Studies toward the total synthesis of ingenol, and, Stereoselective synthesis of polycyclic ring systems via the tandem Diels-Alder reaction

Ingenol 1 is a highly oxygenated tetracyclic diterpene which mimics the function of diacylglycerol, the endogenous activator of protein kinase C. One of the most imposing challenges in the synthesis of ingenol is the establishment of the highly strained inside-outside or trans-intrabridgehead stereochemical relationship of the carbocyclic ring system of the ingenanes. Previous work from our laboratories has demonstrated that the intramolecular dioxenone photocycloaddition leads to this unique stereochemical feature of ingenol.* This dissertation describes the studies for the total synthesis of ingenol with a method for the preparation of C-3 oxygenated ingenane tricycles 3. Also, it addresses the preparation of biologically active ingenol analogs, along with compound 18 which includes all the functionality of the A and B rings of ingenol with correct stereochemistry, to elucidate the structure activity relationships (SAR) for the development of inhibitors.* Stereo- and regioselective oxidations of 116, followed by elimination of the C-6 hydroxyl group via the cyclic sulfate intermediate 305 were the key steps for the completion of the B ring functionalization. The eliminated product 306 has all the functionality of the B ring of ingenol, including the C-4, C-5 hydroxyl groups with correct stereochemistry, as well as the C-3 hydroxyl group, which might be utilized for full functionalization of the A ring. The intermolecular Diels-Alder reaction of a monoprotected or unprotected bis-diene 1 with a bis-dienophile 2, followed by a second, intramolecular Diels-Alder reaction leads to the stereoselective construction of polycyclic ring systems, 3, with high levels of stereochemical control.* This tandem Diels-Alder reaction methodology was applied to the selective construction of the tricyclic core of the taxane diterpenes 53 from two simple acyclic precursors (55 and 2). In an effort to determine the factors governing the observed stereoselectivities, we performed ab initio calculations on the transition state structures of the cycloadditions.* ftn*Please refer to the dissertation for diagrams