The synthesis of diarylpalladium(II) complexes by twofold aryl C−H bond activation was developed. These intermediates of oxidative cyclization reactions are stabilized by chelation with acetyl groups while still maintaining sufficient reactivity to study their reductive elimination. Four distinct triggers were found for the reductive elimination of these complexes to dibenzofurans and carbazoles. Thermal elimination occurs at very high temperatures, whereas ligand-promoted and oxidatively induced reductive eliminations proceed readily at room temperature. Under these conditions, no isomerization occurs. In contrast, weak Brønsted acids, such as acetic acid, lead to a sequence of proto-demetalation, isomerization to a κ³-diarylpalladium(II) complex, and reductive elimination to non-symmetrical cyclization products.

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.

The pentahalogenated 2-arylpyrrole-type alkaloids pentabromopseudilin and pentachloropseudilin represent a new class of isoform-specific allosteric inhibitors of myosin ATPase. Herein, we describe an application of the silver(I)-catalyzed cycloisomerization of N-(homopropargyl)toluenesulfonamides to the total syntheses of these natural products and several non-natural analogues. Moreover, we examine the inhibitiory effect of pentahalogenated pseudilins on myosin ATPase activity.

A Buchwald–Hartwig amination and palladium(II)-catalyzed oxidative cyclization reaction sequence provided efficient access to a series of oxygenated tricyclic carbazoles. In the present work, this approach was applied to the total syntheses of the naturally occurring carbazole alkaloids 2-hydroxy-7-methylcarbazole, glycozolicine, mukoline, mukolidine, sansoakamine, glycozolidine, clausine-H (clauszoline-C), clausine-K (clauszoline-J), and methyl 2-hydroxy-7-methoxycarbazole-3-carboxylate, which was originally proposed as the structure of clausine-TY. The synthesis of the latter led to the structural reassignment of clausine-TY.

We describe the synthesis of the naturally occurring 2,7-dioxygenated formylcarbazole alkaloids 7-methoxymukonal, 7-methoxy-O-methylmukonal, and the murrayalines A–C. The carbazole framework was constructed by a Buchwald–Hartwig amination and a subsequent palladium(II)-catalyzed oxidative cyclization.

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.

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.

We describe the efficient iron-mediated total synthesis of clausine O, clausine H (clauszoline-C) and anti-HIV active 7-methoxy-O-methylmukonal and clausine K (clauszoline-J). Consecutive C–C and C–N bond formations between 3-methoxy-4-methylaniline and a cyclohexadienyliumiron complex salt afforded 2,7-dimethoxy-3-methylcarbazole, which served as common intermediate en route to the four 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).

Covalent coupling of β-secretase inhibitors to a raftophilic lipid anchor via a suitable spacer by using solid-phase peptide synthesis leads to tripartite structures displaying substantially improved inhibition of cellular secretion of the β-amyloid peptide (Aβ). Herein, we describe a series of novel tripartite structures, their full characterization by NMR spectroscopy and mass spectrometry, and the analysis of their biological activity in cell-based assays. The tripartite structure concept is applicable to different pharmacophores, and the potency in terms of β-secretase inhibition can be optimized by adjusting the spacer length to achieve an optimal distance of the inhibitor from the lipid bilayer. A tripartite structure containing a transition-state mimic inhibitor was found to be less potent on Aβ generation from Swedish-mutant amyloid precursor protein (APP) than from the wild-type protein. Moreover, our observations suggest that specific variants of Aβ are generated from wild-type APP but not from Swedish-mutant APP and are resistant to β-secretase inhibition. Efficient inhibition of Aβ secretion by tripartite structures in the absence of appreciable neurotoxicity was confirmed in a primary neuronal cell culture, thus further supporting the concept.

The cover picture shows the bioactivity for rescue of diapause in daf-9(dh6) mutant worms using (25S)-Δ⁷-dafachronic acid (structure, bottom left). The fluorescence label (represented by purple spots) marks the daf-9(dh6); dhEx24 mutant worms that develop into adults without the requirement of exogenous hormonally active steroidal acid. The daf-9(dh6) mutant worms (no fluorescence, at the bottom) can develop into adults by using (25S)-Δ⁷-dafachronic acid at concentrations down to 10 nM (top right). Details are discussed in the article by H.-J. Knölker et al. on p. 3703 ff.

Using a highly stereoselective Evans aldol reaction for the introduction of the stereogenic center at C-25, we describe an efficient synthesis of the orthogonally diprotected (25S)-26-hydroxycholesterol 11. In a few synthetic steps, this crucial intermediate 11 has been converted into the four (25S)-cholesten-26-oic acids 1–4, which have been obtained in 12–15 steps and 19–53 % overall yield based on commercially available 3β-hydroxychol-5-en-24-oic acid (5). Our biological studies of the compounds 1–4 reveal that (25S)-Δ⁷-dafachronic acid (1) represents the most active steroidal ligand for the hormonal receptor DAF-12 in Caenorhabditis elegans. Moreover, the saturated (25S)-dafachronic acid (3) represents a new ligand for this receptor and the (25S)-steroidal acids are more active as compared to their corresponding (25R)-counterparts.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)