Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A practical, convergent route to the key precursor to the tetracycline antibiotics.

ABSTRACT: Here we describe a 5-step sequence to prepare the AB enone 1, the key precursor to fully synthetic tetracyclines, that begins with a diastereoselective Michael-Claisen coupling of two simple starting materials, a cyclohexenone (compound 2 or, in a refinement, a substituted variant, vide infra) and the isoxazole ester 3. This advance defines an 8-step linear sequence to 6-deoxytetracycline antibiotics from three components of similar complexity (cyclohexenone 2, isoxazole ester 3, and structurally diverse D-ring precursors) in which sequential diastereoselective Michael-Claisen cyclization reactions form the A- and C-rings, respectively, of the linearly fused ABCD tetracycline skeleton. In addition to providing a readily scalable, practical route to fully synthetic tetracyclines of broad structural diversity, the sequence reported comprises a series of non-obvious stereoselective transformations, including a novel means for C12a hydroxylation.

SUBMITTER: Kummer DA

PROVIDER: S-EPMC3176682 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

A practical, convergent route to the key precursor to the tetracycline antibiotics.

Kummer David A DA Li Derun D Dion Amelie A Myers Andrew G AG

Chemical science 20110901 9

Here we describe a 5-step sequence to prepare the AB enone 1, the key precursor to fully synthetic tetracyclines, that begins with a diastereoselective Michael-Claisen coupling of two simple starting materials, a cyclohexenone (compound 2 or, in a refinement, a substituted variant, vide infra) and the isoxazole ester 3. This advance defines an 8-step linear sequence to 6-deoxytetracycline antibiotics from three components of similar complexity (cyclohexenone 2, isoxazole ester 3, and structurall ...[more]

PMID: 21949588

Similar Datasets

A practical, enantioselective synthetic route to a key precursor to the tetracycline antibiotics.

Project description:A practical, enantioselective synthetic route to a key precursor to the tetracycline antibiotics is reported. The route proceeds in nine steps (21% yield) from the commercial substance methyl 3-hydroxy-5-isoxazolecarboxylate. Key steps in the route involve enantioselective addition of divinylzinc to 3-benzyloxy-5-isoxazolecarboxaldehyde and an endo-selective intramolecular furan Diels-Alder cycloaddition reaction. The route described has provided more than 40 g of chromatographically pure 1 with 93% ee.

| S-EPMC3178443 | biostudies-literature

Convergent route to the spirohexenolide macrocycle.

Project description:Using key functional dissections, the synthesis of spirohexenolides is examined through a three-component strategy that features a 1,2-addition to couple tetronate and aldehyde components forming the C2-C3 bond and a Stille coupling to install the third sulfone-containing component. The macrocycle is completed by an intramolecular Julia-Kocienski reaction to form the C10-C11 trans-disubstituted olefin. Application of this strategy is described in progress toward the synthesis of (±)-spirohexenolide B.

| S-EPMC2956428 | biostudies-literature

Tetracycline Antibiotics Induce Host-Dependent Disease Tolerance to Infection.

Project description:Several classes of antibiotics have long been known to have beneficial effects that cannot be explained strictly on the basis of their capacity to control the infectious agent. Here, we report that tetracycline antibiotics, which target the mitoribosome, protected against sepsis without affecting the pathogen load. Mechanistically, we found that mitochondrial inhibition of protein synthesis perturbed the electron transport chain (ETC) decreasing tissue damage in the lung and increasing fatty acid oxidation and glucocorticoid sensitivity in the liver. Using a liver-specific partial and acute deletion of Crif1, a critical mitoribosomal component for protein synthesis, we found that mice were protected against sepsis, an observation that was phenocopied by the transient inhibition of complex I of the ETC by phenformin. Together, we demonstrate that mitoribosome-targeting antibiotics are beneficial beyond their antibacterial activity and that mitochondrial protein synthesis inhibition leading to ETC perturbation is a mechanism for the induction of disease tolerance.

| S-EPMC7840524 | biostudies-literature

Practical Route for Catalytic Ring-Opening Metathesis Polymerization.

