Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Stereoelectronic Features of a Complex Ketene Dimerization Reaction.

ABSTRACT: The amidation reaction of a tetrahydroisoquinolin-1-one-4-carboxylic acid is a key step in the multi-kilogram-scale preparation of the antimalarial drug SJ733, now in phase 2 clinical trials. In the course of investigating THIQ carboxamidations, we found that propanephosphonic acid anhydride (T3P) is an effective reagent, although the yield and byproducts vary with the nature and quantity of the base. As a control, the T3P reaction of a 3-(2-thienyl) THIQ was performed in the absence of the amine, and the products were characterized: among them are three dimeric allenes and two dimeric lactones. A nucleophile-promoted ketene dimerization process subject to subtle steric and stereoelectronic effects accounts for their formation. Two novel monomeric products, a decarboxylated isoquinolone and a purple, fused aryl ketone, were also isolated, and mechanisms for their formation from the ketene intermediate are proposed.

SUBMITTER: Barrows RD

PROVIDER: S-EPMC8746406 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Stereoelectronic Features of a Complex Ketene Dimerization Reaction.

Barrows Robert D RD Dresel Mark J MJ Emge Thomas J TJ Rablen Paul R PR Knapp Spencer S

Molecules (Basel, Switzerland) 20211223 1

The amidation reaction of a tetrahydroisoquinolin-1-one-4-carboxylic acid is a key step in the multi-kilogram-scale preparation of the antimalarial drug SJ733, now in phase 2 clinical trials. In the course of investigating THIQ carboxamidations, we found that propanephosphonic acid anhydride (T3P) is an effective reagent, although the yield and byproducts vary with the nature and quantity of the base. As a control, the T3P reaction of a 3-(2-thienyl) THIQ was performed in the absence of the amin ...[more]

PMID: 35011298

Similar Datasets

Discussion on the dimerization reaction of penicillin antibiotics.

Project description:Penicillins are one type of the most important antibiotics used in the clinic. Control of drug impurity profiles is an important part of ensuring drug safety. This is particularly important in penicillins where polymerization can lead to polymers as elicitors of passive cutaneous anaphylaxis. The current understanding of penicillin polymerization is based on reactions with amino groups, but no comprehensive mechanistic understanding has been reported. Here, we used theoretical calculations and column switching - LC/MS techniques to study penicillin dimerization. Ampicillin and benzylpenicillin were selected as representative penicillins with or without amino groups in the side chain, respectively. We identified four pathways by which this may occur and the energy barrier graphs of each reaction process were given. For benzylpenicillin without an amino group in the 6-side chain, dimerization mode A is the dominant mode, where the 2-carboxyl group of one molecule reacts with the β-lactam of another molecule. However, ampicillin with an amino group in the 6-side chain favors dimerization mode C, where the amino group of one molecule attacks the β-lactam of another molecule. These findings can lead to a polymer control approach to maintaining penicillin antibiotics in an active formulation.

| S-EPMC9257443 | biostudies-literature

Stereoelectronic Effects Impact Glycan Recognition.

Project description:Recognition of distinct glycans is central to biology, and lectins mediate this function. Lectin glycan preferences are usually centered on specific monosaccharides. In contrast, human intelectin-1 (hItln-1, also known as Omentin-1) is a soluble lectin that binds a range of microbial sugars, including β-d-galactofuranose (β-Galf), d-glycerol 1-phosphate, d-glycero-d-talo-oct-2-ulosonic acid (KO), and 3-deoxy-d-manno-oct-2-ulosonic acid (KDO). Though these saccharides differ dramatically in structure, they share a common feature-an exocyclic vicinal diol. How and whether such a small fragment is sufficient for recognition was unclear. We tested several glycans with this epitope and found that l-glycero-α-d-manno-heptose and d-glycero-α-d-manno-heptose possess the critical diol motif yet bind weakly. To better understand hItln-1 recognition, we determined the structure of the hItln-1·KO complex using X-ray crystallography, and our 1.59 Å resolution structure enabled unambiguous assignment of the bound KO conformation. This carbohydrate conformation was present in >97% of the KDO/KO structures in the Protein Data Bank. Bioinformatic analysis revealed that KO and KDO adopt a common conformation, while heptoses prefer different conformers. The preferred conformers of KO and KDO favor hItln-1 engagement, but those of the heptoses do not. Natural bond orbital (NBO) calculations suggest these observed conformations, including the side chain orientations, are stabilized by not only steric but also stereoelectronic effects. Thus, our data highlight a role for stereoelectronic effects in dictating the specificity of glycan recognition by proteins. Finally, our finding that hItln-1 avoids binding prevalent glycans with a terminal 1,2-diol (e.g., N-acetyl-neuraminic acid and l-glycero-α-d-manno-heptose) suggests the lectin has evolved to recognize distinct bacterial species.

| S-EPMC7392083 | biostudies-literature

Phytophenol Dimerization Reaction: From Basic Rules to Diastereoselectivity and Beyond.

