Photochemical 1,3-Acyl Shifts in Natural Product Synthesis

Photochemical, sigmatropic 1,3-acyl shifts represent a powerful tool to construct quaternary carbon atoms and the backbones of complex natural products which cannot be constructed easily by conventional methods. This review highlights applications of 1,3-acyl shifts to elegant, partly biomimetic total syntheses of natural products by discussing the underlying photochemical equilibrium

Moonlighting chaperone activity of the enzyme PqsE contributes to RhlR-controlled virulence of Pseudomonas aeruginosa

Pseudomonas aeruginosa is a major cause of nosocomial infections and also leads to severe exacerbations in cystic fibrosis or chronic obstructive pulmonary disease. Three intertwined quorum sensing systems control virulence of P. aeruginosa, with the rhl circuit playing the leading role in late and chronic infections. The majority of traits controlled by rhl transcription factor RhlR depend on PqsE, a dispensable thioesterase in Pseudomonas Quinolone Signal (PQS) biosynthesis that interferes with RhlR through an enigmatic mechanism likely involving direct interaction of both proteins. Here we show that PqsE and RhlR form a 2:2 protein complex that, together with RhlR agonist N-butanoyl-L-homoserine lactone (C4-HSL), solubilizes RhlR and thereby renders the otherwise insoluble transcription factor active. We determine crystal structures of the complex and identify residues essential for the interaction. To corroborate the chaperone-like activity of PqsE, we design stability-optimized variants of RhlR that bypass the need for C4-HSL and PqsE in activating PqsE/RhlR-controlled processes of P. aeruginosa. Together, our data provide insight into the unique regulatory role of PqsE and lay groundwork for developing new P. aeruginosa-specific pharmaceuticals

Studien zur Totalsynthese der Spirochensilide

Im Rahmen der vorliegenden Dissertation wurde an einem totalsynthetischen Zugang zu den Triterpenoiden Spirochensilid A und B gearbeitet, welche durch Gao et al. 2015 aus dem Nadelbaum Abies chensiensis isoliert und strukturell aufgeklärt wurden. Spirochensilid A zeigt in ersten in vitro Evaluierungen eine 30%ige Inhibierung der NO-Produktion mit 12.5 µg/mL. Die zwei Triterpenoide unterscheiden sich in der absoluten Konfiguration des C-3 Alkohols im A-Ring. In dieser Arbeit wurden vier retrosynthetische Wege zu der Synthese der Spirochensilide A und B untersucht. Dazu wurde jeweils der Fokus auf den gezielten intramolekularen Aufbau der anti,anti-Trimethyleinheit sowie des quartären Spirozentrums an C-8 gelegt. Im ersten retrosynthetischen Ansatz konnte eine Claisen-Umlagerung die Einheit der drei jeweils anti-ständigen Methylgruppen generieren. In den ersten zwei retrosynthetischen Ansätzen wurde eine Polyencyclisierung zur Konstruktion des A,B-Ringsystems sowie des Spirozentrums C-8 untersucht. In einem dritten Ansatz wurde untersucht, ob eine Semipinakol-Umlagerung eines tertiären Allylalkohols zum Aufbau des Spirozentrums C-8 führt. Die Synthese des benötigten trans-A,B-Ringsystems wurde ausgehend von dem (S)-Methyl-Wieland-Miescher-Keton über zehn Stufen durch eine Ringkontraktion via Photo-Wolff-Umlagerung mit folgender Ozonolyse des Ketens aufgebaut. Der C,D-Bicyclus wurde über eine intramolekulare Aldolkondensation geschlossen und konnte über neun Stufen erhalten werden. Der benötigte Allylalkohol wurde im Rahmen dieser Arbeit synthetisch dargestellt und in einem Fall mit geringer Ausbeute zum anvisierten Spiroketon umgelagert. Des Weiteren konnten Experimente eine Semipinakol-Umlagerung an einem Modellsystem zeigen. In einem vierten retrosynthetischen Ansatz wurde der Aufbau des Spirozentrums an C-8 durch eine intramolekulare Aldoladdition untersucht. Weiterhin wurden im Rahmen dieser Arbeit Studien zur Synthese der Sesquiterpen-Coumarine Penisarin A und B, welche von Li et al. im Jahre 2020 aus dem endophytischen Penicillium sp. KMU18029 isoliert wurden, durchgeführt. Penisarin B zeigt in ersten in vitro Evaluierungen zytotoxische Aktivitäten gegen die humanen Krebszellinien HL-60 (IC50 = 3.6 µM) und SMMC-7721 (IC50 = 3.7 µM). Strukturell zeigen die Penisarine A und B wie die Spirochensilide A und B zwei benachbarte quartäre Kohlenstoffzentren. Ausgehend von dem trans-Hydrindan, welches im Rahmen der Arbeiten zur Totalsynthese der Spirochensilide dargestellt wurde, konnte der sesquiterpenoide Teil für die Synthese der Penisarine A und B dargestellt werden. This doctoral thesis describes synthetic work towards the triterpenoids spirochensilide A and B that were isolated in 2015 from abies chensiensis by Gao and coworkers. Spirochensilide A shows weak inhibition (30%) of the NO production (12.5 µg/mL). These two triterpenoids differ in the absolute configuration of the secondary alcohol at C-3 in the A-ring. This work consists of four different retrosynthetic analyses of spirochensilide A and B including synthetic work towards each of it. The aimed intramolecular construction of the all-anti unit of three methyl groups and the quaternary spiro center at C-8 was investigated. The unit of three all-anti methyl groups was constructed by a Claisen rearrangement in the first retrosynthetic approach. A polyene cyclization was investigated for the construction of the A,B rings as well as for the all carbon quaternary spiro center at C-8 in an first and second approach. A third retrosynthetic path aimed at a semipinacol rearrangement of a tertiary allylic alcohol to build up the C-8 all carbon quaternary spiro center. Starting from (S)-methyl-Wieland-Miescher ketone the desired trans-hydrindane was obtained in ten steps. The key step of this sequence was a ring contraction effected by a photo Wolff rearrangement followed by an in situ ozonolysis of the intermediary ketene. The required C,D ring was obtained in a sequence of nine steps with an intramolecular aldol condensation for the closure of the D ring. The tertiary allylic alcohol was synthesized and investigations towards the envisioned semipinacol rearrangement were undertaken. The desired spiroketone could be obtained in a very low yield. Further Experiments could show a similar semipinacol rearrangement at a model system. In a fourth retrosynthetic approach the construction of the all carbon quaternary spiro center at C-8 was investigated by an intramolecular aldol addition. Furthermore, in context of this work synthetic studies towards the sesquiterpene coumarins penisarin A and B were initiated. These two natural products were isolated by Li et al. in 2020 from an endophytic Penicillium sp. KMU18029 and show cytotoxic activity against human cancer cell lines HL-60 (IC50 = 3.6 µM) and SMMC-7721 (IC50 = 3.7 µM) in first in vitro evaluations. Penisarin A and B possess two adjacend all carbon quaternary centers. Starting from the trans-hydrindane, which was synthesized towards the synthesis of the spirochensilides, sesquiterpene unit of penisarin A and B could be obtained

