TOWARDS PHORBOXAZOLE B: THE C20-C32 FRAGMENT

Phorboxazole A and phorboxazole B are two potent cytostatic polyketides isolated from Phorbas marine sponge found in the Indian Ocean. Because of their excellent cytostatic activity and unprecedented structure phorboxazoles have been a very attractive target for synthetic chemists and eleven total syntheses have been reported. A novel and efficient synthesis of the C20-C32 core fragment of phorboxazoles has been developed. Key steps were: an enantioselective aldol reaction, a diastereoselective crotylation and, a diastereoselective oxy-Michael reaction. The synthesis was 7 steps long with an overall yield of 31%. A stereodivergent oxy-Michael reaction was further investigated in a computational study and analogue study

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.EPSRC Leverhulme Isaac Newton trus

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.The authors wish to thank Medivir for the generous financial support.This is the final version of the article. It first appeared from the Royal Society of Chemistry via https://doi.org/10.1039/C6OB00015

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.Medivir, Leverhulme Trust and Isaac Newton Trus

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

Gold(I)-catalyzed nucleophilic allylations of pyridinium and quinolinium ions with allylboronates are reported. Transmetalation of the allylboronate with gold produces nucleophilic allylgold(I) species that add to the 4-position of the azinium ion with complete regioselectivity to give functionalized 1,4-dihydropyridines and 1,4-dihydroquinolines. Density functional theory (DFT) calculations provided mechanistic insight

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.EPSRC GSSK ERC Leverhulme Trust Isaac Newton Trus

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

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 used 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. <br /

DFT, Molecular Mechanics and Raw NMR Data for: DP4-AI Automated NMR Data Analysis Straight from Spectrometer to Structure

Archive of DFT and Molecular Mechanics Data for DP4-AI Straight from Spectrometer to Structure. All of the files can be opened in any text editor. The conformational search output structures can be visualised in Schrodinger Maestro. Gaussian output structures can be viewed in Avogadro, jmol and in most other molecular viewers/editors. ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ This archive is separated into folders corresponding to each molecule (X) in the study. ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ For each molecule there are three sets of calculations corresponding to the three levels of theory described in the paper. These are separated into subfolders labelled: MM - molecular mechanics geometries, mPW1PW91 NMR Calculations Opt - DFT optimised geometries, mPW1PW91 NMR Calculations Opt_E - DFT optimised geometries, mPW1PW91 NMR Calculations, M062X Single point energies ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Within these subfolders the X_Y.sdf files correspond to the input molecular geometries for each diastereomer (Y) of the molecule (X), Y = 1 always corresponds to the correct diastereomer. The X_Y.mae files describe the macromodel conformational search for diastereomer. The handwritten NMR description is stored in the file XNMR The raw proton and carbon NMR files are stored in the Proton and Carbon subfolders of the NMR_folder directory at this level ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The DFT calculation files are also then organised into subsubfolders nmr - NMR DFT calculations opt – DFT geometry optimisation calculations (Opt and Opt_E only) e – DFT M062X single point energy caculations (Opt_E only) These files are in the Gaussian input and output file format. The input (.com) file names all have the form X_YginpZ.com this is read as: molecule X, diastereomer Y, Gaussian input, conformer Z. For each (.com) input file there is a corresponding (.out) output file with the same file name. Within each set of calculations (MM, Opt or Opt_E) for each molecule the diastereomer and conformer labels are self consistent