Phosphonate-Directed Catalytic Asymmetric Hydroboration: Synthesis of Functionalized Chiral Secondary and Tertiary Boronic Esters and Mechanistic Insights

Over the past 30 years, catalytic asymmetric hydroboration (CAHB) of alkenes has emerged as a leading methodology to access chiral primary and secondary boronic esters. However, it wasn’t until 2015 that directed-CAHB was for the first time shown to efficiently access chiral tertiary boronic esters. The latter are excellent precursors to synthetically challenging structural motifs such as chiral tertiary alcohols, carbinamines and all-carbon quaternary stereocenters via stereospecific C-B bond substitutions. This dissertation focuses on phosphonate-directed CAHB of diverse alkene substrates, including challenging stereodefined trisubstituted alkenes, to efficiently access multifunctional chiral secondary and tertiary boronic esters. Mechanistic insights obtained via deuterium labelling experiments indicate that CAHB reactions proceed via tertiary-alkyl rhodium intermediates for substrates that lead to chiral tertiary boronic esters. The applications of phosphonate-functionalized chiral secondary and tertiary boronic ester products are discussed in the context of stereospecific C-B bond transformations, through phosphonate unmasking methodologies via thiophosphonate and oxophosphonate intermediates, and through synthesis of the cytotoxic natural product bakuchiol. Advisor: James M. Takac

Hypertension and its risk factors among the Shabar tribe: A community-based cross-sectional study in Odisha, India

In developing countries like India, the increasing trend of hypertension is one of the significant public health problems. In recent times, the Indian tribes are also experiencing a similar trend, which is rarely documented and less emphasized. The objectives of the present study are to assess the prevalence of hypertension among the Shabar tribe and to understand the association with some selected biological, behavioural and socio-economic factors. The data were collected from 816 individuals (389 males and 427 females, aged 20 to 60 years) in the Khurda and Cuttack districts of Odisha. Conventional methodologies were used to collect the cross-sectional data of blood pressure and other parameters. It was found that 9.2% of the respondents suffered from hypertension (SBP ≥ 140 and DBP ≥ 90 mmHg), and 12.3% had high normal blood pressure (SBP ≥ 130 and DBP ≥ 85 mmHg). The unadjusted odd ratios showed that the proportion of hypertension increased significantly as age increased. High normal blood pressure and hypertension were significantly higher in females and people who belonged to the high-income group and consumed more fat. The Shabar people who suffered from overweight and obesity, took extra salt during meals, smokers, smokeless tobacco chewers, and alcoholics were more vulnerable to hypertension and high blood pressure. Interestingly, the participants who perceived their fatty bodies and engaged in light activities were more likely to be hypertensive than their counterparts. Shabar people residing in Odisha state have shown increasing frequencies of hypertension with advancing age. A significant co-occurrence of higher body mass index (BMI), fewer physical activities, increased fat consumption, and changing habits relating behaviour to hypertension may be designated as potential risk factors

Elucidating the mechanism of nucleation near the gas-liquid spinodal

We have constructed a multidimensional free energy surface of nucleation of the liquid phase from the parent supercooled and supersaturated vapor phase near the gas-liquid spinodal. In particular, we remove the Becker-Doring constraint of having only one growing cluster in the system. Close to the spinodal, the free energy, as a function of the size of the largest cluster, develops surprisingly a minimum at a subcritical cluster size. It is this minimum at intermediate size that is found to be responsible for the barrier towards further growth of the nucleus at large supersaturation. An alternative free energy pathway involving the participation of many subcritical clusters is found near the spinodal where the growth of the nucleus is promoted by a coalescence mechanism. The growth of the stable phase becomes collective and spatially diffuse, and the significance of a 'critical nucleus' is lost for deeper quenches

Coarse grained model for exploring voltage dependent ion channels

AbstractThe relationship between the membrane voltage and the gating of voltage activated ion channels and other systems have been a problem of great current interest. Unfortunately, reliable molecular simulations of external voltage effects present a major challenge, since meaningful converging microscopic simulations are not yet available and macroscopic treatments involve major uncertainties in terms of the dielectric used and other key features. This work extends our coarse grained (CG) model to simulations of membrane/protein systems under external potential. Special attention is devoted to a consistent modeling of the effect of external potential due to the electrodes, emphasizing semimacroscopic description of the electrolytes in the solution regions between the membranes and the electrodes, as well as the coupling between the combined potential from the electrodes plus the electrolytes and the protein ionized groups. We also provide a clear connection to microscopic treatment of the electrolytes and thus can explore possible conceptual problems that are hard to resolve by other current approaches. For example, we obtain a clear description of the charge distribution in the entire electrolyte system, including near the electrodes in membrane/electrodes systems (where continuum models do not seem to provide the relevant results). Furthermore, the present treatment provides an insight on the distribution of the electrolyte charges before and after equilibration across the membrane, and thus on the nature of the gating charge. The different aspects of the model have been carefully validated by considering problems ranging for the simple Debye–Huckel, and the Gouy–Chapman models to the evaluation of the electrolyte distribution between two electrodes, as well as the effect of extending the simulation system by periodic replicas. Overall the clear connection to microscopic descriptions combined with the power of the CG modeling seems to offer a powerful tool for exploring the balance between the protein conformational energy and the interaction with the external potential in voltage activated channels. To illustrate these features we present a preliminary study of the gating charge in the voltage activated Kv1.2 channel, using the actual change in the electrolyte charge distribution rather than the conventional macroscopic estimate. We also discuss other special features of the model, which include the ability to capture the effect of changes in the protonation states of the protein residues during the close to open voltage induced transition. This article is part of a Special Issue entitled: Membrane protein structure and function

Gas-Liquid Nucleation in Two Dimensional System

We study the nucleation of the liquid phase from a supersaturated vapor in two dimensions (2D). Using different Monte Carlo simulation methods, we calculate the free energy barrier for nucleation, the line tension and also investigate the size and shape of the critical nucleus. The study is carried out at an intermediate level of supersaturation(away from the spinodal limit). In 2D, a large cut-off in the truncation of the Lennard-Jones (LJ) potential is required to obtain converged results, whereas low cut-off (say, $2.5\sigma$ is generally sufficient in three dimensional studies, where $\sigma$ is the LJ diameter) leads to a substantial error in the values of line tension, nucleation barrier and characteristics of the critical cluster. It is found that in 2D, the classical nucleation theory (CNT) fails to provide a reliable estimate of the free energy barrier. It underestimates the barrier by as much as 70% at the saturation-ratio S=1.1 (defined as S=P/PC, where PC is the coexistence pressure at reduced temperature $T^{\star}= 0.427$). Interestingly, CNT has been found to overestimate the nucleation free energy barrier in three dimensional (3D)systems near the triple point. In fact, the agreement with CNT is worse in 2D than in 3D. Moreover, the existing theoretical estimate of the line tension overestimates the value significantly.Comment: 24 pages, 8 figure