Abstract/Summary

Stemodinone 1, the principal target of the work in this thesis, is a naturally occurring tetracyclic diterpene isolated from the leaves of Stemodia maritima L. (Schrophulariaceae) and used for the treatment of venereal disease. The reported medicinal properties of stemodinone and its analogous compounds such as aphidicolin 2 attracted the attention of organic chemists to the investigation of the complex structure of the compound. The recently described trigoheterone A 3 (Figure 1) has shown significant inhibitory effect towards five cancer cell lines (SW480, HL-60, A549, SMMC-7721 and MCF-7) with IC50 values similar to the cisplatin. From a synthetic viewpoint, preparing the quaternary spiro centre at C9 is complicated by it being adjacent to a second quaternary carbon: a very hindered environment (Figure 1): carbons 9 and 10, highlighted in red). The present work is part of a programme to develop a synthesis of stemodinone 1 that is based upon an intramolecular alkene-arene meta-photocycloaddition. The most advanced example of this type being the conversion of 4 into synthetic intermediate 5. In particular, the adjacent quaternary centres in 5 (highlighted in red) have been formed by the cycloaddition of sp2 hybridised carbon atoms, one component of which is a benzene ring excited to its first singlet excited state (S1). Previous work by Boyd and Chappell established a synthetic route for the preparation of the photocycloaddition precursor 4, beginning from the commercially available starting material dimedone, which has the gem-dimethyl group present on the A-ring of stemodinone 1. However, the synthesis of 4 contains a conjugate addition of an aryl cuprate that proceeds in, at best, 15% yield. Described in the present work is an effort to address an improved synthesis of 4 utilising a Schultz heteroatom-directed photoarylation e.g. 6 to 7 (Scheme 2). Specifically, with the aim of improving the preparation of the quaternary centre in 4 adjacent to the aromatic ring. The general value of generating highly hindered quaternary carbons by the combination of sp2 carbons via their -faces has been illustrated above. Schultz has demonstrated that this class of photoarylation is able to facilitate the synthesis of quaternary centres in the lycoramine and morphine skeletons. iii Set out below is a disconnection of stemodinone 1 that uses both the arene-alkene metaphotocycloaddition and a Schultz heteroatom-directed photoarylation, leading back to dimedone (Scheme 3). In this thesis, an examination of the Schultz cyclisation toward stemodinone is reported, with both sulfur and oxygen linking atoms. The potential value of flow photochemistry methods, as compared to batch photolysis, is also examined.