APPROACHES TO THE TOTAL SYNTHESIS OF DICTYOSTATIN AND SYNTHESIS OF EPI-DICTYOSTATINS

The sponge-derived macrolide (-)-dictyostatin has been reported to exhibit paclitaxel-like effects on cellular microtubules and to inhibit human cancer cell proliferation at low nanomolar concentrations, with superior activity to that of the already very active discodermolide. Moreover, dictyostatin potently inhibits the binding of radiolabeled paclitaxel, discodermolide, and epothilone B to microtubules, and is also very active against paclitaxel-resistant cancer cell lines. Accordingly, (-)-dictyostatin is one of the most potent microtubule stabilizing agents discovered to date. In this PhD thesis, I report on a highly stereoselective total synthesis of (+)-9-epi-dictyostatin, whose key steps is the coupling reaction between two fragments, C1-C9 and C10-C26, followed by Yamaguchi macrolactonization and global deprotection. Eleven stereogenic centers and four stereogenic double bonds were obtained with a high level of stereocontrol. Surprisingly, the addition of vinylzincate C10-C26 to aldehyde C1-C9 led to a complete stereoselectivity in favor of the 9R-epimer, which is opposite to what reported by Ramachandran for a very similar coupling (P. V. Ramachandran, A. Srivastava, D. Hazra, Org. Lett. 2007, 9, 157-160). The synthesis of 12,13-bis-epi-dictyostatin, a non-natural analog of (-)-dictyostatin, has been also started and brought to its final steps. The development of dictyostatin analogs is an appealing goal from a pharmaceutical perspective, which provides interesting opportunities for structural simplification (whilst maintaining biological potency) and for better understanding the structure-activity relationships of this class of antitumor agents.

Grantor dc:publisher

Università degli Studi di Milano

Year dc:date

2010

Author dc:creator

• ZANATO, CHIARA

Contributors dc:contributor

• Tutor: Cesare Gennari ; Coordinator: Silvia Ardizzone
• C. Zanato
• GENNARI, CESARE MARIO ARTURO
• ARDIZZONE, SILVIA

• Antitumor agents
• Asymmetric synthesis
• Macrocycles
• Natural products
• Total synthesis
• Settore CHIM/06 - Chimica Organica

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

eng

Identifier

10.13130/zanato-chiara_phd2010-12-09

OAI identifier oai:identifier

oai:air.unimi.it:2434/150070