Arndt W. Schmidt

Efficient Construction of Pyrano[3,2-a]carbazoles: Application to a Biomimetic Total Synthesis of Cyclized Monoterpenoid Pyrano[3,2-a]carbazole Alkaloids†

We have developed a highly efficient route to 2-hydroxy-3-methylcarbazole (1) via a palladium-catalyzed construction of the carbazole skeleton. Using 1 as relay compound, different methods for annulations of pyran rings by reaction with terpenoid building blocks have been tested. The Lewis acid promoted reaction of 1 with prenal (21) opened up an efficient route to girinimbine (3) and the corresponding reaction with citral (25) afforded mahanimbine (5). Oxidation of compounds 3 and 5 provided murrayacine (4) and murrayacinine (6). Following the biogenetic proposal, mahanimbine (5) has been exploited for efficient biomimetic syntheses of the cyclized monoterpenoid pyrano[3,2-a]carbazole alkaloids cyclomahanimbine (7), mahanimbidine (8) and bicyclomahanimbine (9). The interconversions of 5, 7, 8 and 9 are described and mechanistic implications are discussed. Structural assignments are unambiguously verified by X-ray crystal structure determinations. Moreover, cyclomahanimbine (7) was transformed into murrayazolinine (10) and exozoline (11).

Total Synthesis of 7‐ and 8‐Oxygenated Pyrano[3,2‐a]carbazole and Pyrano[2,3‐a]carbazole Alkaloids via Boronic Acid‐Catalyzed Annulation of the Pyran Ring

The boronic acid-catalyzed annulation of citral opens up a short route to oxygenated cyclized monoterpenoid pyranocarbazole alkaloids. Thus, murrayamine-D is available in only three steps and 55% overall yield from the corresponding carbazole precursor.

Synthesis of Prenyl- and Geranyl-Substituted Carbazole Alkaloids by DIBAL-H Promoted Reductive Pyran Ring Opening of Dialkylpyrano[3,2-a]carbazoles†

The DIBAL-H promoted reductive pyran ring opening of dialkylpyrano[3,2-a]carbazoles provides a direct access to a broad range of prenyl- and geranyl-substituted carbazoles. Formation of a pyran ring followed by reductive ring opening represents a new method for the introduction of prenyl and geranyl groups. In the course of the present work, we achieved the first total syntheses of the following eight carbazole alkaloids: clauraila-E, 7-hydroxyheptaphylline, 7-methoxyheptaphylline, mukoenine-B (clausenatine-A), mukoenine-A (girinimbilol), mahanimbinol (mahanimbilol), euchrestine-A, and isomurrayafoline-B.

Total syntheses of murrayamine E, I, and K.

We describe efficient synthetic routes to murrayamine A (mukoenine C), O-methylmurrayamine A, mahanine, O-methylmahanine, and murrayamine D and the first total syntheses of murrayamine E, I, and K. Key steps are a palladium-catalyzed construction of the carbazole framework and an annulation of the pyran ring, which is either catalyzed by phenylboronic acid or promoted by a Lewis acid.

Determination of 4-nonylphenol in water samples using 4-(2,6-dimethylhept-3-yl)phenol as new internal standard

A new method for determining the endocrine disrupting substance 4-nonylphenol (technical grade=mixture of isomers, 4-NP) from water samples has been developed by using 4-(2,6-dimethylhept-3-yl)phenol (4-sec-NP) as model compound. This branched monoalkylphenol is shown to serve as internal standard (IS) for the determination of technical 4-nonylphenol. To the best of our knowledge, 4-(2,6-dimethylhept-3-yl)phenol (racemic mixture) is a newly synthesized 4-nonylphenol isomer and has not been described elsewhere. Recoveries have been determined by analyzing spiked water samples from distilled water, river water and wastewater. Following acetylation, the compounds were enriched via solid phase extraction (SPE). Analyses of the compounds were performed by capillary column gas chromatography/mass spectrometry (GC/MS), operating in selected ion-monitoring (SIM) mode. The recovery of technical 4-NP using either the newly prepared 4-sec-NP or 4-n-nonylphenol (4-n-NP) as IS have been compared. 4-sec-NP showed slightly better results. However, in the first series of experiments using wastewater, the yields for the derivatization of the two standard compounds were remarkably different. The yield for derivatization of 4-n-NP was approximately 20%, probably due to the difficult matrix of the wastewater. In contrast, the yield for the derivatization of 4-sec-NP was considerably higher (approximately 63%). This problem can be solved by increasing the concentration of the reagent used for derivatization. For better control of the clean-up process, we recommend application of 4-sec-NP as internal standard, at least in water samples with complex matrices (e.g., high content of hydroxylated compounds).

