Total Synthesis of the Terpenoid Phthalazinone Azamerone

• Applicant: Professorin Dr. Tanja Gulder
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2009 to 2010
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 132935049

The presented strategy provides a convergent, efficient, and short (19 overall steps) synthetic pathway to the unprecedented terpenoid phthalazinone azamerone (1). The preparation of 1 comprises three key steps, which all pose rewarding synthetic challenges. The formation of the cyclohexyl fragment 6 is achieved using a tandem deprotection/cyclization sequence. The chemoselective alignment of the synthetic steps towards 6 avoids the use of an orthogonal protective group strategy and therefore drastically reduces the number of steps. Essential for the synthesis of enantiomerically pure azamerone (1) is furthermore the selective generation of the stereocenter at C5 by a chemo- and thus regioselective 1,2-addition of 6 to the quinone moiety of the phthalazindienone 5. In-situ formation of a bidentate chiral Lewis acid complex with 5 does not only account for the chemoselective activation of the carbonyl atom at C5, but also directs the diastereotoposdifferentiating attack of the nucleophile. This concept for the introduction of chirality also avoids a lengthy chiral auxiliary manipulation. Formation of the dihydropyran fragment by a 6-endo-tet cyclization finalizes the framework of the natural product 1. Altogether, the synthesis of the structurally intriguing azamerone (1) provides the opportunity for the development of new synthetic strategies and thus contributes to the extension of the repertoire of modern synthetic chemistry.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Phil S. Baran, Ph.D.