Strategies and Methods for Synthesizing Scytonemin Analogues

Licentiate thesis, 2012

Natural product synthesis is an exciting field of organic chemistry, directed toward constructing naturally occurring compounds, which often are both chemically complex and biologically intriguing. Scytonemin is a unique, dimeric natural product found in cyanobacteria. It is the active compound of the cyanobacterial photoprotective mechanism and is biosynthesized when the bacteria are exposed to solar radiation. Scytonemin has furthermore been proposed to have an ancient history, stretching back to the early photosynthetic life. The natural product is composed of two identical 3-benzylidene cyclopenta[b]indole-2-one moieties connected to each other at position one. Nostodione A, the little brother of scytonemin, is another natural product found in cyanobacteria. It also contains the 3-benzylidene cyclopenta[b]indole-2-one skeleton, but is not symmetrically substituted in C-1. Instead it appears as a 1,2-dione. Nostodione A has been proposed to be a biosynthetic precursor to scytonemin. Both scytonemin and nostodione A have shown anti-proliferative properties. In this project, flexible synthetic routes leading to the core skeleton of scytonemin and nostodione A have been developed. The syntheses are based on different ring closing strategies for the annulation of indoles. The commercially available indole-3-acetic acid was used to prepare a number of 3-alkynyl indoles, which thereafter were used to investigate gold- and palladium-catalyzed ring-closing reactions. Using gold in catalytic amounts gave the symmetrical, and undesired, carbazole skeleton exclusively. However, palladium catalysis could successfully be used to construct a number of derivatives containing the 3-benzylidene cyclopenta[b]indole-2-one skeleton. In paper I, we utilized the developed route for the first total synthesis of scytonemin. The dimeric structure was obtained by coupling two monomeric structures oxidatively in a biomimetic approach. In paper II, we presented the first total synthesis of nostodione A. Here, the C-1 position was functionalized by a DDQ mediated oxidation under aqueous conditions.