Syntheses of furanocembranoid macrocycles with emphasis on the total sof providencin

Furanocembranoide Diterpene sind eine riesige, stets wachsende Klasse mariner Naturstoffe. Sowohl ihre interessanten biologischen Eigenschaften und ihre komplexen molekularen Architekturen, als auch ihre begrenzte Verfügbarkeit, machen sie zu herausfordernden synthetischen Zielen. Die Mehrheit der Vertreter dieser Klasse lässt sich in drei Hauptgruppen unterteilen, die sich im Wesentlichen durch ihre umgelagerten Kohlenstoffgerüste unterscheiden: Pseudopterane, Gersolane und Furanocembranoide. Innerhalb dieser drei Klassen unterscheiden sich deren Vertreter hauptsächlich durch ihren Oxidationsgrad und ihr Oxidationsmuster. Providencin (1) ist ein bekannter Vertreter der Furanocembranoide. Es wurde im Jahr 2003 von Rodriguez et al. isoliert und charakterisiert und besitzt einige seltene Strukturmotive, wie sein, bisher literatur-unbekanntes, hoch oxigeniertes Bicyclo[12.2.0]hexadecan-Skelett. Des Weiteren besitzt Providencin (1) neun stereogene Zentren und eine vierfach substituierte Cyclobutan-Einheit. Wegen der hohen Ringspannung, die das Molekül aufweist, weichen Furan und Butenolid Untereinheit in eine zueinander orthogonale Position aus, welche die Totalsynthese von Providencin (1) erschweren. Bis heute ist keine Totalsynthese literaturbekannt. Im Folgenden werden mehrere Zugänge präsentiert, welche die Ringspannung des Moleküls sukzessive herabsetzen. Die schrittweise Öffnung rigider Strukturmotive ermöglicht eine höhere Flexibilität und deshalb eine Erleichterung der schwierigen Makrozyklisierung. Dazu werden vier gut etablierte Makrozyklisierungsmethoden in zwei Syntheseserien (Cyclobutan- und Isopropenyl-Serie) verwendet: Ringschlussmetathese, Horner-Wadsworth-Emmons Bedingungen, Makro-laktonisierung und (Übergangs-)metall vermittelte Kohlenstoff-Kohlenstoff-Bindungs-knüpfung. Die Fragmente der einzelnen Ansätze wurden stereoselektiv synthetisiert. Ausgangsmaterial für die Cyclobutan-Serie war (±)-cis-Bicyclo[3.2.0]hept-2-en-6-on (180), welches den gewünschten viergliedrigen Ring bereits besitzt. Für die Isopropenyl-Serie wurde (R)-(-)-Carvon (359) als optimales Startmaterial gewählt. Sowohl in der Cyclobutan-, als auch in der Isopropenyl-Serie erwies sich der Metathese Zugang als zielführend. Dadurch konnten hoch funktionalisierte, weit fortgeschrittene Zwischenstufen synthetisiert werden, wie zum Beispiel Verbindung 213 in einer 21-Stufen Sequenz oder Verbindung 369 in einer 14-Stufen Sequenz. Da Providencin (1) unter den furanocembranoiden Diterpenen der einzige Vertreter ist, der eine Cyclobutan-Untereinheit an dieser Position aufweist, ermöglicht die Cyclobutan-Serie lediglich die maßgeschneiderte Synthese von (1). Der Isopropenyl-Ansatz ermöglicht jedoch die Synthese zahlreicher weiterer Vertreter dieser Naturstoffklasse, wie zum Beispiel Iopholide (57), Iophodiol A/B und Bipinnatin E (58).The class of furanocembranoid diterpenes is a huge, still growing family of marine natural products. Their interesting biological activities and complex molecular architectures, accompanied by their limited availability make them challenging synthetic targets. The vast majority of the family’s constituents can be divided in three different classes, depending on their rearranged carbon-skeletons: pseudopteranes, gersolanes and furanocembranoids. Among each other, they mainly differ in their degrees of oxygenation and oxygenation patterns. A well known member of the latter family is Providencin (1). It was first isolated and subsequently structure elucidated in 2003 by Rodriguez et al. The cyclic diterpene has some very interesting structural features. Its highly oxygenated hexacyclic structure is based on a previously undescribed bicyclo[12.2.0]hexadecane ring system. It bears nine stereogenic centers and its cyclobutanol subunit is four-fold substituted. Due to the highly strained ring system, the butenolide moiety is in a perpendicular orientation to the furan moiety, which makes the total synthesis of this molecule considerably difficult. To this day, no total synthesis has been published. Herein several approaches with decreasing the molecule’s ring strain are reported. The stepwise opening of rigid motifs should facilitate the crucial step of the macrocyclization. Four different, well established macrocyclization techniques were tested in two different synthetic series (cyclobutane- and isopropenyl-series): Ring closing metathesis, Horner-Wadsworth-Emmons conditions, macrolactonization, and (transition) metal mediated carbon-carbon-bond forming reactions. The fragments of each approach were synthesized in a stereoselective and convergent manner. The cyclobutane series exhibits this structural motif already in the starting material (±-cis-bicyclo[3.2.0]hept-2-en-6-one; 180), whereas in the isopropenyl series (R)-(-)-Carvone (359) was used. The latter one is a chiral pool starting material and therefore, allows the total synthesis of diterpenes starting with a cyclic monoterpene. The metathesis approaches in the cyclobutane, as well as in the isopropenyl series gave the most promising results and yielded highly advanced intermediates in the synthesis of Providencin (1). Since Providencin (1) is the only depicted member of the cembranoid family bearing a cyclobutane moiety in this position, the cyclobutane series is perfect for the synthesis of (1). In contrast, the isopropenyl series offers a flexible approach to the carbon-skeleton of numerous members of this family. Overall, most promising key intermediate 213 was synthesized in a 21-linear-steps sequence and provided access to a possible total synthesis of Providencin (1). Furthermore, the 14-step-synthesis of key intermediate 369 disclosed the biomimetic synthesis of Providencin (1) en route with numerous other natural products, such as Iopholide (57), Iophodiol A/B and Bipinnatin E (58)

