Bioinspired total syntheses of terpenoids

Nature's highly efficient routes for constructing natural products have inspired chemists to mimic these processes in a laboratory setting. This Perspective presents some recent examples of conceptually different bioinspired total syntheses of complex terpenoids and thereby aims to highlight the vast benefits offered by bioinspired strategies

Synthesis of Xenia diterpenoids and related metabolites isolated from marine organisms

This review describes strategies for the chemical synthesis of xenicane diterpenoids and structurally related metabolites. Selected members from the four different subclasses of the Xenia diterpenoid family, the xenicins, xeniolides, xeniaphyllanes and xeniaethers, are presented. The synthetic strategies are discussed with an emphasis on the individual key reactions for the construction of the uncommon nine-membered carbocycle which is the characteristic structural feature of these natural products. Additionally, the putative biosynthetic pathway of xenicanes is illustrated

Synthesis of Xenia diterpenoids and related metabolites isolated from marine organisms

This review describes strategies for the chemical synthesis of xenicane diterpenoids and structurally related metabolites. Selected members from the four different subclasses of the Xenia diterpenoid family, the xenicins, xeniolides, xeniaphyllanes and xeniaethers, are presented. The synthetic strategies are discussed with an emphasis on the individual key reactions for the construction of the uncommon nine-membered carbocycle which is the characteristic structural feature of these natural products. Additionally, the putative biosynthetic pathway of xenicanes is illustrated

Total syntheses of (-)–kendomycin and (+)–echinopine A and B

Die vorliegende Dissertation beschreibt die Totalsynthesen von (+)–Echinopine A und B, sowie zwei Totalsynthesen des Antibiotikums (-)–Kendomycin. Kendomycin, ein neuratiges ansa–Polyketid, wurde 1996 erstmals isoliert (Reisolierung 1999 aus Streptomyces violaceoruber) und hat seitdem (Bio)Chemiker aufgrund der vielversprechenden biologischen Aktivtät (Endothelin–Rezeptor–Antagonist, antiosteoporotische/antibakterielle Aktivität, zytotoxische Aktivität vergleichbar mit Cisplatin) und der komplexen molekularen Struktur (vollständig kohlenstoffhältige ansa–Kette, neun Stereozentren, fünffach substituierter Tetrahydropyran Ring, einzigartiger p–chinoider Chromophor) fasziniert. Die Totalsynthesen stützten sich auf zwei konvergente Strategien, wobei beide auf einer ungewöhnlich komplexen, diastereoselektiven Claisen–Ireland Umlagerung für den Aufbau der nordöstlichen Domäne basierten. Die Bildung des vollständig substituierten Kohlenstoffskelettes wurde einerseits durch eine äußerst effiziente Photo–Fries Reaktion beziehungsweise durch ringschließende Metathese (RCM) erreicht. Abgesehen von der effizienten RCM Reaktion, wurde die bis jetzt unterschätzte Photo–Fries Reaktion für den Aufbau von Makrozyklen erweitert. Der Aufbau der Chinon–Laktol Einheit konnte mit Hilfe einer chemoselektiven Oxidations–Hydrolyse Sequenz, ohne Hinzunahme von Schutzgruppen, bewältigt werden. Echinopine A und B, neuartige tetrazyklische Sesquiterpene, wurden 2007 aus Echinops spinosus isoliert und lenkten aufgrund ihres einzigartigen 3,5,5,7– Ringgerüstes die Aufmerksamkeit auf sich. Aufgrund der geringen Verfügbarkeit der Naturstoffe und der Probenquelle konnten weder angemessene biologische Tests, noch eine Bestimmung der Absolutkonfiguration durchgeführt werden. Diese Einschränkungen und die komplexe molekulare Architektur machen die Titelverbindungen zu idealen Zielstrukturen für die Totalsynthese. Die Totalsynthesen bestechen durch (1) die Verwendung von 1,5–Cyclooktadien als billiges, leicht zugängliches Startmaterial, (2) die Erweiterung von Myers‘ [3,3]–sigmatropen Umlagerungsprotokolls für die stereoselektive Anlegung von Vinyl– und Isopropenyleinheiten, (3) eine RCM um den gespannten sieben–gliedrigen Ring aufzubauen und (4) die Erweiterung einer ungewöhnlichen Pd(0)–C2–Verlängerung von Phenyltriflaten auf Vinyltriflate. Zusätzlich konnten die ursprünglich vorgeschlagenen Strukturen validiert und die absolute Stereochemie bestimmt werden.This Ph.D. thesis describes the first total syntheses of (+)–echinopine A and B and two total syntheses of the antibiotic (-)–kendomycin. Kendomycin, an unprecedented ansa–polyketide was first isolated in 1996 (in 1999 re–isolation from Streptomyces violaceoruber) and has been fascinating (bio)chemists due to its promising biological activity (endothelin receptor antagonist, antiosteoporotic and antibacterial activity, cytotoxic activity comparable to cisplatin) and remarkable complex molecular framework (fully carbogenic ansa–chain, nine stereocenters, pentasubstituted tetrahydropyran ring, unique p–quinone methide chromophore). The total syntheses focused on two convergent strategies, whereas both took advantage of diastereoselective Claisen–Ireland rearrangements of unusual complexity to construct the north–east domain. Formation of the fully substituted carbon skeleton was either accomplished via a highly efficient photo–Fries rearrangement or ring closing metathesis (RCM) reaction. Apart from the application of the powerful RCM reaction, the so far underestimated photo–Fries rearrangement was extended to the construction of macrocycles. The final steps to install the quinone–methide–lactol unit could be performed by a chemoselective oxidation–hydrolysis sequence, thus avoiding additional protective groups manipulations. Echinopine A and B, novel tetracyclic sesquiterpenoids from Echinops spinosus were isolated in 2007 and have attracted great interest because of their unique 3,5,5,7–membered ring skeleton. Limitation of material and scarcity of sample source prevented proper biological testing and determination of the absolute stereochemistry. These limitations, the complex and novel molecular architecture render the title compounds ideal targets for total synthesis. The concise total syntheses are characterized by (1) 1,5–cyclooctadiene as an inexpensive, easily available starting material, (2) the extension of Myers’ [3,3]–sigmatropic protocol to the stereoselective installation of vinyl and isopropenyl units, (3) RCM as an efficient tool to close the strained seven–membered ring and (4) the extension of an unusual Pd(0)–C2–homologation of phenyltriflates to vinyltriflates. In addition, the proposed structures were validated and the absolute stereochemistry could be determined

