Tetrahydroisoquinolines construction

The Bischler-Napieralski reaction is one of the most widely used methods for the construction of dihydro- and tetrahydroisoquinoline units in the synthesis of alkaloid natural products. A few representative examples of the Bischler-Napieralski reaction in complex alkaloid syntheses are shown below. 

The Pictet-Spengler reaction is one of the key methods for construction of the isoquinoline skeleton, an important heterocyclic motif found in numerous bioactive natural products. This reaction involves the condensation of a P-arylethyl amine 1 with an aldehyde, ketone, or 1,2-dicarbonyl compound 2 to give the corresponding tetrahydroisoquinoline 3. These reactions are generally catalyzed by protic or Lewis acids, although numerous thermally-mediated examples are found in the literature. Aromatic compounds containing electron-donating substituents are the most reactive substrates for this reaction. 

Likewise, a wide range of complex polycyclic systems was constructed from suitable precursors. Compounds 269 and 270 were synthesized in 79% yield in a 1.6 1 ratio from tetrahydroisoquinoline-1-carboxylic acid, while 271 was obtained as a single stereoisomer in 87% yield from tetrahydro-p-carboline-l-carboxylic acid (Scheme 3.91). 

Moreover, this procedure should provide a useful route to construct the 1,2,3,4-tetrahydroisoquinoline nucleus in a modified Pomeranz-Fritsch-type procedure shown in Scheme 5. 

All three syntheses of XX create the spiro carbon by the use of variations of the Pictet-Spengler reaction. This long-known and valuable method of constructing tetrahydroisoquinolines (6) consists in the acid-... 

The enormous number of naturally occurring isoquinoline alkaloids, and their importance biologically, has stimulated a great deal of effort in their synthesis. The asymmetric alkylation of the 1-position of the tetrahydroisoquinoline nucleus affords an extremely valuable method for the construction of... 

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. 

The Pictet-Spengler (PS) reaction is an important method to construct biologically important tetrahydroisoquinoline and tetrahydro- 3-carboline skeletons. Since it represents the intramolecular Friedel-Crafts cyclization of arenes and imines, we cover the asymmetric organocatalytic PS reaction in this chapter [61]. 

Sames et al. reported a highly stereoselective intramolecular amination of benzylic C(sp )-H bonds via cascade [l,5]-HT/cyclization of iV-tosylimine 227 generated in situ from ahphatic aldehyde 226, which constructed 2-arylpiperidines 228 and 3-aryl-l,2,3,4-tetrahydroisoquinolines (Scheme 86) [96]. Remarkably, the conformational freedom of substrates had a profound influence on the chemical behaviors of hydride acceptors the substrates with high conformational rigidity had... 

Shortly after, the development of the intramolecular variant of this reaction was reported by Gaertzen and Buchwald [106]. A simple and flexible route to obtain dihydroisoindole and tetrahydroisoquinoline carboxylic acid derivatives was developed using the palladium-catalyzed intramolecular a-arylation of readily available a-amino acid esters (Scheme 8.58). The construction of quaternary carbon centers that tolerate a number of different substituents around the enolate center, including phenyl or bulky isopropyl groups, was reported. A number of different Af-substituents including alkyl, aryl, or carboxyl groups could be employed [106]. 

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