title: Fully stereocontrolled total syntheses of the prostacyclin analogues 16S-iloprost and 16S-3-oxa-iloprost by a common route, using alkenylcopper-azoalkene conjugate addition, asymmetric olefination, and allylic alkylation.
abstract: In this article we describe fully stereocontrolled total syntheses of 16S-iloprost (16S-2), the most active component of the drugs Ilomedin and Ventavis, and of 16S-3-oxa-iloprost (16S-3), a close analogue of 16S-2 having the potential for a high oral activity, by a new and common route. The key steps of this route are (1) the establishment of the complete C13-C20 omega side chain of the target molecules through a stereoselective conjugate addition of the alkenylcopper derivative 9 to the bicyclic C6-C12 azoalkene 10 with formation of hydrazone 8, (2) the diastereoselective olefination of ketone 7 with the chiral phosphoryl acetate 39, and (3) the regio- and stereoselective alkylation of the allylic acetate 43 with cuprate 42. These measures allowed the 5E,15S,16S-stereoselective synthesis of 16S-2 and 16S-3, a goal which had previously not been achieved. Azoalkene 10 was obtained from the achiral bicyclic C6-C12 ketone 11 as previously described by using as key step an enantioselective deprotonation. The configuration at C16 of omega-side chain building block 9 has been installed with high stereoselectivity by the oxazolidinone method and that at C15 by a diastereoselective oxazaborolidine-catalyzed reduction of the C13-C20 ketone 23 with catecholborane. Surprisingly, a high diastereoselectivity in the reduction of 23 was only obtained by using 2 equiv of oxazaborolidine 24. Application of substoichiometric amounts of 24 resulted in irreproducible diastereoselectivities ranging from very high to nil.
authors.affiliation: Institut für Organische Chemie der Rheinisch-Westfälischen Technischen Hochschule Aachen, Landoltweg 1, D-52056 Aachen, Germany.
authors.forename: Guido J
authors.initials: GJ
authors.lastname: Kramp
authors.forename: Mikhail
authors.initials: M
authors.lastname: Kim
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Gais
authors.forename: Cornelia
authors.initials: C
authors.lastname: Vermeeren
mesh_terms: D000475:Alkenes / Q000737:chemistry; D000478:Alkylation; D001391:Azo Compounds / Q000737:chemistry; D003300:Copper / Q000737:chemistry; D016285:Iloprost / Q000138:chemical synthesis* / Q000737:chemistry; D009942:Organometallic Compounds / Q000737:chemistry; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000737:chemistry; D013237:Stereoisomerism; D017971:Tin Compounds / Q000737:chemistry
chemical_list: D000475:Alkenes; D001391:Azo Compounds; D009942:Organometallic Compounds; D010975:Platelet Aggregation Inhibitors; D017971:Tin Compounds; C031525:stannane; D003300:Copper; D016285:Iloprost