Of protoberberines

Interaction of Protoberberine Alkaloids with Nucleic Acid Structures. . . 176... 

The protoberberine alkaloids (5-75) play important roles as precursors in the biosynthesis of a variety of related isoquinoline alkaloids such as protopine, phthalideisoquinoline, spirobenzylisoquinoline, rhoeadine, inde-nobenzazepine, secoberbine, and benzo[c]phenanthridine alkaloids. Chemical transformations of protoberberines to these alkaloids are particularly interesting and exciting from the biogenetic viewpoint and further from ready availability of starting protoberberines in nature or synthesis. 

The C—N bond cleavage is a fundamental and key reaction in skeletal rearrangements of protoberberines. The remaining two cleavages, that is, of the C—C and C—O bonds, are not always essential to transformation. 

Scheme 3. Hofmann degradation of protoberberines. Reagents a, Mel b. Amberlite IRA-400 c, 20% KOH, MeOH d, B2H6 e, H202, NaOH f, LAH, THF g, 10% NaOH.

Scheme 8. C—N Bond cleavage of protoberberine /V-oxides. Reagents a, Na, air, liq NH3 b, fev, MeOH.

Although C—O bond cleavage is of little importance for transformations of protoberberines to other types of alkaloids, the selective C—O bond cleavage reaction provides access to naturally unabundant or nonnatural protoberberines from naturally abundant protoberberines such as berberine. 

A variety of protoberberines (86 or 88) were treated with primary or secondary amines in refluxing ethanol or methanol to give C-9- or C-l 1-aminated protoberberines (87 or 89) in 60-90% yield (Scheme 21). When bulky amines were used, the demethylation product was also obtained (69,70). 

Protoberberinephenolbetaines are important intermediates in chemical transformations of protoberberines. In this section, their syntheses and some reactions are described. 

The first successful transformation of protoberberines to benzo[c]-phenanthridines was reported by Onda et al. (122,123). Irradiation of the enamines 200 and 195, the Hofmann degradation products of the corresponding protoberberines, in benzene afforded the initial photoproducts 201, which immediately rearranged to the tetrahydrobenzo[c]phenanthridines 202 in 70% yield (Scheme 37). Dehydrogenation of 202 afforded dihydro-chelerythrine (203) and dihydrosanguinarine (204), which were further oxidized with dichlorodicyanobenzoquinone (DDQ) to yield chelerythrine (205) and sanguinarine (206), respectively. 

Regioselective C-8—N bond cleavage of protoberberines is a crucial step for synthesis of secoberbine alkaloids (2). 

Scheme 56. Stevens rearrangement of protoberberines and C- and B-homoprotoberberines. Reagents a, NaCH2SOCH3. 

The first conversion of protoberberines to phthalideisoquinoline alkaloids was achieved by Moniot and Shamma (88,89). 8-Methoxyberberinephenol-betaine (131), derived from berberine (15) (Section III,B,2), is an attractive compound having a carboxyl group masked as an imino ether in ring B. The masking was uncovered by hydration with water-saturated ether to furnish dehydronorhydrastine methyl ester (367) (Scheme 65). On N-methylation (68%) and subsequent sodium borohydride reduction (90%), 367 provided (+ )-/ -hydrastine (368) and ( )-a-hydrastine (369) in a 2 1 ratio. Compound 367 was converted to dehydrohydrastine (370), which also afforded 368 and 369 by catalytic hydrogenation. 

The protopine alkaloids have been reviewed (1,2,7-10,190) and compiled (191). Although conversion of protoberberines to protopine alkaloids was achieved relatively early, only a few methods have since been developed. 

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