title: Synthesis of rac-(1R,4aR,9aR)-2-methyl-1,3,4,9a-tetrahydro-2H-1,4a-propanobenzofuro[2,3-c]pyridin-6-ol. An unusual double rearrangement leading to the ortho- and para-f oxide-bridged phenylmorphan isomers.
abstract: In an attempt to obtain the para-f isomer, rac-(1R,4aR,9aR)-2-methyl-1,3,4,9a-tetrahydro-2H-1,4a-propanobenzofuro[2,3-c]pyridin-6-ol, via mesylation of an intermediate 9[small alpha]-hydroxyphenylmorphan, we obtained, instead, a rearranged chloro compound with a 5-membered nitrogen ring, 7-chloro-3a-(2,5-dimethoxyphenyl)-1-methyl-octahydroindole. This indole underwent a second rearrangement to give us the desired para-f isomer. The structures of the intermediate indole and the final product were unequivocally established by X-ray crystallography. A resynthesis of the known rac-(1R,4aR,9aR)-2-methyl-1,3,4,9a-tetrahydro-2H-1,4a-propanobenzofuro[2,3-c]pyridin-8-ol, the ortho-f isomer, was achieved using the reaction conditions for the para-f isomer, as well as under Mitsunobu reaction conditions where, unusually, the oxide-bridge ring in the 5-phenylmorphan was closed to obtain the desired product. The synthesis of the para-f isomer adds an additional compound to those oxide-bridged phenylmorphans that were initially visualized and synthesized; the establishment of the structure and configuration of 8 of the theoretically possible 12 racemates has now been achieved. The X-ray crystallographic structure analysis of the para-f isomer provides essential data that will be needed to establish the configuration of a ligand necessary to interact with an opioid receptor.
authors.affiliation: Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, 20892-0815, USA. kr21f@nih.gov
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kodato
authors.forename: Joannes T M
authors.initials: JT
authors.lastname: Linders
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Gu
authors.forename: Koichiro
authors.initials: K
authors.lastname: Yamada
authors.forename: Judith L
authors.initials: JL
authors.lastname: Flippen-Anderson
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Deschamps
authors.forename: Arthur E
authors.initials: AE
authors.lastname: Jacobson
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
mesh_terms: D001572:Benzofurans / Q000138:chemical synthesis* / Q000737:chemistry*; D018360:Crystallography, X-Ray; D007536:Isomerism; D008968:Molecular Conformation; D015394:Molecular Structure; D009019:Morphinans / Q000138:chemical synthesis* / Q000737:chemistry*; D010087:Oxides / Q000737:chemistry*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry*
chemical_list: D001572:Benzofurans; D009019:Morphinans; D010087:Oxides; D011725:Pyridines; C488314:rac-(1R,4aR,9aR)-2-methyl-1,3,4,9a-tetrahydro-2H-1,4a-propanobenzofuro(2,3-c)pyridin-6-ol; C042531:phenylmorphan; C023666:pyridine