Morphinane ring closure

Vanadium oxide chloride Oxidative coupling of phenols Morphinane ring closure with subsequent isocyclic ring opening... 

The Delft synthesis makes use of an acid-catalyzed ring closure - in fact an intramolecular aromatic alkylation - of a l-(3,5-dihydroxy-4-methoxybenzyl) isoquinoline derivative that is prepared starting from (natural) gallic acid. One of the hydroxyl groups is removed via a Pd/ C hydrogenation of the benzyl ether. Other catalytic steps play an important role some steps were improved recently [27]. The crucial step in the Rice synthesis makes use of a l-(2-bromo-5-hydroxy-4-methoxybenzyl)isoquinoline derivative that is also cyclized in an acid-catalyzed ring closure to the morphinan skeleton, followed by catalytic removal of the bromo substituent (Scheme 5.8). 

The addition of acid to Az-piperideine results in an iminium ion that readily reacts with nucleophilic species. This reaction has been particularly useful for the formation of carbon-carbon bonds in alkaloid total synthesis. For example, key steps in the total synthesis of ( )-porantherine (equation 36) (74JA6517), coccinelidine (equation 37) (77H(7)685) and eburnamonine (equation 38) (65JA1580) were acid-catalyzed ring closures between A2-piperideine derivatives and ends. Even the weakly nucleophilic carbon-carbon double bond can participate in this type of reaction (80JA5955), as has been demonstrated by a recent total synthesis of a morphinan derivative (Scheme 13). 

Treatment of (16-3) with sodium borohydride leads to the selective reduction of the enamine bond to lead to the tetrahydropyridine (16-4). This intermediate undergoes ring closure with a strong acid to give the benzomorphan (16-5) in direct analogy to the more complex morphinans. The product consists predominantly of the isomer that bears the equatorial secondary methyl group [18],... 

Evans and Mitch( 101 elaborated this synthesis to afford a general approach to morphinans and to include a total synthesis of ( )-morphine (Scheme 3.7). The diastereomerically pure aziridinium salt, 43, was prepared as illustrated and converted to the aldehyde (44) in 95% yield simply by dissolving in anhydrous DMSO at ambient temperature (Kornblum oxidation). Lewis acid catalyzed ring closure occurred in high yield (80%) to the isomorphinan-10-ol... 

With the related 6-methoxy compound shown the cyclisation to a morphinan with hydrochloric acid proceeded to the unwanted product C in 37% yield and the desired one in only a 3% yield (ref. 179). The same precursor, synthesised from 2-(3-methoxyphenyl)ethylamine and 3,4-dimethoxyphenylacetic acid by amide formation and ring closure by the Bischler-Napieralski cyclisation, followed by reduction, methylation and Birch reduction, was used by others with similar results (ref. 180). The route constitutes a synthesis of morphine by the use of the final steps of earlier work (refe. 169,171), albeit in low yield, although in considerably fewer steps than the earlier syntheses. 

Stereochemically, the fusion of rings B/C is cis in the morphinans (as in morphine) and trans in the isomeric isomorphinans. Formation of the B/C ring junction by Gate s procedure (Chapter 3, p. 133) gives a trans closure and thus entry to isomorphinan derivatives/59 Isocyclorphan (12, 14a-H)... 

The closure of the D-ring succeeded under basic conditions via an 8 2 displacement of the mesylate by the secondary amine (Scheme 16). Morphinan 106 was then successfully converted into thebaine (3) via manganese dioxide mediated oxidation following a procedure by Rapoport [67]. 

Alkaloids of the morphinane group. If the tetrahydroisoquinoline alkaloid norlaudanosoline is written in such a way that part of the molecule is rotated around the dotted line (Fig. 280), the relationship to the morphinane-type alkaloids becomes obviously. The actual precursor of these compounds, however, is (R)-reticuline. It is probably attacked by a phenol oxidase (C 2.3.1) yielding a biradical which is stabilized by the formation of the dienone (- -)-salutaridine. After reduction of (-j-)-salutaridine closure of a new 0-heterocyclic ring results in the formation of thebaine. The alkaloids codeine and morphine are synthesized from thebaine in Papaver somniferum,... 

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