Isoquinolines from phenethylamines

Isoquinoline synthesis Irom aromatic aldehydes and an amino acetal (Pomeranz-Fritsch) or from phenethylamines and glyoxal acetal (Schlitter-Muller). 

In support of the hypothetical phytochemical formation of tetrahydro-isoquinoline derivatives from phenethylamine derivatives and aldehydes, Schopf and Bayerle (118) examined the condensation of acetaldehyde with... 

The thermal condensetion of p-benzyloxyphenylacetic acid and of 3-methoxy-4-hydroxy-phenethylamine occurs and gives, with a yield of 86% to 92%, the N-(3-methoxy4-hydroxy-phenethyl-p-benzyloxyphenylacetamide from this latter, by cyclization according to Bischler-Napieralski with phosphorus oxychloride in acetonitrile, followed by reduction with sodium borohydride, there is obtained with a yield of 75% to 80% the 1-(p-benzyloxybenzyl)-6-meth-oxy-7-hydroxy-1,2,3,4-tetrahydroisoquinoline, which is methylated with formaldehyde and formic acid giving 1 (p-benzyloxybenzyl)-2-methyl-6-methoxy-7-hydroxy-1,2,3,4-tetrahydro-isoquinoline with a yieid of 90%. 

The second illustration above is a phthalide THIQ, and these phenethylamines are sometimes referred to as secophthalide-isoquinolines. Here, the oxygen atom of the original isofuranone ring is substituted on the newly formed double bond. This structure can easily open up to the corresponding ketonic carboxylic acid. These seco-modifications of the attacked isoquinoline (first example, illustrated with an aporphine) and the simpler 1-substituted isoquinolines (second example, as illustrated by the isobenzofuranone) are the only ones included in this book. The standard phenethylamines that are commonly found in cacti, compounds which are not from these seco-mecha-nisms, have been tabulated in TIHKAL and will not be repeated here. 

Alkaloid synthesis from yic-tricarbonyl compounds. Wasserman s group1 has used the strongly electrophilic character of the central carbonyl of a Wc-tricarbonyl system for synthesis of several alkaloids. Thus several isoquinoline alkaloids can be prepared by reaction of a phenethylamine with the tricarbonyl 1. 

BISCHLER NAPIERALSKI Isoquinoline Isoqulnoiine synthesis from amides of phenethylamines... 

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... 

Possibly as a result of the social implications of the hallucinogenic j5-phenethyl-amines and simple isoquinoline alkaloids, a large number of new plant species suspected to contain these structural types have been closely scrutinized with the aid of sensitive analytical methods. Thus, extensive screening of a large variety of cactus species has been carried out. G.c. analysis has indicated the presence of trace amounts of dimers and trimers of phenethylamine and tetrahydroiso-quinoline types " while combination g.c.-mass spectrometry has enabled rapid identification of alkaloids of 120 cactus species." High voltage electrophoresis has been used for quantitative alkaloid determination.Useful structural information may be obtained from the technique of chemical ionization mass spectrometry. ... 

Isoquinoline Alkaloids.—This year has seen the solution of a longstanding mystery in alkaloid biosynthesis the origin of the extra skeletal carbons of the peyote cactus alkaloids, anhalonidine (43) and anhalamine (47). The major portion of the skeleton is derived in each case from tyrosine, by a well established29,30 pathway leading to the intermediate phenethylamine (41) but, despite much research, the origin of C(l) of (47) and C(l) + C(9) of (43) remained unsolved. 

BISCHLER-NAPIERALSKI Isoquinoline Synthesis Isoquinoline synthesis from amides or phenethylamines (see 1st edition). 

Since a-amino-acids serve as starting materials for the synthesis of protein and the elaboration of many plant alkaloids, there must be a sharing of any amino-acid which is required for both of these activities. The extent to which this happens has been the subject of a new study in one particular plant, Lophophora williamsii, which produces isoquinoline and j8-phenethylamine alkaloids. These bases are derived from the a-amino-acid tyrosine and the results from feeding L-[f/- C]tyrosine indicate that this amino-acid is incorporated into the alkaloids approximately three times more efficiently than into protein. Only the L-isomer was examined and one wonders what the results with D-tyrosine would be in the light of the known preference for particular optical isomers of lysine in pipecolic acid and piperidine alkaloid biosynthesis. 

Eleven bases have been isolated from Anhalonium lewinii, three phenethylamines mescaline, V-methylmescaline, and V-acetylmescaline (see /8-Phenethylamines Vol. Ill, chap. 22) and eight simple isoquinolines anhalamine, anhalidine, anhalinine, anhalonidine, pellotine, 0-methyl-d-... 

In all of the syntheses discussed, alkoxy derivatives of a-aminoaceto-phenone or of /3-phenethylamine were employed to supply the main structural outline of the isoquinoline system. Some of these amines are hard to obtain, especially if the resistant aromatic methoxyl groups are replaced by more sensitive substituents which may serve in the preparation of partly demethylated derivatives of papaverine or laudanosine. A significant innovation (60) which avoids the preparation of such unstable amines is the degradation of j3-phenylpropionic acid azides (hydrocinnamic acid azides) to the corresponding isocyanates, which add to the required phenylacetic acids probably with the intermediate formation of four-membered cyclic hemiacetals. The latter are transformed to A-carboxylic acids, which lose carbon dioxide and yield amides needed in the isoquinoline syntheses. In practice, the azide is heated with the phenylacetic acid in benzene solution for several hours, and the amide is isolated from the reaction mixture without difficulty. 

