Asymmetrische Totalsynthese von 13,14-Dinor-inter-p-phenylencarbacyclin mittels konjugierter 1,4-Addition an ein Azoen

The topic of this thesis was the total synthesis of a new prostacyclin analog, a phenylogous carbacyclin. The target compound contains an arylic omega-side chain in opposite to the natural prostacyclin. A methodology should be found which would allow the attachment of the complete side chain in one single step to the bicyclic diketone serving as the starting material. This method should also serve as a new synthetic strategy for the synthesis of other prostacyclin analogs with arylic and vinylic omega-side chains. The total synthesis was performed in 12 steps starting from the bicyclic diketone bicyclooctanedione. After the protection of one of the two carbonyl groups as an acetal, the resulting monoketone was deprotonated enantioselectively using a chiral lithium amide. The lithium enolate was trapped with trimethylsilyl chloride and the resulting silyl enol ether obtained with an ee-value of 90%. After the chlorination of the silyl enol ether, the obtained chloroketone was converted to the chlorotosylhydrazone. Treatment of the latter one with sodium bicarbonate gave an azoene. The azoene is, like alpha,beta-unsaturated ketones, a suitable substrate for conjugate additions with organocopper compounds. The conjugate addition to the azoene succeeded with phenyl copper as well as with the aryl copper compound containing the complete omega-side chain fragment. The conjugate addition delivered the alpha-arylated tosylhydrazone. The oxidative cleavage with benzene seleninic anhydride afforded the corresponding ketone. The ketone was reduced with NaBH4 stereoselectively to the desired alcohol. Cleavage of the acetal group and protection of the hydroxy groups led to the ketone which was needed for the following Wittig-reaction. The Wittig-reaction was carried out with (4-carboxybutyl)-triphenylphosphonium bromide / KOtBu in glyme. The protected prostacyclin analog was obtained in a E/Z-ratio of 72:28 in favour of the desired E-compound. Final deprotection of the hydroxy-groups delivered the target compound, the phenylogous carbacyclin. The total yield over 12 steps was 5.9%. The method which was used in this synthesis, the attachment of the complete side chain by a conjugate addition of an organocopper compound to a chiral azoene, can also be applied for the synthesis of other prostacyclin analogs with natural and unnatural side chains.

Grantor dc:publisher

Publikationsserver der RWTH Aachen University

Year dc:date

2002

Author dc:creator

• van Bergen, Marc

Contributors dc:contributor

• Gais, Hans-Joachim

• info:eu-repo/classification/ddc/540
• Chemie
• Carbacyclinderivate
• Phenylenverbindungen
• Totalsynthese
• Asymmetrische Synthese

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

ger

Identifier

https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-123750%22

OAI identifier oai:identifier

oai:publications.rwth-aachen.de:62160