fumiquinazoline-a and chaetominine

A total synthesis of the tripeptide alkaloid (-)-chaetominine (1) was achieved in 9.3% overall yield starting from commercially available D-tryptophan methyl ester, based on a short and straightforward (nine steps) sequence. The early stage introduction (first step) of the quinazolinone moiety and the late stage introduction (penultimate step) of the hydroxy group allowed a synthetic strategy devoid of protective groups. The key step of the process is the a-c tricyclic ring construction via an unprecedented NCS-mediated N-acyl cyclization on an indole ring to give tetrahydro-1H-pyrido[2,3-b]indole 11. In the penultimate step, oxidation of the tetracyclic intermediate 14 with oxaziridine 15 gave only one of the four possible diastereoisomers, the cis-diastereoisomer 16 resulting from the attack of the oxaziridine to the double bond face opposite to the c-d ring substituents. In the last step, the complete stereocontrol of the Et(3)SiH/TFA reduction of compound 16, probably involving a N-acyliminium ion, can be attributed to ring constrain, which forces the b-c ring junction in the more stable cis-orientation. (-)-Chaetominine (1) showed a negligible inhibitory activity on several cancer cell lines.

Topics: Drug Screening Assays, Antitumor; Humans; Indole Alkaloids; Molecular Structure; Peptides, Cyclic; Quinazolines; Stereoisomerism

The tricyclic hydroxy imidazolidinone was converted to chaetominine in seven steps in 22% overall yield. The key step was the construction of the delta-lactam by heating an amino ester with a catalytic amount of DMAP in toluene at reflux.

Topics: Amination; Biological Products; Crystallography, X-Ray; Imidazolidines; Indole Alkaloids; Lactams; Lactones; Molecular Structure; Quinazolines