Isoquinoline tetrahydroisoquinoline alkaloids

A two-phase solvent system composed of chloroform-methanol-dilute inorganic acid has been used for the separation of a variety of alkaloids including isoquinoline alkaloids, naphthyl-tetrahydroisoquinoline alkaloids, fla-vonoid alkaloids, pentacyclic aromatic alkaloids, diterpenoid alkaloids, aporphine alkaloids, etc. The following example illustrates a typical systematic solvent selection for the separation of palmatine, berberine, epiberberine, and coptisine from the crude alkaloids of Coptis chinensis Franch by analytical HSCCC. In Fig. 1, nine chromatograms are arranged in such a way that the effects of the concentration of HCl (0.3-0.1 M) and the relative volumes of methanol (4 3 2-4 1.5 2, v/v) on the separation of alkaloids from C. chinensis Franch are each readily observed. As the concentration of HCl is reduced from 0.3 to 0.1 M in the solvent system, the retention time... 

Isoquinoline alkaloids are found primarily in the Cactaceae, Chenopodiaceae, and Fabaceae (Guinaudeau and Bruneton, 1993 Mata and McLaughlin, 1982). The Cactaceae also elaborate 3-phenylethylamines see chapter 28) that cooccur with tetrahydroisoquinoline alkaloids. The latter appear to have evolved by cyclization of variously substituted phenylethylamines with suitable ring-closing units. A comprehensive listing of isoquinoline alkaloids in cacti has been published (Lundstrom, 1983). 

Tetrahydroisoquinoline alkaloids have a benzenoid fluorophore rather than isoquinoline and so fluoresce at shorter wavelengths. The opiate alkaloids are of this class of alkaloids. Morphine and codeine differ only at the 3 position. Morphine has a hydroxy substituent, making it phenolic, and codeine has a meth-oxy substituent. In water at pH 1 both compounds fluoresce at 350 nm. Both are excited at 285 nm. Codeine has an additional excitation peak at 245 nm. They can be assayed in admixture because morphine loses its fluorescence under basic conditions by way of phenolate formation but codeine retains its fluorescence at high pH. 

The reaction is essentially that described by the submitters.8 The procedure illustrates a convenient method for the synthesis of a type of lactone which could serve as an important intermediate in the synthesis of isoquinolones, tetrahydroisoquinolines, and isoquinoline alkaloids Several analogous and closely related lactones have been reported. 

Intramolecular Diels-Alder reaction of substituted fiirans has been investigated as a route to the synthesis of isoquinoline alkaloids. Tetrahydroisoquinoline 81 was prepared from furan 80 in 40% yield <95JCS(P1)2393>. 

Tetrahydroisoquinoline-l-carboxylic acids have been anodically decarboxylated in MeOH-NaOMe on a graphite felt anode, giving 3,4-di-hydroisoquinolines (50-90%)417 This may be an example of a pseudo-Kolbe reaction in support of Hahn s theory of the biosynthesis of isoquinoline alkaloids by providing a laboratory analogy for the crucial decarboxylation step. 

Benzylated 1,2,3,4-tetrahydroisoquinolines possess important physiological properties and, as illustrated in Scheme 20, also serve as common intermediates for synthesis of naturally ubiquitous isoquinoline alkaloids with different skeletons. Because some natural products have the 1/ configuration while the others possess the IS configuration, the synthesis must be chirally flexible. 

As mentioned above, this third part of the plant psychedelic alkaloid world involves tetrahydroisoquinolines and is the substance of our third book. A very reasonable appendix to be written for this book would be a search of the chemical literature for the known isoquinolines that might be of interest as pharmacological agents. There are certainly many plant products, as well as a monster inventory of synthetics, some of which are made based on plant examples, but many others are simply laboratory creations of the imaginative chemist. 

Noscapine (Nectadon ), 2-methyl-8-methoxy-6,7-methylenedioxy-l-(6,7-di-methoxy-3-phtha-lidyl)-l,2,3,4-tetrahydroisoquinoline, is also one of the isoquinoline derivatives present in opium. Next to morphine, it is the most abundant of the opium alkaloids, present to the extent of 6% in the seed capsules. This drug was formerly known as narcotine but, because it is neither chemically nor pharmacologically related to the narcotics, is more appropriately designated as noscapine. 

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]. 

Similar methodology was used in the synthesis of 3-methyl derivatives of the alkaloids thalactamine, doryanine, and 6,7-dimethoxy-A-methyl-l(2//)-isoquinolone652. The S l reaction between 0rr/20-halogenobenzylamines and enolates derived from a series of ketones and aldehydes affords 1,2-dihydroisoquinolines, from which the isoquinoline derivatives can be obtained by dehydrogenation and the 1,2,3,4-tetrahydroisoquinolines by reduction653. The products of the S l reactions of (2-halo-4,5-dimethoxyphenyl)acetic... 