Tris(acetylacetonato) Iron(III): Recent Developments and Synthetic Applications

Tris(acetylacetonato) iron(III) [Fe(acac)3] is an indispensable reagent in synthetic chemistry. Its applications range from hydrogen atom transfer to cross-coupling reactions and to use as a Lewis acid. Consequently, the exceptional utility of Fe(acac)3 has been demonstrated in several total syntheses. This short review summarizes the applications of Fe(acac)3 in methodology and catalysis and highlights its use for the synthesis of medicinally relevant structures and in natural product syntheses

Bioinspired Total Synthesis of (±)-Antroalbocin A enabled by a Photochemical 1,3-Acyl Shift

The first bioinspired and protecting group free total synthesis of the antibacterial sesquiterpenoid antroalbocin A has been achieved in five linear steps from a literature-known intermediate with an overall yield of 6.7%. An intramolecular Robinson annulation gave rapid access to the tricyclic enone as starting material for a photochemical domino process of deconjugation and sigmatropic 1,3 acyl shift. Herein we further describe studies towards the use of photolytic sigmatropic 1,3-acyl shifts in the synthesis of bridged terpenoid building blocks

Contiguous Quaternary Carbons: A Selection of Total Syntheses.

Contiguous quaternary carbons in terpene natural products remain a major challenge in total synthesis. Synthetic strategies to overcome this challenge will be a pivotal prerequisite to the medicinal application of natural products and their analogs or derivatives. In this review, we cover syntheses of natural products that exhibit a dense assembly of quaternary carbons and whose syntheses were uncompleted until recently. While discussing their syntheses, we not only cover the most recent total syntheses but also provide an update on the status quo of modern syntheses of complex natural products. Herein, we review (±)-canataxpropellane, (+)-waihoensene, (-)-illisimonin A and (±)-11-O-debenzoyltashironin as prominent examples of natural products bearing contiguous quaternary carbons