Benzylisoquinoline skeleton

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). 

Reticuline.—Reticuline (41) is a pivotal intermediate in the biosynthesis of many alkaloids based on the benzylisoquinoline skeleton, and by association with these... 

Through the examination of diverse examples,21 it is well established that the benzylisoquinoline skeleton originates in two molecules of tyrosine. 

Papaver Alkaloids.—It is well established that the 1-benzylisoquinoline skeleton [as (70)] found in the alkaloids of Papaver species, amongst many others, arises from two molecules of tyrosine, with dopamine serving as an intermediate for one half of the skeleton (see Scheme 11). In spite of the extensive and fruitful studies on H. Rosenberg and S. J. Stohs, Phytochemistry, 1974,13,1861. 

According to Manske, the precursors of corydaline alkaloids (68) are already C-methylated on the benzylisoquinoline skeleton before ring C closure takes place (637). On the contrary, Blaschke reported that labeled reticuline (7f) is converted specifically into corydaline (68h) (638). The experiments have also shown that the radioactivity from [3-14C]tyrosine and from [methyl-14C]methionine is incorporated nonrandomly into predicted positions of corydaline and ochotensimine in Corydalis solida and C. ochotensis, respectively (639). The methyl group of methionine supplies the C-13 methyl group of corydaline and the exocyclic methylene group of... 

New investigation of bisbenzylisoquinoline biosynthesis is welcome (see ref. 32 also this Report, p. 16). Although aporphine alkaloids are the simplest developments of the benzylisoquinoline skeleton, their biosynthesis need not, as several examples show, be simple. It has, however, been found that the biosynthesis of boldine and isocorydine is straightforward. Further detail has been repor-ted on the biosynthesis of Erythrina alkaloids, which were established to be modified benzylisoquinolines some time ago. Further detail on the biosynthesis of morphine (23) and related alkaloids continues to be published. Of particular R. B. Herbert, in ref. 9, p. 11. 

BIA biosynthesis starts with the two tyrosine condensation product 4-hydroxyphenyl acetaldehyde (4-HPAA) and dopamine catalyzed by norco-claurine synthase (NCS) (Figure 6.19) [93, 94]. The so-formed (5)-norcoclaurine represents the first pathway intermediate with a benzylisoquinoline skeleton from which the BIA classes are derived. Methylation of the latter by norcoclaurine 6-0-methyltransferase (6-OMT) leads to (5)-coclaurine, which is methylated by coclaurine A-methyltransferase (CNMT) to yield A-methylcoclaurine. Hydrox-ylation of the 3 position, catalyzed by (5)-A-methylcoclaurine 3 -hydroxylase,... 

Alkaloids possessing the 1-benzylisoquinoline skeleton are biosynthesized from two molecules of tyrosine, which are differentiated at the beginning of the biosynthetic pathway. Namely, the isoquinoline moiety, except for one carbon, originates from 3, 4 -dihydroxyphenylethylamine (dopamine), which is formed from tyramine following the decarboxylation of tyrosine. The other part of the alkaloid is derived from 4 -hydroxyphenylac-etaldehyde, which is formed from tyrosine via 4 -hydroxyphenyl pyruvic acid. These two compounds are coupled stereoselectively to give (S)-norcoclaurine. (S)-Norcoclaurine is transformed into (S)-coclaurine by 6-O-methylation, and further N-methylation, hydroxylation at the... 

All that is required for the transformation of the benzylisoquinoline skeleton [as 6.123)] into that of the aporphines, e.g. bulbocapnine (5.729), is a single new bond. Clearly phenol oxidative coupling (N.B. see Section 1.3.1) is involved here, but there are several possible routes to a particular alkaloid. Interestingly examples of most of these possibilities have been found for the biosynthesis of one or more of the aporphine alkaloids, and in one case, that of boldine (5.757), biosynthesis takes a different course in two different plants. Methylation pattern in the alkaloid produced does not provide a reliable guide to the course of biosynthesis, as witness that of 6.131) in Scheme 6.25 [88]. The methylation pattern suggests a different pathway (see Scheme 6.27), which is followed in another plant. 

