Dimeric Natural Products DOI: 10.1002/anie.201402384 Double Trouble—The Art of Synthesis of Chiral Dimeric Natural Products** Tim Wezeman, Kye-Simeon Masters,* and Stefan Bräse* Dedicated to Professor Armin de Meijere on the occasion of his 75th birthday Diels–Alder reactions · dimerization · natural products · oxidative coupling · secalonic acid The last century brought us a fascinating and broad spectrum of highly complex natural products. A particularly challenging and appealing class comprises dimeric natural products consisting of two complex monomeric units. Many such compounds have been identified as having novel biological properties. [1] Several syntheses of such chiral dimeric natural products consisting of achiral subunits have been reported in the last decade (1–4, Figure 1). [1b–d] In addition, the biosynthetic origins of several of the members of this class—mostly oxidative dimerization processes—have been elucidated in detail. [2] It has been shown that biomimetic oxidative coupling processes are not always suitable for chemical total synthesis using monomeric building blocks, as there are frequently problems with regioselectivity and unwanted side reactions (C À O formation etc.). However, such oxidative coupling pathways have proven highly effective for the synthesis of selected dimeric natural products, for example in the enan- tioselective synthesis of bioactive mold isolates bisisoniger- one and nigerone (7 and 8, Scheme 1) described by Kozlow- ski, Bringmann, and co-workers. [3] In their synthesis, flavas- perone monomer 5 was heated with the chiral 1,5-diaza-cis- decalin copper catalyst 6. In the final step, base-catalyzed isomerization of bisisonigerone (7) to the more stable niger- one (8) was conducted in methanol with sodium hydroxide at 70 8C. Circular dichroism (CD) spectral analysis of 8 con- firmed its absolute stereochemistry as (M)-(À). Another example of dimeric natural product synthesis relying on the oxidative coupling of monomeric subunits is Nicolaous cytoskyrin cascade (Scheme 2) using manga- nese(IV) oxide and triethylamine. [4] The fungal metabolite cytoskyrin is a congener of a large class of dimeric natural products which formally can be derived from anthraquinones. The cytoskyrin cascade, most likely consisting of an enoliza- tion, dimerization, and oxidation followed by two intra- molecular Michael reactions, was applied to monomer 9a and 9b to synthesize (+)-2,2’-epi-cytoskyrin A (10) and (+)-ru- Figure 1. Examples of chiral dimeric natural products consisting of achiral monomers. Scheme 1. Kozlowski and Bringmann’s synthesis of bisisonigerone and nigerone. a) Copper complex (S,S)-6 (1.1 equiv), CH 2 Cl 2 , air, 50 8C, 6 days, 60 %, 80 % ee ; b) NaOH (aq.), methanol, 70 8C, 16 h, 50 %, 90% ee. [*] T. Wezeman, Prof.Dr. S. Bräse Institute of Organic Chemistry (IOC) Karlsruhe Institute of Technology (KIT) Fritz-Haber-Weg 6, 76131 Karlsruhe (Germany) E-mail: braese@kit.edu Dr. K.-S. Masters Chemistry, Physics and Mechanical Engineering Faculty of Science and Engineering Queensland University of Technology (QUT) GPO Box 2434, Brisbane, Queensland, 4001 (Australia) E-mail: kye.masters@qut.edu.au Prof. Dr. S. Bräse Institute of Toxicology and Genetics (ITG) Karlsruhe Institute of Technology (KIT) Eggenstein-Leopoldshafen (Germany) [**] We acknowledge continuous funding through the DFG (BR 1750) and the Helmholtz Association. K.-S.M. acknowledges a Vice Chancellor’s Research Fellowship from QUTand T.W. acknowledges the Marie-Curie ITN ECHONET (grant no. 316379). . Angewandte Highlights 2  2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2014, 53,2–5 Ü Ü These are not the final page numbers!