Isoquinoline, structure

To understand the unpredictable nature of the Pictet-Gams reaction, Hartwig and Whaley conducted the first mechanistic studies in 1949. Their work focused on substituent effects when directly attached to the ethylamine side chain. They also investigated a variety of dehydration agents in order to identify optimal reaction conditions. It was determined that formation of the isoquinoline structure was virtually impossible when alkyl or phenyl substituents were placed in the 4-position of the ethylamine side chain. 

A quinoline rather than an isoquinoline structure was later determined248. 

On the basis of comparison of the physical constants of 0,0-dimethylphellodendrine methine with those of laudanosine methylmethine (LXXII) (mp 94°-95° hydrobromide, mp 209.5°-211°), these bases were supposed by Tomita and Kunitomo (68) to be identical. Thus phellodendrine was represented by the isoquinoline structure LXXIII. 

In this review, the natural phthalides of plant origin are classified into four types based on chemical structure (Fig. (2-6)) 1) 3-substituted phthalides 2) non-3-substituted phthalides 3) phthalide dimers and 4) phthalide isoquinolines. The 3-substituted phthalide derivatives are further classified into two subtypes, namely non-alkaloid phthalides (Fig. (2 and alkaloid phthalides (Fig. (3 . Phthalide alkaloids without the isoquinoline structure are always 3-substituted and are accordingly subclassified as the... 

The origin of the colchicine class of molecules thus falls into line with other types of alkaloids in a satisfying manner. A fortuitous combination of molecular circumstances appears to be responsible for the production of the unusual tropolone moiety from a more normal isoquinoline structure. 

In addition to simple monomeric units with isoquinoline structures, a number of dimeric and oligomeric alkaloids of this series are known. An example of this type, pilocereine (8) (Fig. 32.3), known from Pachycereus, Pilocereus, and Lophocereus (all Cactaceae), is derived by coupling of isoquinoline alkaloid units (probably by a free-radical mechanism, although proof for this is lacking), much in the same manner as the dimerization process leading to bisbenzyliso-quinoline alkaloids, a topic discussed below. 

Most of the alkaloids containing an isoquinoline structure that are considered are presented in the following order simple iso quinolines, isoquinolones, and phenethylammonium compounds benzyltetrahydroi-soquinolines bisbenzylisoquinolines and bisbenzyltetrahydroisoquino-lines protoberberines and tetrahydroprotoberberines proaporphines aporphinoids dehydroaporphines 7-substituted aporphines oxoapor-phines phenanthrenes miscellaneous isoquinohne-type alkaloids and nonisoquinoline alkaloids. 

The study of this class of alkaloids has acquired renewed interest because of the finding of new members of the group, several of w hich are quaternary bases. The recent discovery that one of the components of the original corpaverine sample (1) has an A-benzyltetrahydro-isoquinoline structure (2) has introduced a new aspect into their research. 

One of the new methods studied for the building of the isoquinoline structure made use of the condensation of nitrilium salts with j3-chloro-ethylbenzene 181). It has been used for the preparation of many 3,4-dihydroisoquinolines, which can be easily dehydrogenated to the corresponding isoquinolines. 3,4-Dihydropapaverine was obtained as picrate, in 21% yield, by condensing a-chloro-j8-(3,4-dimethoxyphenyl)-ethane (CIX) with homoveratronitrile-stannic chloride (CX), a reaction which involves the ring closure of the mesomeric ion CXI (182). 

In the case of the 2-dimethylamino- (or 2-amino-)methylene derivatives, the products were at first thought to be pyrimido[4,5-c]isoquinolines (267), but later work with 6-(N-substituted amino)uracils assigned the structures of the products (268) as belonging to the isomeric pyrimido[4,5-f>]quinoline system (74CB2537), in agreement with the regioselection rules above. 

A -pyrazolines from, 5, 250 structure, 5, 169 Isoquinoline, 4-acetamido-reduction, 2, 327... 

For consistency, structures are drawn as the isoquinoline-1,4-diol throughout regardless of tautomer drawn in the original reference. The actual tautomeric structure is dependent on the pH of the solution. See Caswell, L. R. Campbell, R. D. J. Org. Chem. 1961, 26,4175. 

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. 

The Pictet-Spengler condensation has been of vital importance in the synthesis of numerous P-carboline and isoquinoline compounds in addition to its use in the formation of alkaloid natural products of complex structure. A tandem retro-aldol and Pictet-Spengler sequence was utilized in a concise and enantioselective synthesis of 18-pseudoyohimbone. Amine 49 cyclized under acidic conditions to give the condensation product 50 in good yield. Deprotection of the ketone produced the indole alkaloid 51. 

The most plausible mechanism involves condensation between aldehyde 1 and amine 5 to give the corresponding imine 6. Cyclisation and subsequent elimination yields the fully unsaturated isoquinoline ring structure 4. 

In the isoquinoline series, infrared spectral data favor nonaromatic forms of type 50 for homophthalimide," a series of substituted homo-phthalimides, and certain iV-hydroxyhomophthalimides the predominance of this structure type gains support from the ultraviolet spectra of homophthalimide and A"-ethylhomophthalimide. ... 

Leptopinine 82 possesses the 3,4-dihydro-isoquinolin-7-ol moiety without further conjugation and was isolated as yellow powder from Hypecoum leptocarpum after several extractions with hydrochloric acid so that this alkaloid was finally isolated as a chloride (Scheme 29). The formation of a mesomeric betaine from this dihydroisoquinoline derivative is unlikely because on addition of base no significant changes of the UV spectra were observed (99P339). A similar structure is Pycnarrhine Pycnarrhena longifolia), which was isolated as a hydroxide (81P323). 

As shown in Scheme 26, Papaverine hydrochloride yields a separable mixture of Protopapaverine (67) and the salt norpapaverinium chloride (68) when heated slightly beyond its melting point for several minutes. Molecule 67 can exist as conjugated mesomeric betaine 67A (7-hydroxy form) or as 2-substituted-2//-isoquinolin-6-one 67B (6-hydroxy form) (66TL1177). Similar structures were described as zwitterionic pentacyclic... 

Structure of 4//-pyrido[l,2-a]pyrazines 348-350 was confirmed by X-ray investigations (99JPR332). The stereostructure of 1,3,4,6,1 l,lla-hexahydro-2/f-pyrazino[l,2-A]isoquinoline-l,4-dione 351 was determined by X-ray investigation (01TL543). 

Although this isoquinoline at first bears little structural resemblance to morphine (108), careful rearrangement of the structure (A) shows the narcotic to possess the benzylisoquinoline fragment within its framework. Indeed, research on the biogenesis of morphine has shown that the molecule is formed by oxidative coupling of a phenol closely related to papaverine. 

Abstract Protoberberine alkaloids and related compounds represent an important class of molecules and have attracted recent attention for their various pharmacological activities. This chapter deals with the physicochemical properties of several isoquinoline alkaloids (berberine, palmatine and coralyne) and many of their derivatives under various environmental conditions. The interaction of these compounds with polymorphic DNA structures (B-form, Z-form, H -form, protonated form, triple helical form and quadruplex form) and polymorphic RNA structures (A-form, protonated form, triple helical form and quadruplex form) reported by several research groups, employing various analytical techniques such as spectrophotometry, spectrofluorimetry, circular dichro-ism, NMR spectroscopy, viscometry as well as molecular modelling and thermodynamic analysis to elucidate their mode and mechanism of action for structure-activity relationships, are also presented. 

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