Tetrahydroisoquinoline Pictet-Spengler synthesis

Tetrahydroisoquinolines from condensation of P-arylethylamines and carbonyl compounds followed by cyclization. 

Tinsley, J. M. Pictet-Spengler Isoquinoline Synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J. Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2005, 469 79. (Review). 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 201, Springer-Verlag Berlin Heidelberg 2009 

Nakagawa, M. Nishida, A. Tetrahedron Asymmetry 2003,14,177-180. Couture, A. Deniau, E. Grandclaudon, P. Lebrun, S. Tetrahedron Asymmetry 2003, 14,1309-1320. 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 215, Springer International Publishing Switzerland 2014 

O-alkyl, usually an electron-donating group (EDG) R = H, alkyl, aryl R = H, alkyl, aryl orotic acid  

The research group of S.J. Danishefsky investigated model systems in an effort directed toward the total synthesis of ET 743 and its analogues. The stereoselective formation of the spiro stereocenter of the ABFGH subunit of ET 743 was installed via a Pictet-Spengler reaction. The electron-rich phenylethylamine was mixed with a slight excess of the ketone substrate and the cyclization took place at room temperature in the presence of silica gel. 

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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. 

Pictet-Spengler tetrahydroisoquinoline synthesis Condensation of a P-arylethylamine with carbonyl compounds to form tetrahydroisoquinolines. 348... 

The Pictet-Spengler reaction has been carried out on various solid support materials " and with microwave irradiation activation.Diverse structural analogues of (-)-Saframycin A have been prepared by carrying out the Pictet-Spengler isoquinoline synthesis on substrates attached to a polystyrene support. Amine 20 was condensed with aldehyde 21 followed by cyclization to give predominantly the cis isomer tetrahydroisoquinoline 22 which was further elaborated to (-)-Saframycin A analogues. 

Another useful variation is the Pictet-Spengler isoquinoline synthesis, also known as the Pictet-Spengler reaction. The reactive intermediate is an iminium ion 49 rather than an oxygen-stabilized cation, but attack at the electrophilic carbon of the C=N unit (see 16-31) leads to an isoquinoline derivative. When a p-aryla-mine reacts with an aldehyde, the product is an iminium salt, which cyclizes with an aromatic ring to complete the reaction and generate a tetrahydroisoquinoline." ° A variety of aldehydes can be used, and substitution on the aromatic ring leads to many derivatives. When the reaction is done in the presence of a chiral thiourea catalyst, good enantioselectivity was observed." ... 

Model studies directed toward the synthesis of Ecteinascidin 743 employed an elegant Pictet-Spengler cyclization of phenethylamine 54 and the 1,2-dicarbonyl compound 55 to assemble the spiro tetrahydroisoquinoline 56 in a stereospecific fashion. " The silica-catalyzed condensation reaction provided 56 in excellent yield. 

The mechanistically similar Pictet-Spengler synthesis is also much used for the preparation of 1,2,3,4-tetrahydroisoquinolines, starting from a... 

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. 

The 1.2.3.4-tetrahydroisoquinoline skeleton represents the framework found in many isoquinoline alkaloid derivatives and not only from plants. Some derivatives attracted much interest because of their anti-cancer activity [124], which has prompted many groups to invest in their chemical synthesis. The Pictet-Spengler reaction has become an important method in the preparation of this alkaloid type, and has often been described with phenylalanine derivatives and pyruvates as starting materials. Synthesis of appropriate tetrahydroisoquinoline-3 and the corresponding tetrahydroisoquinoline-1-carboxylic acid has been the key target [125]. 

Chirality can be induced at the C-l position by the cyclization of o-vinylphenethylamine in the presence of a chiral selenium reagent (Equation 68) <1998S162>. Removal of the selenide gives the 2-methyltetrahydroisoquinoline. The use of the Pictet-Spengler reaction in the asymmetric synthesis of tetrahydroisoquinolines remains active. Therefore the intramolecular reaction of /3-iminosulfoxide 33 yields the chiral product 34 (Equation 69) <1998EJ0435>. 

The Pictet-Spengler reaction, the cyclization of an electron-rich aryl or heteroaryl group onto an imine electrophile, is the established method for the synthesis of tetrahydroisoquinoline and tetrahydro-/ -carboline ring systems. Catalytic asymmetric approaches to these synthetically important structures are mostly restricted to asymmetric hydrogenations of cyclic imines [77, 78]. In a noteworthy... 

The Pictet-Spengler synthesis is usually used when the tetrahydroisoquinoline oxidation level is required. 

Variations and improvements of the Pictet-Spengler reaction continued to be a popular area of research for the synthesis of isoquinolines. Ruchirawat et al. reported a new version of the Pictet-Spengler reaction where V-acylcarbamatcs 122 were partially reduced with DIBAL-H followed by the sequential addition of BF3-OEt2 to provide 1,2-disubstituted tetrahydroisoquinoline derivatives 123 <07TL8182>. 

A titanium precatalyst is described which the authors use in a one-pot synthesis of tetrahydroisoquinolines from phenethylamines and alkynes <03OL4733>. The reaction is a modification of the Pictet-Spengler reaction. 

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