H. Yagi

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.

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 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).

An approach to the synthesis of sinomenine

The modified Pschorr reaction of 1-(2-amino-4,5-dimethoxybenzyl)-6-benzyloxy-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline (VIII) gave (±)-benzylpredicentrine (X), (±)-predicentrine (XI), and morphinandienone (XII). The (±)-predicentrine (XI) was also obtained by treatment of (X) with acid. Debenzylation of the morphinandienone (XII) afforded a diketone (IV), which had the same basic structure as a precursor (V) in the biogenesis of the sinomenine (I) proposed by Barton.

Configuration and rearrangements of homoproaporphines

The configuration of homoproaporphine at the spiro-centre is deduced from c.d. data for the derivatives (VII) and (X). An enol-ether addition reaction and a dienone-phenol rearrangement of the homoproaporphine (IX) are described. Dienol–benzene rearrangements of dienols (XIIIa) and (XIIIb) are also described.

Synthesis and stereochemistry of 1,2,3,4-tetrahydro-6-methoxy-2-methyl-1-phenylisoquinoline and related compounds

The absolute configurations of (1R,4R)-1,2,3,4-tetrahydro-4-hydroxy-6-methoxy-2-methyl-1-phenylisoquinoline (XIa) and its epimer, which were synthesised by cyclisation of D-(+)-2-amino-1-(3-hydroxyphenyl)ethanol with benzaldehyde, followed by Eschweiler-Clarke methylation, were determined by their n.m.r. spectra. The relationship between the absolute configuration of (1R)-1,2,3,4-tetrahydro-6-methoxy-2-methyl-1-phenylisoquinoline and its o.r.d. curve was also revealed.

Total synthesis of O-methylflavinantine

The diazotisation of 6,7-dimethoxy- and 7-ethoxy-6-methoxy-1-(2-amino-4,5-dimethoxybenzyl)-1,2,3,4-tetrahydro-2-methylisoquinoline (XIII) and (XVIII), followed by thermal decomposition of the resulting diazonium salt, gave O-methylflavinantine (VI), whose synthesis has proved structure (IV) for flavinantine to be correct.

Studies on the syntheses of heterocyclic compounds. Part CCCI. Biogenetic syntheses of the morphinandienone-type compounds, isosalutaridine and O-methylflavinantine

Phenolic oxidative coupling of (±)-reticuline (I) with potassium ferricyanide afforded isoboldine (III) and iso-salutaridine (VIII), which were methylated with diazomethane to give glaucine (IV) and O-methylflavinantine (XII), respectively. This work also implies formal biogenetic syntheses of amurine (IX) and flavinantine (X), which are biogenetically equivalent to isosalutaridine (VIII).

Rearrangement and novel enol-ether addition in homoproaporphines

The dienone–phenol rearrangements of the two stereoisomers (IIa) and (IIb) of 2,3,7,8,9,9a-hexahydro-6-hydroxy-5-methoxy-1-methyl-1H-benzo[de]quinoline-7-spiro-3′-methoxycyclohexa-2′,5′-dien-4′-one and the dienol–benzene rearrangement of the corresponding dienol (VIII) are described. The configurations of (IIa) and (IIb) have been assigned by chemical and spectroscopic methods.

One-step synthesis of an androcymbine-type compound

The diazotisation of 6,7-dimethyoxy- and 7-benzyloxy-6-methoxy-1-(2-amino-4,5-dimethoxybenzyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline (VIII) and (XXI), followed by decomposition of the resulting diazonium salts, gave demethoxy-O-methylandrocymbine (VII), whose structure has been assigned by spectroscopic methods. The syntheses of the aminoisoquinolines (VIII) and (XXI) are also described.