Endobronchial intubation detected by insertion depth of endotracheal tube, bilateral auscultation, or observation of chest movements: randomised trial

Objective To determine which bedside method of detecting inadvertent endobronchial intubation in adults has the highest sensitivity and specificity

A selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo

Targeted protein degradation offers an alternative modality to classical inhibition and holds the promise of addressing previously undruggable targets to provide novel therapeutic options for patients. Heterobifunctional molecules co-recruit a target protein and an E3 ligase, resulting in ubiquitylation and proteosome-dependent degradation of the target. In the clinic, the oral route of administration is the option of choice but has only been achieved so far by CRBN- recruiting bifunctional degrader molecules. We aimed to achieve orally bioavailable molecules that selectively degrade the BAF Chromatin Remodelling complex ATPase SMARCA2 over its closely related paralogue SMARCA4, to allow in vivo evaluation of the synthetic lethality concept of SMARCA2 dependency in SMARCA4-deficient cancers. Here we outline structure- and property-guided approaches that led to orally bioavailable VHL-recruiting degraders. Our tool compound, ACBI2, shows selective degradation of SMARCA2 over SMARCA4 in ex vivo human whole blood assays and in vivo efficacy in SMARCA4-deficient cancer models. This study demonstrates the feasibility for broadening the E3 ligase and physicochemical space that can be utilised for achieving oral efficacy with bifunctional molecules

Superparamagnetic Ironoxide Nanoparticles via Ligand Exchange Reactions: Organic 1,2-Diols as Versatile Building Blocks for Surface Engineering

