1 -Benzyltetrahydroisoquinoline system

An alternative approach to synthesis of this ring system involves insertion of CO into the brominated secondary base (43), by treatment with carbon monoxide, lead tetra-acetate, and triphenylphosphine in tributylamine, the product being the amide (44), reduction of which affords the amine.81 Govadine (42 R1 = R4 = OMe, R2 = R5 = OH, R3 = H) has been synthesized by the conventional ring-closure, with formaldehyde, of the diphenolic base (45), or of its dibenzyl ether, in acid solution.82 Tetrahydroberberines, together with N-benzyltetrahydroisoquinolines, have also been obtained by the electrolytic reduction of 3,4-dihydroisoquinolines of structure (46).83... 

Laudanosine (6,7,3, 4 -tetramethoxy-1 -benzyltetrahydroisoquinoline) was isolated for the first time by Hesse (371) from opium. Intravenous administration of this substance to rabbits reduced the intraocular pressure (372). The whole effect manifested itself by motor restlessness, convulsions, disorders in coordination of movements, salivation, etc., which indicated an involvement of the extrapyramidal system and the mesencephalon. The effect produced by synthetic racemic laudanosine on rabbits was similar to that of the (+) form, but it was more toxic (373). The pharmacological properties of laudanosine have also been described (374). 

Herveline A (66) is a pavine-benzyltetrahydroisoquinoline dimer, and its molecular formula was determined as C39H44O7N2 by HREIMS (obsd m/z 652.3140) [11]. The UV absorptions at 282 and 319 nm were indicative of a bisbenzylisoquinoline skeleton [37], The H-NMR spectrum of 66 revealed the presence of two JV-methyl groups, five methoxy groups, one A2B2 system, and five aromatic singlet protons [11]. In addition, three CH-CH2 and one CH2-CH2 units were identified by H-... 

The syntheses of l-(3,4-dihydroxybenzyl)-2-propyl-l,23,4-tetrahydroisoquinoline (18) and l-(4-hydroxybenzyl)-2-propyl-l,2,3,4-tetrahydroisoquinoline (19) were carried out in order to examine the structure-activity relationships when the rigid aporphine ring system is replaced by the more flexible benzyltetrahydroisoquinoline moiety which still contained all of the necessary substituents of the potent NPA molecule (4b) (Neumeyer et al. 1977). 

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... 

Phenethylisoquinoline alkaloids constitute another important group of tyrosine-derived secondary metabolites. This class of natural products with colchicine (54) as most prominent member is obtained when aldehyde 43 is employed in a condensation reaction with dopamine, followed by a Pictet-Spengler cyclization reaction. The difference to benzyltetrahydroisoquinoline alkaloids is an additional carbon between the tetrahydroisoquinoline core and the aromatic ring. As outlined in Scheme 12.9, aldehyde 43 is derived from phenylalanine (42) via intermediary formation of 4-hydroxycinnamaldehyde. The formation of the tetrahydroisoquinoline system 44 from dopamine (4) and 4-hydroxydihydrocinnamaldehyde (43) is followed... 

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