Ab initio study on N,N′,N″‐triaminoguanidine

Electronic structure calculations and second‐order delocalizations in N,N′,N′′‐triaminoguanidine ( TAG ) have been studied by employing ab initio MO and density functional methods. There are total 10 rotational isomers on the potential energy (PE) surface of TAG . The effect of three amino groups substitution on guanidine ( Gu ) has been studied in terms of the primary and the secondary electron delocalizations in TAG by employing Natural Population Analysis (NPA). An increased electron delocalization is observed in protonated triaminoguanidine ( TAGP ) due to the three strong intramolecular hydrogen bonds and hence accounts for its extra stability. The increase in the electron delocalization upon protonation in TAG can be compared to that in guanidine. The absolute proton affinity (APA) of TAG is less than that of Gu . HOMA and NICS studies have been carried out to understand electron delocalization in TAGP . Copyright © 2007 John Wiley & Sons, Ltd.     

Total synthesis and stereochemical revision of acortatarins A and B

A first total synthesis of acortatarins A, B, and an enantiomer of the proposed structure of acortatarin B is described by using readily available d-sugars. This convergent total synthesis revealed the revision of the absolute configuration of acortatarin A and structural revision of acortatarin B. The key steps involved are regioselective epoxide opening with deprotonated 2,5-disubstituted pyrrole and spiroketalization.     

S-oxidation of thiazolidinedione with hydrogen peroxide, peroxynitrous acid, and C4a-hydroperoxyflavin: a theoretical study

Quantum chemical analysis was carried out to model metabolism of glitazone class of drugs through oxygen transfer process to the sulfur atom of thiazolidinedione ring with different oxidants such as H(2)O(2), HOONO, and C4a-hydroperoxyflavin. Complete optimization (geometric and energy parameters) of all the required structures and transition states on the reaction path was carried out using MP2(full)/6-31+G(d,p). Charge and second-order delocalization analyses of important structures were carried out using the NBO method. The effect of solvent on the oxygen transfer to sulfur of thiazolidinedione was studied by including one, two, or three explicit water molecules. These calculations revealed that explicit solvent (water) effectively contributed in the sulfoxidation of thiazolidinedione and led to remarkable reduction in the energy barrier by ～10 kcal/mol as compared to the gas phase. These results were found to be consistent with previously reported S-oxidation of dimethyl sulfide. When explicit water molecules were included, solvent molecules stabilize the charge separation at the transition state via specific interactions, and oxidation occurs via stretching of the O-O bond of oxidants and gradual formation of S-O bond. This study is helpful in understanding the metabolite generation due to the S-oxidation process in the glitazone series of antidiabetic drugs under physiological conditions.     

The importance of four-membered NHCs in stabilizing Breslow intermediates on benzoin condensation pathway

N-heterocyclic carbenes (NHCs) have been established to be effective organocatalysts for facilitating the benzoin condensation and many other reactions. These reactions involve the formation of a Breslow intermediate (BI), which exhibits umpolung chemistry. To facilitate organocatalysis, several new cyclic carbenes are being introduced, four-membered NHCs are of special interest. Whether these NHCs can exhibit catalytic influence or not, can be evaluated by exploring the potential energy surface (PES) of the benzoin condensation reaction. Quantum chemical analysis has been carried out to compare the PES of these four-membered NHCs with that of standard five-membered NHCs to explore their catalytic ability. The barrier for the first step of the reaction for the formation of BI is comparable in all the cases. But the barrier for the second step of the reaction leading to the benzoin formation from BI is estimated to be very high for the four membered NHCs. These results indicate that the probability of identifying and isolating the BI is very high in comparison to the completion of benzoin condensation reaction in the case of the four-membered NHCs.     

