Benzylisoquinolines

Other unusual alkaloids are the 4-pyrrol idyl-compounds mac-rostomine (25, R=Me), two of its A -oxides, arenine (25, R=H) and dehydronormacrostomine (26), obtained from Papaver macrostoma and Papaver arenarium (V.A. Muatsakanyan et al.. Coll. Czech.chem.Commun., 1977, 1421 I. Israilov, M.A.Manush- 

The benzylic carbanion from papaverine has been converted into a variety of substituted bases of general structure (30) by treatment with alkyl halides, aminoalkyl halides and ethyl acrylate (A. Buzas and G. Lavielle, Patent, Chem.Abs., 1981, 95, 25378, 150978) and the ion from dihydropapaverine (31) has been found to react with cyclohexan-1,2-dione in the presence of excess base to give the spiro ketone (35) presumably via the intermediates (32), (33) and (34). 

An analogue of (35) has been prepared from the anion (31) and benzil. (S. Ruchirawat and V. Somchitman, Tetrahedron Letters. 1976, 4159). 

Both cis and trans laudanosine 4 -oxides (39) have been prepared. On pyrolysis the trans oxide gives only the product of Cope degradation (40), whereas the cis oxide gives in addition the rearranged bases (41), (42) and (43). (J.B. Bremner and 

Bisquaternary salts of laudanosine with itself and with other tetrahydroisoquinolines and long chain dihalides have been prepared as potential neuromuscular blocking agents of the same type as tubocurarine. The most widely studied of such salts is atracurium (44) (R. Hughes and D.J. Chappie, Brit.J.Anaesth., 1981, 31 J.B. Stenlake et al., Eur.J. 

Venkov and N. Mollov, Dokl. Bolg. Akad. Nauk, 1979, 32, 895. 

Carbon-13 n.m.r. spectroscopy has been used to study benzylisoquinoline and tetrahydroisoquinoline alkaloids and their JV-methyl quaternary salts.30 N-Benzylpapaverinium bromide has been shown to undergo aerial oxidation in alkaline solution to 2-benzyl-6,7-dimethoxyisoquinolone and to give bases of general structure (10) with methylamine, benzylamine, and pyrrolidine.31 Chlorosulphonation of papaverinol affords the sulphonic acid ester (11), mild hydrolysis of which yields the acid (12), which with diazomethane is esterified and dehydrated to (13).32 N-Methyl-l,2-dihydropapaverine has been shown by kinetic studies and orbital-symmetry requirements to rearrange to the salt (14) by the route previously postulated.33 

The secondary base (15) has been shown to react with formaldehyde and hydrochloric acid, with loss of bromine and rearrangement to the carbinolamine 

Kerekes, S. Makleit, and R. Bognar, Acta Chim. Acad. Sci. Hung., 1978, 98, 491. 

Koltai, D. Banfi, J. Engler, J. Volford, and Z. Meszaros, J. Labelled Compd. Radiopharm., 1979,16, 351. 

Walterova, V. Preininger, L. Doljes, F. Grambal, M. Kysely, I. Valka, and V. Simanek, Collect. Czech. Chem. Commun., 1980, 45,956. 

Chlorination and bromination of iV-formyl- and N-ethoxycarbonyl-nor-reticuline have been shown to give 8,6 -dihalogenated compounds32 and anodic oxidation of the bridged hexamethylene diether of reticuline has been found to give the proerythradienone (17) and the morphinandienone (18).33 

Papaverine has been synthesized from the oxazole (19), obtained from the 2-lithio-derivative of 5-(3,4-dimethoxyphenyl)oxazole with veratric aldehyde, by catalytic reduction to the acyl-/ -phenylethylamine followed by Bischler- 

Szantay, G. Blasko, M. Barczai-Beke, G. Dornyei, and L. Radies, Heterocycles, 1980, 14, 1127. 

Methods of purification38 and estimation39,40 of papaverine and of estimation of ethaverine41 have been described and the stereochemistry of the quaternization of laudanosine has been studied.42 The effects of papaverine on cerebral circulation of 

Two new benzylisoquinoline alkaloids have been reported. Ledecorine, found in Corydalis ledebouriana, has been assigned the structure (22) on the basis of spectroscopic studies, and it appears to be the first alkaloid of this group to be 

The quaternary alkaloid tembetarine has been isolated from Zanthoxylum bouetense  

The selective demethylation of papaverinol by 90% sulphuric acid or 89% phosphoric acid has been shown to give the phenol (24) rather than the 3 -hydroxy-4 -methoxy-compound previously reported, and this has been confirmed by the synthesis of the phenol from O-benzylvanillin.  

