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 (CH3COAla- NHCH3) conformers and the intramolecular Cope reaction of the uxional barbaralane molecule

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. This journal i

Effects of H-bond asymmetry on the electronic properties of liquid water – An AIMD analysis

The effects of an asymmetric environment on the electronic properties of a water molecule in liquid water are in focus in this paper and were analysed from ab initio molecular dynamics simulations of liquid water at 300 and 350 K with the BLYP-D3 functional. We make the following observations. (1) The electronic DOS and the net molecular charge are more affected by the asymmetry of the water molecule's H-bond surroundings than by the number of H-bonded neighbours. The reverse is true for the dipole moment. (2) For all three properties, a 3-coordinated water molecule is more perturbed by accepting two H-bonds and donating one than by donating two and accepting one. (3) This order is not maintained in the calculated XES spectrum, which is less straightforward to interpret in terms of structure-property relationships than the DOS spectrum

Pregnancy Rate after Controlled Ovarian Hyperstimulation and Intrauterine Insemination for the Treatment of Endometriosis following Surgery

Objective. To compare pregnancy rate after controlled ovarian hyperstimulation and intrauterine insemination (COH-IUI) with no treatment in patients with endometriosis-associated infertility treated with laparoscopy. Design. A clinical cohort study. Setting. University-level tertiary care center. Patients. 238 women with various stages of endometriosis after laparoscopic treatment. Interventions. Either COH-IUI or follow-up for 12 months. Main Outcome Measures. The primary outcome measures were clinical pregnancy and live birth rate. Predictive factors evaluated were female age, maternal BMI, and duration of infertility. Results. The pregnancy rate attained after the integrated laparoscopy-COH-IUI approach was 53.4%, while it was significantly lower (38.5%) in the control group. Similarly, a significant difference was observed in live births (48.3% versus 34.2%). Patients with severe endometriosis were less likely to achieve pregnancy (38%) and live birth (35%) than their counterparts with milder forms (57% and 53%). Conclusions. In patients with endometriosis-based infertility, surgery followed by COH-IUI is more effective than surgery alone

Bioinspired Synthesis of (–)-Hunterine A: Deciphering a Unique Deconstructive Route

A short, bioinspired, and enantioselective synthesis of (–)- hunterine A, an odd 6/7/6/6/5 pentacyclic natural product, is described. The key step in the synthesis of this daunting structure is the 6-exo selective epoxide ring-opening reaction, which is interwoven with a deconstructive step of the indolenine part to create the unusual 7-membered azepine bridge motif. Our work also reveals the possible mechanism and stereochemical prerequisite of this unique skeletal rearrangement, which provides a vantage point for understanding how (–)-hunterine A is likely to be generated in nature

Curse or Blessing? Influence of Impurities on Cross-Coupling— Guideline for Elucidating Catalysts

Several efforts have been made for the replacement of noble metal palladium in cross-coupling reactions, maintaining high efficiency of the target transformation. In several cases it is possible to perform the chemistry of palladium with related metals, and their activity was supported with mechanistic studies. Moreover, the complete exclusion of palladium is also in focus. Very recently it was demonstrated that special amine organocatalysts could catalyse Suzuki-Miyaura coupling reaction. Here we show that in this recent transformation homeopathic palladium impurities and trace phosphorous species originated from the conditions used for the organocatalyst synthesis are responsible for the catalytic effect instead of the amine species. This finding confirms the power of palladium in cross-coupling and draw the attention of impurity effect in this field of chemical research. In this article, we represent general guidelines for elucidating the real catalyst of reactions.<br /

Syntheses and structural plasticity of kratom pseudoindoxyl metabolites

Pain management is one of the oldest challenges for medicine. Although opioids have been used in the treatment of moderate-to-severe acute and chronic pain for centuries, they cause various adverse effects and addiction. The intertwined societal, economic and public health issues of pain management and the risks of opioid abuse continue to receive attention and drive the development of safer analgesics. Recently, a kratom metabolite, mitragynine pseudoindoxyl has attracted increasing attention as a promising analgesic alternative for pain management with considerably fewer side effects. Here, we describe the first enantioselective and scalable total synthesis of this natural product in addition to its C-20 epimeric congener, speciogynine pseudoindoxyl. The characteristic spiro-5-5-6 tricyclic system of these alkaloids is formed via a protecting group-free cascade relay process in which oxidized tryptamine and secologanin analogs are used. Furthermore, we uncovered that mitragynine pseudoindoxyl exists and 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 analogs, which can guide the development of next-generation analgesics