Iron-Catalyzed Photoinduced LMCT: a 1° C-H Abstraction Enables Skeletal Rearrangements and C(sp3)-H Alkylation.

Herein we disclose an iron-catalyzed method to access skeletal rearrangement reactions akin to the Dowd-Beckwith ring expansion from unactivated C(sp3)-H bonds. Photoinduced ligand-to-metal charge transfer at the iron center generates a chlorine radical, which abstracts electron-rich C(sp3)-H bonds. The resulting unstable alkyl radicals can undergo rearrangement in the presence of suitable functionality. Addition to an electron deficient olefin, recombination with a photoreduced iron complex, and subsequent protodemetallation allows for redox-neutral alkylation of the resulting radical. Simple adjustments to the reaction conditions enable the selective synthesis of the directly alkylated or the rearranged-alkylated products. As a radical clock, these rearrangements also enable the measurement of rate constants of addition into various electron deficient olefins in the Giese reaction

Cobalt-catalyzed Wagner–Meerwein rearrangements with concomitant nucleophilic hydrofluorination

The authors acknowledge funding from the Royal Society (University Research Fellowship URF\R1\180017 (CPJ) and associated Enhancement Award RGF\EA\181022 (CPJ and RHH)), and the EaSI-CAT Centre for Doctoral Training (RHH and NM).We report a cobalt-catalyzed Wagner-Meerwein rearrangement of gem-disubstituted allylarenes that generates fluoroalkane products with isolated yields up to 84%. Modification of the counteranion of the N-fluoropyridinium oxidant suggests the substrates undergo nucleophilic fluorination during the reaction. Subjecting the substrates to other known metal-mediated hydrofluorination procedures did not lead to observable 1,2-aryl migration. Thus, indicating the unique ability of these cobalt-catalyzed conditions to generate a sufficiently reactive electrophilic intermediate capable of promoting this Wagner-Meerwein rearrangement.Publisher PDFPeer reviewe

The discovery and application of metal-free cyclobutanol ring expansion reactions

Cyclobutanol ring expansions have emerged as a powerful tool to access functionalised five- and six-membered rings and have thus, in particular over the last decade, attracted considerable interest from the synthetic community. Despite the surge of novel methodologies for the expansion of four-membered rings reported, those enabling the expansion to benzofused cyclohexanones (tetralones) remain notably underdeveloped. Herein, the discovery and development of functional group-tolerant, mild synthetic methodologies for the cyclobutanol ring expansion to tetralones is described. Initially, a regioselective N-bromosuccinimide-mediated cyclobutanol ring expansion to heteroaryl-fused tetralones is reported, which is characterised by its notably short reaction durations. Investigations into optimal reaction conditions, the substrate scope, and the underlying mechanism are detailed here. Our understanding gained through these studies culminated in the application of this methodology to the total synthesis of the 5-lipoxygenase inhibitor carbazomycin B. Then, in collaboration with Alessia Petti and Dr Kevin Lam from the University of Greenwich, a mild electrochemical cyclobutanol ring expansion to 1-tetralones was developed. This enabled the extension of the ring expansion substrate scope, as a variety of electronically and sterically different aryl-substituted cyclobutanols were found to be suitable ring expansion precursors. In addition, studies towards the total synthesis of the perfumery agent myrrhone are described.Open Acces

Asymmetric Migratory Tsuji–Wacker Oxidation Enables the Enantioselective Synthesis of Hetero- and Isosteric Diarylmethanes