A patent for the preparation of quaternary salts of papaverine from C5, Ce, and Cg halides been published. N-Alkyl-papaverinium salts have been found to undergo oxidation by oxygen either photolytically or in the presence of cuprous chloride, to give the isoquinolones (25). The corresponding dihydro-papaverinium salts (26), with oxygen and cuprous chloride, do not suffer fission, and oxidation of the N-methyl compound (26 R = Me) in this way, followed by reduction of the product with sodium borohydride, affords a- and -hydroxy-laudanosines 21) The n.m.r. spectrum of laudanosine has been studied in detail. 

A method for the extraction of papaverine from aqueous solution by toluene and organic acids has been described, as have methods for the determination of the alkaloid in blood by gas chromatography. The metabolism of papaverine has been studied, as have its effects on the release of renin in vivo and in 

Benzylisoquinoline is the structural backbone of many alkaloids that possess potent therapeutic properties. Benzylisoquinoline alkaloids (BIAs) include the narcotic analgesics codeine and morphine, the antimicrobials sanguinarine and berberine, the anti-tussive and anticancer agent noscapine, and the muscle relaxants papaverine and tubocurarine. 

Morphine. Morphine, codeine, and its congeners are produced from the opium poppy (Papaver somniferum), but they are also produced in mammalian organisms 

Sanguinarine. Sanguinarine, 13-methyl[ 1,3]benzodioxolo[5,6-c]-l,3-dioxolo[4,5-i]phenanthridium, is a quaternary ammonium salt belonging to the group of BIAs derived and isolated from rhizomes of Sanguinaria canadensis L. (bloodroot) and other poppy-fumaria species, and possesses potent antibacterial, antifungal, antitumor, and anti-inflammatory activities [104-107], 

The second proposed pafhway, involving several A-methylated intermediates, begins with the N-methylation of (5)-coclaurine and continues with a hydroxi-lation and an 0-methylation steps to afford (5)-reticuline, which is converted to (5)-laudanine catalyzed by reticuline 7-OMT. 3 -OMT, laudanosine A-demethylase (LNdeMT), and dehydrogenase (deHase) enzymes catalyze the three latest steps, leading to the formation of papaverine [113]. 

Some biscoclaurine alkaloids (bisbenzylisoqui-noline derivatives) were able to inhibit superoxide production by phorbol ester-stimulated human polymorphonuclear leucocytes (Haisong et al. 1990) and hpid peroxidation in biological membranes (Shiraishi et al. 1980). 

Addition. Iseluxine. In this connection the discovery of an isoquinolinone named iseluxine (Fig. 5.2) as a constituent of the roots and vegetative epigeal parts of Isea 

This alkaloid has also been detected in the roots and stems of Aristolochia elegans Mast. (Aristolochiaceae) together with benzylisoquinoline/bisbenzylisoquinoline alkaloids (Wu et al. 2002 Shi et al. 2004). It was named pericampylinone-A by these authors who apparently did not know its former discovery as iseluxine. 

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Opium is the dried, powdered sap of the unripe seed pod of Papaver somniferum, a poppy plant indigenous to Asia minor. Theophrastus described its medical properties in the third century BC, but the Sumerians, ca BC 4000, probably perceived its utility. Arab physicians knew of the dmg, and Arab traders carried it to the Orient where it was used as a treatment for dysentery. Paracelsus is credited with repopularizing the dmg in western Europe in the early sixteenth century by formulating opium into "laudanum", which is still in use. More than 20 different alkaloids (qv) of two different classes comprise 25% of the weight of dry opium. The benzylisoquinolines, characterized by papaverine [58-74-2] (1.0%), a smooth muscle relaxant, and noscapine [128-62-1] (6.0%), an antitussive agent, do not have any analgesic effects. The phenanthrenes, the second group, are the more common and include 10% morphine (1, = R = H), 0.5% codeine [76-57-3], C gH2 N03, (1, R = H, R = CH3), and 0.2 thebaine [115-37-7], C 2H2 N03, (2). 

Benzylamine, o-chloro-N-(cyanomethyl)-N-methyl-isoindole synthesis from, 4, 323 Benzylisoquinoline alkaloids synthesis, 1, 446 Benzynes... 

