Phthalideisoquinoline

Hydrastine is a minor product, useful when applied topically as an astringent. 

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In addition to the foregoing five phthalideisoquinoline alkaloids obtained from opium, Manske has isolated from genera of the Rhceadales six more alkaloids definitely assigned to, and three, including base F38 (p. 173), which he considers may belong to this group. Hydrastine, already dealt with (p. 162), is also a phthalidcMoquinoline derivative. 

Cordrastinc, Ci8Hi302N(0Me)4. (Item 9 list, p. 170). Colourless needles, m.p. 196°. Its composition and reactions suggest that it belongs to the phthalideisoquinoline group and is represented by formula (I) (with R = H and the two dioxymethylene groups replaced by four methoxyl groups). ... 

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. 

Methoxyberberinephenolbetaine (131) possesses an interesting structural feature, namely, an 8,14-dioxygenated berberine skeleton and a masked carboxylic acid at C-8. It has been converted to phthalideisoquinoline alkaloids (Section V,D,1). Treatment of 131 with methyl iodide, hydrochloric... 

Conversions of 139 to phthalideisoquinoline (Section V,D,4) and isoin-dolobenzazepine alkaloids (Section V,H,2) are described later. 

Transformation of phthalideisoquinolines to spirobenzylisoquinoline alkaloids is described in Section V,D,6. 

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. 

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. 

Kondo et al. (182,183) reported a conversion of a fully aromatized phenolbetaine to a phthalide skeleton through photooxygenation. Reduction of norcoralyne (54) with zinc in acetic acid afforded dihydronorcoralyne (374), which was oxidized with m-chloroperbenzoic acid to the fully aromatized phenolbetaine 375 (Scheme 67). Photooxygenation of 375 in the presence of Rose Bengal, followed by reduction with sodium borohydride, gave rise directly to the phthalideisoquinoline 376 in 70% yield. The same phthalide (376) was also obtained from 2 -acetylpapaveraldine (129) (Section III,B,1). 

Scheme 67. Conversion to phthalideisoquinolines by photooxygenation. Reagents a, Zn, AcOH b, MCPBA c, hv, 02, Rose Bengal, MeOH d, NaBH4 e, NaOBr.

Scheme 68. Synthesis of phthalideisoquinolines from prechilenine (139) and the epidioxide. Reagents a, 25% H2SC>4 b, KOH then cone H2S04 c, py-HCl, py d, Me2S04 e, CH3I. 

Phthalideisoquinoline alkaloids have been suggested to be biosynthesized from 13-oxyberbines with retention of the configuration at C-13 and C-14 through regioselective C-8—N bond cleavage (185). Based on this biogenetic viewpoint, ( )-ophiocarpine and ( )-epiophiocarpine were converted to ( + )-a- and ( )-/ -hydrastine, respectively (Scheme 70) (186). Treatment of... 

Indenobenzazepines have been used as key intermediates for synthesis of rhoeadine, protopine, phthalideisoquinoline, and spirobenzylisoquinoline alkaloids. Several new alkaloids possessing an indenobenzazepine skeleton have been isolated, and they are presumably biosynthesized from proto-berberine alkaloids. 

Parent phthalideisoquinoline alkaloid Configuration Enol lactone Configuration Keto acid Diketo acid Ene lactam Configuration... 

The enol lactones were synthesized by Hofmann degradation of metho salts of classic phthalideisoquinoline alkaloids. The biogenetically relevant transformations were highly stereospecific. In this way aobamidine (96) was obtained from the methiodide of (erythro) bicuculline (88) (2), and ad-lumidiceine enol lactone (97) was produced from both (threo) isomeric adlumidiceine (89) and capnoidine (90) methiodides (14,15,91-93). (Z)- (98) and ( )-N-methylhydrastine (99) were obtained from / - (91, erythro) and a-N-methylhydrastinium (92, threo) iodides (5,87,91,96-98), respectively, as were (Z)- (101) and (JE)-narceine enol lactones (102) synthesized from a- (94, erythro) and /J-narcotine (95, threo) quaternary N-metho salts (87,90), respectively. In a similar process /J-hydrastine (91) JV-oxide heated in chloroform yielded enol lactone 124 of Z configuration (99) however, a-narcotine (94) N-oxide was transformed to benzoxazocine 125 (99). ... 

Secophthalideisoquinoline keto acids are postulated to be biosynthesized from phthalideisoquinoline metho salts via enol lactones. Such transformations occur easily in laboratory experiments (Section III,B,1). There are... 

Preliminary accounts of the preparation and chemistry of betaines 381 (R = H, Me) have appeared. Compound 381 (R = H) is obtained in high yield by oxidation of dihydronorcoralyne (382 R = H) with w-chloroper-benzoic acid. In a similar manner, ethanolic solutions of dihydrocoralyne (382 R = Me) are oxidized to betaine 381 (R = Me) by air. The study of these compounds has so far been restricted to their oxidation products. Photooxidation of betaine 381 (R = H) followed by borohydride reduction gives a high yield of the phthalideisoquinoline 383. Photooxidation of the 8-methylbetaine 381 (R = Me) gives papaveraldine derivatives (384 R = COMe, CO2Me). The mechanisms of these transformations are open to conjecture. 

Heating of the Reissert compound 1 with sodium hydroxide in aqueous methanol gives the phthalideisoquinoline 2 in 58% yield. 

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