Protoberberines from phthalideisoquinolines

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 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. 

Phthalideisoquinoline alkaloids have been reviewed (1,2,176-179) and compiled (180). Because of the potential usefulness of phthalideisoquinoline alakloids such as bicuculline, a competitive antagonist of y-aminobutyric acid, many synthetic methods for these alkaloids have been developed. Several attractive transformations from protoberberines have also been reported. 

Almost all of the studied plants have been found to contain protoberberines, protopines, and phthalideisoquinolines. The occurrence of aporphines and ben-zophenanthridines is frequent. The secoberbines have been isolated from C. incisa and C. ochotensis. The cularines, which are characteristic of some plants of the genus Corydalis, are also found in the genera Dicentra and Sarcocapnos. 

Fumaria chemically resembles Corydalis. Similarly, the genus Fumaria also contains protoberberines, protopines, and phthalideisoquinolines, and more frequently, secophthalideisoquinolines and spirobenzylisoquinolines. They also yield indenobenzazepines, which cannot be demonstrated in the genus Corydalis (Table LVI), but no aporphines and cularines, which have been isolated from the plants of the genus Corydalis. 

Berberine or protoberberine alkaloids [such as stylopine (79)] may be converted into alkaloids of the protopine type (60) (Fig. 32.24) (Geissman and Crout, 1969 Hartmann, 1991). Highly specific microsomal cytochrome P-450-de-pendent enzymes from cells of Eschscholtzia californica (and other species of the Papaveraceae and Fumariaceae) introduce two methylenedioxy bridges into (5)-scoulerine (72) to form (5)-stylopine (79), which is, in turn, an important precursor of the protopine, phthalideisoquinoline, and benzophenanthridine groups (Hartmann, 1991). 

A short sequence to phthalideisoquinolines starts with the known and readily available 6 -hydroxymethylpapaverine (7), derived in high yield from easily available papaverine. Chromium trioxide oxidation of 7 leads in 75% yield to the aromatic phthalideisoquinoline 8, which can be reduced and A-methylated to phthalideisoquinolines 11 and 12, Scheme 24.3. (For the conversion of the norphthalideisoquinolines 9 and 10 to C-13 hydroxylated protoberberines, see Sec. 19.2.9.)... 

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