The first total synthesis of ratjadone was achieved using a highly convergent approach joining three subunits together with a Wittig olefination and a selective Heck reaction as the pivotal steps. Besides establishing a robust and reliable route for the synthesis of this orphan ligand, the configuration of unknown stereocenters could also be determined. This synthesis not only provides an additional access to a biologically important compound but also enables the synthesis of structural analogues for biological target identification.

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[structure: see text] The synthesis of the A,B,C-ring system (2) of hexacyclinic acid (1) is achieved starting from a selective Diels-Alder reaction followed by vinyl cuprate addition. The diastereoselective reduction of the ketone carbonyl at C16 could be achieved with LiAlH(4). An intramolecular Michael addition established the ring system stereoselectively, providing access to the selective generation of 9 out of the 14 stereocenters of hexacyclinic acid.

The coupling of three fragments by a Wittig olefination and a subsequent selective Heck reaction are the pivotal steps in the the first total synthesis of ratjadone (see picture), a cytotoxic as well as antibiotically effective polyketide. This synthesis enabled the elucidation of the absolute configuration of the natural product. In this way it should also be possible to synthesize structural analogues with which the various cellular processes mediated by ratjadone can be studied.