Isoquinolines benzylisoquinolines

S)-(+)-reticuline (20) and orientaline (25). The alkaloids of the Papaveraceae and Fumariaceae can be subdivided into several constitutional types (Fig. 3), viz., simple isoquinolines, benzylisoquinolines, pavines, isopavines, cularines, proaporphines, aporphines, promorphinanes, morphinanes, protoberberines, retroprotoberberines, secoberbines, benzophenanthridines, protopines, phthali-deisoquinolines, secophthalideisoquinolines, indenobenzazepines, spirobenzyl-isoquinolines, and rhoeadines. 

These include alkaloids and non-alkaloids that have phenolic functions in addition to a nitrogen atom. Even the alkaloids containing phenolic functions cannot be classified under one group. They may be phenyl alkyl amines, quinolines, isoquinolines, benzylisoquinolines [47-50], carbazole [51, 52] and others. However, they are included in this entry owing to their phenolic nature. Some of these compounds, like opium alkaloids, are of great medicinal importance. 

Leet JE, Elango V, Hussain SF, Shamma M (1983) Chenabine and Jhelumine secobisbenzyl-isoquinolines or simple isoquinoline-benzylisoquinoline dimers Heterocycles 20 425-429... 

Although this isoquinoline at first bears little structural resemblance to morphine (108), careful rearrangement of the structure (A) shows the narcotic to possess the benzylisoquinoline fragment within its framework. Indeed, research on the biogenesis of morphine has shown that the molecule is formed by oxidative coupling of a phenol closely related to papaverine. 

C-9, and C-10, always with a phenolic hydroxy group at the 8a position. Moreover, they differ from one another by the oxidation state of the benzylic C-13 as well as by substitution and degree of saturation of the isoquinoline fragment. These alkaloids, classified as benzylisoquinoline alkaloids (2,70-74), have recently been called by Shamma et al. (75-77) pseudobenzyliso-quinolines originating from protoberberine alkaloids. In Table V a list of 8,8a-secoberbine alkaloids, sources, and spectral data are presented. 

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. 

Protoberberine and Related Alkaloids.—The benzylisoquinoline skeleton [as (64)], which appears in diversely modified form in various alkaloids [see, e.g., (66)—(71)], is formed from two molecules of tyrosine label from this amino-acid often appears equally divided over the two halves of the alkaloid examined,1,219 but dopa (60), like dopamine (59), is incorporated only into the isoquinoline moiety cf. Vol. 6, pp. 17, 26 Vol. 7, p. 10 Vol. 9, p. 8). 

It has been reported119 that when 2-methyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxylate is heated to about 200° in the presence of benzaldehyde, 4-benzylisoquinoline is formed and can be isolated in 73% yield. It is probable that decarboxylation occurs to form 2-methyl-l,2,3,4-tetrahydroisoquinoline, which then reacts with benzaldehyde via the enamine pathway as before. 

The isoquinolines 70 are an important subclass of the tertiary N-benzylamides, and their lithiation and benzylation is an important way of synthesising a range of benzylisoquinoline alkaloids.4849... 

Isothebaine (= 1-Hydroxy-2,1 1-dimethoxyaporphine) (aporphine isoquinoline) Laudanosine (= Laudanine methyl ether) (benzylisoquinoline)... 

Many dimeric piperidine alkaloids also occur in nature, e.g., carpaine which has been isolated from papaya leaves (Carica papaya) 175 the absolute configuration has been determined.176 Naturally occurring isoquinoline alkaloids177 exist in dimeric forms in some cases, e.g., the bisbenzylisoquinoline alkaloids which have two benzylisoquinoline nuclei joined together through one, two, or even three ether bridges an example is epistephanine isolated from Stephania japonica.178... 

With the assumption that reticulines are also precursors in mammalian synthesis of morphine, it was challenging to investigate whether they could be produced by enzymatic reactions similar to those utilized in benzylisoquinoline-producing plants (274). This plan focused attention on reactions controlled by the enzyme catechol 0-methyltransferase (COMT), using 5-adenosyl-L-methionine (SAM) for the methylation reaction. Mammalian COMT is present in mammalian tissues, particularly the liver, and an enzyme preparation from rat liver was used for the experiments. It was found that (S)-norcoclaurine, which is the first isoquinoline produced in benzylisoquinoline-producing plants, was similarly O-methylated in vitro by SAM in the presence of COMT, and a reverse proportion of methylated products was obtained with the (/ )-enantiomer (277). Similar 0-methylation of (5)-4 -demethylreticuline (3 -hydroxy-N-methylcoclaurine), prepared by total synthesis (162), however, afforded almost exclusively (5)-orientaline, with a methoxy group at C-3 and not at C-4 as in (5)-reticuline (Fig. 37) (762). 

The benzylisoquinolines are formed from two molecules of fhe aromafic amino acid, tyrosine. In the past ten years, this pathway has been probed at the enzyme and gene level. The recent linking of the phloem-specific expression of tyrosine/Dopa decarboxylase (TYDC) genes with the bios)mthesis of the isoquinoline alkaloids in the opium poppy, Papaver somniferum (Facchini and De Luca, 1994, 1995, 2008 Liscombe and Facchini, 2008), and the association with alkaloid accumulation as part of the plant defence mechanism (Wink, 1993 Facchini et al, 1996) are of particular interest in furthering our knowledge of the location of alkaloid biosynthesis. 

The isoquinoline alkaloids are the second largest group of alkaloids, numbering about 6000, and can be viewed as five subgroups—the simple tetrahydroisoquinolines, the benzylisoquinolines, the phenethylisoquinolines, the Amaryllidaceae alkaloids, and the monoterpene isoquinolines. In addition, there are a number of simple phenethylamine derivatives, including ephedrine (originally from Ephedra species, but now synthesized) and pseudoephedrine, used for asthma and nasal... 

Because benzylisoquinolines have been available synthetically (in racemic form) for decades, there is quite a bit of chemistry known regarding their use as key intermediates in the synthesis of a number of more complex isoquinoline alkaloids. The asymmetric synthesis of benzylisoquinolines has been used to complete total synthesis of representative members of several of these alkaloid classes. As shown in Figure 6, the protoberberine alkaloid norcoralydine, the aporphine alkaloid ocoteine, the isopavine alkaloid reframoline and the morphinan 0-methylflavinantine have been made available in optically active form for the first time (except by isolation or resolution) using this approach. 

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