Benzylisoquinoline Derivatives. Papaverine, C20H21O4N Xanthaline, C20H19O5N dZ-Laudanine, C20H25O4N Laudanidine, C20H25O4N Codamine, C20H25O4N Laudanosine, C21H27O4N... 

One complication of the Pictet-Spengler condensation of benzylisoquinolines 24 is regiochemical control in the closure of ring C when activating substituents are present on the D ring. Experimentally, the ring-closure reaction yields predominantly the 10,11-disubstituted product 23 rather than the 9,10-disubstituted product 25. ... 

This problem has been circumvented by utilizing the ipso-directing capability of a silicon substituent at the 2 position of the D ring to facilitate ring closure at this position. Benzylisoquinoline 26 condensed with formaldehyde to give predominantly product 28 when R = H. However, when R = SiMea, 27 was the only product observed and was isolated in excellent yield.Several members of the protoberberine family of natural products have been synthesized using this strategy. 

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. 

This material is dissolved in 500 ml. of ethanol, and the solution is transferred to a 2-1., round-bottomed flask. A solution of 200 g. of sodium hydroxide in 200 ml. of water is added, and the mixture is refluxed for 2 hours. Ethanol is then removed by distillation, and the residue is shaken with 500 ml. of water and 800 ml. of toluene. The toluene layer is separated, washed with two 200-ml. portions of water, and then vigorously shaken with 600 ml. of 2N aqueous hydrochloric acid. A portion of the 1-benzylisoquinoline hydrochloride precipitates at this point and is collected on a Buchner funnel and washed with 200 ml. portions of water and toluene. The filtrate is then transferred to a separatory funnel, the acidic layer is separated, and the crystals from the Buchner funnel are suspended in this layer. After basifying the suspension with 50% aqueous sodium hydroxide, the oil that separates is extracted with three 200-ml. portions of dichloromethane. The combined dichloromethane layers are dried over anhydrous potassium carbonate, filtered, and evaporated under reduced pressure to leave the crude product as a yellow oil. Distillation under reduced pressure then provides 49.8 g. (91%) of pure 1-benzylisoquinoline as a pale yellow oil, b.p. 145-150° (0.01 mm.). The product solidifies on standing and may be crystallized from chloroform-hexane to give colorless prisms, m.p. 54-55° (Note 12). 

BENZYLISOQUINOLINE, 56, 19 Benzyl methyl ketone, 55, 94 Ai-Benzyloxycarbonyl-O-ferr-butyl-L-... 

This example demonstrates how widely chemical profiles can differ between two populations separated by only a matter of kilometers in this case, populations of halictrum minus L. in the Voj vodina area of Serbia (Popovic et al., 1992) (Fig. 2.20). Plants collected at 500 m in the Fruska Gora Mountains (Novi Sad) afforded a comparatively complex mixture of benzylisoquinoline alkaloids that consisted of... 

Kwan CY, Achike FI (2002) Tetrandrine and related bis-benzylisoquinoline alkaloids from medicinal herbs cardiovascular effects and mechanisms of action. Acta Pharmacol Sin 23(12) 1057-1068... 

Scheme 2 Structures of the benzylisoquinoline alkaloid laudanosine and its transformed products (2, 3, and 4) by utilizing Pseudomonas putida incubated at 30 °C for 96 h [47]... 

Benzylisoquinoline alkaloids Leaves Anisocycla jollyana SiOj, AI2O3 Multicomponent eluent — — 13... 

Prior et al. (44) found that 13-methylprotoberberine (44) gave the C-14—N bond cleavage product 45, and Hanaoka et al. (45) also detected the C-14—N bond cleavage product 47 as a minor product along with 40b and 46 in the reaction of tetrahydroberberine (26) (Scheme 10). Finally, the C-8—N bond cleavage reaction was applied to synthesis of benzocycloheptaquinoline 23 (46) and 6 -methyl-l-benzylisoquinoline 50 via 49 (Scheme 11) (47). The bond cleavage was found to proceed smoothly in ethanol-free chloroform under reflux (46). 

C-9, and C-10, always with a phenolic hydroxy group at the 8a position. Moreover, they differ from one another by the oxidation state of the benzylic C-13 as well as by substitution and degree of saturation of the isoquinoline fragment. These alkaloids, classified as benzylisoquinoline alkaloids (2,70-74), have recently been called by Shamma et al. (75-77) pseudobenzyliso-quinolines originating from protoberberine alkaloids. In Table V a list of 8,8a-secoberbine alkaloids, sources, and spectral data are presented. 

