title: A new strategy for the enantioselective synthesis of carba-prostacyclin analogues based on organocopper conjugate addition to a bicyclic azoene and its application to the synthesis of 13,14-dinor-inter-p-phenylene carbacyclin.
abstract: An enantioselective synthesis of E/Z-13,14-dinor-inter-p-phenylene carbacyclin (E/Z-2d) by a new strategy has been realized that holds the prospect of serving as a general route for carba-prostacyclin analogues. The key intermediate in this synthesis is the bicyclic azoene Ts-9, and the key step is the regio- and stereoselective conjugate addition of the chiral arylcopper compound Cu-8d/P-n-Bu3 to the azoene with formation of hydrazone 7d. Enantioselective synthesis of azoene Ts-9 of 95% ee from ketone 4 was accomplished in four and five steps, respectively. Thus, enantioselective deprotonation of bicyclic ketone 4 with chiral base Li-10 and trapping of lithium enolate 11 with ClSiMe3 gave enol ether 12, which was chlorinated with N-chlorosuccinimide (NCS) to afford chloro ketone 13. Alternatively, chloro ketone 13 was also prepared upon chlorination of 11 with NCS. Chloro ketone 13 was converted to chloro hydrazone 14, which upon treatment with a mild base furnished azoene Ts-9. Arylcopper compound 8d of 98% ee was obtained in two steps from alcohol 16, which was prepared by enantioselective reduction of ketone 17 with (-)-diisopinocampheylchloroborane. Carbacyclin derivative E/Z-2d was found to be essentially inactive as an inhibitor of ADP induced human platelet aggregation, having an IC50 of >10 micromol/L.
authors.affiliation: Institut für Organische Chemie der Rheinisch-Westfälischen Technischen Hochschule Aachen, Professor-Pirlet-Strasse 1, D-52056 Aachen, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: van Bergen
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Gais
mesh_terms: D001391:Azo Compounds / Q000737:chemistry; D003300:Copper / Q000737:chemistry*; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry; D009942:Organometallic Compounds / Q000737:chemistry*; D011465:Prostaglandins, Synthetic / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: C456779:13,14-dinor-inter-p-phenylene carbacyclin; D001391:Azo Compounds; D009942:Organometallic Compounds; D011465:Prostaglandins, Synthetic; D003300:Copper; D011464:Epoprostenol