Diarylmethanes play, in part, a pivotal role in the design of highly potent, chiral, nonracemic drugs whose bioactivity is typically affected by the substitution pattern of their arene units. In this context, certain arenes such as para-substituted benzenes or unsubstituted heteroarenes cause particular synthetic challenges, since such isosteric residues at the central methane carbon atom are typically indistinguishable for a chiral catalyst. Hence, the stereoselective incorporation of isosteric (hetero)arenes into chiral methane scaffolds requires the use of stoichiometrically differentiated building blocks, which is typically realized through preceding redox-modifying operations such as metalation or halogenation and thus associated with disadvantageous step- and redox-economic traits. As a counter-design, we report herein a generalized enantioselective synthesis of chiral diarylmethanes by means of an asymmetric migratory Tsuji–Wacker oxidation of simple stilbenes. The title protocol relies on the well-adjusted interplay of aerobic photoredox and selenium-π-acid catalysis to allow for the installation of a broad variety of arenes, including isosteric ones, into the methane core. Facial differentiation and regioselectivity are solely controlled by the selenium catalyst, which (a) renders the E/Z-configuration of the stilbene substrates inconsequential and (b) permits the stereodivergent synthesis of both product enantiomers from a single catalyst enantiomer, simply by employing constitutionally isomeric starting materials. Altogether, this multicatalytic platform offers the target structures with high levels of enantioselectivity in up to 97% ee, which has also been successfully exploited in expedited syntheses of antihistaminic (R)- and (S)-neobenodine

Asymmetric Ion-Pairing Catalysis

Chemistry and Chemical Biolog

Sclareolide as a building block for natural product syntheses and Mechanistic studies on the α-chlorination of aldehydes

