechanism of a thioester oxy-Michael cyclization.

The origins of the stereodivergence in the thioester oxy-Michael cyclization for the formation of 4-hydroxy-2,6-cis- or 2,6-trans-substituted tetrahydropyran rings under different conditions was investigated both computationally and experimentally. Synthetic studies showed that the 4-hydroxyl group was essential for stereodivergence. When the 4-hydroxyl group was present, TBAF-mediated conditions gave the 2,6-trans-tetrahydropyran and trifluoroacetic acid-mediated conditions gave the 2,6-cis-tetrahydropyran. This stereodivergence vanished when the hydroxyl group was removed or protected. Computational studies revealed that: (i) the trifluoroacetic acid catalysed formation of 2,6-cis-tetrahydropyrans was mediated by a trifluoroacetate-hydroxonium bridge and proceeded via a chair-like transition state; (ii) the TBAF-mediated formation of 2,6-trans-tetrahydropyrans proceeded via a boat-like transition state, where the 4-hydroxyl group formed a crucial hydrogen bond to the cyclizing alkoxide; (iii) both reactions are under kinetic control. The utility of this stereodivergent approach for the formation of 4-hydroxy-2,6-substituted tetrahydropyran rings has been demonstrated by the total syntheses of the anti-osteoporotic natural products diospongin A and B.

Expanding DP4: application to drug compounds and automation.

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 modelling programs (TINKER and NWChem) in addition to being able to use output from commercial packages (Schrodinger's Macromodel and Jaguar; Gaussian). The new open-source workflow incorporates a method for the automatic generation of diastereomers using InChI strings and has been tested on a range of new structures. This improved workflow permits the rapid and convenient computational elucidation of structure and relative stereochemistry.

Strategies for the construction of tetrahydropyran rings in the synthesis of natural products.

This review focuses on the methodology used for the construction of tetrahydropyran (THP) rings in the synthesis of natural products over the last seven years. While methods like cyclisation onto oxocarbenium ions, reduction of cyclic hemi-ketals, Michael reactions, hetero-Diels-Alder cycloadditions and cyclisations onto epoxides continue to find application, several other strategies including metal-mediated cyclisations, ring-closing metathesis, radical cyclisations and carbocation cyclisations have also found use. This review is intended to provide an overview of the area for those who are unfamiliar, and to refresh and remind those who do work in the area of the exciting developments in the field.

Synthesis of the C20-C32 tetrahydropyran core of the phorboxazoles and the C22 epimer via a stereodivergent Michael reaction.

A stereoselective synthesis of the C20-C32 tetrahydropyran core of the phorboxazoles has been achieved in only seven steps and in a 31% overall yield. The C22 epimer was also synthesized. The key step was a silyl ether deprotection/oxy-Michael cyclization. When this step was conducted under Brønsted acid conditions, the C20-C32 core was formed with the desired 2,6-cis-stereochemistry. However, when the silyl ether deprotection/oxy-Michael cyclization was conducted under fluoride conditions buffered with acetic acid, the C22 epimer of the core was the sole product.