A total synthesis of the ingenane-derived diterpenoid (+)-euphorikanin A is described. Key to the strategy is a stereocontrolled one-pot sequence consisting of transannular aldol addition reaction, ...hemiketal formation, and subsequent semipinacol rearrangement that efficiently leads to the complete euphorikanin skeleton. Atroposelective ring-closing olefin metathesis proved critical for the stereospecific cascade, leading to formation of a (Z)-bicyclo7.4.1tetradecenone core. An additional salient feature of the route is pyrolysis of a bis-methylxanthate to cleanly furnish the natural product.
Eine allgemeine, intramolekulare Zykloisomerisierung nichtaktivierter Olefine mit Nukleophilen wird beschrieben. Die Reaktion erfolgt unter milden Bedingungen und toleriert Ether, Ester, geschützte ...Amine, Acetale, Pyrazole, Carbamate und Arene. Sie ist zugänglich für N‐, O‐ und C‐Nukleophile, wobei eine Reihe verschiedener Heterozyklen gebildet werden kann, darunter Pyrrolidine, Piperidine, Oxazolidinone und Lactone. Durch die Kombination eines Benzothiazinoquinoxalins als Organophotokatalysator und eines Cobaltsalen‐Katalysators sind keine stöchiometrischen Oxidations‐ oder Reduktionsmittel erforderlich. Wir zeigen den Nutzen des Protokolls für die Diversifizierung von Arzneimitteln sowie die Synthese mehrerer kleiner Naturstoffe.
Eine allgemeine, intramolekulare Zykloisomerisierung nichtaktivierter Olefine mit N‐, O‐ und C‐Nukleophilen wird beschrieben. Die Reaktion läuft unter milden Bedingungen ab und liefert eine Reihe verschiedener Heterozyklen, darunter Pyrrolidine, Piperidine, Oxazolidinone und Lactone. Durch die Verwendung eines Benzothiazinoquinoxalins als Organophotokatalysator und eines Cobaltsalen‐Katalysators sind keine stöchiometrischen Oxidations‐ oder Reduktionsmittel erforderlich.
In the forebrain, synaptic glycine concentrations are regulated through the glycine transporter GlyT1. Because glycine is
a coagonist of the N -methyl- d -aspartate (NMDA) receptor (NMDAR), which has ...been implicated in schizophrenia, inhibition of GlyT1 is thought to provide
an option for the treatment of schizophrenia. In support of this hypothesis, GlyT1 inhibitors facilitate in vivo NMDAR function
and demonstrate antipsychotic-like effects in animal models. Among the specific GlyT1 inhibitors, substituted N -methyl-glycine (sarcosine) derivatives (e.g., ( R )- N 3-(4â²fluorophenyl)-3-(4â²phenyl-phenoxy)propyl-sarcosine NFPS, ( R )- N 3-phenyl-3-(4â²-(4-toluoyl)phenoxy)-propylsarcosine (R)-NPTS, and ( R , S )-(±) N -methyl- N -(4-trifluoromethyl)phenoxy-3-phenyl-propylglycine Org24589), and non-sarcosine-containing inhibitors, such as 2-chloro- N -( S )-phenyl(2 S )-piperidin-2-yl methyl-3-trifluoromethyl benzamide, monohydrochloride (SSR504734), have been described. In the present
study, we analyzed the mode of interaction of these compounds with GlyT1 by using electrophysiological measurements in Xenopus laevis oocytes, and with two binding assays, using 3 H(R)-NPTS or 2-chloro- N -( S )-phenyl(2 S )- N -methylpiperidin-2-yl-methyl-3-trifluoromethyl benzamide monohydrochloride ( 3 H N -methyl-SSR504734) as radioligands. Inhibition of electrogenic glycine transport by sarcosine-based compounds was apparently
irreversible and independent of glycine concentration. The latter indicates a noncompetitive mode of action. In contrast,
both SSR504734 and N -methyl-SSR504734 exhibited reversible and competitive inhibition of glycine transport. In GlyT1-expressing membranes, the
binding of the novel radioligand 3 H N -methyl-SSR504734 to a single site on GlyT1 was competitively displaced by glycine and SSR504734 but noncompetitively by sarcosine-based
compounds. Inversely, 3 H(R)-NPTS binding was competitively inhibited by sarcosine-based compounds, whereas glycine, SSR504734, and N -methyl-SSR504734 noncompetitively decreased maximal binding. Our data indicate that besides exerting an apparently irreversible
or reversible inhibition, GlyT1 inhibitors differ by exhibiting either a noncompetitive or competitive mode of inhibition.
