Here we interrogate the structurally dense (1.63 mcbits/Å 3 ) GABA A receptor antagonist bilobalide, intermediates en route to its synthesis and related mechanistic questions. 13 C isotope labeling identifies an unexpected bromine migration en route to an α-selective, catalytic asymmetric Reformatsky reaction, ruling out an asymmetric allylation pathway. Experiment and computation converge on the driving forces behind two surprising observations. First, an oxetane acetal persists in concentrated mineral acid (1.5 M DCl in THF-d 8 /D 2 O); its longevity is correlated to destabilizing steric clash between substituents upon ring-opening. Second, a regioselective oxidation of des-hydroxybilobalide is found to rely on lactone acidification through lone-pair delocalization, which leads to extremely rapid intermolecular enolate equilibration. We also establish equivalent effects of (−)-bilobalide and the nonconvulsive sesquiterpene (−)-jiadifenolide on action potential-independent inhibitory currents at GABAergic synapses, using (+)-bilobalide as a negative control. The high information density of bilobalide distinguishes it from other scaffolds, and may characterize natural product (NP) space more generally. Therefore, we also include a Python script to quickly (ca. 132,000 molecules/minute) calculate information content (Böttcher scores), which may prove helpful to identify important features of NP space.

The mechanism of the aza-Diels−Alder reaction catalyzed by tetraalkylammonium or trialkylsulfonium salts is explored with density functional theory. Favorable electrostatic interactions between the dienophile and the charged catalyst stabilize the highly polar transition state, leading to lower free energy barriers and higher dipole moments. Endo selectivity is predicted for both uncatalyzed and catalyzed systems. We also computationally evaluate the effects of oriented external electric fields (EEFs) on the same aza-Diels−Alder reaction, demonstrating that very strong EEFs would be needed to achieve the catalytic strength of these cationic catalysts.

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...

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 structurally diverse molecules, most of which are flexible. CONFPASS gives a confidence estimate that the global minimum structure has been found, and based on our dataset, we can have 90% confidence after optimizing half of the FF structures. Re-optimizing conformers in order of the FF energy often generates duplicate results; using CONFPASS, the duplication rate is reduced by a factor of 2 for the first 30% of the re-optimizations, which include the global minimum structure about 80% of the time.

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 epigenetic feature. We report a xanthone‐photosensitised process that introduces a 4‐pyridine modification at a C(sp3)−H bond in the methyl group of 5‐methylcytosine. We propose a reaction mechanism for this type of reaction based on density functional calculations and apply transition state analysis to rationalise differences in observed reaction efficiencies between cyanopyridine derivatives. The reaction is initiated by single electron oxidation of 5‐methylcytosine followed by deprotonation to generate the methyl group radical. Cross coupling of the methyl radical with 4‐cyanopyridine installs a 4‐pyridine label at 5‐methylcytosine. We demonstrate use of the pyridination reaction to enrich 5‐methylcytosine‐containing ribonucleic acid.