Mammalian isoquinoline alkaloids include simple tetrahydroisoquinolines, catecholic congeners such as salsolinol and its methyl ether analogs,... 

The mammalian isoquinolines so far detected and characterized are shown in Figs. 28 and 29. Tetrahydroisoquinoline (117) and its 1-methyl congener TIQ 118a were found in rat brain (181) and in food (182). TIQ 117 produces a Parkinson-like syndrome in rats, and the levels of dopamine were markedly decreased (168). GC-MS techniques and chiral reagents identified the major alkaloid present in animal tissue as the (5)-configured TIQ 118a (183,184). The 4-hydroxy-substituted TIQ 79, detected in rat liver and in rat urine (163), is probably the most interesting of the simple mammalian TIQs, and its relevance to MPTP in parkinsonism was mentioned earlier. 

Enantioselective hydrogenation of certain a- and 3-(acylamino)acrylic acids or esters in alcohols under 1-4 atm H2 affords the protected a- and 3-amino acids, respectively (eqs eq 3 and eq 4). Reaction of N-acylated 1-alkylidene-1,2,3,4-tetrahydroisoquinolines provides the IR- or 15-alkylated products. This method allows a general asymmetric synthesis of isoquinoline alkaloids (eq 5). ... 

The isoquinoline alkaloids are the second largest group of alkaloids, numbering about 6000, and can be viewed as five subgroups—the simple tetrahydroisoquinolines, the benzylisoquinolines, the phenethylisoquinolines, the Amaryllidaceae alkaloids, and the monoterpene isoquinolines. In addition, there are a number of simple phenethylamine derivatives, including ephedrine (originally from Ephedra species, but now synthesized) and pseudoephedrine, used for asthma and nasal... 

Seebach also compared the same pivaloylisoquinoline to a tetrahydroisoquinoline formamidine to evaluate die face-selectivity in the addition of die metalated derivatives to aldehydes. 2,i63 cases, the organolithium showed significantly lower diastereoselectivity than the Grignard obtained by transmetalation with MgBr2-Et20, as shown by the examples in Scheme 47. The transmetalation protocol was used to prepare a number of racemic isoquinoline alkaloids. 

This method of asymmetric alkylation has been performed in a number of other systems with equally good enantioselectivity. Tetrahydroisoquinolines have been alkylated (Eq 1) with various alkyl halides to give l substituted tetrahydroisoquinolines in 50-70% overall yields and with excellent ee s. Several naturally occurring isoquinoline alkaloids have also been prepared (compounds A-C) in 95-98.5% ee. A number of chiral auxiliaries other than the valine-based tert-butyl ether also have been examined and gave 80-99% ee s after alkylation. However, the authors consider the chiral auxiliary used in the present procedure to be superior to the others. 

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... 

Perhaps the simplest of the isoquinoline alkaloids is salsolidine. It has been synthesized by asymmetric alkylation of 6,7-dimethoxytetrahydroisoquinoline using either a formamidine ° or oxazoline chiral auxiliary. Scheme 25 illustrates the recently published Organic Syntheses preparation of salsolidine on a 5 g scale. It is of interest to note that, in this and all subsequent examples of asymmetric alkylation of tetrahydroisoquinolines, formamidines derived from L-valine afford (IS)-tetrahydroisoquinolines, while oxazolines derived from L-valine afford the (lf )-enantiomer. The reason is simply the opposite orienta-... 

The range of simple isoquinoline alkaloids, principally obtained from cacti, has recently been greatly expanded by the isolation of isoquinolines, 3,4-dihydroisoquinolines and 1,2,3,4-tetrahydroisoquinolines bearing one, two, three and... 

An attempt to prepare cephalotaxine and 11-hydroxycephalotaxine from chiral precursors by means of a ring expansion of isoquinoline derivatives prepared by the Pictet-Spengler condensation was made by Hudlicky in 1981 (70,71) as shown in Scheme 37. Acid 210 was prepared by condensation of biogenic amines 208 (X = H or OH) with the pyruvate 209. Borane reduction to the corresponding alcohols 211, followed by acid-catalyzed solvolysis, led to the tricyclic enamines 212 and 213 (77). This approach was modeled on the biogenetic condensation of amines with pyruvates to generate 1,1-disubstituted tetrahydroisoquinolines, ubiquitous in alkaloid biogenesis (70). 

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