The total syntheses of (+)-9-epi-dictyostatin (1a) and (-)-12,13-bis-epi-dictyostatin (1b), diastereomers of the antimitotic marine sponge-derived macrolide (-)-dictyostatin (1), were achieved by creating 11 stereogenic centers and 4 stereogenic double bonds with a high level of stereocontrol. The yield for the 29-step longest linear sequence from Roche ester was 1.53 and 1.52%, respectively. The final key steps to these unnatural products were the addition of vinylzincates C10-C26 to aldehyde C1-C9 (leading surprisingly to complete stereoselectivity for the 9R-configuration in 28a and for the 9S-configuration in 12,13-bis-epimeric 28b), followed by Yamaguchi macrolactonization and global deprotection. (-)-12,13-Bis-epi-dictyostatin (1b) displayed a dramatic decrease of cytotoxicity and of the affinity toward the paclitaxel binding site of microtubules.

Highly stereoselective total synthesis of (+)-9-epi-dictyostatin and (–)-12,13-bis-epi-dictyostatin / C. Zanato, L.L. Pignataro, A. Ambrosi, Z. Hao, C. Trigili, J.F. Díaz, I. Barasoain, C.M.A. Gennari. - In: EUROPEAN JOURNAL OF ORGANIC CHEMISTRY. - ISSN 1434-193X. - 2011:14(2011), pp. 2643-2661. [10.1002/ejoc.201100244]

Highly stereoselective total synthesis of (+)-9-epi-dictyostatin and (–)-12,13-bis-epi-dictyostatin

C. Zanato
Primo
;
L.L. Pignataro
Secondo
;
C.M.A. Gennari
2011

Abstract

The total syntheses of (+)-9-epi-dictyostatin (1a) and (-)-12,13-bis-epi-dictyostatin (1b), diastereomers of the antimitotic marine sponge-derived macrolide (-)-dictyostatin (1), were achieved by creating 11 stereogenic centers and 4 stereogenic double bonds with a high level of stereocontrol. The yield for the 29-step longest linear sequence from Roche ester was 1.53 and 1.52%, respectively. The final key steps to these unnatural products were the addition of vinylzincates C10-C26 to aldehyde C1-C9 (leading surprisingly to complete stereoselectivity for the 9R-configuration in 28a and for the 9S-configuration in 12,13-bis-epimeric 28b), followed by Yamaguchi macrolactonization and global deprotection. (-)-12,13-Bis-epi-dictyostatin (1b) displayed a dramatic decrease of cytotoxicity and of the affinity toward the paclitaxel binding site of microtubules.
Medicinal chemistry; Natural products; Total synthesis; Asymmetric synthesis; Antitumor agents; Macrocycles
Settore CHIM/06 - Chimica Organica
2011
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/156347
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