Tetrahydroisoquinoline systems

An elegant one-pot bicycloannulation method for the synthesis of tetrahydroisoquinoline systems has been disclosed by Pawda et al. <1998TL4757, 2000JOC2684>. This method generates a transient thioisomilnchnone 423 that undergoes an intramolecular dipolar cycloaddition. The thus obtained cycloadduct 424 is next reduced with Raney-Ni, followed by LAH to furnish ( )-alloyohimbane 425 in 31% overall yield from 421 (Scheme 109). 

Pictet-Spengler synthesis is another method of preparing isoquinolines. (3-phenylethylamine reacts with an aldehyde to produce an imine, which undergoes acid-catalysed cyclization, resulting in the synthesis of the tetrahydroisoquinoline system. Again, tetrahydroisoquinoline can he aromatized hy palladium dehydrogenation to produce an isoquinoline system. 

Using tryptamine as the nucleophile, the Michael addition-cyclization strategy was extended to the enantioselective synthesis of the /J-carboline alkaloid system. Michael addition of tryptamine to the chiral acetylenic sulfoxides took place smoothly at room temperature. Either trifluoroacetic acid or p-toluene-sulfonic acid was effective as a catalyst for the cyclization step (Scheme 7). The results of the Michael addition-cyclization reaction sequence are summarized in Table 3. In general, we found that the indole moiety is more reactive than the dimethoxyaryl ring used in the tetrahydroisoquinoline synthesis. Therefore, the cyclization step could take place at a temperature as low as -60 °C. Also, p-tolu-enesulfonic acid resulted in a better diastereoselectivity. However, the diastereo-selectivity of the system is much less sensitive to the aryl substituents of the acetylenic sulfoxides compared to that of the tetrahydroisoquinoline system. Also, to our surprise, the steric factor on the chiral acetylenic sulfoxide has little effect on the diastereoselectivity. Even with the bulky 2-methoxy-naphthyl acetylenic sulfoxide lc [11], the diastereoselectivity still remained roughly the same as for 1 a and 1 b (Scheme 7) (Table 3). 

One of the most powerful methods for the construction of tetrahydroisoquinoline systems is the Pictet-Spengler cyclisation. The reaction consists of the condensation of a b-phenylethylamine derivative with a carbonyl compound, generating an imine (Schiffs base), which undergoes cyclisation via an intramolecular electrophilic aromatic substitution yielding the isoquinoline derivative. The Pictet-Spengler reaction is traditionally carried out in a protic solvent with acid catalysts, usually acetic acid or trifluoroacetic acid. 

Racemisation of (-)-norreticuline has been accomplished by aromatisation of the tetrahydroisoquinoline system, N-benzylation, reduction of the isoquinolinium salt, and reductive N-debenzylation. Aryloxy radical intermediates arising from both phenolic rings... 

Consult ref [118] and compare problem 95. For another modem approach to the 1,2,3,4-tetrahydroisoquinoline system see ref [119]. 

DL-Dimethylcoclaurine was synthesized by the Bischler-Napieralski method starting with homoveratrylamine and p-methox3q)henylacetyl chloride. The 3,4-dihydroisoquinoline derivative first obtained was hydrogenated in the presence of palladium. The necessary comparison with material from the optically active alkaloid was achieved by subjecting the synthetic dimethylcoclaurine to exhaustive methylation, which robs Ci of the tetrahydroisoquinoline system of its asymmetric character. The meth-... 

Having now appended both tetrahydroisoquinoline systems onto the central C-ring piperazine, the only major synthetic objective remaining to complete the total synthesis of ecteinascidin 743 (1) was the formation of the ten-membered macrocyclic F-ring lactone through the envisioned biomimetic o-quinone methide capture. Before this operation could be explored, however, several func-... 

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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