K. Fukumoto

Studies on the syntheses of heterocyclic compounds. Part CCCXV. Modified total synthesis of (±)-galanthamine through phenol oxidation

Oxidation of 2-bromo-5-hydroxy-N-(4-hydroxyphenethyl)-4-methoxy-N-methylbenzamide (VIII) with ferricyanide afforded the narwedine-type enone (X) in an excellent yield (40%). Reduction of (X) with lithium aluminium hydride gave (±)-galanthamine (II) and (±)-epigalanthamine (XXI) in yields of 50 and 40% respectively. Oxidation of (II) with manganese dioxide afforded (±)-narwedine (XIX) This work also constitutes a formal synthesis of (±)-lycoramine.

Studies on the syntheses of heterocyclic compounds. Part CCCLXXXVI. Alternative total syntheses of galanthamine and N-benzylgalanthamine iodide

Alternative total syntheses of galanthamine (Ia) and N-benzylgalanthamine iodide (VIa) were carried out by phenolic oxidative reactions of the corresponding amides (IIIf and e). Both (–)-and (±)-galanthamine showed analgesic activity comparable to that of morphine.

Studies on the syntheses of heterocyclic compounds. Part CDXLIII. An alternative synthesis of (±)-glaziovine by photolysis and phenolic oxidation

Photolysis of 8-bromo-1,2,3,4-tetrahydro-7-hydroxy-1-(4-hydroxybenzyl)-6-methoxy-2-methylisoquinoline (12) afforded (±)-glaziovine (1). Phenolic oxidative coupling of compound (12) also gave the alkaloid (1).

Total synthesis of (±)-flavinantine

Diazotisation of 1-(2-amino-4-benzyloxy-5-methoxybenzyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyliso-quinoline (XII), followed by thermal decomposition, gave the dienone (XIV), the debenzylation of which afforded (±)-flavinantine (VII).

Studies on the syntheses of heterocyclic compounds. Part CDI. Rearrangement of β-hydroxylaudanosine

1,2,3,4-Tetrahydro-1-(α-hydroxy-3,4-dimethoxybenzyl)-6,7-dimethoxy-2-methylisoquinoline (β-hydroxylaudanosine)(5) was treated with toluene-p-sulphonyl chloride in the presence of triethylamine to afford 2,3-dihydro-7,8-dimethoxy-5-(3,4-dimethoxyphenyl)-3-methyl-1H-3-benzazepine (6), whose reduction product (9) was also obtained by dehydrative cyclisation of β-hydroxy-3,4-dimethoxy-N-(3,4-dimethoxyphenethyl)phenethylamine (15), followed by an Eschweiler–Clarke reaction of the resulting benzazepine (18).

Studies on the syntheses of heterocyclic compounds. Part CDXXXII. Synthesis of (±)-thalicsimidine by a possible biosynthetic route

Phenolic oxidative coupling of the diphenolic benzylisoquinolines (21) and (22) with potassium ferricyanide afforded the aporphine (3) and the spirocyclohexadienones (23a and b), respectively. The dienones (23a and b) were treated with acid to give two aporphines (4) and (5). Methylation of compounds (3) and (5) with diazomethane gave (±)-thalicsimidine (1).

Total synthesis of (±)-amurine

The diazotisation of 6,7-dimethoxy- and 7-ethoxy-6-methoxy-1-(2-amino-4,5-methylenedioxybenzyl)-1,2,3,4-tetrahydro-2-methylisoquinoline (XII) and (XV), followed by thermal decomposition, gave amurine (Ib), as a result of which Dopkes structure for the alkaloid was proved to be correct.

Studies on the syntheses of heterocyclic compounds. Part CCC. Syntheses of salutaridine, sinoacutine, and thebaine. Formal total syntheses of morphine and sinomenine

The diazotisation of (±)-1-(2-amino-3-benzyloxy-4-methoxybenzyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methylisoquinoline (VIII) followed by the thermal decomposition of the resulting diazonium salt, gave (±)-salutaridine (II)[or (±)-sinoacutine], which was converted into (±)-thebaine (III). The 2-aminobenzylisoquinoline (VIII) was resolved, and the (–)- and (+)-enantiomers (VIIIa and b) were used for the syntheses of salutaridine (IIa), sinoacutine (IIb), and thebaine (IIIa) and its antipode (IIIb). This work also constitutes the fifth total synthesis of morphine (I).

Total synthesis of O-methylandrocymbine by a photo-Pschorr reaction and synthesis of thalifoline

The total synthesis of O-methylandrocymbine (4) has been accomplished by photolysis of the diazonium salts (10) and (15) of 6,7-dimethoxy-(11) and 7-benzyloxy-6-methoxy-1-(2-amino-3,4-5-trimethoxyphenethyl)-1,2,3,4-tetrahydr-2-methylisoquinoline (14). On the other hand, pyrolysis of the diazonium salt (15) gave the spiroisoquinoline (32). Moreover, thalifoline (24) was obtained by debenzylation of the by-product (23) in the photolysis and pyrolysis of the latter compound (15).

Studies on the syntheses of heterocyclic compounds. Part CCCLXXXII. Phenolic oxidative coupling of reticuline by use of various reagents

The phenolic oxidative coupling of reticuline (III) to give pallidine (IV) and isoboldine (V), with the reagents potassium ferricyanide, vanadyl trichloride, and silver carbonate, has been examined. The reactions of p-cresol with silver carbonate and with silver nitrate are also described.