Papers by Arkajyoti Sengupta
Lactam rings are found in many biologically active natural products and pharmaceuticals, includin... more Lactam rings are found in many biologically active natural products and pharmaceuticals, including important classes of antibiotics. Given their widespread presence in bioactive molecules, methods for the asymmetric synthesis of these molecules, in particular through the selective functionalization of ubiquitous yet unreactive aliphatic C–H bonds, are highly desirable. In this study, we report the development of a novel strategy for the asymmetric synthesis of 4-, 5-, and 6-membered lactams via an unprecedented hemoprotein-catalyzed intramolecular C-H amidation reaction with readily available dioxazolone reagents. Engineered myoglobin variants serve as excellent biocatalysts for this transformation producing an array of β-, γ-, and δ-lactam molecules in high yields, with high enantioselectivity, and on preparative scale. Mechanistic and computational studies elucidate the nature of the C–H amination and enantiodetermining steps in these reactions and provide insights into protein-me...
The Journal of Organic Chemistry
An entry from the Cambridge Structural Database, the world's repository for small molecule cr... more An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
An entry from the Cambridge Structural Database, the world's repository for small molecule cr... more An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
An entry from the Cambridge Structural Database, the world's repository for small molecule cr... more An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
An entry from the Cambridge Structural Database, the world's repository for small molecule cr... more An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
The Journal of Physical Chemistry A, 2018
Connectivity-Based Hierarchy (CBH) is an effective error-cancellation scheme for the determinatio... more Connectivity-Based Hierarchy (CBH) is an effective error-cancellation scheme for the determination of chemically accurate thermochemical properties of a variety of organic and biomolecules. Neutral molecules and open-shell radicals have already been treated successfully by this approach utilizing inexpensive computational methods such as density functional theory. Herein, we present an extension of the method to a new class of molecules, specifically, organic cations. Because of the presence of structural rearrangements involving hydrogen migrations as well as unusual structures such as bridged cations, the application of the standard CBH protocol to a test set of 25 cations leads to significant errors due to ineffective bond-type matching. We propose an adjusted protocol to overcome such limitations to achieve highly effective error cancellation. The modified CBH methods, in conjunction with a wide range of density functionals, reproduce G4 energies for the test set of organic cations accurately within 1−2 kcal/mol at a reduced computational cost.
The Journal of Physical Chemistry A, 2019
Chemistry – A European Journal, 2018
Organic Letters, 2017
The failure of available density functional methods to compute accurate reaction enthalpies of co... more The failure of available density functional methods to compute accurate reaction enthalpies of common organic reactions is well documented. Herein, we demonstrate that the disparate results from different functionals stem from the systematic errors in the underlying elementary reactions that represent the changes in the bonding environment between reactants and products. We develop a rigorous protocol to correct for these systematic errors and obtain dramatically improved results with deviations of only 1−2 kcal/mol for most functionals.
Chem, 2017
Real-world manipulation of anions needs receptors to operate in solution. By combining experiment... more Real-world manipulation of anions needs receptors to operate in solution. By combining experiment and theory, Flood and colleagues discovered a 1/ 3 r solvent dependence of solution-phase anion affinities. Surprisingly, electrostatics no longer dominates affinity in solutions of even moderate polarity. Their findings also enable accurate predictions of anion affinities across a wide range of solutions.