Component-Based Syntheses of Trioxacarcin A, DC-45-A1, and Structural Analogs

The trioxacarcins are polyoxygenated, structurally complex natural products that potently inhibit the growth of cultured human cancer cells. Here we describe syntheses of trioxacarcin A, DC-45-A1, and structural analogs by latestage, stereoselective glycosylation reactions of fully functionalized, differentially protected aglycon substrates. Key issues addressed in this work include the identification of an appropriate means to activate and protect each of the two 2-deoxysugar components, trioxacarcinose A and trioxacarcinose B, as well as a viable sequencing of the glycosidic couplings. The convergent, component-based sequence we present allows for rapid construction of structurally diverse, synthetic analogs that would be inaccessible by any other means, in amounts required to support biological evaluation. Analogs arising from modification of four of five modular components are assembled in 11 steps or fewer. The majority of these are found to be active in antiproliferative assays using cultured human cancer cells

The chemistry of isoindole natural products

This review highlights the chemical and biological aspects of natural products containing an oxidized or reduced isoindole skeleton. This motif is found in its intact or modified form in indolocarbazoles, macrocyclic polyketides (cytochalasan alkaloids), the aporhoeadane alkaloids, meroterpenoids from Stachybotrys species and anthraquinone-type alkaloids. Concerning their biological activity, molecular structure and synthesis, we have limited this review to the most inspiring examples. Within different congeners, we have selected a few members and discussed the synthetic routes in more detail. The putative biosynthetic pathways of the presented isoindole alkaloids are described as well

De Novo Synthesis of Benzannelated Heterocycles

Benzannelated heterocycles such as indoles and indazoles are prominent structural motifs found in natural products, pharmaceuticals and agrochemicals. For their synthesis, chemists traditionally either functionalize commercially available heterocycles or resort to transformations that make use of benzenederived building blocks. Here, we report a powerful cascade reaction that enables the de novo construction of variously substituted indoles, indazoles, benzofurans and benzothiophenes from readily available bicyclo[3.1.0]hexan2ones. The transformation can be conducted under mild, nonanhydrous conditions. For the synthesis of indoles, mechanistic studies revealed that the electrocyclic ringopening of the bicyclic ringsystem and aromatization precedes the 3,3sigmatropic rearrangement.(VLID)4045878Accepted versio

A General Entry to Ganoderma Meroterpenoids: Synthesis of Lingzhiol via Photoredox Catalysis

Ganoderma meroterpenoids are a fungal-derived hybrid natural product class containing a 1,2,4-trisubstituted benzene ring and a polycyclic terpenoid part. The representatives applanatumol E, H and I, lingzhilactone B and meroapplanin B share the same bicyclic lactone moiety connected to the arene via a flexible C2-linker. This flexibility is lost for lingzhiol as the b-position of the lactone is fused to the arene to form a tetralone subunit. Employing a diastereoselective iodocarbocyclization and a photo-Fries rearrangement as the key-steps enabled a general entry to these natural products. For the synthesis of the tetracyclic framework of lingzhiol, we made use of a powerful photoredox oxidative decarboxylation/Friedel–Crafts sequence

Total Synthesis of the Leucosceptroid Family of Natural Products

A highly efficient strategy enabled the asymmetric total synthesis of 15 antifeedant leucosceptroid natural products. The advanced tricyclic core, available in gram quantity, served as the pivotal intermediate for the preparation of norleucosceptroids B, C, F, and G and leucosceptroids A, B, G, I, J, L, and M. Additionally, the bioinspired oxidative transformation of leucosceptroid A to leucosceptroids C, K, O, and P using singlet oxygen supports the hypothesis that leucosceptroids A and B are most likely the biogenetic precursors of all other members of this natural product family