Synthesis of Glycoborine, Glybomine A and B, the Phytoalexin Carbalexin A and the β‐Adrenoreceptor Antagonists Carazolol and Carvedilol

We describe a regioselective synthesis of 4- or 5-substituted carbazoles by oxidative cyclisation of meta-oxygen-substituted N-phenylanilines. Using the regiodirecting effect of a pivaloyloxy group, we prepared 4-hydroxycarbazole, a precursor for the enantiospecific synthesis of the β-adrenoreceptor antagonists (-)-(S)-carazolol (5) and (-)-(S)-carvedilol (6). Regioselective palladium(II)-catalysed cyclisation of different diarylamines led to total synthesis of glycoborine (7) and the first total syntheses of the phytoalexin carbalexin A (8), glybomine A (9) and glybomine B (10). For glybomine B (10), a 5-hydroxycarbazole was converted into the corresponding triflate and utilized for introduction of a prenyl substituent.

Membrane domain-disrupting effects of 4-substitued cholesterol derivatives.

A wide range of cellular functions are thought to be regulated not only by the activity of membrane proteins, but also by the local membrane organization, including domains of specific lipid composition. Thus, molecules and drugs targeting and disrupting this lipid pattern, particularly of the plasma membrane, will not only help to investigate the role of membrane domains in cell biology, but might also be interesting candidates for therapy. We have identified three 4-substituted cholesterol derivatives that are able to induce a domain-disrupting effect in model membranes. When applied to giant unilamellar vesicles displaying liquid-ordered-liquid-disordered phase coexistence, extensive reorganization of the membrane can be observed, such as the budding of membrane tubules or changes in the geometry of the domains, to the point of complete abolition of phase separation. In this case, the resulting membranes display a fluidity intermediate between those of liquid-disordered and liquid-ordered phases.

Synthesis of Methylene-Bridged Biscarbazole Alkaloids by using an Ullmann-type Coupling: First Total Synthesis of Murrastifoline-C and Murrafoline-E.

We describe the total synthesis of methylene-bridged biscarbazole alkaloids by using a late-stage Ullmann-type coupling of fully functionalised carbazole subunits. The carbazole derivatives were synthesised via a sequence of palladium(0)- and palladium(II)-catalysed coupling reactions. Our approach has provided bismurrayafoline-A, bismurrayafolinol, chrestifolines B-D, and the first total synthesis of murrastifoline-C and murrafoline-E.

Inhibitory effect of oxygenated cholestan-3β-ol derivatives on the growth of Mycobacterium tuberculosis

A variety of cholestan-3β-ol derivatives, which are oxygenated at different positions of the steroid ring system, were prepared and tested for their inhibition of the Mycobacterium tuberculosis H37Rv strain. Several compounds showed significant antitubercular activities with MIC90 values in the range 4-8 μM and low or non-detectable toxicity against mammalian cells.

Chemical constituents isolated from Zygophyllum melongena Bunge growing in Mongolia

Abstract We report the first investigation of the chemical constituents of Zygophyllum melongena Bunge, a species growing in Mongolia. The quinovic acid glycosides 3-O-(β-D-glucopyranosyl)quinovic acid and 3-O-(β-D-glucopyranosyl)quinovic acid (28→1)-(β-D-glucopyranosyl) ester were identified in the chloroform fraction along with the flavonoid glycoside astragalin. The n-butanol fraction contained (+)-D-pinitol as the major component, a cyclitol with anti-diabetic properties. The structures of the isolated natural products were confirmed using ESI-MS and NMR spectroscopy (1H, 13C, COSY, HSQC, HMBC, NOESY and ROESY). This is the first report of the isolation of (+)-D-pinitol from the genus Zygophyllum.