Phenethylamine and its derivatives are the most likely precursors of the isoquinoline system. Their sources are undoubtedly /S-phenylalanine and its nuclear substituted derivatives, from which they can arise by carboxylase-catalyzed decarboxylation. 

There have been recorded a number of other syntheses of hydrohydrastinine, some of which are in the patent literature, but most of them depend upon the formation of the isoquinoline ring from /3-3,4-methylenedioxy-phenethylamine or of its V-methyl derivative (47, 48) or upon the N-methylation of norhydrohydrastinine (49). When the above phenethyl-amine as its hydrochloride is heated with aqueous formaldehyde in a sealed tube for three hours at 130° it generates hydrohydrastinine in 88 % yield (50). There takes place not only the now well-known ring closure of the isoquinoline, but also the V-methylation reaction studied in detail by Hess, Merck, and Uibrig (51, 52). 

Peyote Alkaloids.—An O-methyltransferase has been isolated from the peyote cactus. Its ability to catalyse the methylation of various phenolic phenethylamines and isoquinolines, and the site of methylation, has indicated possible biosynthetic relationships within the peyote cactus cf. ref. 3. 

A stereospecific conversion of berberine into ( )-/3-hydrastine has been reported. Photolytic oxidation of oxyberberine yields the lactol (123), the N-methyl quaternary salt of which can be reduced with sodium borohydride to give racemic jS-hydrastine in 95% yield. Both phthalide-isoquinolines (e.g. adlumine) and spirobenzylisoquinolines e.g. corydaine) have been synthesized from /3-phenethylamines and methylenedioxyphthalide carboxylic acid (124). Several ethers of narcotoline have been prepared and converted into derivatives of nornarceine. The biotransformation of narcotine in rats has been examined and di-O-desmethylnarcotine, cotarnine, hydrocotarnine, oxocotarnine, and O-demethylmeconine have been isolated from urine. " Bicuculline, which has... 

A new acid catalyst of potential use in the Bischler-Napieralski cyclization is P2O5 in methanesulfonic acid. The phenethylamines used in isoquinoline syntheses are usually prepared from the reduction of the corresponding /S-nitrostyrenes. A more versatile procedure starts with a substituted benzyl chloride which is converted to the nitrile using sodium cyanide in DMSO (dimethylsulfoxide). Reduction of the nitrile with LiAlH4 in the presence of AICI3 gives the desired amine in excellent yield. Benzylamines or their quaternary salts may also be utilized in appropriate solvents in place of benzylic chlorides, so that they too may act as nitrile precursors. ... 

No new TV-benzyltetrahydroisoquinolines have been isolated from natural sources in recent years. However, the structure of corgoine has been confirmed by three syntheses. The first involves reduction of the 7V-benzyl quaternary salt derived from isoquinoline 1, whereas the second approach utilizes the Pictet-Spengler reaction to cyclize the substituted phenethylamine 2 (see Scheme 31.1). The third synthesis of corgoine involves heating 6-methoxy-7-hydroxy-tetrahydroisoquinoline with / -hydroxybenzyl alcohol to afford the alkaloid in 44% yield. The A -benzylation probably occurs through the intermediacy of /7-benzoquinone methide which adds to the basic nitrogen of the isoquinoline. ... 

There are no reports on phenethylamine derivatives from Lophocereus species however, these cacti are rich in dopamine, a possible progenitor of the various isoquinolines found (Lundstrom unpublished). 

The simple isoquinolines, anhalonidine (12) and anhalamine (13) are bio nthesized in the peyote cactus along with the hallucinogenic phenethylamine, mescaline (6). It is clear, by inspection, that the isoquinoline alkaloids, (12) and (13), are formed from an Ar-C2-N unit like that seen in mescaline (6) with the inclusion of an additional or C2 unit. 

The pathways leading to these bases, which begin in primary metabolism with the a-amino-acid, tyrosine (1) are known in considerable detail. This is the result of quite extensive experiments particularly with various phenethylamine precursors (Lund-strom 1971, Herbert 1980). A key intermediate is 3,4-dihydroxy-5-methoxyphene-thylamine (5) which stands at a fork leading separately to mescaline (6) and the isoquinoline alkaloids methylation at C-3 leads to mescaline (6) whereas methylation at C4 ultimately affords anhalonidine (12) and anhalamine (13) (Fig. 1). The pathways which have been deduced leading to mescaline (6) and to (7) are nicely supported by a Study which explored the specificity of methylation by an O n ethyl transferase isolated from peyote (Basmadjian and Paul 1971, Basmadjian et al. 1978). 

Lophocerine (19) derives from tyrosine and the C5 unit, formed from C-1 and the pendant isobutyl group, derives from mevalonic acid. In contrast to the isoquinoline alkaloids just discussed the molecule which condenses with a phenethylamine inter-... 

There is considerable variation in structure between the groups of isoquinoline alkaloids, some being simple isoquinolines while others are complex dimers. About 50 simple isoquinolines occur in plants and they are characteristic of some families such as the Cactaceae. Interest in these compounds has stemmed from the well-known hallucinogenic phenethylamine, mescaline, and in one chapter, the occurrence of these simple isoquinolines is reviewed. 

---