Isoquinoline alkaloids, phenol coupling

Morphine alkaloids are a subgroup of isoquinoline alkaloids and are derived biogenetically from laudanosine bases by oxidative phenolic coupling/6,7 Alkaloids of the opposite enantiomorphic group occur in several Japanese Sinomenium and Stephania species, the most important compounds being sinomenine, hasubanonine, metaphenin, and protometaphenine. 

Since the mid-1950s, phenol oxidative coupling (7) has been actively applied to the synthesis of many types of alkaloids, with considerable progress being achieved especially in the field of isoquinoline alkaloids (8-H). As to aporphine synthesis, employment of new reagents such as vanadium oxyfluoride (12) greatly improved yields as compared to classical methods such as oxidation with potassium ferricyanide and ferric chloride. 

The existence of homoerythrina alkaloids has been anticipated from biosynthetic considerations. Homoerythrina dienone 77 was synthesized in the following way. Oxidation of the diphenolic isoquinoline 86 with vanadium oxytrichloride in methylene chloride afforded the expected prohomoerythrinadienone 87 (47), which was transformed to the imine 88 in quantitative yield by 1 N sodium hydroxide at 0°C. Sodium borohydride reduction of the iminium chloride of 88 gave 76. Oxidative phenolic coupling of 76 with potassium hexacyanoferrate in methylene chloride afforded homoerythrina dienone 77 in 45% yield and homoery-sodienone 89a in 15% yield (48). Moreover, the lactam dienone 91 was prepared in excellent yield by oxidation of the N-acyltetrahydroquinoline 90 with potassium ferricyanide (49). 

Excellent reviews are available concerning the synthesis of various types of isoquinoline alkaloids by phenolic cyclization, by biogenetic type reactions, by the thermolysis of benzocyclobutanes, and by the coupling of phenols or of related non-phenolic compounds. ... 

Other isoquinoline alkaloids are derived from the biogenetic key compound 81 by further transformations, mainly by oxidative phenol coupling of the isoquinoline ring and on the benzyl residue. A number of structural types of isoquinoline alkaloids are known, e.g. the systems 82-87 (for individual examples and further details, see textbooks of natural products). 

The electrooxidation of vanillin, 7, to dehydrovanillin, 8, in 65% yield was reported in 196 by VermiIlian and Pearl (15). They combined a thorough voltammetric study with preparative experiments and were able to clarify the mechanisms of phenol and phenoxide oxidation. Specifically, they pointed out that the oxidation of phenols in neutral solution was a two-electron oxidation and that oxidation of the phenoxide ion (in base) produced a one-electron oxidation and coupling reactions. This work prompted us to apply the method to the synthesis of some isoquinoline alkaloids. 

Figure 3. Phenol Coupling in Isoquinoline Alkaloid Biosynthesis...

In isoquinoline alkaloid biosyntheses, several unique P450 reactions have been reported, such as methylenedioxy bridge formation, intramolecular C-C phenol-coupling and intermolecular C-0 phenol-coupUng reactions. Salutaridine... 

One-electron withdrawing inorganic reagents have been used to perform biomimetic syntheses of phenolic phenethylisoquinoline alkaloids. In order to obtain androcymbine compounds of type 85, the diphenolic isoquinoline 82a was subjected to phenol oxidation with manganese dioxide. The homoaporphine 83a coupled at the ortho-ortho position to the hydroxy group was the only product formed under these reaction... 

Although the biosynthesis of the homoproaporphines has not yet been elucidated, these alkaloids could be biosynthesized by phenolic oxidative coupling of the diphenolic isoquinoline 76. 

There are many reports on the biogenetic synthesis of these alkaloids by phenol oxidation. These reactions were carried out using a diphenolic isoquinoline with one-electron oxidizing reagents ferric chloride, potassium ferricyanide, manganese dioxide, and so on. In order to obtain the androcymbine-type compound 82 the diphenolic isoquinoline 81 was subjected to phenol oxidation with potassium ferricyanide (3a) and with ferric chloride (2b), respectively, but instead the homo-aporphine 83 (2a) coupled at the ortho-ortho position to the hydroxy groups. 

Phenolic oxidative coupling of the diphenolic bis(phenethyl)amine 101 to the 11-membered ring structure (102) controls the formation of the isoquinoline system at the stage of iminium salt 103 and explains the 7,8-substitution pattern in the isoquinoline part of cularine alkaloids (40, 63). However, to date, no such precursors have been isolated from natural sources. Moreover, phenolic oxidative coupling of synthetic precursors such as 101, using a variety of one electron oxidation reagents, gives rise to polymerized compounds or products with the skeleton of erythrine alkaloids (104) (68). 

The protoberberine alkaloids are comprised of a tetracyclic ring system which is based on the dibenzo[a,g]quinolizidine system. These tetracyclic alkaloids are derived from benzylisoquinolines through phenolic oxidation and coupling with the isoquinoline A-methyl group, which becomes the berberine bridge carbon. 

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