Tetrahydroisoquinoline alkaloids, biosynthesis

Mannich and Mannich-like reactions are widely used for the chemical synthesis of heterocycles, and in alkaloid biosynthesis in plants. One such reaction important in nature is a biological equivalent of the Pictet-Spengler tetrahydroisoquinoline synthesis (see Section 11.10.4), and offers a slight twist, in that the enol nucleophile is actually a phenol. 

Stadler, R. and Zenk, M.H. (1990) A revision of the generally accepted pathway for the biosynthesis of tetrahydroisoquinoline alkaloid reticuline. Liebigs Ann. Chem., 555-62. 

RS)-1 -benzyl-1,2,3,4-tetrahydroisoquinoline A -methyltransferase norreticuline A -methyltransferase transferases Isoquinoline alkaloid biosynthesis (m00950)... 

Barton DHR, Cohen T (1957) In Festschrift Dr A Stoll, Birkhauser, Basel, p 117 Barton DHR, Kirby GW, Taylor JB, Thomas GM (1963) Phenol oxidation and biosynthesis, part VI. The biogenesis of amaryllidaceae alkaloids. J Chem Soc 4545—4558 Barton DHR, Hesse RH, Kirby GW (1965) Phenol oxidation and biosynthesis, part VIII. Investigations on the biosynthesis of berberine and protopine. J Chem Soc 6379-6389 Barton DHR, Bracho RD, Potter CJ, Widdowson DA (1974) Phenol oxidation and biosynthesis, part XXIV. Origin of chirality in the erythrinan system and derivation of the lactone rings of a- and ]3-erythroidine. J Chem Soc Perkin Trans 1 2278-2283 Basmadjian GP, Paul AG (1971) The isolation of an O-methyltransferase from peyote and its role in the biosynthesis of mescaline. Uoydia 34 91-93 Basmadjian GP, Hussain SF, Paul AG (1978) Biosynthetic relationships between phenethylamine and tetrahydroisoquinoline alkaloids in peyote. Lloydia 41 375-380 Battersby AR, Binks R, Francis RJ, McCaldin DJ, Ramuz H (1964) Alkaloid biosynthesis, part IV. 1-Benzylisoquinolines as precursors of thebaine, codeine and morphine. J Chem Soc 3600-3610... 

Exemplarily, the biosynthesis of salsolinol (11) is outlined in Scheme 12.2. Salsolinol has been isolated from various plant sources, such as the cacao plant [8], banana fruits [9], marine sponges [10], and several Corydalis species (Papaveraceae) [11]. Generally, tetrahydroisoquinoline alkaloids can be obtained via condensation of the corresponding phenylethylamine with an aldehyde (top hne. Scheme 12.2) and subsequent Pictet-Spengler reaction, or alternatively via condensation of the requisite ketoacid, followed by... 

Tetrahydroisoquinoline-l-carboxylic acids have been anodically decarboxylated in MeOH-NaOMe on a graphite felt anode, giving 3,4-di-hydroisoquinolines (50-90%)417 This may be an example of a pseudo-Kolbe reaction in support of Hahn s theory of the biosynthesis of isoquinoline alkaloids by providing a laboratory analogy for the crucial decarboxylation step. 

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 family Papaveraceae Juss. is subdivided into the subfamilies Hypecoideae Prantl and Kiindig and Papaveroideae A. Br. It embraces 23 genera and 430 species. The Fumariaceae DC. include 7 genera with 350 species. In the literature, the alkaloids of about 168 species of the Papaveraceae and 90 species of the Fumariaceae have been described. A characteristic feature of these two families is (with a few exceptions, e.g.. Section IV) the presence of alkaloids derived from tetrahydroisoquinolines. These alkaloids arise from phenylalanine by condensation of dopamine with 3,4-dihydroxyphenylacetaldehyde and subsequent Mannich condensation to yield norlaudanosoline as the primary condensation product (Fig. 2). Other intermediates formed during the biosynthesis of more complicated constitutional types of isoquinoline alkaloids are (/ )-(-)- or... 

A possible way to avoid intermediate stable isoquinolines like 33 and 35 is reductive amination of the more reactive carbonyl function of A (representing 31 or 32), [which is biochemically plausible, e.g., with pyridoxylamine (36)], leading directly to the dihydroisoquinolines B, which then might very easily be further oxidized to isoquinolines C or reduced to tetrahydroisoquinolines D (see Scheme 4). This possible pathway closely resembles the known 39, 39a) biosynthesis of the hemlock alkaloid coniine (39), where reductive amination of the more reactive carbonyl function of the diketo precursor 37 leads to the cyclic imine y-coniceine (38), which is further reduced to 39 (see Scheme 5). 

In many of the isoquinoline alkaloids the tetrahydroisoquinoline skeleton is clearly seen as part of the stmcture, in others it is somewhat obscured, e.g. chelidonine (76) (Sect. 3.4), and in still others, e.g, colchicine (77) (Sect. 4), which is a phen-ethylisoquinoline, and the Erythrina alkaloids (Sect. 3.3) severe modification in the course of biosynthesis has obliterated any suggestion of an isoquinoline moiety. 

The biosynthesis of benzyltetrahydroisoquinoline alkaloids has been thoroughly studied—mainly because of the medicinal and commercial importance of opium alkaloids— and commences with the preparation of (5)-reticuline (19). Reticuline then presents a point of divergence and as starting point for the biosynthesis of the previously named tyrosine-derived alkaloids with different skeletal structures [14-16]. The route to (5)-reticuline is outlined in Scheme 12.3. Both reaction partners for the condensation reaction and formation of (S)-norcoclaurine (16) are derived from tyrosine. The aromatic portions in (S)-reticuline (19) possess an ortho-dihydroxylation pattern as present in dopamine (4). However, only the northern portion in 19 is derived from dopamine, and the second hydroxyl functionality in the southern part is introduced after the formation of the tetrahydroisoquinoline ring system. The synthesis of the southern portion in... 

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