Phthalide-isoquinolines

The following species have been shown to contain the alkaloids stated  

Corydalis pseudo-adunca151 Fumaria judaica111 Fumaria parviflora2 Fumaria schleicheri112,152 Hydrastis canadensis153 

Corftaline and isohydrastidine have been assigned the same structure. Fumschleicherine has been assigned the structure (79) on the basis of its spectra and its conversion into fumaramine 152 fumaridine is identical with hydrastinimide.112 

The reaction between narcotine and cyanogen bromide has been examined. In tetrahydrofuran, the product is the alcohol (83 R = H) in chloroform that contains ethanol, the ether (83 R = Et) is obtained. These products may be hydrolysed and cyclized to narcotine by heating with hydrochloric acid, the 

Kerekes, G. Gaal, and R. Bognar,Acta Chim. Acad. Sci. Hung., 1980, 103, 339. 155 T. Shono, Y. Usui, and H. Hamaguchi, Tetrahedron Lett., 1980, 21, 1351. 

A second synthesis of cordrastine starts from a Reissert compound, the 6,7-dimethoxy-analogue of (9), which was condensed with 2-methoxycarbonyl-3,4-dimethoxybenzaldehyde the product was hydrolysed, lactonized, hydrogenated, and N-methylated.118 

In addition to the preparation of a- and /3-hydrastine described above from the betaine (64), another conversion of a tetrahydroberberine into hydrastine has been reported. Acetylophiocarpine, on treatment with ethyl chloroformate, gives the acetoxy-derivative of (88), which can be hydrolysed to the hydroxymethyl compound and then oxidized to the aldehyde by pyridinium perchlorate. Hydrolysis of the acetoxyl group afforded the hemi-acetal (93 R = H), conversion of which into the mixed acetal (93 R = Et) protected the aldehyde system during reduction of N—C02Et to NMe by lithium aluminium hydride. Hydrolysis of the acetal, followed by oxidation, then gave a-hydrastine, and a similar sequence of reactions starting from O-acetyl-13-epi-ophiocarpine afforded / -hydrastine.119 Methods of synthesis of alkaloids of this group have been reviewed.120 

Pharmacological properties of bicuculline have been studied.121 124 

The electrolysis of narcotine in a diaphragmless cell with graphite anode and pre-polarized nickel cathode has been shown to give yields of 80% opianic acid and 55% cotarnine. Addition of potassium chloride prevents cathodic reduction of the narcotine. 

A route for the synthesis of phthalide-isoquinoline alkaloids from Reissert compounds has been reported. The Reissert compound (111) reacts with methyl opianate in the presence of sodium hydride to give the isoquinoline (112), hydrolysis of which yields dehydrohydrastine (113) this can be reduced in 

A patent that covers the equilibration of narcotine and hydrastine to the a- and /3-forms, with racemization, by ultraviolet light has been published. The circular dichroism of the phthalide-isoquinoline alkaloids has been studied and correlations have been made between the stability of the a- and /8-forms and the intensity of the Cotton effect. The effects of solvents on the parameters of the n.m.r spectra of a- and /3-hydrastines, adlumine, and corlumine have been studied.  

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Opium (Papaver somniferum) Benzylfsoquinolines Phthalide isoquinolines Morphine Sub-group, Sinomenium acutum Other Papaver spp. Rhoeadine, etc.. ... 

The sequence was successfully applied to the synthesis of the phthalide isoquinoline hemiacetals (-)-egenine (6) and (-)-corytensine (7) from the bis-oxygenated precursor 513,14. 

Phthalide isoquinoline alkaloids Hydrastine. narceine, narcotine... 

Protoberberine Alkaloids.—In the course of the bioconversion of the proto-berberine scoulerine (65) into chelidonine (62) and phthalide-isoquinolines, e.g. narcotine (63), C-13 becomes oxidized.61 Ophiocarpine (68), with a hydroxy-group at C-13, represents an intermediate stage in the modification of the protoberberine skeleton, and results62 of tracer experiments have shown that scoulerine (65) is also to be included in the biosynthesis of this alkaloid. Tetrahydro-protoberberine (67) is also a precursor, its incorporation indicating that C-13 hydroxylation is a terminal step. As for other protoberberine derivatives,63 nandinine (64) was not assimilated,62 and it follows then that (65) is probably converted into (67) by way of isocorypalmine (66). 

A new synthetic route to the phthalide-isoquinoline and spiro-benzyl-isoquinoline alkaloids has been developed. The indeno[2,l-a]benzazepine (105),... 

