Studies on complex pyridine alkaloids: Total synthesis of cystodytin J, diplamine, shermilamine B and of Micrococcin P1
Ciufolini, Marco A.
Doctor of Philosophy
Concise, efficient total syntheses of cystodytin J, diplamine and shermilamine B have been accomplished. These cytotoxic marine alkaloids display a novel pyridoacridine architecture that was readily assembled by a combination of two new processes developed in our laboratory: a pyridine-forming reaction and a photochemical insertion of a triplet nitrene into a C-H bond. The overall yield of diplamine is 12% over 7 steps. The synthesis of shermilamine B involves 11 steps with the overall yield of 8%. The first total synthesis of the antitumor agent, Micrococcin P1, a member of the biologically important family of thiostrepton antibiotics, is also described. Central to the success of this endeavor was the development of a greatly improved Hantzsch-type pyridine forming reaction. Additional chemical technologies featured in this synthesis include the use of transformations that remove the need for extensive purification of the various intermediates, the use of specially protected threonine units as precursors to the dehydroaminoacid components of micrococcin, extensive use of chemoselective thionation reactions in the presence of multiple reactive functionality, minimal protection, and closure of a 26 member ring. The longest linear sequence involves 23 steps and the overall yield along this pathway is 5.7%
Organic chemistry; Pharmaceutical chemistry