From Phthalideisoquinolines

In a preliminary paper by a Canadian team, it was reported that treatment of the known dehydrocordrastine with diisobutylaluminum hydride (Dibal) leads to equimolar amounts of the diastereomeric spirobenzylisoquinolines 18 and 19 in 76% yield. The reaction proceeds by reductive opening of the oxygen ring, and reclosure of the resulting enolate.  

In a subsequent and more complete study, Nalliah, MacLean, Rodrigo, and Manske have shown that diisobutylaluminum hydride reduction of the dehydrophthalideisoquinoline 20 gives corydaine and sibiricine. A novel and significant finding was that sibiricine can be isomerized into corydaine by simple 

3-dimethoxy analogs of corydaine, sibiricine, and ochrobirine, namely yenhusomidine, raddeanone, and yenhusomine, were synthesized by a route similar to that described above.  

Indandiones analogous to those discussed in Sec. 25.2.3 above may be obtained in high yield from phthalideisoquinolines. The key step is the base- 

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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... 

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. 

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. 

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 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. 

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). ... 

The reduction of the phthalideisoquinoline alkaloids to the corresponding diols has been exhaustively studied namely, those from a- and... 

From the plant Stylomecon heterophylla, a new alkaloid stylophylline was isolated. Since it is the enantiomer of the already known (— )-)3-hydrastine, it represents (— )-a-hydrastine. Recently, the isolation of (— )-bicuculline from Corydalis severtzovii was reported. The elucidation of the relative and absolute configuration of phthalideisoquinoline alkaloids was independently and simultaneously achieved by several groups of workers (60, 78, 79, 365-368, 419, 540). Although different methods were applied [model compounds, IR, and NMR spectroscopy, pAgo mcs optical rotation, preparation of corresponding diols (type II), 1-benzyl-tetrahydroisoquinoline (VII), and tetrahydroprotoberberine compounds... 

Phthalideisoquinoline alkaloids have been isolated from the following ... 

The eryt/iro-phthalideisoquinoline (165 R = Me) has also been synthesized from the papaveraldine derivative (171) (Scheme 18). ... 

Scheme 46. Synthesis of chlorobenz[d]indeno[l,2-d]azepine (c) and phthalideisoquinoline compounds (125) from 3,4-dihydropapaoeraldine methiodide (134) (698).

Phthalideisoquinolines.—The new alkaloid narceine imide (162) has been obtained from extracts of Papaver somniferum L. (Papaveraceae). Gnoscopine [( )-narcotine] has been synthesized by a classical route. 

The interesting conversion of nornarceine (181) into the rhoeadine analogues (187) and (188) has been carried out as shown in Scheme 9. Nornarceine (181), obtained from (— )-a-narcotine, was heated in base to afford the enamine (182) which readily cyclized in dilute acetic acid to the y-lactone (183). Upon standing, (183) was oxidized to the ketone (184). Lithium borohydride reduction led to the c/.s-acid (185). The derived ds-fused lactone (186) was then reduced to the hemi-acetal (187) which upon O-methylation with trimethyl orthoformate gave (188). The structure of the methiodide salt of (187) was confirmed by an X-ray analysis. The phthalideisoquinoline alkaloid (— )-bicuculline (189) was then converted into naturally occurring (+ )-rhoeadine (190) by an analogous route. Since (— )-bicuculline was obtained from (—)-)3-hydrastine, whose synthesis had been reported in 1950, this transformation represents the first total synthesis of a rhoeadine alkaloid. ... 

The preparation of hydrastinine, hydrohydrastinine and hydrocotarnine, starting from narcotine and cotarnine has been described by Pyman and Remfry (43), Tanaka, Midzuno and Okami (44) and Topchiev (45). See Narcotine and Cotarnine under Phthalideisoquinoline Alkaloids, Vol. IV, chap. 32. 

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