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En-route to 3-Spiroindolizines Containing Isoindole Ring Through Intra-molecular Arylation of Spiro-N-Acyliminium Species. A new Family of Potent Farnesyltransferase Inhibitors

Abstract

Based on N-acyliminium species, two efficient and rapid approaches to diversify spirocyclic systems connected with two different carbon centers to the isoindole ring have been developed. The imide reduction and the tandem oxidative cleavage of olefin/formyl-amide equilibration seemed to be, respectively, the key steps for these strategies. The ultimate intramolecular α-amidoalkylation reaction was finally achieved through arylation of α-acetoxy lactams or α-hydroxy lactams using, respectively, a Lewis acid or a Brönsted acid depending on the nature of N-acyliminium precursors. The latter led, in addition to the spiro-6–membered aza-heterocycles, to the formation of scarce spiro-5–membered analogues which shown promising inhibitory activities on human farnesyltransferase in the nanomolar range improving excellent IC50 values up to 1.5 nM.

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Publication details

The article was received on 21 Oct 2018, accepted on 07 Feb 2019 and first published on 07 Feb 2019


Article type: Paper
DOI: 10.1039/C8OB02612B
Citation: Org. Biomol. Chem., 2019, Accepted Manuscript

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    En-route to 3-Spiroindolizines Containing Isoindole Ring Through Intra-molecular Arylation of Spiro-N-Acyliminium Species. A new Family of Potent Farnesyltransferase Inhibitors

    A. Pesquet, H. Marzag, M. Knorr, C. Strohman, A. M. Lawson, A. GHINET, J. DuBois, F. Amaury, A. Daïch and M. Othman, Org. Biomol. Chem., 2019, Accepted Manuscript , DOI: 10.1039/C8OB02612B

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