The Phenethylisoquinolines

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... 

Homopavinane (57) and homoisopavinane (58) ring systems represent examples of the phenethylisoquinoline alkaloid class. A synthesis of racemic... 

Although biosynthesis of the phenethylisoquinoline alkaloids has not yet been studied in full, that of androcymbines, homoaporphines, and homoerythrinans has been examined by work with radioactive tracers. In this section tracer experiments as well as hypothetical biogenetic routes in the synthesis of the phenethylisoquinoline alkaloids are discussed. 

In view of the importance of the isoquinoline system in biosynthesis it is surprising that so little effort has been devoted in the past to the biosynthesis of the basic ring system. No doubt the success of this investigation in the peyote cactus will stimulate further work in other systems. It is likely that the normal pattern will involve condensation of a phenethylamine with the appropriate pyruvic acid. However, reference has already been made to ipecoside (27) (Scheme 3) in which the isoquinoline system is formed by condensation of the phenethylamine with an aldehyde [secologanin]. Presumably the corresponding aldehyde, rather than a pyruvic acid, will be found to serve as precursor for the phenethylisoquinolines,3 5 and also for the isoquinoline alkaloids of the Lophophora cactus such as lopho-cerine (66). 

Phenethylisoquinoline alkaloids are classified into six major alkaloid groups based on structural differences, namely, simple 1-phenethyliso-quinoline (1), homomorphinandienone (2), bisphenethylisoquinoline (3), homoproaporphine (4), homoaporphine (5), and homoerythrina alkaloids (6). These alkaloids are related to the benzylisoquinoline alkaloids such as morphinandienone, bisbenzylisoquinoline, proaporphine, apor-phine, and erythrina alkaloids. Although colchicine and its derivatives also belong to the phenethylisoquinoline alkaloids group, these alkaloids are not included in this review as they have been reviewed earlier 1). 

Although the phenethylisoquinoline alkaloids represent a wide diversity of chemical types, it appears nevertheless that they share a common origin from the 1-phenethylisoquinoline precursor, and that their biosyntheses parallel the formation of analogous alkaloids from... 

The phenethylisoquinoline homopetaline which possesses the unusual 7,8-dioxygenation pattern in the isoquinoline moeity, has been synthesized along classical lines, utilizing a bromine blocking group to direct the Bischler-Napieralski cyclization. ... 

The pharmacological properties of the phenethylisoquinolines are reviewed in Ref. 8. The most interesting of the synthetic phenylisoquinolines is metho-pholine (Versidyne, 4 -chloro-2-methyl-6,7-dimethoxytetrahydroisoquinoline), whose analgesic properties were investigated at the Hoffman-La Roche laboratories. 

The crucial test for the hypothesis lay in the examination of compounds of type 6.171) and 6.173) as colchicine precursors. In the event [119-121], 0-methylandrocymbine 6.172) was a spectacularly good precursor for colchicine. The phenethylisoquinoline 6.171), called autumnaline, was also clearly implicated in biosynthesis only the (5)-isomer of autumnaline, with the same absolute configuration as colchicine is involved, and oxidative coupling of this base occurs in a para-para sense rather than the alternative, ortho-para. Results of other experiments, together with those discussed here, led to the pathway illustrated in Scheme 6.34. 

These alkaloids have a phenyl or phenylpropyl nucleus. The group includes simple phenyl amine (tyramine, hordenine), catecholamine (dopamine, noradrenaline, adrenaline), simple tetrahydroisoquinoline (mescaline, anhalamine, anhalonine, anhalonidine), benzylisoquinoline (e.g., papaverine), phthalideiso-quinoline (e.g., noscapine), phenethylisoquinoline (autumnaline, floramultine and kreysigine), tetrahydroisoquinoline (emehne and cephaeline) and terpenoid tetrahydroisoquinoline (secologanin and ipecoside) alkaloids. 

The first homopavine, ( )-homoargemonine (174), was synthesized in 1973 in an attempt to construct pavine analogs with improved analgesic activity (Scheme 38) (777). The corresponding 1-phenethylisoquinoline 173 was obtained by a Bischler-Napieralski condensation of 2-(3,4-dimethoxyphenyl)-ethylamine (170) and 3-(3,4-dimethoxyphenyl)propionic acid (171) via the hy-droxyamide intermediate 172. Compound 173 was then successively quater-nized, reduced by lithium aluminum hydride, and treated with acid to afford the tetracyclic compound ( )-174. 

Lilaceae also contain 1-phenethylisoquinoline alkaloids, it was suggested [82) that the homoerythrina derivatives are biosynthesized along a pathway analogous to that followed by the Erythrina alkaloids themselves (Scheme 35). Some preliminary results from feeding experiments (121) support this view ( )-[2-14C]tyrosine causes specific labeling of C-8 in 77a. 

