New directions in natural product synthesis

Huw M. L. Davies a, Kenichiro Itami b and Brian M. Stoltz c
aEmory University, Atlanta, USA
bDepartment of Chemistry, Graduate School of Science, Nagoya University, Japan
cDivision of Chemistry and Chemical Engineering, Caltech, USA

Received 11th October 2018
Research in the total synthesis of natural products has changed considerably in recent years. Much of the research effort has moved away from only focusing on the synthesis of a specific natural product, and instead toward the development of general synthetic strategies that enable the synthesis of a broad family of natural products. The new approach offers considerable advantages because the new synthetic strategies are often very flexible and thus, can have lasting influence on the field of organic synthesis. This thematic issue highlights several of the recently developed synthetic strategies and illustrates their flexibility for the synthesis of complex natural products. The thematic issue also includes reviews on visual algorithms to compare the efficiency of different total syntheses and computational approaches that can assist in the design of new total synthesis approaches.

Two reviews illustrate the power of radical processes for the synthesis of natural products. Pratt and Stephenson and coworkers describe recent advances in the use of radical intermediates for the rapid construction of complex targets, and illustrate the effectiveness of incorporating intramolecular reactions into the synthetic strategy (DOI: 10.1039/C8CS00379C). Nagaraju and Ma describe oxidative coupling strategies for the synthesis of indole alkaloids, in which enolates or phenoxides are oxidized to radical intermediates capable of rapidly coupling complex structures (DOI: 10.1039/C8CS00305J).

C–H Functionalization has now matured to the stage whereby it can compete with the conventional approach of designing a complex synthesis by relying on functional groups transformation. An interesting development is the use of amide activation reactions as key steps in total synthesis, and the recent advances in this field are highlighted by Maulide and coworkers (DOI: 10.1039/C8CS00335A). Li and Yu describe the utility of a mild gold-catalyzed glycosylation reaction (DOI: 10.1039/C8CS00209F). Due to the mildness of the transformation, a variety of elaborate coupling partners can be introduced, leading to the streamlined synthesis of complex carbohydrate-containing natural products.

Two reviews describe the utility of readily available and simple cyclic frameworks for elaboration into a wide range of complex structures. Sarlah and coworkers describe the range of methodologies available to rapidly build up structural complexity by dearomatization of unactivated arenes (DOI: 10.1039/C8CS00389K). Zhu and coworkers illustrate the diverse array of indole alkaloids that can be prepared beginning with cyclohexenes (DOI: 10.1039/C8CS00454D). This review described how computational chemistry has assisted in understanding the reactivity of the intricate molecular architectures encountered in natural product synthesis.

Cycloaddition strategies have played a central role to streamline total synthesis because often multiple stereocenters can be generated and controlled in a single step. Yang and Gao describe the synthetic utility of the Diels–Alder reactions of o-quinodimethanes and related compounds (DOI: 10.1039/C8CS00274F). Two other reviews are related to cycloaddition reactions. Schindler and coworkers describe the metal-catalyzed metathesis reaction between alkenes and carbonyls, the intramolecular version of which generate cycloalkanes that can be broadly applied in total synthesis (DOI: 10.1039/C8CS00391B). Suzuki and coworkers summarize recent advances in the use of arynes in total synthesis, and again, the intramolecular reaction has broad applications (DOI: 10.1039/C8CS00350E).

Often, several strategies are possible for the synthesis of natural products, and it is not always clear which synthetic process is most efficient. Schwan and Christmann describe a new visualization system that can be used to compare the effectiveness of different syntheses (DOI: 10.1039/C8CS00399H). It operates by having a color code to distinguish which steps proceed directly toward the desired natural products and which ones are adjustments to the functionality that must be made before the sequence can progress effectively toward the target.

Computational methods play an increasingly important role in predicting the likely outcome of key synthetic strategies. Tantillo's tutorial review illustrates, by means of a series of selected case studies, the value of computational methods to understand the cause of unusual reaction outcomes that have occurred during total synthesis research programs (DOI: 10.1039/C8CS00298C). Elkin and Newhouse highlight the power of calculations to understand subtle structural features of key intermediates and their impact on the reactivity and stereoselectivity in critical steps of selected total synthesis examples (DOI: 10.1039/C8CS00351C).

In conclusion, this thematic issue shows that the field of natural product total synthesis remains vibrant and is an excellent venue for challenging the development of broadly applicable synthetic methodologies. The use of computational chemistry to rationalize and design new total synthesis strategies will continue to gain in value and will become and indispensable tool for synthetic chemists. Expanded tools and visualization techniques to compare between total synthesis schemes will be of value as the field continues to search for the most effective approaches for total synthesis.

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Huw M. L. Davies

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Kenichiro Itami

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Brian M. Stoltz

This journal is © The Royal Society of Chemistry 2018