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Development of a Common Fully Stereocontrolled Access to the Medicinally Important and Promising Prostacyclin Analogues Iloprost, 3‐Oxa‐Iloprost and Cicaprost
Author(s) -
Gais HansJoachim,
Kramp Guido Johannes,
Wolters Dennis,
Reddy Leleti Rajender
Publication year - 2006
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200600187
Subject(s) - iloprost , prostacyclin , enantiopure drug , bicyclic molecule , ketone , stereoselectivity , chemistry , alkyne , stereochemistry , enantioselective synthesis , organic chemistry , catalysis , biochemistry
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 (15 S )‐ 29 . The highly stereoselective conversions of alcohol (15 S )‐ 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.