A straightforward total synthesis of (-)-chaetominine

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 - https://www.scopus.com/pages/publications/68349101069

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 -