A straightforward total synthesis of (-)-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.
Malgesini
Beatrice
B
Chemical Core Technologies, Nerviano Medical Sciences, Viale Pasteur 10, 20014 Nerviano (MI) (Italy).
Forte
Barbara
B
Medicinal Chemistry, Nerviano Medical Sciences, Viale Pasteur 10, 20014 Nerviano (MI) (Italy), Fax: (+39) 0331581347.
Borghi
Daniela
D
Chemical Core Technologies, Nerviano Medical Sciences, Viale Pasteur 10, 20014 Nerviano (MI) (Italy).
Quartieri
Francesca
F
Chemical Core Technologies, Nerviano Medical Sciences, Viale Pasteur 10, 20014 Nerviano (MI) (Italy).
Gennari
Cesare
C
Dipartimento di Chimica Organica e Industriale, Centro Interdipartimentale C.I.S.I. Università degli Studi di Milano, Via G. Venezian 21, 20133 Milano (Italy).
Papeo
Gianluca
G
Medicinal Chemistry, Nerviano Medical Sciences, Viale Pasteur 10, 20014 Nerviano (MI) (Italy), Fax: (+39) 0331581347.
D004354:Drug Screening Assays, Antitumor; D006801:Humans; D026121:Indole Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000737:chemistry; D011799:Quinazolines / Q000737:chemistry; D013237:Stereoisomerism
D026121:Indole Alkaloids; D010456:Peptides, Cyclic; D011799:Quinazolines; C522312:chaetominine; C419468:fumiquinazoline A; C541864:kapakahine B