GIAO NMR shift calculation has been applied to the challenging task of reliably assigning stereochemistry with quantifiable confidence when only one set of experimental data are available. We have compared several approaches for assigning a probability to each candidate structure and have tested the ability of these methods to distinguish up to 64 possible diastereoisomers of 117 different molecules, using NMR shifts obtained in rapid and computationally inexpensive single-point calculations on molecular mechanics geometries without time-consuming ab initio geometry optimization. We show that a probability analysis based on the errors in each 13C or 1H shift is significantly more successful at making correct assignments with high confidence than are probabilities based on the correlation coefficient and mean absolute error parameters. Our new probability measure, which we have termed DP4, complements the probabilities obtained from our previously developed CP3 parameter, which applies to the case of assigning a pair of diastereoisomers when one has both experimental data sets. We illustrate the application of DP4 to assigning the stereochemistry or structure of 21 natural products that were originally misassigned in the literature or that required extensive synthesis of diastereoisomers to establish their stereochemistry.

The Potentiometric Cycling for Polymorph Creation [PC]2 has been applied to sparfloxacin, a third-generation fluoroquinolone antibiotic. Two different trihydrate phases precipitate from aqueous solution. X-ray data indicate that one of these is a previously unknown polymorph of sparfloxacin trihydrate. Because both forms crystallize from solution at the same time, the two crystalline forms are concomitant polymorphs that precipitate in a thermodynamically controlled ratio.

Solubility is a key physicochemical property of molecules. Serious deficiencies exist in the consistency and reliability of solubility data in the literature. The accurate prediction of solubility would be very useful. However, systematic errors and lack of metadata associated with measurements greatly reduce the confidence in current models. To address this, we are accurately measuring intrinsic solubility values, and here we report results for a diverse set of 100 druglike molecules at 25 °C and an ionic strength of 0.15 M using the CheqSol approach. This is a highly reproducible potentiometric technique that ensures the thermodynamic equilibrium is reached rapidly. Results with a coefficient of variation higher than 4% were rejected. In addition, the Potentiometric Cycling for Polymorph Creation method, [PC]2, was used to obtain multiple polymorph forms from aqueous solution. We now challenge researchers to predict the intrinsic solubility of 32 other druglike molecules that have been measured but are yet to be published.

DFT computed transition states quantitatively explain the surprising stereochemical outcome of unsubstituted enolborinates in diastereoselective and enantioselective boron aldol reactions.

Synthetic chemistry is hard because some reasonable looking molecules cannot be made, because there are errors in the chemical literature, because it is easy to miss reaction possibilities and because even the shape of molecules is very difficult to determine. We propose an approach to the computational analysis of reactions that tries to circumvent these difficulties, by restricting the analysis to simple rules for reactivity that can generate a large number of competing pathways. This huge ensemble is filtered using computational methods to pick out the most likely pathways, and to suggest possible products.

Using a D-mannitol derived chiral sulfide, terminal epoxides are formed in up to 76% ee; the first example of double asymmetric induction in a sulfonium methylide epoxidation is reported and an improved method of generating sulfonium ylides is detailed.

A Java applet that predicts solute losses during evaporation from a binary or ternary mixture has been developed which gives good agreement with experiment and can be used to estimate the boiling points of solutes, making use of information which is often collected and then discarded (http://www.ch.cam.ac.uk/magnus/rotavap/).

The relative and absolute stereochemistry of amphidinoketide I has been determined by the total synthesis of all the diastereoisomers. Molecular modelling suggests that the natural product is not the thermodynamically preferred diastereoisomer.

The appearance and disappearance of polymorphs is no longer a mysterious and inexplicable process. Although methods for polymorph control are still imperfect, there is a large armoury of methods that can be used to tackle this important and challenging problem. We survey the methods and their successes over the last few years.

DFT computed transition states quantitatively explain the surprising stereochemical outcome of unsubstituted enolborinates in diastereoselective and enantioselective boron aldol reactions.