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

• Published in: Journal of the American Chemical Society Vol. 127; no. 50; pp. 17910 - 17920
• Main Authors: Kramp, Guido J, Kim, Mikhail, Gais, Hans-Joachim, Vermeeren, Cornelia
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 21.12.2005; Amer Chemical Soc
• Subjects: Alicyclic compounds; Alicyclic compounds, terpenoids, prostaglandins, steroids; Alkenes - chemistry; Alkylation; Antianginal agents. Coronary vasodilator agents; Azo Compounds - chemistry; Biological and medical sciences; Cardiovascular system; Chemistry; Chemistry, Multidisciplinary; Copper - chemistry; Exact sciences and technology; Iloprost - chemical synthesis; Iloprost - chemistry; Medical sciences; Organic chemistry; Organometallic Compounds - chemistry; Pharmacology. Drug treatments; Physical Sciences; Platelet Aggregation Inhibitors - chemical synthesis; Platelet Aggregation Inhibitors - chemistry; Preparations and properties; Science & Technology; Stereoisomerism; Tin Compounds - chemistry; INHALED ILOPROST; CROSS-COUPLING REACTIONS; CICAPROST; PGI; ABSOLUTE-CONFIGURATION; PHARMACOKINETICS; STEREOSELECTIVE-SYNTHESIS; DERIVATIVES; WITTIG REACTIONS; PROSTAGLANDIN ANALOGS; Stereoselectivity; Iloprost; Vasodilator agent; Prostaglandin I2; Asymmetric synthesis; Olefination; Arachidonic acid derivatives; Addition reaction; Bicyclic compound; Fibrinolytic; Total synthesis; Allylation
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja0558037

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 ω 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 ω-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.