The divergent modes of inhibition may significantly affect the efficacy and tolerability of these drugs.
Alkyl fluorides modulate the conformation, lipophilicity, metabolic stability, and pKa of compounds containing aliphatic motifs and, therefore, have been valuable for medicinal chemistry. Despite ...significant research in organofluorine chemistry, the synthesis of alkyl fluorides, especially chiral alkyl fluorides, remains a challenge. Most commonly, alkyl fluorides are prepared by the formation of C−F bonds (fluorination), and numerous strategies for nucleophilic, electrophilic, and radical fluorination have been reported in recent years. Although strategies to access alkyl fluorides by C−C bond formation (monofluoroalkylation) are inherently convergent and complexity‐generating, they have been studied less than methods based on fluorination. This Review provides an overview of recent developments in the synthesis of chiral (enantioenriched or racemic) secondary and tertiary alkyl fluorides by monofluoroalkylation catalyzed by transition‐metal complexes. We expect this contribution will illuminate the potential of monofluoroalkylations to simplify the synthesis of complex alkyl fluorides and suggest further research directions in this growing field.
This Review provides an overview of recent developments in the synthesis of chiral (enantioenriched or racemic) secondary and tertiary alkyl fluorides by monofluoroalkylation catalyzed by transition‐metal complexes. Strategies to access alkyl fluorides by C−C bond formation (monofluoroalkylation) are inherently convergent and complexity‐generating, but they have been studied less than strategies to access alkyl fluorides by C−F bond formation (fluorination).
Pick any color of electrochrome: Sensors, photovoltaic cells, non‐volatile memories, tintable glass etc.—all of these technologies include thiophene‐based materials. They need to be tailor‐made, and ...therefore customization and modularization is highly desirable. We have synthesized a kit of 16 thiophene‐based heterophenoquinones, carefully investigated their optoelectronic properties and uncovered their structure–property relationships. The absorption of the heterophenoquinones covers the entire visible spectrum (structure and hexagons at the front). Upon reduction they change their color (structure and hexagons at the back), thus making them applicable in tintable glass. More information can be found in the Research Article by J. Freudenberg, U. H. F. Bunz and co‐workers (DOI: 10.1002/chem.202203862).
In this study we aimed to reduce tau pathology, a hallmark of Alzheimer's Disease (AD), by activating mTOR-dependent autophagy in a transgenic mouse model of tauopathy by long-term dosing of animals ...with mTOR-inhibitors. Rapamycin treatment reduced the burden of hyperphosphorylated and aggregated pathological tau in the cerebral cortex only when applied to young mice, prior to the emergence of pathology. Conversely, PQR530 which exhibits better brain exposure and superior pharmacokinetic properties, reduced tau pathology even when the treatment started after the onset of pathology. Our results show that dosing animals twice per week with PQR530 resulted in intermittent, rather than sustained target engagement. Nevertheless, this pulse-like mTOR inhibition followed by longer intervals of re-activation was sufficient to reduce tau pathology in the cerebral cortex in P301S tau transgenic mice. This suggests that balanced therapeutic dosing of blood-brain-barrier permeable mTOR-inhibitors can result in a disease-modifying effect in AD and at the same time prevents toxic side effects due to prolonged over activation of autophagy.
•mTOR-inhibition facilitated tau aggregate clearance in the cortex of hTau.P301S mice.•PQR530 exhibited much better brain exposure than rapamycin.•Chronic, therapeutic dosing of PQR530 leads to intermittent mTOR target engagement.•Pulse-like mTOR inhibition was sufficient to lower tau pathology in the mouse brain.•Balanced mTOR-inhibition, preventing toxic side effects, might be beneficial in AD.
A novel class of endothelin-A receptor ligands was discovered by high-throughput screening. Lead structure optimization led to highly potent antagonists which can be synthesized in a short sequence. ...The compounds are endothelin-A-selective, are orally available, and show a long duration of action.