Because the benzylisoquinoline skeleton derives from tyrosine 6.94) which has a phenolic hydroxy-group at C-4, the aporphines should have hydroxy-groups at equivalent positions. Isothebaine 6.135) lacks such a group at one expected site, C-10. It follows that a hydroxy-group is lost from this site in the course of biosynthesis, plausibly via dienol-benzene rearrangement in 6.134) (see Section 1.3.1). This suggests the route shown in Scheme 6.26, which experiments have shown is correct [92]. Orientaline 6.132), and the key... 

The idea that the opium alkaloid morphine is a modified benzyliso-quinoline provided the key to the structure 6.152) for the alkaloid twisting of the benzylisoquinoline skeleton into that shown for reticuline (6.127) in (6.148) illustrates this relationship and suggests a possible biogenesis. This was later proved correct in the course of a study which is one of the classics of alkaloid biosynthesis. In the first experiments ever to be carried out with complex plant-alkaloid precursors, [1- C]- and [S- Cj-norlaudanosoline [as (6.123) were fed to opium poppies [99, 100]. They were found to label morphine (6.152), codeine (6.153) and thebaine (6.151) specifically, thus establishing that these alkaloids are indeed benzylisoquinoline derivatives. The key intermediate [101] proved to be reticuline (6.148). Both (R) and (5)-isomers were utilized, the latter by way of (6.155) [101, 102] which allowed its conversion into (i )-reticuline (6.148), the correct intermediate, with the same configuration as the three opium alkaloids [as (6.151). ... 

Elaboration of the benzylisoquinoline skeleton in ways different from those already discussed involve the inclusion of an extra carbon atom (the berberine bridge ) as seen in, e.g. berberine 6.161) (the extra atom is C-8). The question of how this occurs was answered simply in terms of an oxidative cyclization of the A -methyl group of a benzylisoquinoline precursor in a manner (Scheme 6.32) analogous... 

The benzylisoquinoline skeleton is formed from two molecules of tyrosine, and one of these molecules is utilized via dopamine (Fig. 4). From the work of Professor Zenk and his colleagues it is now clear that the other tyrosine molecule is used either via 4-hydroxyphenylacetaldehyde (20) or 3,4-dihydroxyphenylacetaldehyde (21) yielding, respectively, (22) or norlaudanosoline (23) (Schumacher et al. 1983). It is worth noting that labelled norlaudanosoline (23) was the first compound ever to be tested as an alkaloid precursor apart from a-amino acids and closely related compounds (Battersby et al. 1964). The successful study of plant alkaloid biosynthesis with advanced precursors was built upon that first successful experiment, which was... 

The essential difference between the simple benzylisoquinoline skeleton, as in reticu-line (25), and that of berberine (69) is the presence of an extra carbon atom (C-8) the so-called berberine bridge . Less oxidized than berberine are the protoberberine alkaloids, e.g. scoulerine (73). This protoberberine skeleton serves as a substrate for further modification leading to alkaloids such as protopine (75), alpinigenine (65), chelidonine (76), corydaline (67) and hydrastine (66) (Herbert 1980). To do justice to all the various alkaloids would require a separate chapter and so we must be content with a brief outline of the biosynthetic routes to berberine (69) and to chelidonine (76), which are illustrative. 

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%. 

The foregoing results are in consonance with the ideas proposed many years ago by Robinson and others, and are best interpreted as tyrosine giving rise to 3,4-dihydroxy-2-phenylethylamine and 3,4-dihydroxy-phenylacetaldehyde which condense to form the 1-benzylisoquinoline intermediate, norlaudanosoline. Insertion of the C-1 unit of the berberine bridge would then complete the skeleton of the protoberberine alkaloids. 

MAO was used in vivo and in vitro as a catalyst for the production of norlaudano-sine from dopamine (Fig. 16.7-14)[35]. Norlaudanosine is an important synthon for benzylisoquinoline alkaloids, providing the upper isoquinoline portion of the morphinan skeleton. In vitro and in vivo yields were in the range of 20 %. 

Photoinduced itniniutn ion-benzylsilane cydizations have also been employed to construct the protoberberine and spiro benzylisoquinoline alkaloid skeletons. For example, the spiro benzylisoqui-noline (138) can be accessed in 50% yield by the photocyclization of isoquinolinium salt (137). Photo-cyclization of the electron rich isoquinolinium salt (118) gave a 70% yield of ( )-xylopinine (Scheme 45). This photocyclization is claimed to proceed more cleanly and with higher efficiency than the corresponding fluoride-promoted ground state cyclization. 

