A total synthesis of the tripeptide alkaloid (-)-chaetominine (1) was achieved in 9.3% overall yield starting from commercially available dtryptophan 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 constructionvia 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 Et3SiH/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.

A Straightforward Total Synthesis of (-)-Chaetominine / B. Malgesini, B. Forte, D. Borghi, F. Quartieri, C.M.A. Gennari, G. Papeo. - In: CHEMISTRY-A EUROPEAN JOURNAL. - ISSN 0947-6539. - 15:32(2009), pp. 7922-7929. [10.1002/chem.200900793]

A Straightforward Total Synthesis of (-)-Chaetominine

C.M.A. Gennari
Penultimo
;
2009

Abstract

A total synthesis of the tripeptide alkaloid (-)-chaetominine (1) was achieved in 9.3% overall yield starting from commercially available dtryptophan 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 constructionvia 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 Et3SiH/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.
alkaloids ; amino acids ; lactams ; natural products ; total synthesis
Settore CHIM/06 - Chimica Organica
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/66240
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