Abstract
Norzoanthamine (1), a marine alkaloid isolated from the colonial zoanthid Zoanthus sp., has a densely functionalized heptacyclic ring system including two aminal structures and four quaternary asymmetric carbon centers on the C-ring. Since 1 not only inhibits IL-6 production, but also suppresses the decrease in bone weight and strength in ovariectomized mice, norzoanthamine has been regarded as a promising candidate for an osteoporotic drug. One of the critical problems in the total synthesis of zoanthamine alkaloids may be the stereoselective construction of the four quaternary asymmetric carbon centers in the C-ring. In order to overcome this critical problems, we designed a synthetic strategy employing an intramolecular Diels-Alder reacion as the key step. Triene 8, the key precursor for the Diels-Alder reaction, was efficientry and highly stereoselectively synthesized by a tandem conjugate addition-aldol strategy and subsequent photosensitized oxidation of a furan derivative. Stereoselective synthesis of the ABC ring system of the norzoanthamine bearing five asymmetric centers including two quaternary carbon atoms has been successfully accomplished by the intramolecular Diels-Alder reaction of the triene 8. The alkyne 4, a precursor of coupling reaction was synthesized from diketone 7 via stereoselective construction of C9 quaternary carbon atoms by intramolecular acylation and subsequent methylation. By the coupling reaction of the alkyne 4 with the amine segment 3 followed by several synthetic transformations, we have achieved the synthesis of the carboxylic acid 2, the key precursor of succsesive cyclization to the DEFG ring system. Further studies toward total synthesis of the norzoanthamine (1) are in progress.