Project description:Phytophenol dimerization, which is a radical-mediated coupling reaction, plays a critical role in many fields, including lignin biosynthesis. To understand the reaction, 2,2-diphenyl-1-picrylhydrazyl radical was used to initiate a series of phytophenol dimerization reactions in methanol. The products were identified using ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UHPLC-ESI-Q-TOF-MS/MS) analysis in situ. The identified products mainly included biphenols, magnolol, honokiol, gingerol 6,6'-dimers, 3,6-dimethoxylcatechol β,β' dimer, euphorbetin, bis-eugenol, dehydrodiisoeugenol, trans-ε-viniferin, (+) pinoresinol, and (-) pinoresinol. Structure-function relationship analysis allowed four basic rules to be defined: meta-excluded, C-C bonding domination, ortho-diOH co-activation, and exocyclic C=C involvement. The exocyclic C=C involvement, however, required conjugation with the phenolic core and the para-site of the -OH group, to yield a furan-fused dimer with two chiral centers. Computational chemistry indicated that the entire process was completed via a radical coupling reaction and an intramolecular conjugate addition reaction. Similar results were also found for the horseradish peroxidase (HRP)-catalyzed coniferyl alcohol dimerization, which produced (+) and (-) pinoresinols (but no (-) epipinoresinol), suggesting that the HRP-catalyzed process was essentially an exocyclic C=C-involved phytophenol dimerization reaction. The reaction was highly diastereoselective. This was attributed to the intramolecular reaction, which prohibited Re-attack. The four basic rules and diastereoselectivity can explain and even predict the main products in various chemical and biological events, especially oxidase-catalyzed lignin cyclization.

| S-EPMC9369853 | biostudies-literature

Efficient polymer dimerization method based on self-accelerating click reaction.

Project description:An efficient polymer dimerization method is developed on a self-accelerating double strain-promoted azide-alkyne cycloaddition (DSPAAC) click reaction. In this approach, varied polymer dimers can be efficiently prepared by coupling azide terminated polymer building blocks by sym-dibenzo-1,5-cyclooctadiene-3,7-diyne (DIBOD) small linkers. The distinct advantages of this method can be summarized as follows. First, the azide terminated polymer building blocks can be easily prepared with varied molecular topologies such as linear, star, and dendritic shapes. Second, the self-accelerating property of DSPAAC coupling reaction allows the method to efficiently prepare pure polymer dimers in the presence of excess molar amounts of DIBOD small linkers to azide-terminated polymer building blocks. Third, the click property of DSPAAC coupling reaction facilitates the dimerization reaction with a very mild ambient reaction condition. As a result, this method provides a powerful tool to fabricate topological polymers with a symmetrical molecular structure such as block, star, and dendritic polymers.

| S-EPMC9049738 | biostudies-literature

Remarkable features of the McMurry reaction conditions in dimerization of formyl- and 2-formylvinylpurpurinimides. Electrochemistry of monomeric Ni(II) purpurinimide and the corresponding dyads.

Project description:To investigate the electrochemical properties of purpurinimide dyads and electron transfer sites for their reduction and oxidation, a series of dimers with variable C-C linkages were synthesized. For the preparation of these novel structures, the formyl and 2-formylvinyl substituents were regioselectively introduced at positions 3 and 20 of Ni(II) purpurinimides by the Vilsmeier reaction. The Ni(II) complexes were then subjected to the McMurry reaction under two different conditions with unexpected results. For example, the reaction of formyl purpurinimides with TiCl(3)(DME)(1.5) failed to produce the desired C-C dimers, and the starting compounds were recovered almost quantitatively. Under similar reaction conditions, the 20-(2-formylvinyl)purpurinimide also did not dimerize but produced instead unexpected benzoisobacteriochlorins via an intramolecular cyclization. However, treatment of the 3-formyl- and 20-formylpurpurinimides with TiCl(4)/Zn produced corresponding dimers linked with one double bond (trans) in modest yields. Under similar conditions, Ni(II) purpurinimides containing a 2-formylvinyl substituent either at position 3 or at position 20 afforded the respective C-C dimers, where the purpurinimide moieties were joined with a trans-trans-trans hexatriene linker. Molecular modeling data suggest that the nature of the conformational energy difference found in all trans vs trans-cis-trans conformers of the dimers connected by a hexatriene linker at the meso- or beta-position of the macrocycle is not because of the intrinsic conformational energy difference of the linker region, which is identical for both dimers.

| S-EPMC2699560 | biostudies-literature

Mechanism of dimerization and structural features of human LI-cadherin.