Angewandte Chemie International Edition, 2016
Contrary to the simple expectations from Coulombs law, Weinhold proposed that anions can stabiliz... more Contrary to the simple expectations from Coulombs law, Weinhold proposed that anions can stabilize each other as metastable dimers, yet experimental evidence for these species and their mutual stabilization is missing. We show that two bisulfate anions can form such dimers, which stabilize each other with self-complementary hydrogen bonds, by encapsulation inside a pair of cyanostar macrocycles. The resulting 2:2 complex of the bisulfate homodimer persists across all states of matter, including in solution. The bisulfate dimers OH•••O hydrogen bonding is seen in a 1 H NMR peak at 13.75 ppm, which is consistent with borderline-strong hydrogen bonds. The fundamental role of Coulombs law [1] is so ingrained in all areas of chemistry, biology, and physics that it is the starting point for formulating hypotheses on the behavior of matter. It governs the bonding in ionic solids, the salt-bridges that guide protein structure and function, and the movement of ions in electric fields. We rely daily upon the notion that like charges repel (Figure 1 a) and opposite charges attract (Figure 1 b). For this reason, it came as some surprise when Weinholds recent theoretical work [2] and its commentary [3] suggested that anions can attract, instead of repel, each other to form dimers. [4] Propositions that anions can stabilize each other are rare and the only unequivocal evidence for this phenomenon is in the solid state. [5] We found over 80 examples of HSO 4 À dimers (see the Supporting Information, Table S1), [6] as well as chains of HSO 4 À , [7] water-bridged sulfates, [8] and oligomers [9] and cyclic forms of hydrogen-bonded phosphates. [10] However, many forces other than anti-electrostatic hydrogen bonding, [2] for example, ionic bonding, can stabilize such anion dimers in crystals. In solution, where solvation overtakes ionic bonding, dimer salts do not appear to survive. Supramolecular encapsulation offers a way to stabilize unstable species in solution. [11] The only reports of complexes of anion dimers are with H 2 PO 4 À and are based on the observation of a 2:1 ratio of phosphate and receptor. Nevertheless, there are no direct observations of anion dimers in solution. With good reason, the authors of those works, Reinhoudt, [5a, 12] Kubo, [13] Fabbrizzi, [5b, 14] Sessler, [15] and Tomisič, [16] took care to circum
Journal of the American Chemical Society, Jan 25, 2016
Shape-persistent macrocycles are attractive functional targets for synthesis, molecular recogniti... more Shape-persistent macrocycles are attractive functional targets for synthesis, molecular recognition, and hierarchical self-assembly. Such macrocycles are non-collapsible and geometrically well-defined, and they are traditionally characterized by having repeat units and low conformational flexibility. Here, we find it necessary to refine these ideas in the face of a highly flexible yet shape-persistent macrocycles. A molecule is shape-persistent if it has a small change in shape when perturbed by external stimuli (e.g., heat, light, and redox chemistry). In support of this idea we provide the first examination of the relationships between a macrocycle's shape persistence, its conformational space, and the resulting functions. We do this with a star-shaped macrocycle called cyanostar that is flexible as well as being shape-persistent. We employed molecular dynamics (MD), density functional theory (DFT), and NMR experiments. Considering a thermal bath as a stimulus we found a singl...
The Journal of Physical Chemistry B, 2014
In this study we have used the connectivity-based hierarchy (CBH) method to derive accurate heats... more In this study we have used the connectivity-based hierarchy (CBH) method to derive accurate heats of formation of a range of biomolecules, 18 amino acids and 10 barbituric acid/uracil derivatives. The hierarchy is based on the connectivity of the different atoms in a large molecule. It results in errorcancellation reaction schemes that are automated, general, and can be readily used for a broad range of organic molecules and biomolecules. Herein, we first locate stable conformational and tautomeric forms of these biomolecules using an accurate level of theory (viz. CCSD(T)/6-311++G(3df,2p)). Subsequently, the heats of formation of the amino acids are evaluated using the CBH-1 and CBH-2 schemes and routinely employed density functionals or wave function-based methods. The calculated heats of formation obtained herein using modest levels of theory and are in very good agreement with those obtained using more expensive W1-F12 and W2-F12 methods on amino acids and G3 results on barbituric acid derivatives. Overall, the present study (a) highlights the small effect of including multiple conformers in determining the heats of formation of biomolecules and (b) in concurrence with previous CBH studies, proves that use of the more effective error-cancelling isoatomic scheme (CBH-2) results in more accurate heats of formation with modestly sized basis sets along with common density functionals or wave function-based methods.
Journal of Chemical Theory and Computation, 2014
Accurate modeling of the chemical reactions in many diverse areas such as combustion, photochemis... more Accurate modeling of the chemical reactions in many diverse areas such as combustion, photochemistry, or atmospheric chemistry strongly depends on the availability of thermochemical information of the radicals involved. However, accurate thermochemical investigations of radical systems using state of the art composite methods have mostly been restricted to the study of hydrocarbon radicals of modest size. In an alternative approach, systematic error-canceling thermochemical hierarchy of reaction schemes can be applied to yield accurate results for such systems. In this work, we have extended our connectivity-based hierarchy (CBH) method to the investigation of radical systems. We have calibrated our method using a test set of 30 medium sized radicals to evaluate their heats of formation. The CBH-rad30 test set contains radicals containing diverse functional groups as well as cyclic systems. We demonstrate that the sophisticated error-canceling isoatomic scheme (CBH-2) with modest levels of theory is adequate to provide heats of formation accurate to ∼1.5 kcal/mol. Finally, we predict heats of formation of 19 other large and medium sized radicals for which the accuracy of available heats of formation are less well-known.
