| Chapter 1. The synthesis of the fully functionalized A/B ring system of arisugacin A, a potent acetylcholinesterase inhibitor, using various synthetic methodologies is described. Cycloaddition reactions such as the Diels-Alder reaction and 1,3-dipolar cycloadditions were successful in constructing the trans decalin ring structure. During these efforts, we have discovered the novel formation of pyrazolines via the 1,3-dipolar cycloaddition of diazoketones and methyl vinyl ketone. The highly functionalized A/B ring system was finally synthesized, via a triene electrocyclization followed by a [4+2] cycloaddition of singlet oxygen as key steps, in 16 steps and 9.3% overall yield starting from hydroxy beta-ionone.; Chapter 2. As part of the synthesis of arisugacin A, the intramolecular Diels-Alder reaction of furans (IMDAF) having allene dienophiles to generate oxatricyclic systems is described. The IMDAF reaction of the precursors having alkene dienophiles gave the cycloadducts in low yield, presumably due to a facile retro Diels-Alder reaction. However, the analogous allenic ketone afforded the desired cycloadduct in 91% yield in the presence of dimethylaluminum chloride. The allene bearing an alkyl substituent on the terminal carbon produced only the single diastereomer presumably due to greater steric hindrance between the terminal alkyl substituent and the furan methyl group. We finally were able to achieve complete chirality transfer of the stereochemistry of an optically active allene to the carbon framework of the oxatricyclic system starting from an optically active propargylic alcohol.; Chapter 3. The synthesis of the pyrone unit of the arisugacin A and the coupling reactions of the advanced A/B ring system with the pyrone unit are described. During the transformation of the functional groups in the A/B ring system, we discovered a novel rearrangement of the highly oxygenated A/B ring to a bridged bicyclic furan via a multistep process involving a retro-aldol reaction followed by cyclization. Successful coupling of the two pieces was achieved by two methods: (a) the indium-catalyzed reaction of the lactol and a 4-hydroxy-2-pyrone; (b) Knoevenagel condensation of the aldehyde and the hydroxy pyrone. However, to date all synthetic efforts from these compounds to arisugacin A have failed. |
