Isoquinoline-derived alkaloids

Isoquinolines and Isoquinoline-Derived Alkaloids from the Plants of Thailand... 

Marek et al. [108] reported the chemical shifts and long-range correlation pathways for the alkaloid roemeridine (90) in 1996 in conjunction with data for a number of isoquinoline-derived alkaloids that are discussed below. 

Isoquinoline and isoquinoline derived alkaloids are mainly distributed in the families Annonaceae, Lauraceae and Menispermaceae. 

Emetine (48) is an isoquinoline derived alkaloid from Cephaelis species (Rubiaceae) [104]. It was first isolated in 1817 [167] and was the lead compound for the development of the drug tetrabenazine (49). Tetrabenazine was originally developed as an antipsychotic drug in the 1960s, but in 2008 was approved by the US Food and Drug Administration for use in Huntington s disease chorea [168, 169]. The mode of action of tetrabenazine is reversible inhibition of the human vesicular monoamine transporter 2 to deplete monoamines, including DA, from nerve terminals [168]. Consequently, adverse effects can include extrapyra-midal dysfunction and parkinsonism [109] (Scheme 42.12). 

In some alkaloid reference volumes, alkaloids such as berberine and related molecules have been classified as benzo[r]phenanthrene alkaloids. We have chosen to classify these alkaloids, for the purposes of this review, as isoquinoline-derived alkaloids, which are discussed in Section 7.9. Isoquinoline is the largest constituent of these alkaloids that falls into a trivial classification, which was the basis of our decision. 

Shamma M, Lan H-Y, Freyer AJ, Leet JE, Urziia A, Fajardo V (1983) Chiloenamine and Chiloe-nine Two unusual isoquinoline derived alkaloids. A new insight into the catabolism of aporphines. J Chem Soc Commun 799-800... 

Isoquinolines are used in catalytic (191), photographic (192), and dye appHcations (193). A great many alkaloids and synthetic medicinal compounds are isoquinoline derivatives. The principal dmgs containing this stmcture marketed in the United States are Hsted in Table 4. 

Dihydropyridines have also been starting points for stereospecific syntheses of hydro-phenanthridines and isoquinolines. Interest exists in these compounds because of the occurrence of this structural feature in alkaloids. For example, isoquinuclidine (263), derived from JV-alkoxycarbonyl-l,2-dihydropyridine, undergoes a Cope rearrangement to give the isoquinoline derivative (264) (80JA6157). Further chemical transformations of (264) provided a formal total synthesis of reserpine (Scheme 50). 

The opium is obtained from the opium poppy Papaver somniferum. It contains two type of alkaloids e.g. phenanthrene derivatives (morphine, codeine thebaine) and benzyl isoquinoline derivatives (papaverine and noscapine). 

Makosza118 has also shown that Reissert compounds, A-benzoyl-1,2-dihydroisoquinaldenitrile (67), can be alkylated in the presence of NaOH and TEBA. Alkaline hydrolysis of alkylated 68 will give isoquinoline derivatives, which are starting materials for the synthesis of alkaloids. 

A great many alkaloids and synthetic medicinal compounds are isoquinoline derivatives... 

Following their syntheses of ( )-pancracine and related alkaloids (vide supra), Hoshino et al [106] had described a different approach involving radical cyclisation of an isoquinoline derivative which permitted a rapid assembly of keto-5,11-methanomorphanthridine skeleton. The syntheses of 413, 414 and 415 commenced with the known 4-hydroxy-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoIine (439) (Scheme 62). Subsequent to protection of the amino group as the trifluoroacetyl derivative, the amide alcohol 440 was converted into the amide thioether 441, by reaction with phenylthiol in the presence of zinc iodide. Alkaline hydrolysis of 441,... 

The opium alkaloids, which are obtained from Papaver somniferum, contain two groups of compounds compounds with phenanthrene derivatives, consisting of morphine, codeine, and thebaine and compounds with isoquinoline derivatives, consisting of papaverine and noscapine. 

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. 

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... 

A number of guesses had already been made concerning the over-all structure of these alkaloids all such structures contained a quinoline or isoquinoline ring system because of the unproved view, current for a long time, that dinitrostrycholcarboxylic acid was a quinoline or isoquinoline derivative. Thus Robinson, in his Bakerian lecture to the Royal Society in 1930 (19), proposed structure XIV1 for strychnine. Not long... 

The first total synthesis of ( + )-dauricine was reported by Kametani and Fukumoto in 1964 (18,19). Arndt-Eistert reaction of homoveratryl-amine with the acid chloride XIX afforded the amide XXII. Bischler-Napieralski cyclization of the above amide gave the dihydro isoquinoline derivative XXIV, the methiodide of which when reduced with zinc dust and ethanol-hydrochloric acid afforded + )-dauricine. The identity of the synthetic product with ( )-dauricine w as concluded through a comparison of its physical properties (spectra and chromatographic behavior) with those of an authentic sample of the alkaloid. Melting-point determination of a mixture of derivatives of the two specimens is not recorded. 

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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