Convergent and asymmetric total synthesis of (-)-Tetrangomycin and (-)-8-O-Methyltetrangomycin via intramolecular cobalt-mediated [2+2+2]-cycloaddition

In der Dissertation "Konvergente und asymmetrische Totalsynthese von (-)-Tetrangomycin und (-)-8-O-Methyltetrangomycin via intramolekularer kobalt-vermittelter [2+2+2]-Cycloaddition" werden zwei konvergente und asymmetrische Naturstoffsynthesen von (-)-8-O-Methyltetrangomycin und (-)-Tetrangomycin beschrieben. Neben den beiden erfolgreichen Naturstoffsynthesen wird eine Studie zur einer dritten Totalsynthese von Urdamycinon B dargestellt, zu deren Zweck zwei verschiedene Deoxy-Zucker synthetisiert und deren Synthesen gegenüber den literaturbekannten optimiert wurden. Des weiteren wurden Untersuchungen zur Baeyer-Villiger-Oxidation von aromatischen Aldehyden, einer Anwendungsmöglichkeit der Siletan-Schutzgruppe und der kobalt-vermittelten intramolekularen [2+2+2]-Cycloaddition von Diinnitrilen im Hinblick auf die Totalsynthese von Phenanthroviridon beschrieben

Total synthesis of (-)-8-O-methyltetrangomycin (MM 47755)

A stereoselective total synthesis of the natural antibiotic (-)-8-O-methyltetrangomycin 1 is reported. The essential steps for this convergent synthesis are the transformation of a geraniol epoxide into a chiral octadiyne derivative, which was converted into a triyne. The cobalt-mediated [2+2+2] cycloaddition of the triyne led to a benz[a]anthracene system, which was oxidized with Ag(Py)2MnO4 to a benz[a]anthraquinone. Deprotection with aqueous HF in acetonitrile and photooxidation afforded the desired product (-)-1

Total Synthesis of (-)-Chokol A by an Asymmetric Domino Michael Addition-Dieckmann Cyclization

A convergent and asymmetric total synthesis of (-)-chokol A was accomplished in six steps starting from the α,β-unsaturated ester (E)-9 in an overall yield of 27% with an enantiomeric excess of 95%. The key step of this synthesis is the asymmetric tandem conjugate addition-Dieckmann cyclization of the higher-order cuprate 8 derived from vinyl bromide 7 with the α,β-unsaturated ester (E)-9

Diastereoselective addition of organocerium(III) reagents derived from 3-substituted propargyl bromides to aldehydes

Various cerium allenyl reagents were generated by transmetallation of allenyl Grignard compounds with CeCl3 and sub­sequent conversion into homopropargylic alcohols by addition to various aliphatic and aromatic aldehydes. The α-acetylenic alcohols were obtained with regioselectivities and diastereoselectivities up to 98% de in favor of the threo-diastereomers

Cobalt-mediated regioselective synthesis of substituted tetrahydroquinolines

A regioselective synthesis of polycyclic substituted ­pyridines is reported. Key step is the cobalt-catalyzed intramole­cular cyclization of diynenitriles, tethered by a silicon oxygen bond. Subsequent opening of the Si-O ring led then to the related tetra­hydroquinolines

Cu-64 antibody-targeting of the T-cell receptor and subsequent internalization enables in vivo tracking of lymphocytes by PET

