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En Route to Terpene Natural Products Utilizing Supramolecular Cyclase Mimetics Cite This: Nat Natural Product Reports View Article Online HIGHLIGHT View Journal | View Issue En route to terpene natural products utilizing supramolecular cyclase mimetics Cite this: Nat. Prod. Rep.,2019,36, 1619 Qi Zhang, a Lorenzo Catti, b Leonidas-Dimitrios Syntrivanisc and Konrad Tiefenbacher *cd 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 Received 23rd January 2019 years, however, the development of manmade binding pockets that allow such reactions to take place DOI: 10.1039/c9np00003h has been reported. This Highlight provides an overview of this nascent field, and outlines the challenges rsc.li/npr that need to be overcome moving forward. Creative Commons Attribution-NonCommercial 3.0 Unported Licence. 1 Introduction the other hand, trigger reactions via protonation of the terminal olen or a previously installed epoxide moiety. Ryan Shenvi Nature's way of synthesizing natural products has fascinated proposed the term “tail-to-head” cyclization for chemical reac- and inspired chemists for decades. One of the most complex tions similar to reactions observed in class I cyclase enzymes organic transformations performed in nature is the terpene since the reaction is initiated at the tail end of the molecule and 4 cyclization. This kind of reaction provides the chemically and propagates towards the head group (Scheme 1b). Accordingly, structurally most diverse class of natural products, the terpe- the term “head-to-tail” cyclization refers to a process similar to This article is licensed under a 4 noids.1 More than 80 000 members of the terpenoid family have those catalyzed by class II enzymes. This terminology is very been described so far. Nevertheless, the currently known well suited to differentiate between these two reaction pathways structures constitute just a fraction of potential structures, as in a non-enzymatic setting, the main focus of this article. Open Access Article. Published on 25 2019. Downloaded 26-09-2021 19:24:35. was recently highlighted for monoterpenes in a computational Interestingly, the structural variety of products formed by class study.2 Interestingly, this whole variety is produced from just II cyclase enzymes is rather limited. Mainly six-membered rings a handful of relatively simple acyclic terpenes via cyclization are formed from the energetically most preferred chair confor- and oxidation processes. Geranyl pyrophosphate (GPP 1, mation of the exible substrate. As an example, the reaction 5 Scheme 1a), farnesyl pyrophosphate (FPP 2), and geranylgeranyl product ent-copalyl diphosphate (4) is displayed in Scheme 1b. pyrophosphate (GGPP 3) are the three most common substrates Chemists have had some success in mimicking the head-to-tail 6 utilized for cyclizations. These linear isoprenoid diphosphates cyclization mode in solution, and even some enantioselective are formed in nature by prenyltransferases utilizing the simple cyclizations using chiral Lewis acids have been reported. The C5 building blocks dimethylallyl diphosphate and isopentenyl reproducibility of this cyclization mode in solution using diphosphate.1 abiotic catalysts is likely due to the reliance on the energetically In nature, two classes of enzymes are responsible for the preferred substrate conformation, which translates into the subsequent cyclization processes.3 Class I cyclase enzymes product structure. Nevertheless, the head-to-tail cyclization initiate the reaction by cleaving the pyrophosphate residue of mode is still far away from being generally applicable in the molecule via a trinuclear metal cluster. Class II cyclases, on a solution setting. In contrast to class II cyclases, class I enzymes produce a much larger variety of products. This is due to their ability to a Key Laboratory of Green Chemistry and Technology of Ministry of Education, College bind a specic conformation of the exible precursor, enabling of Chemistry, Sichuan University, China cyclization modes not observed with the unrestrained confor- bLaboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, 4259 Nagatsuta, Midori-ku, Yokohama 226-8503, Japan mations in solution. Additionally, the tail-to-head cyclization is cDepartment of Chemistry, University of Basel, St. Johanns-Ring 19, CH-4056 Basel, stepwise and the cationic intermediates formed can undergo Switzerland. E-mail: [email protected] a variety of reactions like rearrangements, hydride shis, dDepartment of Biosystems Science and Engineering, ETH Zurich,¨ Mattenstrasse 26, proton transfers and eliminations. Again, the