Biomimetic tail-to-head terpene cyclizations using the resorcin[4]arene capsule catalyst.

The tail-to-head terpene (THT) cyclization is a biochemical process that gives rise to many terpene natural product skeletons encountered in nature. Historically, it has been difficult to achieve THT synthetically without using an enzyme. In this protocol, a hexameric resorcin[4]arene capsule acts as an artificial enzyme mimic to carry out biomimetic THT cyclizations and related carbocationic rearrangements. The precursor molecule bears a leaving group (usually an alcohol or acetate group) and undergoes the THT reaction in the presence of the capsule catalyst and HCl as a cocatalyst. Careful control of several parameters (including water content, amount of HCl cocatalyst, temperature and solvent) is crucial to successfully carrying out the reaction. To facilitate the application of this unique capsule-catalysis methodology, we therefore developed a very detailed procedure that includes the preparation and analysis of all reaction components. In this protocol, we describe how to prepare two different terpenes: isolongifolene and presilphiperfolan-1ß-ol. The two procedures differ in the water content required for efficient product formation, and thus exemplify the two common use cases of this methodology. The influence of other crucial reaction parameters and means of precisely controlling them are described. A commercially available substrate, nerol, can be used as simple test substrate to validate the reaction setup. Each synthetic procedure requires 5-7 d, including 1-5 h of hands-on time. The protocol applies to the synthesis of many complex terpene natural products that would otherwise be difficult to access in synthetically useful yields.

Computational prediction of complex cationic rearrangement outcomes.

Recent years have seen revived interest in computer-assisted organic synthesis1,2. The use of reaction- and neural-network algorithms that can plan multistep synthetic pathways have revolutionized this field1,3-7, including examples leading to advanced natural products6,7. Such methods typically operate on full, literature-derived 'substrate(s)-to-product' reaction rules and cannot be easily extended to the analysis of reaction mechanisms. Here we show that computers equipped with a comprehensive knowledge-base of mechanistic steps augmented by physical-organic chemistry rules, as well as quantum mechanical and kinetic calculations, can use a reaction-network approach to analyse the mechanisms of some of the most complex organic transformations: namely, cationic rearrangements. Such rearrangements are a cornerstone of organic chemistry textbooks and entail notable changes in the molecule's carbon skeleton8-12. The algorithm we describe and deploy at https://HopCat.allchemy.net/ generates, within minutes, networks of possible mechanistic steps, traces plausible step sequences and calculates expected product distributions. We validate this algorithm by three sets of experiments whose analysis would probably prove challenging even to highly trained chemists: (1) predicting the outcomes of tail-to-head terpene (THT) cyclizations in which substantially different outcomes are encoded in modular precursors differing in minute structural details; (2) comparing the outcome of THT cyclizations in solution or in a supramolecular capsule; and (3) analysing complex reaction mixtures. Our results support a vision in which computers no longer just manipulate known reaction types1-7 but will help rationalize and discover new, mechanistically complex transformations.

Molecular Capsule Catalysis: Ready to Address Current Challenges in Synthetic Organic Chemistry?

Self-assembled molecular capsules, host structures that form spontaneously when their building blocks are mixed, have been known since the 1990s. They share some basic similarities with enzyme pockets, as they feature defined hydrophobic binding pockets that are able to bind molecules of appropriate size and shape. The potential to utilize such host structures for catalysis has been explored since their discovery; however, applications that solve current challenges in synthetic organic chemistry have remained limited. In this short article, we discuss the challenges associated with the use of molecular capsules as catalysts, and highlight some recent applications of supramolecular capsules to overcome challenges in synthetic organic chemistry.

Four-Step Access to the Sesquiterpene Natural Product Presilphiperfolan-1ß-ol and Unnatural Derivatives via Supramolecular Catalysis.

Terpenes constitute one of the most structurally varied classes of natural products. A wide range of these structures are produced in nature by type I terpene cyclase enzymes from one single substrate. However, such reactivity has proven difficult to reproduce in solution with man-made systems. Herein we report the shortest synthesis of the tricyclic sesquiterpene presilphiperfolan-1ß-ol to date, utilizing the supramolecular resorcinarene capsule as catalyst for the key step. This synthetic approach also allows access to unnatural derivatives of the natural product, which would not be accessible through the biosynthetic machinery. Additionally, this study provides useful insight into the biosynthesis of the presilphiperfolanol natural products, including the first experimental evidence consistent with the proposed biosynthetic connection between caryophyllene and the presilphiperfolanols.

En route to terpene natural products utilizing supramolecular cyclase mimetics.

Covering: literature up to 2018 Terpenes are a class of natural products characterized by remarkable structural diversity. Much of this diversity arises biosynthetically from a handful of linear precursors through the so-called tail-to-head terpene cyclization reaction. This reaction is one of the most complex observed in nature, and historically attempts to replicate it with non-enzymatic means have met with little success. In recent years, however, the development of manmade binding pockets that allow such reactions to take place has been reported. This Highlight provides an overview of this nascent field, and outlines the challenges that need to be overcome moving forward.