Tetrahydroprotoberberine precursor

Some modifications of the previous processes (23,36,72) were also reported (78,79) for the preparation of the ( )- and (—)-ethyl esters 29 and the corresponding ( )-methyl ester 30, another emetine precursor (34,37,61,72). The latter ( )-precursor 30 was alternatively synthesized by Takano et al. (80) who utilized cleavage of an a-diketone monothioketal intermediate. Birch reduction of the starting ( )-tetrahydroprotoberberine... 

Another important route stems from the formation of the N-methylated moieties of the (S)-tetrahydroprotoberberines, which serve as precursors for the protopine, benzophenanthridine, tetrahydrobenzazepines (rhoeadines) and spirobenzylisoquinoline alkaloids (Kutchan and Zenk, 1993 Liscombe and Facchini, 2008 Ziegler and Facchini, 2008) (Fig. 2.7). 

Based on knowledge of a biosynthetic pathway one can select certain steps which could be of interest for bioconversion of (a) readily available precursor(s). This could, for example, be stereospecific reactions, like the reduction of quinidinone in quinine or quinidine and the epoxidation of atropine to scopolamine. For the bioconversion one can consider using plant cells [e.g., the production of L-dopa from tyrosine by immobilized cells of Mucuna pruriens (10)] or isolated enzymes from the plant itself. An interesting example of the latter is the (5)-tetrahydroprotoberberine oxidase (STOX) enzyme, which oxidizes (5)-reticuline but not its stereoisomer (11). This feature can be used in the production of (i )-reticuline from a racemic mixture (see below). Immobilized strictosidine synthase has been successfully used to couple secologanin and tryptamine. The gene for this enzyme has been isolated from Rauvolfia (6) and cloned in Escherichia coli, in which it is expressed, resulting in the biosynthesis of active enzyme (7). The cultured bacteria produced 20 times more enzyme... 

Secoberbines, as implied by their name, must be catabolic products from protoberberine salts or tetrahydroprotoberberines (berbines). But proof of the biogenesis of the secoberbines can come only from in vivo experiments with labeled precursors. 

In a more recent study, and working with Corydalis incisa and Chelidonium majus, Takao and co-workers have demonstrated that only the cis B/C fused A -metho salts of tetrahydroprotoberberines such as stylopine, tetrahydro-corysamine, and mesotetrahydrocorysamine, are converted into the corresponding protopines, while the trans fused salts are inefficient precursors. ... 

By feeding to Corydalis incisa ( )-tetrahydrocoptisine labeled with tritium at C-8 and C-14, it has been demonstrated that this tetrahydroprotoberberine can be converted to corynoline, corydalic acid methyl ester, and corydamine. Additionally, tetrahydrocorysamine acts as a precursor for corynoline and corydalic acid methyl ester by oxidative fission of the C-6 to N-7 bond (Scheme 22.3). ... 

Takano s group has recently reported on a high-yield synthesis of emetine starting with the tetrahydroprotoberberine IS. iV-Chorosuccinimide treatment of 19 afforded the thermodynamically more stable isomer 20 which underwent a stereospecific catalytic reduction to the ketone 21. The thioketal 22 was prepared through the intermediacy of the pyrrolidine enamine, and was then cleaved in high yield. Subsequent esterification with diazomethane and desulfurization supplied the known protoemetine precursor 23 which was converted to emetine by established methods ... 

Leete and Murrill (15, 16) have given information about the simple precursors from which chelidonine is formed. Battersby and co-workers (17) have shown by the use of labeled compounds that (-1- )-reticuline is clearly the precursor of chelidonine, protopine, and stylopine in Cheli-donium majus L. Furthermore degradation of the active chelidonine showed that the tetrahydroprotoberberine skeleton is converted in vivo into chelidonine and that the former is derived from (-t )-reticuline Avithout degradation. The biogenesis of chelidonine from stylopine had been mooted much earlier (18). 

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