Isoquinoline frameworks, synthesis

For a preparation of alkaloids 35 configurated beyond all doubt, synthetic pathways from the ehiral pool were also elaborated (71). The C3N unit destined to represent the crucial chiral center at C-3 turned out to be the amino acid alanine, in its natural L-form 118, which should easily be incorporated into the isoquinoline framework by reductive amination with the acetophenone 119 and subsequent intramolecular acylation, as outlined in Scheme 29. The practical realization of such a non-biomimetic synthesis (see Scheme 30), however, differs from this very simple concept in three ways ... 

Nowadays, several modifications of the Pictet-Gams reaction exist in the literature, constituting the reaction as the method of choice for the synthesis of isoquinoline frameworks when acid labile substituents are not present in the molecule. Modifications include the use of cinnamic esters, instead of 2-phenyl-2-hydroxy ethanamines, as starting materials... 

Synthesis of tetrahydroimidazo[2,l-a]isoquinolines is another example of the reaction s utility in a fused core synthesis. Formation of compounds of structure 57 starts with 7-phenyl-5,6,7,8-tetrahydroiso-quinoline (56) amination in either DMA or tetralin in autoclave at 220 C for 18 h, which gives 53 in 41-48% yield, consecutively, although a higher yield is achieved when heating the starting material in DMA in the microwave for 12 h, which gives 58 in a 59% yield. The product is then used to construct the tetrahydroimidazo[2,l-a]isoquinoline framework using chloroacetone or 3-bromobutanone, which affords 58a,b in 46% and 75% yields, respectively... 

More than one fluorine atoms were introduced onto the isoquinoline framework (Scheme 4). In 1960, Bayer patented the synthesis of 1,3-difluoroisoquinoline, which was derived from 1,3-dihydroxyisoquinoline and cyanuric fluoride [15], Six years later. Chambers and Musgrave successfully prepared heptafluoroisoquinoline, [16] in which all hydrogen atoms of the parent isoquinoline were replaced by fluorine atoms via a chlorine-fluorine exchange reaction. In this case, heating the mixture of heptachloroisoquinoline and potassium fluoride to 420 °C facilitated global fluorination to provide an excellent yield of heptafluoroisoquinoline. 

The Bischler-Napieralski reaction [20] and the Pictet-Gams reaction [22] are both known as typical methods for the construction of the isoquinoline framework as described in Sect 2. Gambon et al. synthesized l-(trifluoromethyl)isoquinolines via the Bischler-Napieralski reaction of A(-(phenethyl)trifluoroacetamides, [104] whereas Simig et al. utilized the Pictet-Gams reaction of Af-(2-aryl-3,3,3-trifluoro-2-methoxypropyl)amides of acetic or cinnamic acids for the synthesis of 4-(trifluo-romethyl)isoquinolines (Scheme 30) [105]. 

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]. 

The asymmetric total synthesis of rauwolfia alkaloids (-)-yohimbane and (-)-alloyohimbane was carried out by S.C. Bergmeier et al. by utilizing a novei aziridine-allylsilane cyclization and the Bischler-Napieralski isoquinoline synthesis as key steps.These alkaloids have a characteristic pentacyclic ring framework and exhibit a wide range of interesting biological activities such as antihypertensive and antipsychotic properties. 

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