title: Asymmetric synthesis of 3-oxa-15-Deoxy-16-(m-tolyl)-17,18,19,20-tetranorisocarbacyclin and its neuroprotective analogue 15-Deoxy-16-(m-tolyl)-17,18,19,20-tetranorisocarbacyclin based on the conjugate addition-azoalkene-asymmetric olefination strategy.
abstract: A fully stereocontrolled synthesis of 3-oxa-15-deoxy-16-(m-tolyl)-17,18,19,20-tetranorisocarbacyclin (3-oxa-15-deoxy-TIC, 7 b) and a formal one of 15-deoxy-16-(m-tolyl)-17,18,19,20-tetranorisocarbacyclin (15-deoxy-TIC, 7 a) are described. 15-Deoxy-TIC is specific for the neuronal prostacyclin receptor (IP2) and exhibits neuroprotective activities, and the new 3-oxa-15-deoxy-TIC is expected to be metabolically more stable than 15-deoxy-TIC. The syntheses of 7 a and 7 b are based on the convergent conjugate addition-azoalkene-asymmetric olefination strategy. Key building blocks are the readily available bicyclic azoalkene 14 and the alkenylcopper derivative 15. The stereoselective conjugate addition of 15 to 14 gave hydrazone 13, which was stereoselectively converted to the bicyclic ketone 11. The key steps for the construction of the alpha side chain of 7 a and 7 b and the regioselective introduction of the endocyclic Delta6,6a double bond are: 1) a highly selective asymmetric olefination of ketone 11 with the chiral Horner-Wadsworth-Emmons reagent 28 and 2) a regioselective deconjugation of the alpha,beta-unsaturated ester (E)-10 with the chiral lithium amide 29, which gave the beta,gamma-unsaturated ester anti-9 with high selectivity. The homoallylic alcohol 8 served at a late stage as the joint intermediate in the syntheses of 7 a and 7 b. While an etherification of 8 furnished, after hydrolysis and deprotection, 3-oxa-15-deoxy-TIC, its alkylation afforded alcohol 37, the known precursor for the synthesis of 15-deoxy-TIC.
authors.affiliation: Institut für Organische Chemie, Rheinisch-Westfälischen Technischen Hochschule (RWTH) Aachen, Landoltweg 1, 52056 Aachen, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: van de Sande
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Gais
mesh_terms: D000475:Alkenes / Q000737:chemistry*; D000959:Antihypertensive Agents / Q000138:chemical synthesis*; D001391:Azo Compounds / Q000737:chemistry*; D001643:Bridged Bicyclo Compounds / Q000737:chemistry; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D006835:Hydrazones / Q000737:chemistry; D007202:Indicators and Reagents; D007659:Ketones / Q000737:chemistry; D008956:Models, Chemical; D009942:Organometallic Compounds / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: C449380:15-deoxy-(16-m-tolyl)-17,18,19,20-tetranorisocarbacyclin methylester; C401841:15-deoxy-16-m-tolyl-17,18,19,20-tetranorisocarbacyclin; D000475:Alkenes; D000959:Antihypertensive Agents; D001391:Azo Compounds; D001643:Bridged Bicyclo Compounds; D006835:Hydrazones; D007202:Indicators and Reagents; D007659:Ketones; D009942:Organometallic Compounds; D011464:Epoprostenol