Oxidative Coupling as a Biomimetic Approach to the Synthesis of Scytonemin Andreas Ekebergh,† Isabella Karlsson,‡ Rudi Mete,‡ Ye Pan,† Anna Bo€rje,‡ and Jerker Ma˚ rtensson*,† Department of Chemical and Biological Engineering/Organic Chemistry, Chalmers University of Technology, SE-412 96 Gothenburg, Sweden, and Dermatochemistry and Skin Allergy, Department of Chemistry, University of Gothenburg, SE-412 96 Gothenburg, Sweden jerker@chalmers.se Received July 6, 2011 ABSTRACT ORGANIC LETTERS 2011 Vol. 13, No. 16 4458–4461 The first total synthesis of the dimeric alkaloid pigment scytonemin is described. The key transformations in its synthesis from 3-indole acetic acid are a Heck carbocyclization and a Suzuki Miyaura cross-coupling, orchestrated in a stereospecific tandem fashion, followed by a biosynthetically inspired oxidative dimerization. The tandem sequence generates a tetracyclic (E)-3-(arylidene)-3,4-dihydrocyclopenta[b]indol- 2(1H)-one that is subsequently dimerized into the unique homodimeric core structure of scytonemin. The cyanobacterial dimeric alkaloid pigment scytone- min (Figure 1) is characterized by a homodimeric core structure that is unique among natural products and composed of two 1,10 linked cyclopent[b]indole-2(1H)- ones. This core in scytonemin is symmetrically appended by 4-hydroxybenzylidene in the 3-position of the fused tricyclic system. The parent skeleton comprising the eight rings has been given the trivial name scytoneman by Proteau et al. who, in 1993, were the first to elucidate the chemical structure of the scytonemin pigment.1 Scytone- min has been proposed to be formed biosynthetically by a putative tyrosinase NpR1263 promoting an oxidative dimerization of the R,β-unsaturated ketone (2) (Scheme 1).2 The biosynthetic route to the reduced form of this mono- meric precursor has been disclosed and shown to com- mence from L-tryptophan and p-hydroxyphenylpyruvic † Chalmers University of Technology. ‡ University of Gothenburg. (1) Proteau, P. J.; Gerwick, W. H.; Garcia-Pichel, F.; Castenholz, R. Experientia 1993, 49, 825. (2) Balskus, E. P.; Walsh, C. T. J. Am. Chem. Soc. 2008, 130, 15260. (3) Balskus, E. P.; Walsh, C. T. J. Am. Chem. Soc. 2009, 131, 14648. 10.1021/ol201812n r 2011 American Chemical Society Published on Web 07/25/2011 Figure 1. Structure of scytonemin. The scytoneman skeleton is highlighted by bold lines. acid.3 In an alternative suggestion, nostodione A has been put forward as the actual monomeric precursor, and the putative tyrosinase NpR1263 to be essential for the bio- synthesis of this monomer.4 (4) Soule, T.; Palmer, K.; Gao, Q.; Potrafka, R. M.; Stout, V.; Garcia-Pichel, F. BMC Genomics 2009, 10, 336.