A total synthesis of aphidicolin

A formal total synthesis of aphidicolin, an important antitumor agent, has been accomplished. Completion of this synthesis required the development of novel methodology. Virtually all of the previous syntheses of aphidicolin share a common difficulty in the construction of the C-9 and C-10 vicinal quaternary centers. In order to solve this problem an investigation into the Michael reaction was launched. This study has revealed that steric encumbrance may be overcome by electronic activation of the acceptor. In fact, two withdrawing substituents were found to make possible the addition of the kinetic enolates of cyclohexenones to β, β-disubstituted acceptors. Several combinations of carboethoxy, cyano, and sulfinyl substituents were utilized. Also, use of sulfinyl butenolides as acceptors demonstrated that considerable stereochemical control may be exercised over the Michael reaction. In addition to work on the Michael reaction, the utility of a novel annulation procedure was demonstrated in the one-pot construction of the AB rings of aphidicolin. The required desulfurization of an α-sulfinyl lactone in the presence of an enone resulted in the development of a new, mild desulfurization agent. Some difficulty was encountered in the dissolving metal reduction of the A ring enone to provide the required trans decalin stereochemistry of the AB ring system of aphidicolin. However, this problem was solved by the construction of the D ring of aphidicolin prior to the dissolving metal reduction. This work resulted in the synthesis of an intermediate in Corey's total synthesis of aphidicolin. This synthesis is approximately 15 steps long, which is competitive with the shortest reported synthesis of aphidicolin. Furthermore, this synthesis is the most efficient reported to date, providing the natural product in approximately 10% overall yield.

Name thesis:degree_name

Ph. D.

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Chemistry

Department dc:contributor.department

Chemistry

Grantor dc:publisher

Virginia Polytechnic Institute and State University

Year dc:date.issued

1985

Author dc:creator

• Kennedy, Robert M.

Chair dc:contributor.committeechair

• Holton, R.A.

Committee members dc:contributor.committeemember

• Dorn, Harry C.
• Mason, John G.
• Kingston, David G. I.
• Hanson, Brian E.

Statement dc:rights

• In Copyright

Licence dc:rights.uri

• http://rightsstatements.org/vocab/InC/1.0/

Language dc:language.iso

en_US

Handle dc:identifier.uri

http://hdl.handle.net/10919/54307

OAI identifier oai:identifier

oai:vtechworks.lib.vt.edu:10919/54307