TY - JOUR
T1 - A straightforward total synthesis of (-)-chaetominine
AU - Malgesini, Beatrice
AU - Forte, Barbara
AU - Borghi, Daniela
AU - Quartieri, Francesca
AU - Gennari, Cesare
AU - Papeo, Gianluca
N1 - Funding Information:
Italian Grant. Grant Number: FIRB RBNE03 LF7X; Ministero dell′Istruzione, dell′Universitá e della Ricerca.
Copyright:
© 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
PY - 2009/8/10
Y1 - 2009/8/10
N2 - 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 con-struction via an unprecedented NCSmediated 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.
AB - 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 con-struction via an unprecedented NCSmediated 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.
KW - Alkaloids
KW - Amino acids
KW - Lactams
KW - Natural products
KW - Total synthesis
UR - http://www.scopus.com/inward/record.url?scp=68349101069&partnerID=8YFLogxK
U2 - 10.1002/chem.200900793
DO - 10.1002/chem.200900793
M3 - Article
C2 - 19562787
AN - SCOPUS:68349101069
SN - 0947-6539
VL - 15
SP - 7922
EP - 7929
JO - Chemistry - A European Journal
JF - Chemistry - A European Journal
IS - 32
ER -