Protoberberines benzylisoquinoline

Sixteen alkaloids were isolated from extracts of the roots of ThaUctrum longistylum DC among which were nine alkaloids of novel structure including four benzylisoquinoline-protoberberines (berberlongine, berberstyline, longiberine, and O-methyllongiberine), and five... 

This problem has been circumvented by utilizing the ipso-directing capability of a silicon substituent at the 2 position of the D ring to facilitate ring closure at this position. Benzylisoquinoline 26 condensed with formaldehyde to give predominantly product 28 when R = H. However, when R = SiMea, 27 was the only product observed and was isolated in excellent yield.Several members of the protoberberine family of natural products have been synthesized using this strategy. 

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. 

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 is known that berberine (46) and the protoberberine alkaloid (S)-stylopine (44) are elaborated from an intact molecule of (S)-reticuline [as (33)], the 7V-methyl group providing C-8 in each alkaloid1,2,42 (cf. Vol. 7, p. 12). Exactly similar findings were obtained for tetrahydropalmatine (45) and palmatine (47) in C. laurifolius.43 Of several benzylisoquinolines tested, only reticuline (33), nor-reticuline (41), and norlaudanosoline (40) were significantly incorporated. Tetrahydropalmatine (45) was found to be converted into palmatine (47) and the conversion was irreversible. 

In a recent study (61, 62) the plant Thaliclrwm fendleri has been shown to contain berberine, jatrorrhizine, magnoflorine, two new protoberberine bases, thalifendine and thalidastine, and a new benzylisoquinoline alkaloid, thalifendlerine. 

Speculations on the biosynthesis of berberine date back to the beginning of the century (121). Most of the early proposals recognized the structural relationship of the protoberberine alkaloids with the simpler benzylisoquinoline bases, from which it was supposed that they are derived. The additional carbon atom necessary for the formal conversion... 

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. 

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. 

The use of u.v. spectroscopy to determine the nature and position of methoxy-and methylenedioxy-substituted aromatic rings has been systematically applied to protoberberine, protopine, benzophenanthridine, and proto-ochotensimine alkaloids.51 I.r. spectra of examples of almost all subgroups of benzylisoquinoline alkaloids, including emetine, have been recorded and characteristic bands in the 1800—1480 cm-1 region have been used to identify a particular subgroup.52... 

The protoberberines constitute a group of alkaloids that can theoretically be derived from benzylisoquinolines by condensation with S-adenosyl-methionine. Protoberberine alkaloids occur in a wide variety of plant families, including the Annonaceae, Berberidaceae, Menispermaceae, Papa-veraceae, Ranunculaceae, and Rutaceae. Investigation of the stem of Anamirta cocculus (L.) Wight and Arn. (Menispermaceae), a southeast Asian plant collected in Sri Lanka, has afforded two protoberberine alkaloids, (-)-8-oxotetrahydropalmatine (62) and oxypalmatine (63) (46), whereas the stems and roots of the same species occurring in Indonesia have yielded, in addition to 62, berberine, palmatine, magnoflorine, and columbamine (58). 

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. 

Benzylisoquinoline plays an important role as a biosynthesis centre for Annonaceous alkaloids such as isoquinolones, protoberberines,... 

Protoberberines The protoberberine alkaloids are the most widely distributed benzylisoquinoline alkaloids. Hundreds of alkaloids of this series are discovered that they were yielded from the tetrahydroisoquinoline catalyzed by BBE [16], the berberine bridge... 

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). 

Many of the alkaloids of the isoquinoline group— particularly those belonging to the protoberberine, cryptopine, and phthalideisoquinoline subgroups—are uterine stimulants. Their action in vivo, however, is very fleeting. In connection with the isoquinoline alkaloids, it should be mentioned that relaxation of smooth muscle is a property long associated with the benzylisoquinoline compounds. Occasionally we find this property loosely applied to isoquinoline compounds in general. The fact that a large number of isoquinoline compounds are active uterine stimulants clearly indicates that such statements are not entirely in line with the facts. 

Benzylisoquinolines.—An extensive review of Thalictrum alkaloids has appeared. These include benzylisoquinolines, bisbenzylisoquinolines, isoquinolones, apor-phines, aporphine-benzylisoquinoline dimers, phenanthrenes, protoberberines, protopines, pa vines, and isopa vines. The alkaloids of the Lauraceae have also... 

The position of the phenolic hydroxyl group in corpaverine is the same as in the alkaloid capaurine (XC) which accompanies it in the plant. This plant is chiefly noted for the almost exclusive elaboration of protoberber-ines (t q)e XC), and the assumption that benzylisoquinolines are intermediates in their synthesis is quite likely. Such a last step, however, requires another ring closure, and for this purpose a point of attack must be activated by a hydroxyl or methoxyl in the ortho or para position. This activation is lacking in corpaverine, and in consequence this alkaloid is the end-product in the plant. It would be difficult to devise an experiment which would give clearer evidence of the nature of the ultimate intermediate in the biogenesis of the protoberberines. 

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. 

A patent that covers the synthesis of 13-hydroxy-protoberberines by conventional Mannich cyclization of benzylisoquinolines with formaldehyde has been published. ""... 

Several types of data based on feeding experiments, isolation of intermediates and in vivo NMR experiments, indicate that norcoclaurine (23) serves as a precursor to both coclaurine (24) and (S)-reticuline (20) (Stadler et al., 1987, 1989), and that (5)-coclaurine (24) serves as a specific precursor to other classes of benzylisoquinoline alkaloids, such as the protoberberines, benzophenanthridines, and morphinandie-nones, as well as for pavine and benzophenanthridine alkaloids in intact plants (Stadler et al., 1987, 1989). The five enzymes involved in the conversion of dopamine and 4-hydroxyphenylacetaldehyde (19) to (S)-reticuline (20) have been elucidated (Frenzel and Zenk, 1990b). 

The protoberberine alkaloids are one of the most widely distributed groups of the benzylisoquinoline alkaloids (a subgroup of these is called berberine alkaloids ). Approxi-... 

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