Project description:Liver intestine (LI)-cadherin is a member of the cadherin superfamily, which encompasses a group of Ca2+-dependent cell-adhesion proteins. The expression of LI-cadherin is observed on various types of cells in the human body, such as normal small intestine and colon cells, and gastric cancer cells. Because its expression is not observed on normal gastric cells, LI-cadherin is a promising target for gastric cancer imaging. However, because the cell adhesion mechanism of LI-cadherin has remained unknown, rational design of therapeutic molecules targeting this cadherin has been hampered. Here, we have studied the homodimerization mechanism of LI-cadherin. We report the crystal structure of the LI-cadherin homodimer containing its first four extracellular cadherin repeats (EC1-4). The EC1-4 homodimer exhibited a unique architecture different from that of other cadherins reported so far, driven by the interactions between EC2 of one protein chain and EC4 of the second protein chain. The crystal structure also revealed that LI-cadherin possesses a noncanonical calcium ion-free linker between the EC2 and EC3 domains. Various biochemical techniques and molecular dynamics simulations were employed to elucidate the mechanism of homodimerization. We also showed that the formation of the homodimer observed in the crystal structure is necessary for LI-cadherin-dependent cell adhesion by performing cell aggregation assays. Taken together, our data provide structural insights necessary to advance the use of LI-cadherin as a target for imaging gastric cancer.

| S-EPMC8427231 | biostudies-literature

Disulfide Chromophores Arise from Stereoelectronic Effects.

Project description:Bonds between sulfur atoms are prevalent in natural products, peptides, and proteins. Disulfide bonds have a distinct chromophore. The wavelength of their maximal absorbance varies widely, from 250 to 500 nm. Here, we demonstrate that this wavelength derives from stereoelectronic effects and is predictable using quantum chemistry. We also provide a sinusoidal equation, analogous to the Karplus equation, that relates the absorbance maximum and the C-S-S-C dihedral angle. These insights provide a facile means to characterize important attributes of disulfide bonds and to design disulfides with specified photophysical properties.

| S-EPMC7293578 | biostudies-literature

Synthesis of spiroimidazopyridineoxindole, spiropyridopyrimidineoxindole and spiropyridodiazepineoxindole derivatives based on heterocyclic ketene aminals <i>via</i> a four-component reaction.

Project description:Here, we have described the synthesis of novel spiropyridineoxindole derivatives containing a pyridone ring via a four-component reaction between various diamines, 1,1-bis(methylthio)-2-nitroethylene, isatin derivatives and Meldrum's acid in the presence of p-toluenesulfonic acid. This protocol has some advantages such as the availability of starting materials, good yields, facile separation of products, the use of ethanol as an environmentally benign solvent and easy formation of three new bonds in one operation.

| S-EPMC9064345 | biostudies-literature

Synthesis of diverse spiro-imidazo pyridine-indene derivatives via acid-promoted annulation reaction of bindone and heterocyclic ketene aminals

Project description:A new multi-component reaction for the synthesis of novel and diverse spiro-imidazo pyridine-indene derivatives named spiro[imidazo[1,2-a]indeno[2,1-e]pyridine-5,1′-indene and indenylidene-1H-spiro[imidazo[1,2-a]pyridine-7,1′-indene was successfully developed by the reaction between heterocyclic ketene aminals (generated from 1,1-bis(methylthio)-2-nitro ethylene and diamine) and [1,2′-biindenylidene]-1′,3,3′-trione (bindone) (in situ generated from self-condensation of 1,3-indandion) by using malononitrile as a promoter or as one of the precursors respectively in the presence of p-TSA as the acid catalyst in EtOH as reaction medium under reflux conditions. Depending on whether the reaction is single-step or two-step, malononitrile can act as a promoter or reactant. The convenient one-pot operation, straightforward isolation without using additional purification methods, and the use of a variety of diamines and cysteamine hydrochloride causing a variety of structural products are attractive aspects of the present approach. The synthesized bindone and final product contains active methylene and this active site can be involved in further reactions to synthesize more complex heterocycles.

| S-EPMC9307797 | biostudies-literature

Synthesis of the hexacyclic triterpene core of the jujuboside saponins via tandem Wolff rearrangement-intramolecular ketene hetero-Diels-Alder reaction.

Project description:The jujubosides are saponin natural products reported to have immunoadjuvant, anticancer, antibacterial, antifungal, and antisweet activities. The triterpene component, jujubogenin contains a unique tricyclic ketal motif comprising the DEF ring system. Herein, we describe our efforts toward the total synthesis of jujubogenin, using a sterically-demanding intermolecular Diels-Alder reaction to assemble the C-ring and a tandem Wolff rearrangement-intramolecular ketene hetero-Diels-Alder reaction to form the DF-ring system. Acid-catalyzed cyclization of the resulting bicyclic enol ether then closes the E-ring to provide the hexacyclic core of jujubogenin.

| S-EPMC6242285 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data