Tandem reactions morphine

This intramolecular etherification approach has successfully been applied to the syntheses136 of siccanin137 and clusifoliol,136 and a formal synthesis of morphine.138 Examples of tandem inter- and intramolecular etherification reactions have also been reported which convert catechol and o-aminophenol derivatives into benzodioxins (Equation (24)),139-141 benzodioxepines,142 and morpholines.139,140... 

In 1992, Parker and Fokas reported the short step (11 steps) synthesis of racemic dihydroisocodeine, which completes a formal synthesis of codeine and morphine [58]. The key feature of their synthesis are (1) a construction of an aryl ether moiety (connection of the A and C rings) by Mitsunobu reaction, (2) a tandem radical cyclization of aryl bromide possessing the C-ring precursor to generate the A-B-C-E ring of morphine, and (3) a hydroamination for the construction of the D-ring by the reaction of a tosylamide with Li/NH3. In 2006, they reported the chiral version of the synthesis of dihydrocodeinone [59]. 

In this original and imaginitive approach, a rapid assembly of the phenanthrene core of morphine, containing a novel non-aromatic A ring, was achieved in an intermolecular Diels-Alder reaction between quinone 173 (prepared from 3-methoxy-2-hydroxy benzaldehyde in 7 steps and an overall yield of 35%) and diene 174 (from 1,4-cyclohexanedione monoethylene ketal in 2 steps with an overall yield of 30%), Scheme 20. In one of several unsuccesful attempts to aromatize ring A, an unexpected tandem... 

The elegant formal total synthesis of morphine, accomplished by Parker, shows some similarities to that of Fuchs through analogous disconnections. In both syntheses, the core of the molecule was formed as a result of a tandem process in this case as a result of a radical cascade.79 80 The immediate cyclization precursor 191 was prepared via a Mitsunobu reaction between monoprotected cw-diol 189 (prepared in 8 steps from 2-((3-methoxyphenyl)ethylamine) in 47% overall yield) and phenol 188, followed by cleavage of the silyl ether, Scheme 21. The key step, homolytic cleavage of the Ci2-Br... 

A tandem Heck carbocyclization-intramolecular oxygen trapping reaction was used to construct the fused carbocycle and dihydrobenzofuran 114 moieties of the morphine framework (Scheme 56) (105,106). 

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