Enantioselective total syntheses of acylfulvene, irofulven, and the agelastatins

I. Enantioselective Total Synthesis of (-)-Acylfulvene, and (-)-Irofulven We report the enantioselective total synthesis of (-)-acylfulvene and (-)-irofulven, which features metathesis reactions for the rapid assembly of the molecular framework of these anti tumor agents. We discuss (1) the application of an Evans Cu-catalyzed aldol addition reaction using a strained cyclopropyl ketene thioacetal, (2) an efficient enyne ring-closing metathesis cascade reaction in a challenging setting, (3) the reagent, IPNBSH, for a late stage reductive allylic transposition reaction, and (4) the final ring-closing metathesis/dehydrogenation sequence for the formation of (-)-acylfulvene and (-)-irofulven. II. Total Synthesis of the (-)-Agelastatin Alkaloids The pyrrole-imidazole super-family of marine alkaloids, derived from linear clathrodinlike precursors, constitutes a diverse array of structurally complex natural products. The bioactive agelastatins are members of this family that have a tetracyclic molecular framework incorporating C4-C8 and C7-N12 bond connectivities. We provide a hypothesis for the formation of the unique agelastatin architecture that maximally exploits the intrinsic chemistry of plausible biosynthetic precursors. We report the concise enantioselective total syntheses of the agelastatin alkaloids, including the first total syntheses of agelastatins C and E. Our gram-scale chemical synthesis of agelastatin A was inspired by our hypothesis for the biogenesis of the cyclopentane C-ring and required the development of new transformations including an imidazolone-forming annulation reaction and a carbohydroxylative trapping of imidazolones.

Department dc:contributor.department

Massachusetts Institute of Technology. Dept. of Chemistry.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2010

Author dc:creator

• Siegel, Dustin S. (Dustin Scott), 1980-

Advisor dc:contributor.advisor

• Mohammad Movassaghi.

• Chemistry.

Statement dc:rights

• M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/60817

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/60817