Isoquinoline alkaloids Reissert synthesis

B. Reaction of Reissert Compounds Synthesis of Isoquinoline Alkaloids... 

The chemistry of Reissert compounds has been the subject of numerous general reviews (3-10). In 1973 Popp gave a summary on the use of Reissert compounds in the synthesis of isoquinoline alkaloids and related compounds (7). We now wish to summarize new results that have appeared from 1973 to the end of 1985 for the application of Reissert compounds in the synthesis of isoquinoline as well as indole alkaloids. 

The chemistry of Reissert compounds, for example, N-acyldihydroquin-aldonitriles (1) and Af-acyldihydroisoquinaldonitriles (2), was the subject of a review in an earlier volume of this series. The application of Reissert compounds to the synthesis of isoquinoline alkaloids and related compounds... 

Most work has been in the isoquinoline area, principally because of the usefulness of isoquinoline Reissert compounds in the synthesis of isoquinoline alkaloids. Aside from 5-chloro- and 3-acetylaminomethylquinoline and a few halo, methyl, and carbomethoxyisoquinolines, all the substituted quinoline or isoquinoline Reissert compounds have involved oxygen-type functions in one or more of positions 4-, 5-, 6-, 7-, and 8- of the isoquinoline... 

Reissert synthesis of isoquinoline and indole alkaloids, 31,1 (1987) Reserpine, chemistry, 8, 287 (1965)... 

Photocyclization of an enamide (review [2S9S]) containing a methoxy group leads to the formation of a pyridinone ring of an intermediate in the synthesis of (— )-sincitine. Reviews of numerous syntheses of isoquinoline alkaloids [2487] and of the use of Reissert compounds in such syntheses [2488] are available. 

The partial ether cleavage of methoxy- and methylenedioxy-substituted isoquinoline alkaloids has been reviewed in a new journal. Additional reviews concerning the use of Reissert compounds in the total synthesis of isoquinoline alkaloids and related compounds, electro-oxidation and isoquinoline alkaloid biosynthesis, and the synthesis of isoquinoline alkaloids by a systematic design have appeared in early issues of the same journal. The chemotaxonomy of alkaloids, together with distribution within plants, biosynthesis, structural classification, and physiological activity, has been treated in a monograph. ... 

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... 

For a review of the application of Reissert compound chemistry to the synthesis of isoquinoline alkaloids, see F. D. Popp, Heterocycles, 1, 165 (1973). 

The Reissert method15—conversion of an isoquinoline to a 2-benzoyl-1,2-dihydroisoquinaldonitrile (Reissert compound), alkylation, and hydrolysis—has enjoyed wide success in the synthesis of benzyliso-quinoline and related alkaloids.16,17 In particular, aporphines are prepared conveniently by converting isoquinolines to I-(o-nitrobcnzyl)-isoquinolines via a Reissert sequence, followed by A7-alkylation, reduction, and Pschorr cyclization.17... 

The formation of a Reissert anion (intermediate of type 16) is usually the introductory step in a great number of synthetic routes leading to isoquinoline as well as indole alkaloids and related compounds. On the one hand, the alkylation of a Reissert anion with alkyl halide followed by alkaline hydrolysis is the most frequently used method for the synthesis of 1-alkyl- or 1-arylalkylisoquinolines (20) (Scheme 4). On the other hand, Reissert anions react with aldehydes to form... 

The synthesis of the basic skeleton of 1-benzylisoquinoline alkaloids has been reported by Uff et al. 15) starting from isoquinoline and benzyl chloride (Scheme 5). The preparation of Reissert compound iV-benzyl-l-cyano-l,2-di-hydroisoquinoline (4) was performed in a dichloromethane-water two-phase system with potassium cyanide and benzoyl chloride in about 64-69% yield. The deprotonation of 4 with sodium hydride in dimethylformamide solution, the subsequent alkylation with benzyl chloride, and the final alkaline hydrolysis could be performed as a one-pot reaction sequence to supply 1-benzylisoquinoline (25) in an overall yield of 75-84%. 

Reticuline (38), one of the most important intermediates in the biosynthesis of opium alkaloids, has been synthesized in racemic form (Scheme 7) (78). 6-Methoxy-7-benzyloxyisoquinoline (39), prepared from O-benzylisovanillin via a modified Pomeranz-Fritsch isoquinoline synthesis, was treated with benzoyl chloride and potassium cyanide to obtain Reissert compound 40. Alkylation of the anion generated from 40 with 3-benzyloxy-4-methoxybenzyl chloride gave the corresponding 1-substituted Reissert compound 41 which was hydrolyzed in alkaline medium to 1-benzylisoquinoline derivative 42. Quatemarization of 42 with methyl iodide followed by sodium borohydride reduction and debenzylation led to ( )-reticuline (38) in about 25% overall yield from 39. 

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