https://pubs.rsc.org/en/content/articlepdf/2019/NP/C8NP00092A

Marine natural products.

The design and implementation of cascade reactions is a challenging facet of organic chemistry, yet one that can impart striking novelty, elegance, and efficiency to synthetic strategies. The application of cascade reactions to natural products synthesis represents a particularly demanding task, but the results can be both stunning and instructive. This Review highlights selected examples of cascade reactions in total synthesis, with particular emphasis on recent applications therein. The examples discussed herein illustrate the power of these processes in the construction of complex molecules and underscore their future potential in chemical synthesis.

Cascade reactions in total synthesis.

Photochemical reactions contribute in a significant way to the existing repertoire of carbon-carbon bond-forming reactions by allowing access to exceptional molecular structures that cannot be obtained by conventional means. In this Review, the most important photochemical transformations that have been employed in natural product synthesis are presented. Selected total syntheses are discussed as examples, with particular attention given to the photochemical key step and its stereoselectivity. The structural relationship between the photochemically generated molecule and the natural product is shown, and, where necessary, the consecutive reactions in the synthesis are illustrated and classified.

Photochemical reactions as key steps in natural product synthesis

Die Entwicklung und Umsetzung von Kaskadenreaktionen hat zu beachtlichen neuartigen, eleganten und effizienten Synthesestrategien gefuhrt. Als besonders anspruchsvoll erwies sich die Anwendung von Kaskadenreaktionen in der Naturstoffsynthese, doch gerade hier winken verbluffende und zugleich aufschlussreiche Ergebnisse als Belohnung. In diesem Aufsatz werden ausgewahlte Kaskadenreaktionen in der Totalsynthese erlautert, wobei neuere Anwendungen besonders hervorgehoben werden. Die erorterten Beispiele sollen die Leistungsfahigkeit dieser Prozesse beim Aufbau von komplexen Molekulstrukturen veranschaulichen und ihr Potenzial fur zukunftige chemische Synthesen verdeutlichen.

Kaskadenreaktionen in der Totalsynthese

Pericyclic reactions have long been considered a biosynthetic rarity. In contrast to their prominence in the laboratory, they seemed to play only minor roles in Nature. Over the past decades, however, enough examples have been amassed to demonstrate that pericyclic reactions occur quite frequently in biosynthetic pathways. Pericyclic reactions include cycloadditions, sigmatropic rearrangements, and electrocyclizations. Biosynthetic cycloadditions have been recently featured in a comprehensive review by Williams.1 The aim of the present article is to provide a counterpart highlighting electrocyclic reactions that have been found or suspected in the biosynthesis of natural products. In many cases, these biosynthetic considerations have inspired biomimetic syntheses, whose success in turn validates the proposal. We consider reactions as biosynthetic if they occur in a given organism or in its immediate environment. This definition includes reactions that occur spontaneously and do not require enzyme catalysis, which are very common among electrocyclizations. Biosynthetic and biomimetic electrocyclizations have never been systematically reviewed. Since numerous examples have recently surfaced in the literature, we feel that the time has come to make such an attempt. For the sake of simplicity, we use the term “electrocyclizations” both for the forward reaction and electrocyclic ring openings. This review is organized primarily along the number of electrons involved in a given π system that undergoes the electrocyclic reaction. Following electrocyclizations of 4π systems, electrocyclic reactions involving 6 and 8 π-electrons are discussed. Thermal and photochemical reactions are presented in that order. Systems including heteroatoms (usually oxygen but occasionally nitrogen), which are confined to 6 π-electrons, are presented separately. Finally, the question of whether biosynthetic electrocyclizations require enzyme catalysis is briefly addressed. One of the most attractive features of biomimetic electrocyclizations is that they often participate in pericyclic reaction cascades.2 In combination with cycloadditions, for instance, they are able to rapidly generate molecular complexity and diversity, an aspect that is given ample attention in this review. If the cascade involves several electrocyclizations, priority is given to the highest number of π-electrons. In some cases, the occurrence of electrocyclic reactions or reaction cascades in biosynthetic pathways is quite speculative. Nevertheless, these cases have been included provided they have inspired biomimetic syntheses.2 By contrast, total syntheses featuring electrocyclic reactions that have not been proposed or are unlikely to be biomimetic are generally not covered in this review. This means that many elegant synthetic applications of electrocyclizations, such as Woodward’s celebrated porphyrin to chlorin conversion used in the synthesis of chlorophyll, will not be discussed.3 The theory of electrocyclizations will not be recapitulated here either. The reader is referred to a series of reviews that have appeared on this subject.4 As a reminder, the stereochemical course of electrocyclizations in the ground state and excited state is summarized below:

Biosynthetic and biomimetic electrocyclizations.

Lucidene and alboatrin are complex benzopyran derived natural products. A key step in their biogenesis may involve a hetero Diels–Alder cycloaddition between an o-quinone methide intermediate with a simple, or activated tri-substituted olefin. Experimental evidence is provided to support this hypothesis, with the biomimetic synthesis of both (±)-lucidene and (±)-alboatrin successfully achieved using a new and efficient method for o-quinone methide generation.

A new and efficient method for o-quinone methide intermediate generation: application to the biomimetic synthesis of the benzopyran derived natural products (±)-lucidene and (±)-alboatrin

Our biomimetic hypothesis proposes that families of diverse natural products with complex core structures such as 9,10-deoxytridachione, photodeoxytridachione and ocellapyrone A are derived in nature from a linear and conformationally strained all-( E) tetraene-pyrone precursor. We therefore synthesized such a precursor and investigated its biomimetic transformation under a variety of reaction conditions, both to the above natural products as well as to diverse isomers which we propose to be natural products "yet to be discovered". We also report herein the first synthesis of the natural product iso-9,10-deoxytridachione.

Biomimetic synthesis of pyrone-derived natural products: exploring chemical pathways from a unique polyketide precursor.

Biomimetic synthesis of (+/-)-9,10-deoxytridachione.

A New and Efficient Method for o‐Quinone Methide Intermediate Generation: Application to the Biomimetic Synthesis of the Benzopyran Derived Natural Products (.+‐.)‐Lucidene and (.+‐.)‐Alboatrin.

A tandem Suzuki-coupling/electrocyclisation reaction sequence was employed for the biomimetic synthesis of (±)-9,10-deoxytridachione.

Raphaël Rodriguez

Papers

A new and efficient method for o-quinone methide intermediate generation: application to the biomimetic synthesis of the benzopyran derived natural products (±)-lucidene and (±)-alboatrin

Biomimetic synthesis of pyrone-derived natural products: exploring chemical pathways from a unique polyketide precursor.

Biomimetic synthesis of (+/-)-9,10-deoxytridachione.

A New and Efficient Method for o‐Quinone Methide Intermediate Generation: Application to the Biomimetic Synthesis of the Benzopyran Derived Natural Products (.+‐.)‐Lucidene and (.+‐.)‐Alboatrin.

Biomimetic Synthesis of (.+-.)-9,10-Deoxytridachione.