title: Stereocontrolled synthesis of cis-dibenzoquinolizine chlorofumarates: curare-like agents of ultrashort duration.
abstract: The quaternizations of dibenzoquinolizines 9 and 14 with 3-halo-1-propanols are highly cis-selective (94-100% cis), results consistent with the N-methylation of O-methylcapaurine (7b), but in contrast to the proposed trans-stereochemistry of dibenzo[a,h]quinolizine methiodide 10 and the analogous quaternizations of 1-benzyl- and 1-phenylisoquinoline congeners 5b and 5c. In this report, we describe stereoselective preparation of the unique cis-dibenzoquinolizinium propanols 15 and 16and their transformation into bis- and mixed-onium chlorofumarates 19, 20ab, and 26. Dibenzo[a,g]quinolizinium propanol 15 was prepared enantioselectively in three steps from dihydroisoquinoline 11. Asymmetric transfer hydrogenation of 11 in the presence of triethylamine/formic acid and Noyori's chiral ruthenium catalyst 12 produced R-(-)-5',8-dimethoxynorlaudanosine (13) in 98% yield and 87% ee. Pictet-Spengler cyclization of 13 in formalin/formic acid afforded the dibenzo[a,g]quinolizine 14 in 65% yield. Quaternization of 14 with 3-chloro-1-propanol under Finkelstein conditions generated cis-dibenzoquinolizinium propanol 15 in 85% yield with >94% cis-selectivity. The cis-dibenzo[a,h]quinolizinium propanol 16 was obtained as a single stereoisomer by reaction of the known tetramethoxyquinolizine 9 with neat 3-iodo-1-propanol. Bis-onium chlorofumarates 18 and 19 and the mixed-onium derivative 20ab were prepared by a pool synthesis procedure from (1R)-trans-6a, 16, and chlorofumaryl chloride (17). Mixed-onium alpha-chlorofumarate 26 was synthesized from (1S)-trans-6d, 15 and (+/-)-trans-2,3-dichlorosuccinic anhydride (22), employing a recently disclosed chlorofumarate mixed-diester synthesis. The title compounds (19, 20ab, and 26) displayed curare-like effects of ultrashort duration in rhesus monkeys.
authors.affiliation: Division of Medicinal Chemistry, GlaxoSmithKline Research & Development, Five Moore Drive, Research Triangle Park, NC 27709, USA.
authors.forename: I
authors.initials: I
authors.lastname: Kaldor
authors.forename: P L
authors.initials: PL
authors.lastname: Feldman
authors.forename: R A
authors.initials: RA
authors.lastname: Mook
authors.forename: J A
authors.initials: JA
authors.lastname: Ray
authors.forename: V
authors.initials: V
authors.lastname: Samano
authors.forename: A M
authors.initials: AM
authors.lastname: Sefler
authors.forename: J B
authors.initials: JB
authors.lastname: Thompson
authors.forename: B R
authors.initials: BR
authors.lastname: Travis
authors.forename: E E
authors.initials: EE
authors.lastname: Boros
mesh_terms: D000818:Animals; D005650:Fumarates / Q000138:chemical synthesis / Q000494:pharmacology; D008253:Macaca mulatta; D003473:Neuromuscular Nondepolarizing Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D011807:Quinolizines / Q000138:chemical synthesis / Q000494:pharmacology; D013237:Stereoisomerism; D013997:Time Factors
chemical_list: D005650:Fumarates; D003473:Neuromuscular Nondepolarizing Agents; D011807:Quinolizines