Jonathan M. Goodman

Assigning stereochemistry to single diastereoisomers by GIAO NMR calculation: the DP4 probability.

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 (13)C or (1)H 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 molecular basis for selective inhibition of unconventional mRNA splicing by an IRE1-binding small molecule

IRE1 couples endoplasmic reticulum unfolded protein load to RNA cleavage events that culminate in the sequence-specific splicing of the Xbp1 mRNA and in the regulated degradation of diverse membrane-bound mRNAs. We report on the identification of a small molecule inhibitor that attains its selectivity by forming an unusually stable Schiff base with lysine 907 in the IRE1 endonuclease domain, explained by solvent inaccessibility of the imine bond in the enzyme-inhibitor complex. The inhibitor (abbreviated 4μ8C) blocks substrate access to the active site of IRE1 and selectively inactivates both Xbp1 splicing and IRE1-mediated mRNA degradation. Surprisingly, inhibition of IRE1 endonuclease activity does not sensitize cells to the consequences of acute endoplasmic reticulum stress, but rather interferes with the expansion of secretory capacity. Thus, the chemical reactivity and sterics of a unique residue in the endonuclease active site of IRE1 can be exploited by selective inhibitors to interfere with protein secretion in pathological settings.

Theoretical study of the mechanism of hantzsch ester hydrogenation of imines catalyzed by chiral BINOL-phosphoric acids.

The mechanism of the Hantzsch ester hydrogenation of imines catalyzed by chiral BINOL-phosphoric acid has been investigated using DFT methods. Despite the importance of this reaction, there are a number of possible detailed mechanisms, and the preferred pathway has not been firmly established. Our calculations show that the catalyst not only activates the imine group for the reaction by acting as a Brønsted acid but also establishes an interaction with the Hantzsch ester that can lead to an explanation for the enantioselectivity.

Polymorph control: past, present and future

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.

Enantio- and diastereoselective aldol reactions of achiral ethyl and methyl ketones with aldehydes: the use of enol diisopinocampheylborinates

Abstract Enol diisopinocampheylborinates, derived from achiral ethyl and methyl ketones by enolisation in the presence of tertiary amine bases (iPr2NEt or Et3N), undergo enantio- and diastereoselective aldol reactions with aldehydes. The reagents employed, (+)- and (-)-(Ipc)2BOTf, are easily prepared in enantiomerically pure form in two steps from (-)- and (+)-α-pinene, respectively. The aldol reaction between ethyl ketones and aldehydes using (+)- or (-)- (Ipc)2BOTf/iPr2NEt in dichloromethane gives, via the derived chiral Z-enol borinates, syn-α-methyl-β-hydroxy ketones in good enantiomeric excess (66-93% ee) and with high diastereoselectivity (>-95%). In contrast, the anti-selective aldol reaction of diethylketone via the isomeric E-enol diisopinocampheylborinate (by enolisation with (-)-(Ipc)2BCl) with methacrolein proceeds with negligible enantioselectivity. Use of both the triflate and chloride reagents in the aldol reaction of methyl ketones with aldehydes gives β-hydroxy ketones in moderate enantiomeric excess (53–78% ee) with a reversal in the enantioface selectivity of the aldehyde compared to the corresponding ethyl ketone syn aldol. This variable selectivity is interpreted as evidence for the participation of competing chair and boat transition states. Other chiral dialkylboron triflate reagents investigated led to reduced enantioselectivities in diethylketone-aldehyde aldol reactions.

Aldol reactions in polypropionate synthesis: High π-face selectivity of enol borinates from α-chiral methyl and ethyl ketones under substrate control

Abstract Use of ( c -C 6 H 11 ) 2 BCl in the anti -selective aldol reaction of the α-chiral ethylketone 2 leads to high stereoselectivity (>94%) for the 1,2- anti -2,4- anti isomer 7 . The related α-chiral methylketone aldol reaction, 8 → 9 , proceeds with 84–93% diasteroselectivity for a range of boron reagents.

Hydrogen Bonding and π-Stacking: How Reliable are Force Fields? A Critical Evaluation of Force Field Descriptions of Nonbonded Interactions

We have evaluated the performance of a set of widely used force fields by calculating the geometries and stabilization energies for a large collection of intermolecular complexes. These complexes are representative of a range of chemical and biological systems for which hydrogen bonding, electrostatic, and van der Waals interactions play important roles. Benchmark energies are taken from the high-level ab initio values in the JSCH-2005 and S22 data sets. All of the force fields underestimate stabilization resulting from hydrogen bonding, but the energetics of electrostatic and van der Waals interactions are described more accurately. OPLSAA gave a mean unsigned error of 2 kcal mol(-1) for all 165 complexes studied, and outperforms DFT calculations employing very large basis sets for the S22 complexes. The magnitude of hydrogen bonding interactions are severely underestimated by all of the force fields tested, which contributes significantly to the overall mean error; if complexes which are predominantly bound by hydrogen bonding interactions are discounted, the mean unsigned error of OPLSAA is reduced to 1 kcal mol(-1). For added clarity, web-based interactive displays of the results have been developed which allow comparisons of force field and ab initio geometries to be performed and the structures viewed and rotated in three dimensions.

A Model for the Enantioselectivity of Imine Reactions Catalyzed by BINOL−Phosphoric Acid Catalysts

BINOL-phosphoric acid catalysts have been used successfully in many reactions involving imines. In this paper, we present a model, based on DFT calculations, for describing the degree and sense of the enantioselectivity of these reactions that is able to predict the correct enantioselectivity for the reactions in more than 40 recent publications. We rationalize the different factors on which the enantioselectivity depends, focusing on the E- or Z-preference of the transition structures and the orientation of the catalyst with respect to the electrophile.

Solubility Challenge: Can You Predict Solubilities of 32 Molecules Using a Database of 100 Reliable Measurements?

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 degrees 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.

Mechanistic Insights into the BINOL-Derived Phosphoric Acid-Catalyzed Asymmetric Allylboration of Aldehydes

BINOL-derived phosphoric acids catalyze the asymmetric allylboration of aldehydes. DFT and QM/MM hybrid calculations showed that the reaction proceeds via a transition state involving both a hydrogen-bonding interaction from the catalyst hydroxyl group to the pseudoaxial oxygen of the cyclic boronate and a stabilizing interaction from the phosphoryl oxygen of the catalyst to the formyl hydrogen of the aldehyde. These interactions lower the energy of the transition structure and provide extra rigidity to the system. This mechanistic pathway is consistent with the experimentally observed enantioselectivity except in one case. We have used our models predictions to guide our own experimental work. The conflict is resolved in favor of our calculations.