shape of the CH-4058 Basel, Switzerland. E-mail: [email protected] This journal is © The Royal Society of Chemistry 2019 Nat. Prod. Rep.,2019,36,1619–1627 | 1619 View Article Online Natural Product Reports Highlight active site determines the accessible conformations of these surprising, since even a very large Lewis or Brønsted acid is carbocationic intermediates, thereby determining the reaction hardly able to inuence the conformation of the exible acyclic outcome. The active site of the enzyme, additionally, stabilizes terpene substrate. Moreover, nucleophiles in solution may cationic intermediates and transition states via a range of intercept cationic intermediates, thereby preventing the interactions: coulombic, cation–dipole and cation–p interac- formation of polycyclic products. tions.7 As an example of a tail-to-head cyclization product, tax- adiene (5), the carbon framework of the anti-cancer drug Taxol (6),8 is depicted in Scheme 1b. This cyclization involves several 2 Tail-to-head terpene cyclizations in cationic intermediates, an intramolecular proton transfer and 1 solution an elimination reaction as the terminating step. Computa- tional chemistry is increasingly utilized to learn more about the There have been some reports about the tail-to-head cycliza- 9–14 mechanisms involved in terpene cyclizations. Such studies tions of monoterpene alcohols (Scheme 2a) in solution using for have provided insight into how cyclase enzymes exert control instance phosphoric acid17 or ferric chloride.18 These studies over the cyclization outcome, via specic interactions between did not employ internal standards for the quantication of the 9,11,14,15 active site moieties and carbocations. The enzyme, products formed and reported the relative percentage yields however, not necessarily has to intervene throughout the whole only. Reproduction of the reaction conditions19 indicated that cascade reaction; some steps can be driven by the intrinsic only traces of tail-to-head products were formed in solution 16 reactivity of the cationic intermediates. Nevertheless, in solu- under such conditions and that substitution products domi- tion the tail-to-head cyclization mode of class I enzymes proved nated. In fact, in the case of phosphoric acid catalysis, the head- 4 to be very challenging to reproduce. This may not be too to-tail product cyclogeranyl acetate 8 was formed as the major Creative Commons Attribution-NonCommercial 3.0 Unported Licence. Qi Zhang obtained his master Leonidas-Dimitrios Syntrivanis degree in 2012 at the Technical received his master's degree University of Munich and began from the University of Bologna his Ph.D. studies under the in 2013. In the same year he supervision of Prof. Konrad Tie- moved to Oxford to join the fenbacher in the same year. Aer Oxford Innovative Organic receiving his Ph.D degree at the Synthesis for Cancer Research Technical University of Munich doctoral programme. There he This article is licensed under a in 2016, he re-joined the worked with Prof. Jeremy Rob- research group of Prof. Konrad ertson and Prof. Luet Wong on Tiefenbacher at the University of the synthesis of eleuthoside Open Access Article. Published on 25 2019. Downloaded 26-09-2021 19:24:35. Basel as a postdoctoral fellow. structures and their selective In late 2018, he started his hydroxylation through bio- independent career at Sichuan catalytic means, obtaining his DPhil in 2017. He is currently University in Chengdu, China. a postdoctoral researcher in the group of Prof. Konrad Tie- fenbacher at the University of Basel. Lorenzo Catti received his Konrad Tiefenbacher is a dual master degree in organic chem- tenure track Assistant Professor istry from the Technical Univer- of Chemistry at the University of sity of Munich in 2013 under the Basel and the ETH Zurich. He supervision of Prof. Konrad Tie- obtained his master degree at fenbacher. In 2016, he moved the Technical University of with the Tiefenbacher group to Vienna in 2004 and the Ph.D. the University of Basel and, in degree at the University of 2017, completed his Ph.D. Vienna in the group of Prof. research on the application and Johann Mulzer in 2009. He con- development of resorcinarene- ducted postdoctoral research based supramolecular catalysts. with Prof. Julius Rebek at The He is currently a JSPS/AvH Scripps Research Institute in La postdoctoral fellow in the Yoshizawa research group at the Jolla in 2010/2011. In December 2011 he joined the faculty of TU Tokyo Institute of Technology. Munich as assistant professor (no tenure track) before switching to his current position
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