An efficient and short enantioselective synthesis of (S)- and (R)-tolterodine was performed by asymmetric hydrogenation of a coumarin intermediate, easily obtained by a Heck reaction from inexpensive and commercially available starting materials.
Advantage being taken of the versatility of the siloxydiene TBSOP in asymmetric synthesis, (6S,7R,8S,8aR) -6,7,8-trihydroxyindolizidine 11 has been assembled from the L-threose derivative 1 in six or eight steps in 22-30% overall yield. Pivotal to the success of this total synthesis venture is the ready availability of unsaturated lactam 2 with complete stereocontrol. As a corollary, the synthesis of the k n o w n indolizidine enantiomer ent-I 1 confirms the feasibility of the procedure. The structure of compound 5 has been determined by X-ray crystallography.
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