Scheme 2. Synthetic Route to Scytoneman-2,20-dione and Scytonemin currently being undertaken. Acid catalyzed acetal hydro- lysis and fluoride induced desilylation completed the synthesis of the monomers 11a and 11b. The last carbon carbon bond required to complete the scytoneman skeleton is part of a 1,4-carbonyl moiety. There are ample examples in the literature of successful assembly of this structural element by oxidative coupling of carbonyl enolates.16 18 Often oxidative coupling of enolates entails copper or iron, in the form of different salts, similar to enzymatic coupling conditions.16 Hyper- valent iodine reagents are also employed to accomplish the oxidative coupling of enolates.17 To find appropriate re- action conditions for the oxidative coupling, the more accessible monomer 11a together with a small set of diverse coupling reagents were selected for screening. Thus, the monomer 11a was treated with LDA to give the corre- sponding lithium enolate, which was subsequently treated with an appropriate oxidant (Table 1). Cuprous triflate showed poor reactivity giving the monomer back, whereas cupric chloride consumed the monomer but without pro- ducing the wanted product. The hypervalent iodine de- monstrated very potent reactivity with polymerization as a possible side reaction. In accordance with the mechanism for oxidative coupling with hypervalent iodine reagents proposed by Kita et al.,19 it was found that about 0.5 equiv of the oxidant in combination with 1 equiv of LDA gave a (16) DeMartino, M. P.; Chen, K.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 11546. (17) Kim, J. W.; Lee, J. J.; Lee, S. H.; Ahn, K. H. Synth. Commun. 1998, 28, 1287. (18) Krygowski, E. S.; Murphy-Benenato, K.; Shair, M. D. Angew. Chem., Int. Ed. 2008, 47, 1680. (19) Kita, Y.; Yakura, T.; Tohma, H.; Kikuchi, K.; Tamura, Y. Tetrahedron Lett. 1989, 30, 1119. 4460 better yield compared to equimolar amounts. Of the screened oxidants, ferric chloride showed the most poten- tial. Slightly more than 2 equiv of LDA combined with 2 equiv of FeCl3 with respect to the monomer gave the highest yield (Table 1, entry 5). Reducing the reagents to 1 equiv each decreased the yield by 16% (Table 1, entry 4). On the other hand a cleaner reaction where the unreacted monomer could be recovered quantitatively was obtained. Employing the iron based conditions on the scytonemin precursor 11b afforded its dimeric counterpart 12b in higher yield than that obtained for the monomer 11a used in the small prescreening study. This agrees with a recent report showing that enolates conjugated with electron-rich aromatic groups increase the efficiency of iron mediated couplings, while electron-deficient aromatic groups sup- press the reactivity.13 Table 1. Screening of Reaction Conditions for Oxidative Cou- pling of the Unsaturated Ketones 12a and 12ba entry 1 2 3 4 5 6 R (compda) H (12a) H (12a) H (12a) H (12a) H (12a) OMe (12b) oxidant (equiv) CuOTf (2.4) CuCl2 (1.2) PhI(OAc)2 (0.6) FeCl3 (1.1) FeCl3 (2.2) FeCl3 (2.2) LDA (equiv) 2 1.1 1.1 1.1 2.1 2.1 yield (%) traceb 0 25 40 56 70 time (h) 70 0.7 2 24 24 24 a See Scheme 2, step 8. General conditions: THF, 78 C to rt. CuOTf was added as a MeCN solution. CuCl2 and FeCl3 were added as DMF solutions. b Trace quantity could be observed by LC/MS. Org. Lett., Vol. 13, No. 16, 2011