Asymmetric Total Synthesis of (+)-Codeine via Intramolecular Carbenoid Insertion

Abstract

A strategy was devised for the synthesis of codeine that employed intramolecular insertion of a carbenoid into a benzylic methine CH bond for creation of the C13 quaternary center and construction of the pentacyclic skeleton of the alkaloid. The synthesis began from isovanillin, and asymmetry was introduced through catalytic hydrogenation of its Stobbe condensation product 7 over a chiral catalyst (8). The product (S)-9 was advanced to tetralone 12, which underwent Robinson annulation to give the phenanthrenone 33. The latter was brominated and treated with base to afford the fused benzofuran 35. Reduction with hydride followed by catalytic hydrogenation produced the tetracycle 44, which was converted to diazoketone 48. The latter was reacted in the presence of catalytic Rh2(OAc)4 to furnish the pentacyclic product 49. Beckmann rearrangement of the derived oxime brosylate 59 gave lactam 57, and the synthesis of (+)-1 (the nonnatural enantiomer of codeine) was completed after oxidation to 63, introduction ...