Total Synthesis and Structural Plasticity of Kratom Pseudoindoxyl Metabolites.

Mitragynine pseudoindoxyl, a kratom metabolite, has attracted increasing attention due to its favorable side effect profile as compared to conventional opioids. Herein, we describe the first enantioselective and scalable total synthesis of this natural product and its epimeric congener, speciogynine pseudoindoxyl. The characteristic spiro-5-5-6-tricyclic system of these alkaloids was formed through a protecting-group-free cascade relay process in which oxidized tryptamine and secologanin analogues were used. Furthermore, we discovered that mitragynine pseudoindoxyl acts not as a single molecular entity but as a dynamic ensemble of stereoisomers in protic environments; thus, it exhibits structural plasticity in biological systems. Accordingly, these synthetic, structural, and biological studies provide a basis for the planned design of mitragynine pseudoindoxyl analogues, which can guide the development of next-generation analgesics.

Coupled Cluster Molecular Dynamics of Condensed Phase Systems Enabled by Machine Learning Potentials: Liquid Water Benchmark.

Coupled cluster theory is a general and systematic electronic structure method, but in particular the highly accurate "gold standard" coupled cluster singles, doubles and perturbative triples, CCSD(T), can only be applied to small systems. To overcome this limitation, we introduce a framework to transfer CCSD(T) accuracy of finite molecular clusters to extended condensed phase systems using a high-dimensional neural network potential. This approach, which is automated, allows one to perform high-quality coupled cluster molecular dynamics, CCMD, as we demonstrate for liquid water including nuclear quantum effects. The machine learning strategy is very efficient, generic, can be systematically improved, and is applicable to a variety of complex systems.

Restricting Solvation to Two Dimensions: Soft Landing of Microsolvated Ions on Inert Surfaces.

In an effort to scrutinize dimensional restriction effects on finite hydrogen-bonded networks, we deposit ion-doped water clusters by computational soft landing on a chemically inert supported xenon surface. In stark contrast to the much studied metal or metal oxide surfaces, the rare gas surface interacts only rather weakly and nondirectionally with these networks. Surprisingly, the strongly bound Na+-doped networks undergo very significant plastic deformations, whereas the weakly bound Cl- counterparts barely change upon surface deposition. This counterintuitive finding is traced back to the significantly less favorable water-water interactions enforced by the cation, which results in an easier adaption to geometric restrictions, whereas H-bonding stabilizes the anionic clusters.

Terahertz Spectra of Microsolvated Ions: Do They Reveal Bulk Solvation Properties?

Complementing mid-infrared (mid-IR) spectroscopy mainly in the OH stretching region, liquid-state far-IR spectroscopy is successful in elucidating the properties of aqueous solutions by providing direct access to the hallmark of H-bonding at terahertz (THz) frequencies, namely, the H-bond network peak of water at roughly 200 cm-1 and its modifications in the hydration shells around solutes. Here, the idea is scrutinized whether ion hydration can be understood by studying the THz regime of "small" ion-water clusters in the gas phase as a function of size with subsequent extrapolation to the bulk limit. Our ab initio simulations of Na+(H2O) n clusters followed by rigorous decomposition of their THz response demonstrate that the 200 cm-1 network peak is suppressed even at n = 20 in the gas phase, yet it emerges when transferring ion-water complexes as small as n = 7 out of the liquid into vacuum. The underlying physical reason is not missing electronic polarization or charge-transfer effects in the gas phase, but rather the distinctly different structural dynamics of finite ion-water clusters in the gas phase compared to ion-water complexes of the same size in the liquid phase.

Efficient direct 2,2,2-trifluoroethylation of indoles via C-H functionalization.

A novel highly C3 selective metal free trifluoroethylation of indoles using 2,2,2-trifuoroethyl(mesityl)-iodonium triflate was developed. The methodology enables the introduction of a trifluoroethyl group in a fast and efficient reaction under mild conditions with high functional group tolerance. Beyond the synthetic developments, quantum chemical calculations provide a deeper understanding of the transformation.

Mechanistic study of silver-mediated furan formation by oxidative coupling.

Density functional calculations and experiments have been carried out to unravel the mechanism of a silver-mediated furan formation by oxidative coupling. Various possible reaction paths were considered and the most favorable channel has been identified on the basis of the calculated solvent-corrected Gibbs free-energy profiles. The mechanism represented by this route consists of a radical and a subsequent ionic route. The silver cation has a double role in the mechanism: it is the oxidant in the radical steps and the catalyst for the ionic steps, which is in accordance with the experimental observations. The two most important aspects of the optimal route are the formation of a silver-acetylide, reacting subsequently with the enolate radical, and the aromatic furan-ring formation in a single step at the latter, ionic segment of the reaction path. Our findings could explain several experimental observations, including the "key-promoter role" of silver, the preference for ionic cyclization, and the reduced reactivity of internal acetylides.

Divided Saddle Theory: A New Idea for Rate Constant Calculation.

We present a theory of rare events and derive an algorithm to obtain rates from postprocessing the numerical data of a free energy calculation and the corresponding committor analysis. The formalism is based on the division of the saddle region of the free energy profile of the rare event into two adjacent segments called saddle domains. The method is built on sampling the dynamics within these regions: auxiliary rate constants are defined for the saddle domains and the absolute forward and backward rates are obtained by proper reweighting. We call our approach divided saddle theory (DST). An important advantage of our approach is that it requires only standard computational techniques which are available in most molecular dynamics codes. We demonstrate the potential of DST numerically on two examples: rearrangement of alanine-dipeptide (CH3CO-Ala-NHCH3) conformers and the intramolecular Cope reaction of the fluxional barbaralane molecule.

Mechanism of the Pechmann reaction: a theoretical study.

One of the most widespread synthetic routes to coumarins is the condensation of esters and phenols via the Pechmann reaction. Despite the industrial and technological importance of the reaction, its mechanism is still poorly understood. We have explored several possible reaction paths by DFT calculations at the M05-2X/6-31+G* level. Amphoteric groups and the solvent have a crucial role in the frequent proton-transfer steps of the mechanisms; therefore, we have employed a mixed solvent model, where we combined the implicit PCM model together with an explicit water molecule placed at the actual proton transfer region. The Gibbs free-energy profiles of the possible routes suggest that three parallel channels (featuring water elimination, trans-esterification, and electrophilic attack) operate simultaneously. Enolic routes have prohibitively high activation barriers rendering these paths untenable. The calculated profiles indicate that in each feasible route the first elementary step has the highest activation energy. Reaction intermediates identified on the free-energy profiles can explain several experimental observations.