Project description:Norbornene derivatives are typical monomers for ring-opening metathesis polymerization (ROMP) for synthesizing highly functional polymers. However, the lack of catalytic methods, that is, the lack of readily available chain transfer agents (CTAs) for these monomers has been a significant cost limitation when large-scale syntheses are required. Here, we report commercially available styrene and its derivatives as efficient regioselective CTAs for the catalytic synthesis of metathesis polymers requiring up to 1000 times less ruthenium than in classical ROMP experiments. The molecular weight of the synthesized polymers was controlled by the monomer-to-CTA ratio. Low molecular weight ROMP polymers known for their antimicrobial properties were also synthesized on a gram scale in this report. Polymers were characterized by SEC, 1H NMR spectroscopy, and isotopically resolved MALDI-TOF MS. This approach describes a greener, more cost-effective, and eco-friendly methodology for the preparation of metathesis-based materials on the multigram scale.

| S-EPMC9795566 | biostudies-literature

A robust platform for the synthesis of new tetracycline antibiotics.

Project description:Tetracyclines and tetracycline analogues are prepared by a convergent, single-step Michael-Claisen condensation of AB precursor 1 or 2 with D-ring precursors of wide structural variability, followed by removal of protective groups (typically in two steps). A number of procedural variants of the key C-ring-forming reaction are illustrated in multiple examples. These include stepwise deprotonation of a D-ring precursor followed by addition of 1 or 2, in situ deprotonation of a D-ring precursor in mixture with 1 or 2, and in situ lithium-halogen exchange of a benzylic bromide D-ring precursor in the presence of 1 or 2, followed by warming. The AB plus D strategy for tetracycline synthesis by C-ring construction is shown to be robust across a range of different carbocyclic and heterocyclic D-ring precursors, proceeding reliably and with a high degree of stereochemical control. Evidence suggests that Michael addition of the benzylic anion derived from a given D-ring precursor to enones 1 or 2 is quite rapid at -78 degrees C, while Claisen cyclization of the enolate produced is rate-determining, typically occurring upon warming to 0 degrees C. The AB plus D coupling strategy is also shown to be useful for the construction of tetracycline precursors that are diversifiable by latter-stage transformations, subsequent to cyclization to form the C ring. Results of antibacterial assays and preliminary data obtained from a murine septicemia model show that many of the novel tetracyclines synthesized have potent antibiotic activities, both in bacterial cell culture and in vivo. The platform for tetracycline synthesis described gives access to a broad range of molecules that would be inaccessible by semisynthetic methods (presently the only means of tetracycline production) and provides a powerful engine for the discovery and, perhaps, development of new tetracycline antibiotics.

| S-EPMC2681267 | biostudies-literature

The Development of Third-Generation Tetracycline Antibiotics and New Perspectives.

Project description:The tetracycline antibiotic class has acquired new valuable members due to the optimisation of the chemical structure. The first modern tetracycline introduced into therapy was tigecycline, followed by omadacycline, eravacycline, and sarecycline (the third generation). Structural and physicochemical key elements which led to the discovery of modern tetracyclines are approached. Thus, several chemical subgroups are distinguished, such as glycylcyclines, aminomethylcyclines, and fluorocyclines, which have excellent development potential. The antibacterial spectrum comprises several resistant bacteria, including those resistant to old tetracyclines. Sarecycline, a narrow-spectrum tetracycline, is notable for being very effective against Cutinebacterium acnes. The mechanism of antibacterial action from the perspective of the new compound is approached. Several severe bacterial infections are treated with tigecycline, omadacycline, and eravacycline (with parenteral or oral formulations). In addition, sarecycline is very useful in treating acne vulgaris. Tetracyclines also have other non-antibiotic properties that require in-depth studies, such as the anti-inflammatory effect effect of sarecycline. The main side effects of modern tetracyclines are described in accordance with published clinical studies. Undoubtedly, this class of antibiotics continues to arouse the interest of researchers. As a result, new derivatives are developed and studied primarily for the antibiotic effect and other biological effects.

| S-EPMC8707899 | biostudies-literature

A convergent route to the CDEF-tetracycle of pectenotoxin-2.