ChemElectroChem, 2015
Direct Reduction of Alkyl Monohalides at Silver in Dimethylformamide: Effects of Position and Ide... more Direct Reduction of Alkyl Monohalides at Silver in Dimethylformamide: Effects of Position and Identity of the Halogen Catalysis with a silver lining: Results from cyclic voltammetry and controlledpotential (bulk) electrolysis of alkyl halides at silver cathodes in dimethylformamide are highly dependent on the identity and position of the halogen atom (see picture).
The Journal of Physical Chemistry A, 2013
Computational challenges toward an accurate determination of the enthalpies of formation of amino... more Computational challenges toward an accurate determination of the enthalpies of formation of amino acids are partly due to the nonavailability of systematic error-canceling thermochemical procedures for such biomonomers. Recently, we developed the connectivity-based hierarchy (CBH) to accurately compute the enthalpies of formations of organic molecules composed of main group elements. Advancing the applicability of CBH to biologically relevant molecules, we have computed the enthalpies of formation of the naturally occurring sulfur-containing amino acids cysteine and methionine which act as fertile testing grounds for the error-canceling ability of thermochemical schemes for biomolecules. We establish herein using the sophisticated error-canceling isoatomic scheme (CBH-2) that relatively inexpensive computational methods with modest basis sets can be used to accurately obtain the enthalpies of formations of the amino acids. Overall, we recommend the use of the isoatomic scheme over the currently popular isodesmic bond separation scheme in future applications in theoretical thermochemistry.
Electrochimica Acta, 2014
Cyclic voltammetry and controlled-potential (bulk) electrolysis have been employed to investigate... more Cyclic voltammetry and controlled-potential (bulk) electrolysis have been employed to investigate the direct electrochemical reduction of 2-chloro-N-methyl-N-phenylacetamide (1a), 2-chloro-N-ethyl-Nphenylacetamide (1b), and 2-chloro-N-phenylacetamide (1c) at carbon and silver cathodes, as well as the catalytic reduction of these compounds by electrogenerated nickel(I) salen, in dimethylformamide (DMF) containing 0.050 M tetramethylammonium tetrafluoroborate (TMABF 4). Cyclic voltammograms for reduction of 1a and 1b show a single irreversible cathodic peak for cleavage of the carbon-chlorine bond, but two irreversible cathodic peaks are observed in cyclic voltammograms for reduction of 1c. Controlled-potential reduction of 1a and 1b gives mixtures of dechlorinated amide and N-alkyl-Nphenylaniline, whereas bulk electrolyses of 1c afford N-phenylacetamide in almost quantitative yield. In addition, bulk electrolyses of 1a and 1b result in the formation of very small amounts of dimeric species that arise from coupling of the radical intermediate formed by one-electron cleavage of the carbon-chlorine bond. On the basis of the coulometric n values and product distributions, together with computations based on density functional theory, we propose mechanistic pictures for the reduction of 1a and 1b that involve radical intermediates, whereas reduction of 1c involves carbanion intermediates.
Catalysis with engineered enzymes has provided more efficient and streamlined routes for the synt... more Catalysis with engineered enzymes has provided more efficient and streamlined routes for the synthesis and manufacturing of drug molecules. Despite landmark achievements, the potential of biocatalysis toward assisting early-stage drug discovery campaigns remains largely untapped. We have developed a novel biocatalytic strategy for the construction of sp3-rich polycyclic compounds via an intramolecular cyclopropanation of benzothiophenes and related heterocycles. Despite the inherent challenge presented by this reaction, two regiocomplementary carbene transferases were evolved to catalyze the highly stereoselective cyclization of benzothienyl substrates bearing diazo ester groups at either the C2 or C3 position of the heterocycle. The detailed mechanisms of these reactions were obtained by a combination of crystallographic and computational (quantum mechanics calculations and molecular dynamics simulations) analyses. Leveraging these insights, the narrow substrate scope of one of the...
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Papers by Arkajyoti Sengupta