Total synthesis of the cytostatic marine natural product dibromophakellstatin via three-component imidazolidinone anellation.
The tetracyclic pyrrole-imidazole alkaloid dibromophakellstatin from the marine sponge Phakellia mauritiana has been synthesized within seven steps from pyrrole in an 18% overall yield. The key step is a three-component assembly of a tricyclic enamide, a nitrene, and a carbamoyl building block, affording the imidazolidinone ring of dibromophakellstatin in one step. Notably, it is possible to employ the reagent EtO2CNHOTs in a double function as a source of the electrophilic nitrene and of a dipolar carbamoyl component. Use of debrominated precursor dipyrrolopyrazinones leads to much higher anellation yields and allowed us to develop a second generation synthesis. The cytostatic activity of dibromophakellstatin is confirmed.
Zöllinger
Michael
M
Ludwig Maximilian University, Department of Chemistry and Biochemistry, Butenandtstrasse 5-13, D-81377 Munich, Germany.
Mayer
Peter
P
Lindel
Thomas
T
D000588:Amines / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001688:Biological Products / Q000138:chemical synthesis* / Q000494:pharmacology; D001966:Bromine / Q000737:chemistry; D002219:Carbamates / Q000737:chemistry; D045744:Cell Line, Tumor; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D048288:Imidazolines / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008386:Marine Biology; D021241:Spectrometry, Mass, Electrospray Ionization; D013237:Stereoisomerism
D000588:Amines; D000970:Antineoplastic Agents; D001688:Biological Products; D002219:Carbamates; D007093:Imidazoles; D048288:Imidazolines; C104805:dibromophakellstatin; D001966:Bromine