| The potent analgesic properties morphine and its derivatives continue to encourage work aimed at its total synthesis. To date, however, all successful syntheses have proceeded through a common intermediate, viz. dihydrothebainone. The work described in this thesis involves an entirely different approach; in that morphine is envisioned as arising from a 2,3-disubstituted benzofuran functionalized in such a way as to undergo an intramolecular Diels-Alder reaction. The key intermediate in this approach is an enol ether or enol acetate of 2-acetyl-3- 2-(N-methyl-3-bubtenamido)ethyl -7-methoxybenzofuran (46). Although this desired triene was not synthesized, significant progress was made.;First, derivatives of benzaldehyde were elaborated in order to synthesize the necessary side chains at C-3. However, these compounds could not be cyclized to yield benzofurans. Therefore, second, routes were explored that involved the synthesis of the benzofuran and subsequent elaboration of the carbon chain at C-3. Thus, 2-acetyl-3-carbomethoxy-7-methoxybenzofuran (105) was synthesized. This was converted into the desired triene precursor but could not be subsequently converted to the corresponding enol ether or enol ester without concomitant migration of the unconjugated dienophile into conjugation with the carbonyl.;Finally, methods were explored that would protect the critical, migration-prone, double bond through the use of an organoselenium derivative, or preclude its migration by the introduction of a keto-function thereby removing the migrating proton.;The chemistry of related benzofurans was explored using the previously unknown desmethoxy analogue, 2-acetylbenzofuranyl-3-carboxylic acid (48). This work was then superseded by that using the appropriate methoxy substituted analogue which would lead to the desired morphine precursors. |
