Talk Session 2

Design and Synthesis of Polyquinanes Olefin-Metathesis

The synthesis of complex molecules such as polyquinanes is a difficult task for synthetic chemists due to their fascinating molecular architecture include (i) contiguous stereocenters, (ii) all-carbon quaternary centers, and (iii) dense functional groups. In this context, the cascade olefin-metathesis is proved as the most prominent process to create highly complex systems by minimizing the total number of linear steps.¹ The ring-rearrangement metathesis (RRM) and ring-closing metathesis (RCM) processes are explored for the synthesis of several natural products skeletons such as cameroonanol, subergorgic acid, isocomene, silphinene, arnicenone, crinipellin, and presilphiperfolanol from a less explored exo-dicyclopentadiene-1-one.² Our strategies involve readily available starting materials, operationally simple reactions, and produces the highly congested polycyclic frameworks containing up to nine contiguous stereogenic centers which include up to two all-carbon quaternary centers. Hence, these strategies are useful to design medicinally important “drug-like molecules”.

TMSOTf-Mediated Formal [4 + 2] Cycloaddition−Retro-aza-Michael Cascade of Vinylogous Carbamates for the Synthesis of Highly Fluorescent Pyridocarbazoles

Carbazole-containing natural products possess varied biological activities like antibacterial, antimalarial, anticancer, and anti-Alzheimer properties. Carbazole-based fluorescent small molecules and polymers have also been used for sensing applications. Recently, N-centered heterocycles of type have attracted attention because of their π-extended conjugation, which makes them chromophores with excellent photophysical properties. However, one challenge encountered often is with their synthesis, which requires several steps. We envisioned that the Povarov-type [4 + 2] cycloaddition reaction could easily introduce N-centered heterocycles with extended conjugation. Trimethylsilyl trifluoromethanesulfonate mediated dimerization reaction of vinylogous carbamates of carbazoles gave highly fluorescent pyridocarbazoles through a Povarov-type formal [4 + 2] cycloaddition−retro-aza-Michael cascade. The developed strategy was used to access indolo pyridocarbazole and quinolizinocarbazolone in an expeditious manner. Various coupling reactions were successfully performed on synthesized pyridocarbazoles to study the effect of electronics of substitution on photophysical properties. Synthesized carbazoles possess excellent photophysical properties with high quantum yields (ΦF). Fluorescent carbazole dicarboxylic acid showed potential as a pH probe to give a linear response to pH over a very wide range (7.0−3.0) reflecting high efficiency.

Development of whole cell biosensor for detection of aromatic pollutants in water sources

Achieving universal and equitable access to safe and affordable drinking water necessitates the development of simple and inexpensive tools for water quality monitoring. Aromatics such as phenols, benzene, and toluene are carcinogenic xenobiotics that are known to pollute water resources and therefore their persistence in the environment is of great concern. Inherently the MopR genetic system from soil bacteria Acinetobacter sp. can sense and degrade phenol. Thus, by the combinatorial approach of synthetic biology and structure-guided design, we have exploited the existing MopR system to create a tunable array of luciferase-based whole-cell biosensors (WCBs) which can quantitatively detect the presence of these pollutants. We have reported detection sensitivity down to ∼1 ppb, by using a single sensor module engineered with mutations to enable the generation of an array of biosensors towards benzene and its derivatives without losing sensitivity. Currently, we are evolving our approach by replacing the luciferase reporter with different fluorescent genes and have built a palette of biosensors with diverse colored outputs on recognizing the desired aromatic pollutant. By single-cell imaging and spectroscopy, we have developed a plethora of fluorescent biosensors that can be employed for on-site drinking water monitoring.

Machine Learning in Chemical Catalysis using Different Molecular Representations

Design of asymmetric catalysts generally involves time- and resource-intensive heuristic endeavors. In view of the steady increase in interest toward efficient catalytic asymmetric reactions and the rapid growth in the field of machine learning (ML) in recent years, we envisaged dovetailing these two important domains. A total of 368 known asymmetric hydrogenation reactions catalyzed by five different axially chiral binaphthyl catalyst families and a series of alkenes and imines were considered to examine the applicability of ML. Two kinds of ML-based studies are undertaken; one uses the quantum chemically derived molecular descriptors collected from the reactants/catalyst [1] while the other employs the natural language processing (NLP) on a simple text-based representation [2] of the molecular space, to predict the enantioselectivity of reactions. The predictive power of the random forest (RF) built using the molecular parameters of a set of 368 substrate–catalyst combinations is found to be impressive, with a root mean squared error (RMSE) in the predicted enantiomeric excess (%ee) of about 8.4±1.8 compared to the experimentally known values. The highly time-economic NLP based transfer learning model could obtain a comparable RMSE of 8.6±1.1. The proposed methods are expected to provide a leap forward in the design of catalysts for asymmetric transformations.

