Réactivité des noyaux indoliques vis à vis des nitrones alpha-chirales: Application à la synthèse multi-étapes de dérivés 11-aminés de l'azaelliptitoxine

Abstract : Azaelliptitoxin, an antineoplasic compound, has been rationally designed in silico from ellipticine and etoposide structures. The presence of the 2- and 3-indolylmethanamino scaffolds in the structure of the biologically active 11-amino derivatives has led us to develop two stereoselective syntheses of those compounds based on the nucleophilic addition of indoles onto alpha-chiral nitrones, developed in the laboratory. The first strategy has required the enantioselective synthesis of a new serinal, precursor of the desired nitrone, in which the beta-aminoalcool moiety is protected as an oxazolidinone ring. The nucleophilic addition of indole onto this alpha-chiral nitrone in acidic conditions has afforded the formation of two diastereoisomeric hydroxylamines, which could led to the synthesis of four 11-aminoderivatives of azaelliptitoxin in good yields. A second strategy has been imagined, based on the nucleophilic addition of 2 lithioindole onto either a N-Bocoxazolidine or a nitrone derivative, both prepared from L-serine. The access of some of those derivatives is here described. This study has led to the newly observed chimioselective pivaloylation of indolic cores vs. secondary benzylic amines. The work upon the depivaloylation of those structures highlighted a new chimioselective deprotection of indoles vs N-pivaloylated primary amines. Furthermore, those conditions allowed the chimioselective deprotection of secondary N pivaloylated amines vs. the N-pivaloylated primary amines.
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Theses
Chemical Sciences. Université Joseph-Fourier - Grenoble I, 2009. French


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Submitted on : Tuesday, October 27, 2009 - 9:46:47 AM
Last modification on : Tuesday, October 27, 2009 - 9:57:44 AM

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Julie Routier. Réactivité des noyaux indoliques vis à vis des nitrones alpha-chirales: Application à la synthèse multi-étapes de dérivés 11-aminés de l'azaelliptitoxine. Chemical Sciences. Université Joseph-Fourier - Grenoble I, 2009. French. <tel-00426625>

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