Development of a common fully stereocontrolled access to the medicinally important and promising prostacyclin analogues iloprost, 3-oxa-iloprost and cicaprost.
We describe new fully stereocontrolled syntheses of the prostacyclin analogues iloprost (2), the most active component of the drugs Ilomedin and Ventavis, and 3-oxa-iloprost (3), a derivative that is expected to have a significantly higher metabolic stability than 2 perhaps allowing an oral application. The syntheses are based on the same strategy and chiral bicyclic building block as used in the synthesis of cicaprost (4), the third most potent analogue that exhibits, besides prostacyclin-like activities, antimetastatic activities. Reaction of the enantiopure C6-C13 bicyclic aldehyde 17 with Cl(3)CCOOH/Cl(3)CCOONa afforded trichlorocarbinol 24 which was converted via mesylate 25 to the C6-C14 bicyclic alkyne 9. The palladium-catalysed hydrostannylation of alkyne 9 gave with high regio- and stereoselectivity the alkenylstannane 26, Sn/Li exchange of which afforded the E-configured alkenyllithium derivative 8. Coupling of the C6-C14 building block 8 with the enantiopure C15-C20 building block, the N-methoxyamide 7, gave the C6-C20 bicyclic ketone 6 in high yield without epimerisation at C16. The configuration at C15 of iloprost (2) and 3-oxa-iloprost (3) was established through a highly diastereoselective reduction of ketone 6 with catecholborane and the chiral oxazaborolidine 28 which furnished alcohol (15S)-29. The highly stereoselective conversions of alcohol (15S)-29 to iloprost (2) and 3-oxa-iloprost (3), which include as key stereoselective steps an olefination with a chiral phosphonoacetate and a copper-mediated allylic alkylation, have already been described.
Gais
Hans-Joachim
HJ
Institut für Organische Chemie der Rheinisch-Westfälischen Technischen Hochschule (RWTH) Aachen, Landoltweg 1, 52056 Aachen, Germany. Gais@RWTH-Aachen.de
Kramp
Guido Johannes
GJ
Wolters
Dennis
D
Reddy
Leleti Rajender
LR
D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D016285:Iloprost / Q000031:analogs & derivatives* / Q000138:chemical synthesis*; D011465:Prostaglandins, Synthetic / Q000138:chemical synthesis*; D013237:Stereoisomerism; D014665:Vasodilator Agents / Q000138:chemical synthesis
D011465:Prostaglandins, Synthetic; D014665:Vasodilator Agents; D011464:Epoprostenol; D016285:Iloprost; C043867:cicaprost