Studies on the intramolecular Diels-Alder reaction: Total synthesis of cochleamycin A and efforts toward the total synthesis of integramycin.

摘要

The intramolecular Diels-Alder reaction is widely recognized as a powerful and versatile method for the assembly of complex bicyclic structures in synthetic organic chemistry and has been utilized as a key step in the total syntheses of a number of interesting bioactive natural products. We have studied the use of the intramolecular Diels-Alder reaction in the assembly of the hexahydroindene ring system of the anti-tumor substance cochleamycin A. This work enabled us to develop a concise, efficient total synthesis of cochleamycin A via the transannular variant of the intramolecular Diels-Alder reaction. This key reaction assembled all four rings of cochleamycin A and established four stereocenters in just one step.; Integramycin is a recently discovered inhibitor of the HIV-1 integrase enzyme that contains spiroketal and acyl tetramic acid side chains connected to an octahydronaphthalene nucleus. We have developed an efficient, highly stereoselective synthesis of the racemic octahydronaphthalene core unit of integramycin via an intramolecular Diels-Alder reaction. In the process, we made interesting observations regarding changes in the ring fusion selectivity of these reactions depending on the dienophilic double bond geometry. We have also prepared the key intermediate of this synthesis in enantiopure form, and have begun efforts toward the construction of the tetramic acid side chain.