Simulating Quantum nuclear effects using semi-classical methods

Using Fewest Switches Surface hopping (FSSH) to quantize vibrations on the fly

Proton transfer reactions are universal in nature happening both within biological systems and in chemical reactions. The incorporation of quantum nuclear effects therefore becomes vital for the study of dynamics of a myriad of processes. On the one hand, classical molecular dynamics approaches for all their merits cannot be used to study the effects of purely quantum mechanical phenomena such as tunnelling, interference, level quantization, ZPE whereas on the other hand purely quantum mechanical calculations cannot be invoked for systems with large degrees of freedom. The motivation for the work that would be discussed in this talk is to develop an efficient ab-intio approach to simulate quantum nuclear effects within the framework of semi-classical molecular dynamics for a model system describing proton transfer in condensed phase. Azzouz-Borgis model for a proton transfer is approximated in terms of a model potential, a DVR basis is used to run the dynamics. The ultimate aim is to simulate this model potential in terms of another approximated potential, which in this case happens to be harmonic empirical valence bond potential (EVB). The motivation to simulate this EVB potential is to quantize the vibrations on the fly and to reduce the DVR grid size required in order to obtain any meaningful dynamics.

Structural and Biochemical studies of rRNA methyltransferase involved in conferring Antibiotic Resistance.

The alarming increase in antibiotics resistance in the bacteria has become a global health crisis. As pathogenic bacteria are developing immunity even towards the newly discovered antibiotics, conventional drugs like macrolide which target protein translational machinery have been rendered ineffective. Pathogens are adopting various mechanisms to protect themselves from antibiotics, prominent ones being methylation of target residue in the ribosomal RNA. The Erm methyltransferase recognizes and modify A2058 (E. coli numbering) residue of 23S rRNA in the 50S precursor conferring resistance against macrolide, lincosamide & streptogramin B. Whereas it’s structural homologue KsgA methylase which plays a significant role in ribosome biogenesis by modifying A1518 and A1519 of 16s rRNA and requires fully assembled 30S subunit as a substrate. There is paucity in information regarding the mode of specific target recognition by these enzymes. Here, we aim to delineate the molecular mechanism of specific target recognition adopted by these resistance conferring elements.

In the direction of our goal, we have determined high –resolution cryo-EM structure of 30S in complex with KsgA. The structure provides important clue about these macromolecular interactions. For example, structure revealed the rRNA helices interacting with positively charged domain of KsgA. The positively charged residue at interface of MTase interacting with RNA helices potentially assist specificity toward complex target recognition. Additionally, mutagenesis studies involving alterations in RNA helices and high resolution cryo-EM structure had highlighted the molecular details of macromolecular interaction. Similar studies involving Erm methyltransferase and 50S precursor particle will pave a path toward the development of new generation antibiotic inhibitors.

Confinement of PEG Matrix in Metal-organic Frameworks for Fluoride Ion Conduction

In solids, ion transport is one of the major research topics in materials chemistry due to its useful application in energy-related devices, in particular, secondary batteries and fuel cells. A better insight into solid-state electrolytes for these devices will endow in achieving better safety and high energy density for conversion and storage devices. In recent times, researchers have focused on utilizing the pores of MOFs as spaces or voids for the transfer of ions i.e., ion-conduction pathways, and investigated new MOFs that display high ionic conductivity. For this purpose, different ions have been employed as ionic carriers in MOFs. There are different types of battery systems investigated based on ions, such as Li+, Na+, Mg2+, H+, and OH- that are currently commercially available. The utilization of F- ion would be another exciting strategy for secondary batteries viz. fluoride ion battery (FIB) given the high electronegativity of fluorine that produces a better reaction potential. However, F- ion conduction in MOFs has rarely been explored. In the present talk, a new strategy of incorporating ammonium bifluoride PEG (polyethylene glycol) matrix into the robust UiO-66 MOF as the host framework to prepare mixed matrix membrane as the solid-state electrolyte material for F- ion conduction will be discussed.