An Enantioselective Synthesis of Cis Perhydroisoquinoline LY235959.
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.
Hansen
Marvin M.
MM
Chemical Process Research and Development Division, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285-4813.
Bertsch
Carl F.
CF
Harkness
Allen R.
AR
Huff
Bret E.
BE
Hutchison
Darrell R.
DR
Khau
Vien V.
VV
LeTourneau
Michael E.
ME
Martinelli
Michael J.
MJ
Misner
Jerry W.
JW
Peterson
Barry C.
BC
Rieck
John A.
JA
Sullivan
Kevin A.
KA
Wright
Ian G.
IG