| Abstract
| - A strategy was devised for the synthesis of codeine that employed intramolecular insertion of acarbenoid into a benzylic methine CH bond for creation of the C13 quaternary center andconstruction of the pentacyclic skeleton of the alkaloid. The synthesis began from isovanillin, andasymmetry was introduced through catalytic hydrogenation of its Stobbe condensation product 7over a chiral catalyst (8). The product (S)-9 was advanced to tetralone 12, which underwent Robinsonannulation to give the phenanthrenone 33. The latter was brominated and treated with base toafford the fused benzofuran 35. Reduction with hydride followed by catalytic hydrogenation producedthe tetracycle 44, which was converted to diazoketone 48. The latter was reacted in the presenceof catalytic Rh2(OAc)4 to furnish the pentacyclic product 49. Beckmann rearrangement of the derivedoxime brosylate 59 gave lactam 57, and the synthesis of (+)-1 (the nonnatural enantiomer of codeine)was completed after oxidation to 63, introduction of Δ7,8 unsaturation, and exhaustive reduction.
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