Highly enantioselective carbon-carbon bond formation by Cu-catalyzed asymmetric [2,3]-sigmatropic rearrangement: application to the syntheses of seven-membered oxacycles and six-membered carbocycles

A concise route for the syntheses of enantioenriched functionalized scaffolds of medium-sized oxacycles and carbocycles employing the chiral auxiliary-mediated Cu-catalyzed ylide formation/[2,3]-sigmatropic rearrangement as a key step was developed.     

Dendrimer building toolkit: Model building and characterization of various dendrimer architectures

We have developed a graphical user interface based dendrimer builder toolkit (DBT) which can be used to generate the dendrimer configuration of desired generation for various dendrimer architectures. The validation of structures generated by this tool was carried out by studying the structural properties of two well known classes of dendrimers: ethylenediamine cored poly(amidoamine) (PAMAM) dendrimer, diaminobutyl cored poly(propylene imine) (PPI) dendrimer. Using full atomistic molecular dynamics (MD) simulation we have calculated the radius of gyration, shape tensor and monomer density distribution for PAMAM and PPI dendrimer at neutral and high pH. A good agreement between the available simulation and experimental (small angle X‐ray and neutron scattering; SAXS, SANS) results and calculated radius of gyration was observed. With this validation we have used DBT to build another new class of nitrogen cored poly(propyl ether imine) dendrimer and study it's structural features using all atomistic MD simulation. DBT is a versatile tool and can be easily used to generate other dendrimer structures with different chemistry and topology. The use of general amber force field to describe the intra‐molecular interactions allows us to integrate this tool easily with the widely used molecular dynamics software AMBER. This makes our tool a very useful utility which can help to facilitate the study of dendrimer interaction with nucleic acids, protein and lipid bilayer for various biological applications. © 2012 Wiley Periodicals, Inc.     

Metabolic‐intermediate complex formation with cytochrome P450: Theoretical studies in elucidating the reaction pathway for the generation of reactive nitroso intermediate

Mechanism‐based inhibition (MBI) of cytochrome P450 (CYP) can lead to drug–drug interactions and often to toxicity. Some aliphatic and aromatic amines can undergo biotransformation reactions to form reactive metabolites such as nitrosoalkanes, leading to MBI of CYPs. It has been proposed that the nitrosoalkanes coordinate with the heme iron, forming metabolic‐intermediate complex (MIC), resulting in the quasi‐irreversible inhibition of CYPs. Limited mechanistic details regarding the formation of reactive nitroso intermediate and its coordination with heme‐iron have been reported. A quantum chemical analysis was performed to elucidate potential reaction pathways for the generation of nitroso intermediate and the formation of MIC. Elucidation of the energy profile along the reaction path, identification of three‐dimensional structures of reactive intermediates and transition states, as well as charge and spin density analyses, were performed using the density functional B3LYP method. The study was performed using Cpd I [iron (IV‐oxo] heme porphine with SH^? as the axial ligand) to represent the catalytic domain of CYP, simulating the biotransformation process. Three pathways: (i) N‐oxidation followed by proton shuttle, (ii) N‐oxidation followed by 1,2‐H shift, and (iii) H‐abstraction followed by rebound mechanism, were studied. It was observed that the proton shuttle pathway was more favorable over the whole reaction leading to reactive nitroso intermediate. This study revealed that the MIC formation from a primary amine is a favorable exothermic process, involving eight different steps and preferably takes place on the doublet spin surface of Cpd I . The rate‐determining step was identified to be the first N‐oxidation of primary amine. © 2012 Wiley Periodicals, Inc.     

Thiourea catalyzed aminolysis of epoxides under solvent free conditions. Electronic control of regioselective ring opening

A reactant economizing process for the regioselective aminolysis of epoxides using equimolar quantities of reactants catalyzed by the double hydrogen bond donor N,N′-bis[3,5-bis(trifluoromethyl)phenyl]thiourea is reported. Regioselectivity of the reaction is controlled by the electronic nature of the substituent on the styrene oxide, which has been substantiated on the basis of ¹³C NMR data and DFT calculations.