Phthalide isoquinolines synthesis

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. 

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. 

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-... 

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... 

The synthesis of 13-hydroxylated tetrahydroprotoberberines from norphthalideisoquinolines has been achieved. Catalytic reduction of the phthalide-isoquinoline 32, derived from papaverine (see Sec. 24.2.3), afforded a separable mixture or erythro- and /Areo-norphthalideisoquinolines. Base-catalyzed lacta-mization followed by lithium aluminum hydride reduction of the threo-nov and rj fAro-norphthalides yielded the 13 - and 13a-hydroxytetrahydroprotober-berines, respectively. The hydroxylactam derived from the / r o-norphthalide tends to dehydrate readily to the oxoprotoberberine system (see Scheme 19.4). ... 

A new electroreductive method for the synthesis of tetrahydro-phthalide-iso-quinolines is also known If isoquinolinium methiodide is used in the reaction the 1,2-dihydrophthalide isoquinoline is obtained... 

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