A useful and convenient strategy for the synthesis of α,α‐disubstituted α‐amino acid (α‐AA) derivatives via aza‐Morita‐Baylis‐Hillman reaction of 2‐aminoacrylates with activated olefins has been ...developed. A variety of α‐AA derivatives containing an α‐amino tertiary center were synthesized in good to excellent yields. The kinetic profiles and calculated methyl anion affinity (MAA) values were employed to rationalize the reactivities of different Michael acceptors used in the reaction.
Alpha Amino Acids: A novel tertiary phosphine catalyzed aza‐MBH reaction of 2‐aminoacrylates with MVK was disclosed, affording the corresponding α‐AAs derivatives under mild conditions.
Ein‐ oder zweizähnige Lewis‐Säuren leiten eine regioselektive Magnesierung oder Zinkierung an Pyridazin in Position C3 (ortho‐Produkt) oder C4 (meta‐Produkt) ein. Die Regioselektivität der ...Metallierung wurde mithilfe der berechneten pKs‐Werte von sowohl Pyridazin als auch den Pyridazin‐Lewis‐Säure‐Komplexen erklärt.
Chelatisiert: Durch die Chelatisierung des Diazins Pyridazin mit einer zweizähnigen Diboranthracen‐Lewis‐Säure konnte eine seltene C4‐Metallierung erreicht werden. Zusätzlich wurde eine hoch regioselektive ortho‐Metallierung erhalten, wenn die einzähnige Lewis‐Säure BF3⋅OEt2 eingesetzt wurde. Die Regioselektivität lässt sich anhand der berechneten pKs‐Werte der Pyridazin‐Lewis‐Säure‐Komplexe erklären.
Abstract
Ein‐ oder zweizähnige Lewis‐Säuren leiten eine regioselektive Magnesierung oder Zinkierung an Pyridazin in Position C3 (
ortho
‐Produkt) oder C4 (
meta
‐Produkt) ein. Die Regioselektivität ...der Metallierung wurde mithilfe der berechneten p
K
s
‐Werte von sowohl Pyridazin als auch den Pyridazin‐Lewis‐Säure‐Komplexen erklärt.
The stereoselectivity and stereospecificity of the triflate‐mediated intramolecular Schmidt reaction of substituted 3‐(1‐azidocyclohexyl)propanol derivatives leading to ...octahydro‐1H‐pyrrolo1,2‐aazepine, the structural skeleton of several important families of alkaloids such as the Stemona alkaloids, has been examined. The reaction involves an initial intramolecular SN2 reaction between the azide moiety and the triflate affording an intermediate spirocyclic aminodiazonoium salt that undergoes the expected 1,2‐shift/N2‐elimination followed by hydride‐mediated iminium salt reduction. Remarkably, chiral alcohols are converted to the azabicyclic derivative with no or limited racemization. The initial asymmetric alcohol center controls the diastereoselectivity of the whole process, leading to the formation of one out of the four possible diastereoisomers of disubstituted octahydro‐1H‐pyrrolo1,2‐aazepine. The origin of the stereoselectivity is rationalized based on theoretical calculations. The concise synthesis of (−)‐(cis)‐3‐propylindolizidine and (−)‐(cis)‐3‐butyllehmizidine, two alkaloids found in the venom of workers of the ant Myrmicaria melanogaster, is reported.
Enantiomerically enriched azabicyclic compounds found in several important families of alkaloids can be prepared by a remarkably stereospecific and stereoselective intramolecular Schmidt reaction. The initial asymmetric alcohol center controls the whole process, leading to the formation of one out of up to four possible diastereoisomers with inversion of the configuration at the original asymmetric center.
The development of a predictive model towards site‐selective deprotometalation reactions using TMPZnCl⋅LiCl is reported (TMP=2,2,6,6‐tetramethylpiperidinyl). The pKa values of functionalized N‐, S‐, ...and O‐heterocycles, arenes, alkenes, or alkanes were calculated and compared to the experimental deprotonation sites. Large overlap (>80 %) between the calculated and empirical deprotonation sites was observed, showing that thermodynamic factors strongly govern the metalation regioselectivity. In the case of olefins, calculated frozen state energies of the deprotonated substrates allowed a more accurate prediction. Additionally, various new N‐heterocycles were analyzed and the metalation regioselectivities rationalized using the predictive model.
Metalation site prediction: The use of simple pKa calculations allowed a reliable prediction of metalation sites in various heterocycles, arenes, olefins, and alkanes, employing the mild base TMPZnCl⋅LiCl. Using this predictive model, also unexplored N‐heterocycles were investigated, and the obtained deprotonation sites rationalized readily.
