Asymmetrische Totalsynthese von 16(S)-Iloprost und 3-Oxa-16(S)-Iloprost mittels der Azoen-Strategie

The present dissertation describes completely stereocontrolled asymmetric syntheses of 16S-iloprost and of 16S-3-oxa-iloprost by a azoene strategy. As Ilomedin and Ventavis registrated iloprost (1:1 mixture of diastereomers at C16) serves as a drug against ischemic heart disease, peripheral vascular disease and primary pulmonary hypertension. The 16S-diastereomer is 5 to 20 times more potent than the 16R-diastereomer in inhibiting collagen-induced platelet aggregation. 3-oxa-16S-iloprost should be more stable against beta-oxidation of the alpha side chain. A bicyclic azoene was prepared in 5 steps with an overall yield of 27% (95% ee). The omega side chain building block was obtained diastereomerically and enantiomerically pure in 9 steps with an overall yield of 22%-26%. Key steps are the diastereoselective alkylation of an acylated oxazolidinone, the synthesis of an Enantiomerically pure Weinreb-Amid and its coupling with a monolithiated stannane with formation of stannylated keton. The diastereoselective reduction of the ketone was performed by using catecholborane and an oxazaborolidine catalyst. One of the major key steps is the conjugate 1,4 addition of an C13-C20 organocopper building block to the bicyclic C6-C12 azoene with formation of the corresponding hydrazone in 84% yield. The E-Isomer of 16S-iloprost was obtained in 11 steps with an overall yield of 5%. 3-Oxa-16S-iloprost was successfully prepared by using an asymmetric HWE-reaction with a chiral phosphonate as a key step in an overall yield of 6% over 14 steps with >99% de and >99% ee. Furthermore a new, asymmetric synthesis of a central building block was developed. From an enantiomerically pure aldehyde the corresponding alkyne was synthesized by using a new method. This alkyne was successfully transformed into an alkenylstannane with a palladium catalysed hydrostannation. After coupling of the Alkenylstannane with an enantiomerically pure Weinreb-amid the resulting ketone was reduced using the oxazaborolidine catalysed CBS-reduction. The corresponding alcohol was obtained in high yield and high diastereoselectivity. Following this route 3-oxa-16S-iloprost was prepared in an overall yield of 14% over 12 steps with >99% de and >99% ee.

Grantor dc:publisher

Publikationsserver der RWTH Aachen University

Year dc:date

2005

Author dc:creator

• Kramp, Guido Johannes

Contributors dc:contributor

• Gais, Hans-Joachim

• info:eu-repo/classification/ddc/540
• Iloprost
• Iloprostanaloga
• Totalsynthese
• Asymmetrische Synthese
• Hydrazon-Methode
• Chemie
• Prostacyclin
• Wirkstoffsynthese
• 1,4-Addition von Organokupfer-Verbindungen an Azoene
• CBS-Reduktion

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

ger

Identifier

https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-121710%22

OAI identifier oai:identifier

oai:publications.rwth-aachen.de:59976