The above syntheses were preceded by model investigations (143), as a result of which several unnatural 1,2-secoisoquinolines, e.g., 175-177 were synthesized (Scheme 30). Finally, a reaction reported by Bentley and Murray (144) is worth mentioning since it may serve as a model for biosynthetic conversion of benzylisoquinoline alkaloids to the seco analogs (Scheme 30). Heating of ketolaudanosine (174) with methyliodide unexpectedly formed a seco derivative 175 along with to the quaternary salt. By all probability it arose from the methiodide of 174 by air oxidation followed by ring opening. 

The following secodimeric alkaloids have been isolated from natural sources (+)-hernandaline (197), from Hernandia ovigera L. (158), (—)-natalinine (198) (759), and (+)-coyhaiquine (199) (160), the two latter from Berberis empetrifolia Lam. with the yields 0.00005 and 0.00008%, respectively. Appropriate aporphine-benzylisoquinoline or proaporphine-benzylisoqui-noline dimers are probably precursors of these seco alkaloids, although... 

This benzylisoquinoline alkaloid inhibits in vitro the specific bonding of [3H] dopamine to dopamine receptors and abrogates amphetamine-induced circling behavior in rodents with unilateral degeneration of dopaminergic neurons in the corpus striatum (109). 

The photocyclization of enamides has been widely employed in the construction of heterocyclic systems the N-acryloyl-2-aminopyridines 37, for example, are converted on irradiation to the lactams 38.36 Numerous benzylisoquinoline alkaloids have been prepared using this approach, and in particular, the syntheses of benzo[c]phenanthridine alkaloids have been reviewed.37 Thus, irradiation of the [Z]-l-ethylidene-2-benzoyltetra-hydroisoquinoline 39 affords the corresponding 8-oxoberberine 4038 competing photoisomerization to the E-isomer is observed but cyclization occurs only via the Z-isomer. Examples of syntheses of Amaryllidaceae and indole alkaloids have also been reported. In this way, the precursor 41 of ( )-lycoran has been obtained by oxidative cyclization of the enamide 42.39... 

Michael addition of di- and tri-hydric phenols to /V-cinnamoylimidazoles followed by a lactonisation offers a route to 4-aryI-3,4-dihydrocoumarins and their [/]-benzologues <00S123>. The lactonisation of the naphthoquinone derivative 66 is sensitive to the acidic cyclising medium and it is possible to obtain the thermodynamically less stable o-quinone derivative exclusively (Scheme 44) <00TL3007>. Some related quinones have been obtained from 1-benzylisoquinolines via an arylnaphthoquinone <00T6O23>. 

PAULI, H.H., KUTCHAN, T.M., Molecular cloning and functional heterologous expression of two alleles encoding (5)-Y-methylcoclaurine 3 -hydroxylase (CYP80B1), a new methyl jasmonate-inducible cytochrome P-450-dependent monooxygenase of benzylisoquinoline alkaloid biosynthesis, Plant J., 1998,13, 793-801. 

Whereas the Annonaceae are characterized primarily by benzylisoquinoline alkaloids, two pyrrolidine alkaloids have recently been found in species belonging to this family. Squamolone (29) was isolated from Annona squamosa L. by Chinese workers in 1962 (68). Despite careful spectroscopic investigation and a total synthesis (Eq. 1), squamolone was assigned the incorrect diazepine formula 30. The correct structural formula (29) was later established by an unambiguous synthesis of 30 (Eq. 2). Compounds 29 and 30 proved to have very similar spectroscopic properties, which could justify the early confusion (69). 

Corydalis is a genus of the family Fumariaceae that is represented by some 320 species growing in the temperate climates of the northern hemisphere. Corydalis pallida Pers. var. tenuis from Japan was simultaneously examined for alkaloids by two groups of investigators (88, 89). Besides benzylisoquinoline-type alkaloids, rra/w-3-ethylidene-2-pyrrolidone (50) (alkaloid P) was present. The alternative formula 51 was ruled out by the nonidentity of the hydrogenation product of 50 with an authentic sample of 5-ethyl-2-pyrrolidone (52). Alkaloid... 

These transformation reactions are similar in part to those previously observed for laudanosine (201) and for the aporphine-benzylisoquinoline alkaloid thalicarpine (202). Laudanosine underwent regiospecific O-demethylation at... 

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