Synthetic approaches to the total synthesis of agelastatin A and intramolecular Diels-Alder reactions of 4-vinylimidazole derivatives

The work presented in this dissertation focuses on the development of new methods for the elaboration of simple imidazoles into complex molecules and is divided into two parts. The first part describes the development of ring closing metathesis (RCM) as a means to prepare bicyclic imidazoles. It was initially planned to apply this reaction in an approach to the oroidin-derived marine alkaloid agelastatin A. A number of RCM precursors were synthesized and evaluated in the RCM reaction either using the first or second generation Grubbs' catalysts. Unfortunately, none of the attempts to construct the 5-5 fused bicyclic system turned out to be successful except for substrates which possessed an allyl group at N1 and a vinyl group at C5. Attempts to transform the imidazole ring of a number of these substrates into an imidazolone also failed. It was found that, by using the second generation Grubbs' catalyst, and protonating N3, the RCM reaction works well for forming 5–6 fused bicyclic compounds in high yields and low catalyst loadings (5 mol%). This is the first demonstration that RCM reactions can be applied to imidazole-containing substrates. This method could be utilized to synthesize a number of imidazole-containing polycyclic compounds and natural products.; The second part of this dissertation describes the intramolecular Diels-Alder reactions of 4-vinylimidazole derivatives. This research seeks to develop the intramolecular Diels-Alder reaction of 4-vinylimidazole derivatives as a means to construct polycyclic compounds and for application in an approach to the total synthesis of ageliferin and congeners. Initial investigations have centered on investigation of the influence of protecting groups (such as trityl, benzyl and N-dimethylsulfamoyl) on the imidazole N1 position and on the dienophile structure. The synthesis and Diels-Alder reactions of a number of imidazole-based trienes from urocanic acid are described. To date only acetylenic dienophiles and precursors containing amino linkers participate successfully in the intramolecular Diels-Alder reaction. This may in part be due to the bulky nature of the protecting group. Future investigations of the 5-vinylimidazole derivatives may address this issue and the work to synthesize the 5-vinylimidazole D-A precursors has been initialized. An efficient method to prepare amino-containing D-A precursors has been developed.