ABSTRACT
The use of more than one catalyst in one-pot reaction conditions has become a rapidly evolving protocol in the development of asymmetric catalysis. The lack of molecular insights on the mechanism and enantioselectivity in dual-catalytic reactions motivated the present study focusing on an important catalytic asymmetric Heck-Matsuda cross-coupling. A comprehensive density functional theory (M06 and B3LYP-D3) investigation of the coupling between a spirocyclic cyclopentene and 4-fluorophenyl diazonium species under a dual-catalytic condition involving Pd2(dba)3 (dba = trans, trans-dibenzylideneacetone) and chiral 2,2'-binaphthyl diamine (BINAM)-derived phosphoric acids (BDPA, 2,2'-binaphthyl diamine-derived phosphoric acids) is presented. Among various mechanistic possibilities examined, the pathway with explicit inclusion of the base (in situ generated sodium bicarbonate/sodium biphosphate) is found to be energetically more preferred over the analogous base-free routes. The chiral phosphate generated by the action of sodium carbonate on BDPA is found to remain associated with the reaction site as a counterion. The initial oxidative addition of Pd(0) to the aryl diazonium bond gives rise to a Pd-aryl intermediate, which then goes through the enantiocontrolling migratory insertion to the cyclic alkene, leading to an arylated cycloalkene intermediate. Insights on how a series of noncovalent interactions, such as C-H···O, C-H···N, C-H···F, C-H···π, lp···π, O-H···π, and C-F···π, in the enantiocontrolling transition state (TS) render the migration of the Pd-aryl to the si prochiral face of the cyclic alkene more preferred over that to the re face are utilized for modulating the enantioselectivity. Aided by molecular insights on the enantiocontrolling transition states, we predicted improved enantioselectivity from 37% to 89% by changes in the N-aryl substituents of the catalyst. Subsequent experiments in our laboratory offered very good agreement with the predicted enantioselectivities.
ABSTRACT
A mild, asymmetric Heck-Matsuda reaction of five-, six- and seven-membered ring alkenes and aryl diazonium salts is presented. High yields and enantioselectivities were achieved using Pd0 and chiral anion co-catalysts, the latter functioning as a chiral anion phase-transfer (CAPT) reagent. For certain substrate classes, the chiral anion catalysts were modulated to minimize the formation of undesired by-products. More specifically, BINAM-derived phosphoric acid catalysts were shown to prevent alkene isomerization in cyclopentene and cycloheptene starting materials. DFT(B3LYP-D3) computations revealed that increased product selectivity resulted from a chiral anion dependent lowering of the activation barrier for the desired pathway.
Subject(s)
Diazonium Compounds/chemistry , Anions , Catalysis , Cyclohexenes/chemistry , Molecular Structure , Phase Transition , Phenol/chemistry , StereoisomerismABSTRACT
A number of studies have proposed an anti-diabetic effect for tarchonanthuslactone based on its structural similarity with caffeic acid, a compound known for its blood glucose-reducing properties. However, the actual effect of tarchonanthuslactone on blood glucose level has never been tested. Here, we report that, in opposition to the common sense, tarchonanthuslactone has a glucose-increasing effect in a mouse model of obesity and type 2 diabetes mellitus. The effect is acute and non-cumulative and is present only in diabetic mice. In lean, glucose-tolerant mice, despite a slight increase in blood glucose levels, the effect was not significant.
Subject(s)
Blood Glucose/drug effects , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Type 2/metabolism , Obesity/metabolism , Pyrones/administration & dosage , Animals , Disease Models, Animal , Injections, Intraperitoneal , Male , Mice , Pyrones/chemistry , Pyrones/pharmacologyABSTRACT
The interface between synthetic organic chemistry and natural products was explored in order to unravel the structure of coibacin A, a metabolite isolated from the marine cyanobacterium cf. Oscillatoria sp. that exhibits selective antileishmanial activity and potent anti-inflammatory properties. Our synthetic plan focused on a convergent strategy that allows rapid access to the desired target by coupling of three key fragments involving E-selective Wittig and modified Julia olefinations. CD measurements and comparative HPLC analyses of the natural product and four synthetic stereoisomers led to determination of its absolute configuration, thus correcting the original assignment at C-5 and unambiguously establishing those at C-16 and C-18. Additionally, we synthesized coibacin B on the basis of the assignment of configuration for coibacin A.
Subject(s)
Ketones/chemistry , Ketones/chemical synthesis , Lactones/chemistry , Lactones/chemical synthesis , Oscillatoria/chemistry , Ketones/isolation & purification , Lactones/isolation & purification , Molecular Conformation , StereoisomerismABSTRACT
In this study, we describe the rational design, molecular modeling and pharmacological profile of a novel IKK-ß inhibitor (E)-N-(4-nitrobenzylidene)-2-naphthohydrazide (LASSBio-1524). The design based on the IKK-ß active site, and a privileged structure template yielded a novel IKK-ß inhibitor scaffold with significant selectivity over IKK-α and CHK2, as assessed by an in vitro kinase assay. For a better understanding of the structural requirements of IKK-ß inhibition, molecular dynamics simulations of LASSBio-1524 (3) were performed. The NAH derivative LASSBio-1524 (3), was able to suppress arachidonic acid-induced edema formation in a dose-dependent manner, demonstrating an in vivo anti-inflammatory effect. The molecular architecture of this novel, low-molecular weight IKK-ß inhibitor is encouraging for further lead optimization toward the development of innovative anti-inflammatory drug candidates.
Subject(s)
Benzylidene Compounds/chemistry , Benzylidene Compounds/pharmacology , Drug Design , Hydrazones/chemistry , Hydrazones/pharmacology , I-kappa B Kinase/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Amino Acid Sequence , Animals , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Benzylidene Compounds/chemical synthesis , Benzylidene Compounds/therapeutic use , Catalytic Domain , Cell Line , Edema/chemically induced , Edema/drug therapy , Female , Humans , Hydrazones/chemical synthesis , Hydrazones/therapeutic use , I-kappa B Kinase/chemistry , Ligands , Male , Mice , Molecular Dynamics Simulation , Molecular Sequence Data , Molecular Weight , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/therapeutic useABSTRACT
This Letter describes the results of two combined approaches: homology modeling and molecular docking studies, in order to propose the molecular basis of IKKbeta inhibition by staurosporine and quercetin as ATP-competitive inhibitors. The results provides a rationale and structural frameworks for designing potent ATP binding-site inhibitors of IKKbeta, which is an attractive drug target for inflammatory diseases and has been found to be responsible for some of the already observed pharmacological effects for marketed drugs.