In the following thesis, the syntheses of two natural products and of a natural products’ skeleton starting from (+)-sclareolide are presented. The second part of this thesis deals with the mechanistic studies on the organocatalytic α-chlorination of aldehydes. The first synthesis of (+)-vitepyrroloid A and B, which are labdane-type diterpene alkaloids isolated from the dried leaves of the shrub Vitex trifolia L. in 2017, is outlined. The natural products share an unprecedented 2-cyanopyrrole labdane core but differ in the substitution pattern of the pyrrole ring. Furthermore, (+)-vitepyrroloid A displayed an interesting biological activity. The low isolation yield prompted the development of an efficient synthesis. Therefore, the natural product was divided into two fragments. (+)-Sclareolide formed the base for the four-step synthesis of the alkyl iodide, which featured simultaneous methanolysis and tertiary alcohol elimination. The aryl bromide was synthesized starting from 3-bomopyrrole-2-carboxylic acid in three steps. The key step was the Csp2–Csp3 cross-electrophile coupling of both fragments in a concise and protecting-group-free manner. This cross-coupling illustrates a rare application of this method in natural product synthesis. In the end, (+)-vitepyrroloid B was accessible by late-stage N-alkylation of its congener. The second project comprises the formal synthesis of actinoranone, a meroterpenoid isolated from the marine actinomycete strain CNQ-027 in 2013. This natural product constitutes of a tetralone-type polyketide connected with a bicyclic diterpenoid fragment and displayed a cytotoxicity against HCT-116 human colon carcinoma. This work addressed a new and more efficient formal synthesis in comparison to the two recently published synthesis routes. 3,5-Dimethoxybenzaldehyde and (+)-sclareolide served as starting points for the two fragments envisioned by the disconnection between C14 and C15 of actinoranone. The first fragment, a vinyl iodide, was obtained in a concise five-step route featuring NEGISHI’s zirconium-catalyzed carboalumination/iodination sequence as the main step. The key step of the tetralone fragment synthesis featured a LEWIS acid-mediated rigorous chirality transfer of the previously synthesized epoxy silyl ether to the β-siloxy aldehyde via a rearrangement inspired by YAMAMOTO. Subsequent WITTIG olefination led to the conjugated ester. The last steps to the actinoranone skeleton were similar to the already published routes. In the second part of this thesis, the mechanistic investigation of the organocatalytic α-chlorination of aldehydes is discussed. Preliminary studies revealed a high catalyst loading in a procedure using N-chlorosuccinimide and MACMILLAN’s imidazolidinone catalyst. In this study, the α-chlorination of hydrocinnamaldehyde served as a model reaction. An unusual aminal intermediate, consisting of the substrate, the catalyst, and the chlorinating agent, was isolated and fully characterized. This work aimed at a deeper understanding of the aminal formation and its decay with the aid of 1H MR measurements. The results enabled the optimization of the α-chlorination by suppressing the aminal accumulation and enhancing the turnover by applying an improved reaction system (yields up to 87%, >99% ee).In der vorliegenden Arbeit sind die Synthesen von zwei Naturstoffen und von einem Naturstoffgerüst ausgehend von Sclareolid beschrieben. Der zweite Teil der Arbeit beinhaltet die mechanistische Untersuchung der organokatalysierten α-Chlorierung von Aldehyden. Die erste Synthese von (+)-Vitepyrroloid A und B, zwei 2017 aus den getrockneten Blättern des Vitex trifolia L. Busches isolierte Labdan-artigen Diterpenalkaloide, ist beschrieben. Sie besitzen einen beispiellosen 2-Cyanopyrrollabdankern, unterscheiden sich jedoch im Substitutionsmuster des Pyrrolringes. Darüber hinaus wurde eine interessante biologische Aktivität von (+)-Vitepyrroloid A festgestellt. Die geringe Isolationsmenge spornte uns für die Entwicklung einer effizienten Synthese an. Dafür wurde der Naturstoff in zwei Fragmente unterteilt. (+)-Sclareolid diente als Ausgangsverbindung für die vierstufige Synthese des Alkyliodides, welche eine Methanolyse und gleichzeitige Eliminierung des entstehenden tertiären Alkohols aufwies. Das Arylbromid wurde in drei Stufen ausgehend von 3-Brompyrrol-2-carboxylsäuremethylester aufgebaut. Der Schlüsselschritt der Synthese war die präzise und schutzgruppenfreie kreuzelektrophilen Kupplung der beiden Fragmente. Die Csp2–Csp3-Kreuzkupplung stellt ein seltenes Beispiel dieser Methode in der Naturstoffsynthese dar. (+)-Vitepyrroloid B konnte durch eine Alkylierung des Stickstoffatoms von (+)-Vitepyrroloid A dargestellt werden. Das zweite Projekt beinhaltet die Formalsynthese von Actinoranon, ein Meroterpenoid, welches aus dem marinen Actinomycetstrang CNQ-027 2013 isoliert wurde. Dieser Naturstoff ist aus einem tetralon-artigen Polyketid verbunden mit einem bizyklischen Diterpen aufgebaut und besitzt eine Cytotoxizität gegenüber HCT-116 humanen Darmkrebs. Es wurde auf eine neue und effizientere Route zu diesem Naturstoff im Vergleich zu den beiden kürzlich veröffentlichten Routen abgezielt. 3,5-Dimethoxybenzaldehyd und (+)-Sclareolid bildeten die Ausgangsverbindungen für die Synthese der Fragmente von Actinoranon, welche durch den retrosynthetischen Schnitt zwischen C14 und C15 entstanden. Das Vinyliodidfragment wurde durch eine fünfstufige Route kennzeichnend durch NEGISHI’s Zirconium-katalysierte Carboaluminierung/Iodierungssequenz erhalten. Der Schlüsselschritt der Tetralonsynthese war der durch Lewissäure unterstützte rigorose Chiralitätstransfer von dem dargestellten Epoxysilylether auf den β-Siloxyaldehyd durch eine von YAMAMOTO inspirierte Umlagerung. Der Aldehyd wurde sofort mittels WITTIG-Reaktion zum ungesättigten Ester umgesetzt. Die abschließenden Schritte zum Actinoranongerüst waren ähnlich den bereits veröffentlichten Routen. Der zweite Teil dieser Arbeit handelt von mechanistischen Untersuchungen der organokatalytischen α-Chlorierungen von Aldehyden. In einer vorausgehenden Studie wurden hohe Katalysatorbeladungen bei der Verwendung von N-Chlorsuccinimid und MACMILLAN’s Imidazolidinonkatalysator beobachtet. In dieser Studie diente die α-Chlorierung von Hydrozimtaldehyd als Modellreaktion. Ein ungewöhnliches Aminal-Intermediat, bestehend aus dem Substrat, dem Katalysator und dem Chlorierungsmittel, wurde isoliert und charakterisiert. Die Untersuchungen mittels 1H-NMR Spektroskopie zielten auf die Bildung und den Zerfall des Aminals ab. Die Ergebnisse dieser Untersuchungen führten zu einem optimierten System mit erhöhter Reaktionsrate und verminderter Katalysatorbeladung (Ausbeuten bis zu 87%, >99% ee)