Project description:A convergent synthesis of the CDEF-tetracyclic region of pectenotoxin-2 (PTX-2) is described. The synthetic pathway derives from a head-to-tail union of 2 equiv of linalool to establish a stereodefined DEF-tricyclic aldehyde. Subsequent coupling with a "northern" fragment enolate, followed by a tandem Sharpless epoxidation/cyclization, delivers the C10-C26 polycyclic region of the natural product.

| S-EPMC3156112 | biostudies-literature

Development of a Convergent Enantioselective Synthetic Route to (-)-Myrocin G.

Project description:Myrocins are a family of antiproliferative antibiotic fungal metabolites possessing a masked electrophilic cyclopropane. Preliminary chemical reactivity studies imputed the bioactivity of these natural products to a DNA cross-linking mechanism, but this hypothesis was not confirmed by studies with native DNA. We recently reported a total synthesis of (-)-myrocin G (4), the putative active form of the metabolite myrocin C (1), that featured a carefully orchestrated tandem fragment coupling-annulation cascade. Herein, we describe the evolution of our synthetic strategy toward 4 and report the series of discoveries that prompted the design of this cascade coupling. Efforts to convert the diosphenol (-)-myrocin G (4) to the corresponding 5-hydroxy-γ-lactone isomer myrocin C (1) are also detailed. We present a preliminary evaluation of the antiproliferative activities of (-)-myrocin G (4) and related structures, as well as DNA cross-linking studies. These studies indicate that myrocins do not cross-link DNA, suggesting an alternative mode of action potentially involving a protein target.

| S-EPMC7520802 | biostudies-literature

Resistance and phylogeny guided discovery reveals structural novelty of tetracycline antibiotics.

Project description:Tetracyclines are a class of antibiotics that exhibited potent activity against a wide range of Gram-positive and Gram-negative bacteria, yet only five members were isolated from actinobacteria, with two of them approved as clinical drugs. In this work, we developed a genome mining strategy using a TetR/MarR-transporter, a pair of common resistance enzymes in tetracycline biosynthesis, as probes to find the potential tetracycline gene clusters in the actinobacteria genome database. Further refinement using the phylogenetic analysis of chain length factors resulted in the discovery of 25 distinct tetracycline gene clusters, which finally resulted in the isolation and characterization of a novel tetracycline, hainancycline (1). Through genetic and biochemical studies, we elucidated the biosynthetic pathway of 1, which involves a complex glycosylation process. Our work discloses nature's huge capacity to generate diverse tetracyclines and expands the chemical diversity of tetracyclines.

| S-EPMC9645399 | biostudies-literature

Effect of pH on Adsorption of Tetracycline Antibiotics on Graphene Oxide.

Project description:Graphene oxide (GO) has good dispersibility and adsorption capacity for antibiotics adsorption, a complex process influenced by many factors. In this work, the adsorption mechanism of GO on tetracycline antibiotics at different pH was studied to address its attenuated effects on the microbial growth. The results showed that the adsorption process of GO on three antibiotics, namely, tetracycline (TC), oxytetracycline (OTC), and chlortetracycline (CTC), followed the pseudo-second-order kinetic model. The maximum adsorption capacities were observed at pH5 which were 133.0 mg/g for TC, 125.4 mg/g for OTC, and 167.0 mg/g for CTC. Furthermore, the reaction was uniform adsorption with a single layer on the surface of GO, and heating was conducive to the reaction. In the microbial growth experiment, the growth of E. coli and B. subtilis senses was optimal at pH5, which was consistent with the adsorption experiment. This study analyzed the effect of pH on the adsorption of antibiotics by GO and provided a theoretical basis for the further application of GO in various aquatic environments.

| S-EPMC9915905 | 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