title: An Enantioselective Synthesis of Cis Perhydroisoquinoline LY235959.
abstract: A novel synthesis of NMDA receptor antagonist LY235959 (1) has been achieved in 13% overall yield and 17 steps from (R)-pantolactone (7). Highlights of the synthesis include (a) use of a chiral auxiliary controlled asymmetric Diels-Alder reaction to provide the desired absolute and relative stereochemistry at C-4a, C-6, and C-8a, (b) an efficient alkylation of hindered iodide 13 using a novel amide benzophenone imine, (c) oxidative ring opening of the [2.2.2] bicyclic system to simultaneously functionalize the molecule for intramolecular cyclization and phosphonate introduction, and (d) an increased understanding of how the C-3 stereochemistry may be controlled by thermodynamic equilibration. Synthesis of epimer 20 in high overall yield makes this synthetic route attractive for future development efforts.
authors.affiliation: Chemical Process Research and Development Division, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285-4813.
authors.forename: Marvin M.
authors.initials: MM
authors.lastname: Hansen
authors.forename: Carl F.
authors.initials: CF
authors.lastname: Bertsch
authors.forename: Allen R.
authors.initials: AR
authors.lastname: Harkness
authors.forename: Bret E.
authors.initials: BE
authors.lastname: Huff
authors.forename: Darrell R.
authors.initials: DR
authors.lastname: Hutchison
authors.forename: Vien V.
authors.initials: VV
authors.lastname: Khau
authors.forename: Michael E.
authors.initials: ME
authors.lastname: LeTourneau
authors.forename: Michael J.
authors.initials: MJ
authors.lastname: Martinelli
authors.forename: Jerry W.
authors.initials: JW
authors.lastname: Misner
authors.forename: Barry C.
authors.initials: BC
authors.lastname: Peterson
authors.forename: John A.
authors.initials: JA
authors.lastname: Rieck
authors.forename: Kevin A.
authors.initials: KA
authors.lastname: Sullivan
authors.forename: Ian G.
authors.initials: IG
authors.lastname: Wright