The alkaloids listed in Table II can be grouped on the basis of their skeletons as follows (A) benzylisoquinoline (1-benzylisoquinoline, 1 -benzyltetrahydroisoquinoline, and A-benzyltetrahydroisoquinoline),... 

The number of alkaloids based on the 1-substituted tetrahydroisoquinoline skeleton is legion and the structural variation which this skeleton affords, particularly in the case of 1-benzylisoquinolines, is rich. The 1-substituted isoquinoline skeleton of each kind probably arises by the common step of condensing a j8-arylethylamine with an appropriate carbonyl compound, for which the Pictet-Spengler reaction provides an analogy. In some cases the participation of a carbonyl compound is established but in others it is still speculative. Recently progress has been made in this area in studies on the biosynthesis of lophocerine, the Papaver alkaloids, and to some extent the cryptostyline alkaloids with their novel 1-phenylisoquinoline structures. 

The alkaloids of the narcotine type can also be synthesized from benz[d]indeno(l,2-f ]azepine (133a) (698) (Scheme 45). Moreover, compound 133a forms a key substance for the synthesis of the tetrahydro-protoberberine (58), protopine (101), rhoeadane (154), and spiroben-zylisoquinoline (191) ring skeletons. The compounds 133a and 133b arise also by rearrangement from the spirobenzylisoquinoline, protoberberine, and 1-benzoylisoquinoline skeletons. Therefore, it is assumed that even in the plants it plays a key role in the formation and interconversion of the benzylisoquinoline alkaloids with 17 carbon atoms in the skeleton (Scheme 45). 

The terpenoid indole alkaloids are a group of plant bases derived by multiple variation on the strictosidine [(79) p. 20] skeleton. Arguably the most important work in the past five years has been done on these alkaloids with enzyme preparations from plant tissue cultures, and the research is of great potential significance for other studies in alkaloid biosynthesis. The results have allowed close definition of the early stages of biosynthesis (this Report, p. 19). Use of crude enzyme preparations in this way has been extended to the study of benzylisoquinoline biosynthesis, with enzyme-catalysed formation of norlaudanosoline-1-carboxylic acid [(57) p. 16] this compound had earlier been identified as the first of the benzylisoquinolines (this Report, p. 15). It seems that amino-acids of this general formula (6) are key intermediates in the biosynthesis of all isoquinoline alkaloids. Lophocereine (7) is exceptional in that two routes (from leucine and mevalonate) may lead to it, only one of which potentially involves an acid like (6). ... 

Robinson and Gulland (1925) were the first to observe that the formation of aporpine alkaloids was by oxidative coupling of benzylisoquinoline precursors. They also pointed out that by a different mode of coupling, the basic carbon skeleton of the morphine alkaloids thebaine (59), codeine (62) and morphine (58) could arise (Fig. 32.20). ( — )-(/ )-Reticuline serves well as a postulated precursor be-... 

The classical preparation of the tetrahydroprotoberberine skeleton involves Mannich condensation of a benzylisoquinoline such as 1 with formaldehyde, giving products possessing the 2,3,9,10- and 2,3,10,11-oxygenation patterns. ... 

The 1-benzyltetrahydroisoquinoline skeleton is one of preeminence in the elaboration of plant alkaloids. Only the terpenoid indole skeleton (Section 6.6.2) appears in more diversely modified form. Among the benzylisoquinolines, reticuline (6.127) is of outstanding importance as a substrate for modification. Formation of the... 

Correlations within a stereochemically homogeneous series of compounds, such as monosaccharides and steroids, which are well documented elsewhere in the literature are considered in outline only. Series of compounds which are essentially dimeric or polymeric types built up from chiral monomeric units are not covered in detail, since their configurations follow readily from those of the monomeric unit. Examples of such polymeric-type compounds are di-, oligo- and polysaccharides bis (benzylisoquinoline) and other dimeric alkaloids biflavonoids and polypeptides. Series of natural products having essentially the same carbon skeleton but known in a variety of stereochemical types due to epimerism at one or more chiral centres are frequently covered by general notes rather than by large numbers of examples. This treatment is given, for example, to the labdane-type diterpenes and the yohimbane-type alkaloids. 

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