Simple monocyclic diketopiperazine (DKP)-derived alkoxyamines exhibit an unprecedented activation of a remote C-O bond for homolysis by amide distortion. The combination of strain release-driven ...amide planarization and the persistent radical effect (PRE) enable a unique, irreversible and quantitative trans→cis isomerization under much milder conditions than typically observed for such homolysis-limited reactions. This isomerization is shown to be general and independent of the steric and electronic nature of both amino acid side chains and substituents at the DKP nitrogen atoms. Homolysis rate constants have been determined and they significantly differ for both, the labile trans-diastereomers and the stable cis-diastereomers. To reveal the factors influencing this unusual process, structural features of the kinetic trans- and thermodynamic cis-diastereomers were investigated in the solid state and in solution. X-ray crystallographic analysis and computational studies indicate a substantial distortion of the amide bond from planarity in the trans-alkoxyamines, which is the cause for the facile and quantitative isomerization. Thus, these amino acid-derived alkoxyamines are the first examples that exhibit a large thermodynamic preference for one diastereomer over the other upon thermal homolysis, which allows controlled switching of configurations and configurational cycling.
In the present study, five detour/distance matrix based molecular descriptors (MDs) termed as relative eccentric distance sum/product indices (denoted by Rξ1 SV, Rξ2 SV, Rξ3 SV, RPξ1 SV, and RPξ2 ...SV), as well as their topochemical versions denoted by (Rξ1 cSV, Rξ2 cSV, Rξ3 cSV, RPξ1 cSV, and RPξ2 cSV) have been conceptualized for exclusive use for molecules containing cyclic moieties. The said MDs exhibited exceptionally high discriminating power and high sensitivity toward branching/relative position of substituents in cyclic structures amalgamated with negligible degeneracy. Subsequently, the proposed MDs along with other MDs were successfully utilized for the development of models for the prediction of human glutaminyl cyclase (hQC) inhibitory activity using decision tree (DT), random forest (RF) and moving average analysis (MAA). A data set comprising of 45 analogues of substituted 3-(1H-imidazol-1-yl) propyl thiourea derivatives was used. DT identified proposed relative eccentric distance sum topochemical index-1 as the most important MD. High accuracy of prediction up to 96%, 93%, and 95% was observed in case of models derived from decision tree, random forest, and MAA, respectively. The statistical significance of proposed models was assessed through specificity, sensitivity, overall accuracy, Mathew’s correlation coefficient (MCC), and intercorrelation analysis.
In the present study four topology-based molecular descriptors (MDs) termed as augmented adjacent path eccentricity descriptors 1-4 (denoted by ... along with their topochemical counterparts (denoted ...by ... have been developed. The values of the said MDs were computed for all the linear, branched and cyclic structures containing three, four and five vertices through an in-house computer program. Proposed MDs were evaluated for degeneracy, discriminating power, intercorrelation and sensitivity towards branching as well relative position(s) of substituent(s) in the molecules containing cyclic/polycyclic moieties. These MDs demonstrated exceptionally high discriminating power, negligible degeneracy and high sensitivity towards branching/relative position(s) of substituent(s) particularly in cyclic structures. Mathematical properties of one of the proposed MDs were also studied. Exceptionally high discriminating power amalgamated with high sensitivity towards branching as well as relative position(s) of substituent(s) in cyclic structures and negligible degeneracy offer proposed MDs a vast potential in lead identification and optimization, similarity/dissimilarity studies, combinatorial library design, isomer discrimination, characterization of structures, chemical documentation, (Q)SAR, QSPR, QSTR and QSPkR studies so as to accelerate drug discovery process.
Chloroform and Halothane are well known hepatotoxic anesthetics for which toxicity is attributed to their reactive metabolites. The molecular level details of reactions leading to the formation of ...reactive metabolites from chloroform and halothane have not been explored. Potential energy surface (PES) for the formation of phosgene (a toxic intermediate) from Chloroform has been studied using quantum chemical methods. The HOOH mediated reaction of chloroform to give phosgene has been found to be exothermic by 81.24 kcal/mol with a barrier of ~ 3 kcal/mol through the water catalyzed transition sate. The quantum chemical studies on the reactivity profile of phosgene indicated that urea derivatives need to be considered on the mechanism leading to toxicity. Similarly, metabolic pathways of Halothane oxidation have been studied. The C-H bond dissociation energies (BDE) and radical stabilization energies (RSE) for Chloroform and Halothane (< 95 kcal/mol and > 10 kcal/mol) were found to be significantly different for these toxic anesthetics in comparison to their safer analogues (> 100 kcal/mol and < 5 kcal/mol) respectively; thus these parameters can be employed to distinguish toxic and non-toxic general anesthetics. Enthalpy for the Cpd I, a widely used model for CYP450 enzymes, mediated reactions also agreed well with these results.
Radical chain reactions are commonly initiated through the thermal or photochemical activation of purpose‐built initiators, through photochemical activation of substrates, or through well‐designed ...redox processes. Where radicals come from in the absence of these initiation strategies is much less obvious and are often assumed to derive from unknown impurities. In this situation, molecule‐induced radical formation (MIRF) reactions should be considered as well‐defined alternative initiation modes. In the most general definition of MIRF reactions, two closed‐shell molecules react to give a radical pair or biradical. The exact nature of this transformation depends on the σ‐ or π‐bonds involved in the MIRF process, and this Minireview specifically focuses on reactions that transform two σ‐bonds into two radicals and a closed‐shell product molecule.
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