Scheme 1. Retrosynthetic Analysis of Scytonemin The biological role of scytonemin has been ascertained to be as a UV-absorbing pigment to protect important cellular components in the cyanobacteria against harmful UV radiation.5 Its critical biological importance for the cyanobacterial survival is highlighted by the facts that the pigment is found in more than 300 species of cyanobacteria and that the scytonemin biosynthetic gene cluster is highly conserved across several studied cyanobacterial lineages.6 Scytonemin received attention when it was reported to be the first characterized small molecule inhibitor of polo- like kinase 1 and to inhibit other cell cycle regulatory kinases as well.7 In compliance with these observations, it has been shown to possess both anti-inflammatory and antiproliferative properties.8 Scytonemin has therefore been proposed to serve as a new pharmacophore that could be used in the development of a chemically new class of therapeutically useful drugs. In a project aimed at exploring the photochemistry and photophysics of scytonemin we need access to derivatives of both the dimeric form as well as its monomeric pre- cursor. Our plan to prepare these compounds takes its starting point in the molecular symmetry and the prospect of stereospecific formation of the exocyclic double bond; see Scheme 1. Initial disconnection of the C1 C10 bond generates the monomeric precursor (2). Inspired by the proposed biosynthetic route to scytonemin, and attracted by the possibility to couple two identical moieties without the need of prior installation of any functional group lost in the subsequent coupling, we set out to complete the syn- thesis of the scytoneman skeleton by an oxidative coupling of two identical halves. Further disconnection of two cis- vinylic bonds at the exocyclic double bond produces an alkynyl haloindole (3). This intermediate was expected to participate in a palladium-mediated syn-addition of the indolyl group and an aryl group to the triple bond, to create both the fused tricyclic skeleton and the exocyclic double bond with the correct stereochemistry in a single operation.9 The final disconnection, which corresponds to an acyl substitution, generates the commercially available 3-indole acetic acid (4). (5) Cockell, C. S.; Knowland, J. Biol. Rev. Cambridge Philos. Soc. 1999, 74, 311. (6) Sorrels, C. M.; Proteau, P. J.; Gerwick, W. H. Appl. Environ. Microbiol. 2009, 75, 4861. (7) Stevenson, C. S.; Capper, E. A.; Roshak, A. K.; Marquez, B.; Eichman, C.; Jackson, J. R.; Mattern, M.; Gerwick, W. H.; Jacobs, R. S.; Marshall, L. A. J. Pharmacol. Exp. Ther. 2002, 303, 858. Org. Lett., Vol. 13, No. 16, 2011 Thus, our synthetic sequence toward scytonemin com- menced with a standard transformation of 3-indole acetic acid (4) into its corresponding Weinreb amide (5) (Scheme 2),10 which was subsequently iodinated in the 2-position using molecular iodine and silver triflate.11 Careful addition of silver triflate and use of slightly less than 1 equiv of iodine were crucial to avoid formation of a diiodinated product, which in our hands was impossible to separate from the desired product. Treatment of the iodinated Weinreb amide 6 with preformed trimethylsily- lethynyl lithium gave the alkynyl ketone 7. This ketone was converted into its corresponding acetal (8) by the proce- dure reported by Tsunoda et al.12 Accordingly, 1,2-bis- (trimethylsiloxy)ethane was used as the acetalizing agent and trimethylsilyl trifluoromethanesulfonate as the cata- lyst. Of several screened conditions these were the only ones that effected satisfactory acetal formation. The for- mation of the tricyclic cyclopent[b]indole-2-one skeleton and the exocyclic double bond with correct stereochemis- try was accomplished by a tandem Heck Suzuki Miyaura reaction. Effective use of the tandem sequence of Heck carbocyclization of five-membered rings and Suzuki Miyaura coupling in stereoselective formation of substi- tuted exocyclic double bonds has recently been reported in the literature.9,13 We chose to follow a protocol described by Littke et al.14,15 It has been successfully applied to both Suzuki Miyaura and Heck-type cross couplings sepa- rately but, to the best of our knowledge, not in tandem reactions. Consequently, the alkynyl iodoindole 8 was treated with an arylboronic acid in the presence of cesium carbonate and a catalytic amount of palladium and tri- tert-butylphosphine. It was discovered that the conditions of this domino reaction needed careful tuning to favor the desired reaction pathway. Using phenylboronic acid in excess (1.5 equiv of PhB(OH)2 and 2.5 equiv of Cs2CO3) yielded the cyclized product 9a exclusively, while the same excess of 4-methoxyboronic acid produced a significant amount of the undesired 2-(4-methoxyphenyl)-indole to- gether with the wanted product 9b. The electron-rich boronic acid increased the rate of reaction for the inter- molecular Suzuki coupling to the degree where it success- fully competed with the intramolecular Heck cyclization. Decreasing the excess of boronic acid and base (1.1 equiv of MeOPhB(OH)2 and 1.8 equiv of Cs2CO3) suppressed the unwanted cross coupling but had an unfortunate effect on the overall conversion. Further screening and evalua- tion of reaction conditions to circumvent this problem are (8) Stevenson, C. S.; Capper, E. A.; Roshak, A. K.; Marquez, B.; Grace, K.; Gerwick, W. H.; Jacobs, R. S.; Marshall, L. A. Inflammation Res. 2002, 51, 112. (9) Arthuis, M.; Pontikis, R.; Florent, J. C. Tetrahedron Lett. 2007, 48, 6397. (10) Duval, E.; Cuny, G. D. Tetrahedron Lett. 2004, 45, 5411. (11) Baran, P. S.; Shenvi, R. A. J. Am. Chem. Soc. 2006, 128, 14028. (12) Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980, 21, 1357. (13) Cheung, W. S.; Patch, R. J.; Player, M. R. J. Org. Chem. 2005, 70, 3741. (14) Littke, A. F.; Fu, G. C. J. Org. Chem. 1999, 64, 10. (15) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020. 4459