Codeine 1 and morphine 2, the principal constituents of opium, continue to attract the attention of organic chemists thanks to both their biological activities and their unique structure.[1] Their complex pentacyclic skeleton, which includes a quaternary carbon center, has stimulated extensive efforts. To date there have been more than 20 total syntheses of codeine (1), morphine (2), and thebaine (3).[2] We were interested in the synthesis of codeine for two reasons: first, codeine was found to be an allosteric potentiating ligand of nicotinic receptors, [3] and second we have a general program underway in the laboratory in which we have shown that tricyclic spirocyclohexadienones are valuable intermediates for the synthesis of natural products in the Amaryllidacea galanthamine-type, maritidine-type, and Aspidosperma alkaloids. [4] In an effort to develop new allosteric potentiating ligands of nicotinic receptors with a codeine-type scaffold, we initiated our own studies of a total synthesis of codeine. Herein we disclose a total diastereoselective synthesis of (AE )-codeine (1), which involves a new construction of the morphinan skeleton. The present study provides an efficient method for the elaboration of the quaternary carbon at C-13 and for the highly diastereoselective introduction of the C-14 stereogenic center of the morphinan system.Our retrosynthetic analysis of (AE )-codeine (1) is shown in Scheme 1. Codeine could be obtained from amine intermediate 4 by using an intramolecular hydroamination reaction to form the D ring. Compound 4 could in turn be prepared from aldehyde 5. In our synthetic pathway, we planned to use for the first time a Claisen-type rearrangement to introduce the C-14 substituent. This type of rearrangement applied to compound 6 would provide a precursor of the aldehyde 5 and control the stereochemistry of the substituent at C-14 of 5. The tricyclic amine 6 would be obtained from the spirocyclohexadienone 7 by a lactone ring opening with an amine followed by a spontaneous intramolecular Michael

In this paper we report the rearrangement of spirocyclohexadienones into dihydrotropones in basic conditions as a new method for the preparation of seven-membered ring ketones, which are key building blocks for the synthesis of tropoloalkaloids. DFT calculations and deuterium labeling studies support the mechanism we propose for this rearrangement, involving the ring opening of a spirocyclopropane intermediate followed by successive base-catalyzed 1,3-hydrogen shifts. The X-ray structure of the resulting dihydrotropone shows near-perfect planarity and the conjugation gain is likely to be the driving force of the reaction.