J.D. Phillipson, Phytochemistry, 1977, j 6, 2009). Hypecorin-ine (236, X=0) has been reduced by lithium aluminium hydride to a mixture of bicuculline diol (247, R =0H, R =H) and adlu-mine diol (247, R =H, R =0H), obtained by the reduction of the diastereoisomeric phthalide-isoquinoline alkaloids bicuculline and adlumine (see section 12) with the same reagent (Nonaka and Nishioka, loc.dt.). Hypecorinine has been synthesised from dehydrobicucul1ine by reduction with lithium aluminium hydride and re-oxidation with mercury (II) acetate (B.C. Nall-iah and MacLean, Canad.J.Chem., 1978, 56, 1378). 

Novel syntheses of the phthalide-isoquinoline alkaloids have been achieved as follows. Condensation of the Reissert compound (289, R R =CH2) with methyl opianate (290) in the presence of sodium hydride gave the isoquinoline (291), which is hydrolysed, reduced and then A -methylated to racemic a and g hydrastine. The isomeric cordrastines are prepared in the same way from the compound (289, R =R =Me) (P. Kerekes, et al., Acta Acad.Sci.Hung., 1978, 97, 353 1980, 105, 283). Hydra-... 

In the seco-phthalide-isoquinoline series the benzil derivatives bicucullinidine (278, R =R =Me) and bicucullinine (278, R R -CHa) have been prepared by oxidation of the deoxybenzoin alkaloids adlumiceine and adlumidiceine (Kh.Kiryakov and Mard-irosyan, Dokl.Bolg.Akad.Nauk, 1981, 1717), the analogue... 

The phthalides occur in several natural products . They are also intermediates for the synthesis of a variety of natural products like naphthols, anthraquinone natural products, anthracyclic antibiotics, the phthalide isoquinolines, protoberberine alkaloids etc. 

Phthalides are valuable synthons for obtaining several biologically active compounds and natural products. Naphthols, anthraquinones and anthraquinone antibiotics, isoquinolones, phthalide isoquinolines, indolizidine and quinolizidine alkaloids, and berbine alkaloids have been synthesised with phthalides as the starting compounds. Some of the syntheses, which have interesting chemistry, are described below. The required phthalides, in some cases, have been synthesised through aromatic lithiation reactions, while in others by more conventional methods. 

The 7,8-dimethoxy homophthalic anhydride 52 prepared via lithiation of 2,3-di-methoxy N,N-diethylbenzamide has been used to obtain some phthalide isoquinolines, while the 7,8-methylenedioxy homophthalic anhydride 53 has been used to prepare ( ) chelidonine (58) a benzophenthridine alkaloid... 

NOSCAPINE (NARCOTINE) As an optically active, laevorotatory substance noscapine is found in opium (2-12%). This alkaloid is, next to morphine, the most plentiful of the opium alkaloids. Structurally it differs from the phenanthrene derivatives morphine and codeine by its phthalide isoquinoline— skeleton. 

The Mannich reaction has been reviewed comprehensively by Blicke (1942), Reichert (1959), Hell-mann and Opitz (1960), and Tramontini (1973). These reviews also include synthetic applications of Mannich bases. Mechanistic studies of the Mannich reaction have been reviewed by Thompson (1968). Some variants of the Mannich reaction have been covered as subtopics in other reviews for example. Layer (1963) and Harada (1970) have reviewed general additions of stabilized carbanions to imines, while Bdhme and Haake (1976) have reviewed similar additions to methyleneiminium salts. In more specific reviews, Pai and coworkers (1984) have summarized stabilized carbanion additions to 3,4-dihy-droisoquinolines and 3,4-dihydroisoquinolinium salts in connection with the total synthesis of protober-berines and phthalide isoquinolines, and Evans et al. (1982) " have analyzed the stereochemical aspects of ester enolate and silyl ketene acetal additions to imines. 

Preformed cyclic /V,A-dialkyliminium salts i.e. where a ring Joins the a-caibon and positively charged nitrogen) have been used in enolate condensation reactions. The number of examples, however, is rather limited, probably because of complications arising through abstraction of enolizable protons. A -Dehy-droindolizidinium salt (69) represents one of the few examples of an enolizable, cyclic A, -dialkylimi-nium salt known to react with an enolate (equation 8). The use of a soft zinc enolate in this reaction may be crucial. The relative stereochemistry of the resulting 3-amino ester (70) is undefined. /V-Alkyl-3,4-dihydroisoquinolinium salts e.g. 71), a class of nonenolizable, cyclic iminium salts, have had extensive applications in the total synthesis of protoberberine and phthalide isoquinoline alkaloids. A review by Pai and coworkers has covered much of this work. In a more recent application by Yamazaki and co-... 

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