Synthetic studies of himbacine, a potent antagonist of the muscarinic M2 subtype receptor 1.: Stereoselective total synthesis and antagonistic activity of enantiomeric pairs of himbacine and (2′S,6′R)-diepihimbacine, 4-epihimbacine, and novel himbacine congeners

Total synthesis of an enantiomeric pair of himbacine 1 and ent-1 was achieved in a highly stereoselective manner by employing an intermolecular Diels-Alder reaction of tetrahydroisobenzofuran 8 with chiral furan-2(5H)-one (S)-9 and (R)-9, respectively, as a key step. An enantiomeric pair of (2'S,6'R)-diepihimbacine 24 and ent-24, 4-epihimbacine 4-epi-1, and novel himbacine congeners bearing the same tricyclic moiety as that of 1 were also successfully prepared by utilizing the key synthetic intermediates for 1, establishing the convergency and flexibility of the explored synthetic route. All of the synthesized compounds used were subjected to muscarinic M-2 subtype receptor binding affinity assay, disclosing novel aspects of the structure-activity relationships for 1. (C) 2002 Elsevier Science Ltd. All rights reserved.