title: Experiments towards the synthesis of the ergot alkaloids and related structures. Part 8. The total synthesis of 4-methyl-2,3,4,4a,5,6-hexahydrobenzo[f]quinoline-2-carbonitrile hydrochloride hemihydrate, an immediate precursor of the despyrrole analogues of lysergic acid and its amides.
abstract: Exposure of the N-methoxycarbonyl-bicyclic-keto-acid 5 (improved preparation) to the Barnick beta-keto-acid synthesis yielded an aqueous solution of the sodium salts of the beta-keto-acids 26 and 27 which on heating at 60-65 degrees C furnished the N-methoxycarbonyl-tricyclic-ketone 9 (55%) plus the hydroxy-ketone 28 which on acid treatment raised the yield of 9 to 68%. Reduction (NaBH4) of 9 yielded the alcohol 32 (94%) which was treated with thionyl chloride followed by copper (I) cyanide and sodium iodide in acetonitrile to give the tricyclic-N-methoxycarbonyl nitrile 35 whose relative configuration was obtained by X-ray analysis. Attempts to remove the N-methoxycarbonyl group from 35 were unsuccessful. Conversion of the alcohol 32 to its methoxypropyl ether 41 followed by reaction with ethereal MeLi-LiBr yielded the amino-alcohol 39 (75%) converted to the N-formyl-tricyclic alcohol 42 with formic-acetic anhydride (70%). The alcohol 42 was then converted into the N-formyl nitrile 44 via the chloride 43 as employed in the earlier synthesis of the nitrile 35. Removal of the N-formyl group from the nitrile 44 was achieved by refluxing methanolic hydrochloric acid to give the required amino-nitrile hydrochloride 46 (91%) whose structure was confirmed by X-ray analysis. Reaction of the free base with methyl iodide in ethyl acetate in the presence of calcium carbonate furnished the N-methyl base 48 isolated as its hydrochloride, hemihydrate 49 (59%). The overall yield of 49 via this eleven-step synthesis was 3.4%.
authors.affiliation: Welsh School of Pharmacy, Cardiff University, UK.
authors.forename: Mark A E
authors.initials: MA
authors.lastname: Bowman
authors.forename: Ralph E
authors.initials: RE
authors.lastname: Bowman
authors.forename: Roy V
authors.initials: RV
authors.lastname: Davies
authors.forename: Gerry
authors.initials: G
authors.lastname: Haran
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Harris
authors.forename: H John
authors.initials: HJ
authors.lastname: Smith
authors.forename: Robert W
authors.initials: RW
authors.lastname: Steele
authors.forename: Nigel
authors.initials: N
authors.lastname: Walker
authors.forename: Keith
authors.initials: K
authors.lastname: Whiting
mesh_terms: D000577:Amides / Q000737:chemistry; D018360:Crystallography, X-Ray; D004876:Ergot Alkaloids / Q000138:chemical synthesis*; D008237:Lysergic Acid / Q000737:chemistry*; D015394:Molecular Structure; D011758:Pyrroles; D011804:Quinolines / Q000138:chemical synthesis*; D013237:Stereoisomerism
chemical_list: C476564:4-methyl-2,3,4,4a,5,6-hexahydrobenzo(f)quinoline-2-carbonitrile; D000577:Amides; D004876:Ergot Alkaloids; D011758:Pyrroles; D011804:Quinolines; D008237:Lysergic Acid