A method for the preparation of ligand-covered superparamagnetic iron oxide nanoparticles via exchange reactions is described. 1,2-diol-ligands are used to provide a stable binding of the terminally modified organic ligands onto the surface of γ-Fe2O3-nanoparticles (r∼4 nm). The 1,2-diol-ligands are equipped with variable terminal functional groups (i.e., hydrogen bonding moieties, azido- bromo-, fluorescent moieties) and can be easily prepared via osmium tetroxide-catalyzed 1,2-dihydroxylation reactions of the corresponding terminal alkenes. Starting from octylamine-covered γ-Fe2O3-nanoparticles, ligand exchange was effected at 50∘C over 24–48 hours, whereupon complete ligand exchange is taking place as proven by thermogravimetric (TGA)- and IR-spectroscopic measurements. A detailed kinetic analysis of the ligand exchange reaction was performed via TGA analysis, demonstrating a complete ligand exchange after 24 hours. The method offers a simple approach for the generation of various γ-Fe2O3-nanoparticles with functional organic shells in a one-step procedure

Application of the Rodriguez–Pattenden Photo-Ring Contraction: Total Synthesis and Configurational Reassignment of 11-Gorgiacerol and 11-Epigorgiacerol

A stereospecific photochemical ring contraction was used as the key step in the first total synthesis of the marine pseudopteranyl diterpene 11-gorgiacerol and its 11-epimer. The synthesis allowed the correction of the configurations that had been misassigned in the literature. In addition, some novel pseudopteranyl derivatives have been made

Application of the Rodriguez–Pattenden Photo-Ring Contraction: Total Synthesis and Configurational Reassignment of 11-Gorgiacerol and 11-Epigorgiacerol

A stereospecific photochemical ring contraction was used as the key step in the first total synthesis of the marine pseudopteranyl diterpene 11-gorgiacerol and its 11-epimer. The synthesis allowed the correction of the configurations that had been misassigned in the literature. In addition, some novel pseudopteranyl derivatives have been made

Application of the Rodriguez–Pattenden Photo-Ring Contraction: Total Synthesis and Configurational Reassignment of 11-Gorgiacerol and 11-Epigorgiacerol

A stereospecific photochemical ring contraction was used as the key step in the first total synthesis of the marine pseudopteranyl diterpene 11-gorgiacerol and its 11-epimer. The synthesis allowed the correction of the configurations that had been misassigned in the literature. In addition, some novel pseudopteranyl derivatives have been made

Circulating procoagulant microparticles in cancer patients

International audienceAccumulating evidence indicates that microparticles (MPs) are important mediators of the interaction between cancer and the hemostatic system. We conducted a large prospective cohort study to determine whether the number of circulating procoagulant MPs is elevated in cancer patients and whether the elevated MP levels are predictive of occurrence of venous thrombembolism (VTE). We analyzed plasma samples of 728 cancer patients from the ongoing prospective observational Vienna Cancer and Thrombosis Study. Study endpoint was the occurrence of symptomatic VTE. Sixty-five age- and sex-matched healthy controls were recruited for defining the cut-off point for elevated MPs (4.62 nanomolar phosphatidylserine [nM PS]), which was set at the 95th percentile of MP levels in healthy controls. The measurement of MPs was performed after capture onto immobilized annexin V, and determination of their procoagulant activity was quantified with a prothrombinase assay. During a median observation period of 710 days, 53 patients developed VTE. MP levels (nM PS) were significantly higher in cancer patients than in healthy controls (median [25th-75th percentile], 3.95 [1.74-7.96] vs. 1.19 [0.81-1.67], < 0.001). Multivariate analysis including age, sex, surgery, chemo- and radiotherapy showed no statistically significant association of the hazard ratio of elevated MPs with VTE (0.95 [95% CI, 0.55-1.64], = 0.856). In conclusion, MP levels were elevated in cancer patients compared to healthy individuals in this study. However, elevated MP levels were not predictive of VTE