T cells are key players in inflammation, autoimmune diseases, and immunotherapy. Thus, holistic and noninvasive in vivo characterizations of the temporal distribution and homing dynamics of lymphocytes in mammals are of special interest. Herein, we show that PET-based T-cell labeling facilitates quantitative, highly sensitive, and holistic monitoring of T-cell homing patterns in vivo. We developed a new T-cell receptor (TCR)-specific labeling approach for the intracellular labeling of mouse T cells. We found that continuous TCR plasma membrane turnover and the endocytosis of the specific (64)Cu-monoclonal antibody (mAb)–TCR complex enables a stable labeling of T cells. The TCR–mAb complex was internalized within 24 h, whereas antigen recognition was not impaired. Harmful effects of the label on the viability, DNA-damage and apoptosis-necrosis induction, could be minimized while yielding a high contrast in in vivo PET images. We were able to follow and quantify the specific homing of systemically applied (64)Cu-labeled chicken ovalbumin (cOVA)-TCR transgenic T cells into the pulmonary and perithymic lymph nodes (LNs) of mice with cOVA-induced airway delayed-type hypersensitivity reaction (DTHR) but not into pulmonary and perithymic LNs of naïve control mice or mice diseased from turkey or pheasant OVA-induced DTHR. Our protocol provides consequent advancements in the detection of small accumulations of immune cells in single LNs and specific homing to the sites of inflammation by PET using the internalization of TCR-specific mAbs as a specific label of T cells. Thus, our labeling approach is applicable to other cells with constant membrane receptor turnover

Skeletal Muscle Disorders: A Noncardiac Source of Cardiac Troponin T

BACKGROUND: Cardiac troponin (cTn) T and cTnI are considered cardiac specific and equivalent in the diagnosis of acute myocardial infarction. Previous studies suggested rare skeletal myopathies as a noncardiac source of cTnT. We aimed to confirm the reliability/cardiac specificity of cTnT in patients with various skeletal muscle disorders (SMDs). METHODS: We prospectively enrolled patients presenting with muscular complaints (≥2 weeks) for elective evaluation in 4 hospitals in 2 countries. After a cardiac workup, patients were adjudicated into 3 predefined cardiac disease categories. Concentrations of cTnT/I and resulting cTnT/I mismatches were assessed with high-sensitivity (hs-) cTnT (hs-cTnT-Elecsys) and 3 hs-cTnI assays (hs-cTnI-Architect, hs-cTnI-Access, hs-cTnI-Vista) and compared with those of control subjects without SMD presenting with adjudicated noncardiac chest pain to the emergency department (n=3508; mean age, 55 years; 37% female). In patients with available skeletal muscle biopsies, TNNT/I1-3 mRNA differential gene expression was compared with biopsies obtained in control subjects without SMD. RESULTS: Among 211 patients (mean age, 57 years; 42% female), 108 (51%) were adjudicated to having no cardiac disease, 44 (21%) to having mild disease, and 59 (28%) to having severe cardiac disease. hs-cTnT/I concentrations significantly increased from patients with no to those with mild and severe cardiac disease for all assays (all P<0.001). hs-cTnT-Elecsys concentrations were significantly higher in patients with SMD versus control subjects (median, 16 ng/L [interquartile range (IQR), 7-32.5 ng/L] versus 5 ng/L [IQR, 3-9 ng/L]; P<0.001), whereas hs-cTnI concentrations were mostly similar (hs-cTnI-Architect, 2.5 ng/L [IQR, 1.2-6.2 ng/L] versus 2.9 ng/L [IQR, 1.8-5.0 ng/L]; hs-cTnI-Access, 3.3 ng/L [IQR, 2.4-6.1 ng/L] versus 2.7 ng/L [IQR, 1.6-5.0 ng/L]; and hs-cTnI-Vista, 7.4 ng/L [IQR, 5.2-13.4 ng/L] versus 7.5 ng/L [IQR, 6-10 ng/L]). hs-cTnT-Elecsys concentrations were above the upper limit of normal in 55% of patients with SMD versus 13% of control subjects (P<0.01). mRNA analyses in skeletal muscle biopsies (n=33), mostly (n=24) from individuals with noninflammatory myopathy and myositis, showed 8-fold upregulation of TNNT2, encoding cTnT (but none for TNNI3, encoding cTnI) versus control subjects (n=16, P$_{Wald}$<0.001); the expression correlated with pathological disease activity (R=0.59, P$_{t-statistic}$<0.001) and circulating hs-cTnT concentrations (R=0.26, P$_{t-statistic}$=0.031). CONCLUSIONS: In patients with active chronic SMD, elevations in cTnT concentrations are common and not attributable to cardiac disease in the majority. This was not observed for cTnI and may be explained in part by re-expression of cTnT in skeletal muscle. CLINICALTRIALS: gov; Unique identifier: NCT03660969