An approach to the cephalotaxine skeleton, based upon the presumed biogenetic route, has been reported (164) and involves the oxidation of the 1-phenethylisoquinoline derivative (260) with VOF3 (Scheme 54). Alkaline cleavage of the dienone (261) gave 262 which, as the hydrochloride salt, was reduced 263. A-trifluoroacetylation followed by O-methylation yielded 264 which, after hydrogenolysis to 265, was oxidized with potassium ferricyanide to give the dienone (266). 

Cephalotaxus Alkaloids.—Preliminary results indicate that the homo-Erythrina alkaloid schelhammeridine (52) derives from phenylalanine and tyrosine by way of a phenethylisoquinoline precursor [as (53)].52 Previous evidence for the biosynthesis of the related alkaloid cephalotaxine (54), obtained with tyrosine labelled in the side-chain, has indicated a different pathway which involves two molecules of this amino-acid.53 Recently, however, tyrosine labelled in the aromatic ring was examined as a cephalotaxine precursor and was found54 to label ring A of (54) almost exclusively, i.e. only one unit of tyrosine is used for biosynthesis. This is obviously inconsistent with the previous evidence and the early incorporations are... 

The oxidation of phenethylisoquinolines in biogenetically modelled syntheses has been studied. Orientaline, when oxidized with oxygen, copper(i) chloride, and pyridine, yields ( )-orientalinone, and the base (31) gives ( )-kreysiginone and its... 

Morphinandienones have also been synthesized by the oxidation of mono-phenolic benzylisoquinolines with vanadium oxyfluoride in trifluoroacetic acid, other products of the reaction being proaporphines, and similar oxidations have been accomplished with phenethylisoquinolines.183 The same reagent will oxidize the lactam (150) to the dienone (151), which is an analogue of dehydrometatheb-ainone, and the same cyclization may be effected by electrochemical oxidation.184... 

Melanthioidine (CLXVI) was isolated from Androcymbium melan-thioides Willd. (124) with androcymbine, an alkaloid containing the 1-phenethylisoquinoline system. 

Appropriate phenolic 1,2,3,4-tetrahydro-l-phenethylisoquinolines gave miscellaneous C-homoaporphines by the same methodology as mentioned in Section II. 

The chapter on phenethylisoquinoline alkaloids that appeared in Volume 14 of this treatise reviewed the literature up to the middle of 1972 (/). In the succeeding years covered in this review (1972-1988) significant advances have been made in all aspects of study regarding this family of alkaloids. 

Phenethylisoquinoline alkaloids are classified into seven major alkaloid groups based on structural differences simple 1-phenethylisoquinolines (1), homomorphinanedienones (2), bisphenethylisoquinolines (3), homoproaporphines (4), homoaporphines (5), homoerythrines (6), and dibenz[benzylisoquinoline alkaloids. Although tropolone and Cephalotaxus alkaloids also belong to the... 

Nearly 40 new phenethylisoquinoline alkaloids have been isolated and characterized since the last review in Volume 14 of this treatise (/). These alkaloids are listed in Table I together with their botanical sources and physical properties. 

Of the simple phenethylisoquinoline alkaloids dysoxyline (8), (5)-(-t-)-homolaudanosine (9), and (-)-isoautumnaline (10), 8 and 9 were isolated from Dysoxylum lenticellare Gillespie (5). Alkaloid 10 was isolated from Colchicum ritchii R.B. (4). 

Alkaloids 8 and 9 were identified as simple 1-phenethylisoquinolines by means of their mass spectra. The parent ions of 8, mlz 355 (C21H25NO4), and 9 mlz 371 (C22H24NO4), differ by 16. Both compounds show a base peak at mlz 206 resulting from the loss of a phenethyl radical from the parent ion. A similar loss of the C-1 benzyl radical produces the base peak... 

Extensive tracer experiments show that tropolone alkaloids of the species Colchicum are derived from the I-phenethylisoquinoline system (73) by way of the dienone O-methylandrocymbine (16) (56). These findings, when combined with results of the earlier work (57), support the sequence shown. 

Specifically C-labeled 1 -phenethylisoquinolines were administered to Kreysigia multiflora plants, and the alkaloids were isolated and degraded to unambiguous sequences. The results show that the C-homoaporphine... 

Tracer experiments suggest that schelhammeridine (78) of the species Schelhammera is derived from the 1-phenethylisoquinoline 75 by way of the dibenz[r//]azecine 76a and dienone 77 (59). 

One-electron withdrawing inorganic reagents have been used to perform biomimetic syntheses of phenolic phenethylisoquinoline alkaloids. In order to obtain androcymbine compounds of type 85, the diphenolic isoquinoline 82a was subjected to phenol oxidation with manganese dioxide. The homoaporphine 83a coupled at the ortho-ortho position to the hydroxy group was the only product formed under these reaction... 

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