Aporphines 7-methyl

Tuduranine, CjgHjgOgN. This member of the aporphine group (p. 306) is the most recent addition to Sinomenium alkaloids and was isolated by Goto from the mother liquors of sinomenine. It is crystalline, has m.p. 125° (with softening at 105°), and yields a sparingly soluble hydrochloride, m.p. 286° (dec.), [a] f — 148° (dilute MeOH), is freely soluble in alkali, and gives feeble ferric chloride and diazo-colour reactions and a fuchsin-red colour with formaldehyde and sulphuric acid. It behaves as a secondary base and yields a diacetyl derivative, m.p. 170°, [a] / — 321-71° (MeOH), which does not form a methiodide, but can be hydrolysed to A -acetyl-tuduranine, m.p. 277°, — 395-24°, and this can be methylated to... 

Oxidative conversion of palmatine, berberine, and coptisine to polycarpine, polyberbine, and its analog was described in Section II,B. These products were further transformed to aporphine alkaloids having a phenolic hydroxyl group at C-2 in the bottom ring (55). Hydrolysis with concomitant air oxidation of polyberbine (66) furnished 3,4-dihydrorugosinone, which was further air-oxidized in ethanolic sodium hydroxide to give rise to rugosinone (501) (Scheme 105). Successive reduction of the enamide 68 with lithium aluminum hydride and sodium borohydride afforded a mixture of ( )-norledecorine and (+ )-ledecorine (502). N-Methylation of the former with formaldehyde and sodium borohydride led to the latter. 

N-methyl-actinodaphnine possesses 5-hydroxytryptamine receptor blocking activity and a selective antagonist of cq-adrenoceptors, selective for the a1B. than for the a1A-adrenoceptor subtype (14). What are the activities of N-methyl-actinodaphnine and other aporphines of Illigera and Hernandia species against topoisomerase ... 

The mono-phenolic aporphine derivative (6aR)-( —)-l 1-hydroxyapor-phine (6aR-14) is a DA agonist. Very interestingly, its 10-methyl analogue (6aR-15) is devoid of DA effects but instead it potently binds to and stimulates central 5-HTlA receptors [67]. A ring-contracted aporphine analogue... 

A novel and efficient synthesis of aporphinic alkaloids has been developed by Kupchan and O Brien (55) via oxidative photocyclization of l-(a-hydroxy-2-iodobenzyl)-6-hydroxy-7-methoxyisoquinolines such as 120, 121, or 122, all prepared by the Reissert method shown in Scheme 17. N-Methylation of oxo-aporphines 124 and 125 yielded corunnine (127) and nandazurine (128), respectively. Reduction of 124 with Zn-AcOH resulted in thalicmidine (130), and similar reduction of 125 gave domesticine (131) in racemic form. Caaverine (129) has also been prepared by this route (55). 

Initially Robinson and Sugasawa (8) proposed that laudanosoline (5), prepared from laudanosine (4) by O-demethylation with aluminium chloride in refluxing xylene, could be oxidized to an aporphine or morphine prototype. To demonstrate that no rearrangement had occurred, 4 was regenerated from 5 by O-methylation. Oxidation of 5 was accomplished with chloranil in buffered alcohol solution, and 6 was isolated in 60% yield as the chloride (Scheme 1). Di-benzopyrrocoline 6 was also obtained in 30-50% yield when aqueous solutions... 

Oxidative coupling of (5)-(-)-laudanosoline (5) with horseradish peroxidase in the presence of hydrogen peroxide, studied by Brossi et al. (27), afforded dibenzopyrrocoline (—)-6 in 81% yield, and conversion to (5)-(—)-0-meth-ylcryptaustoline (14) by methylation provided additional proof for the absolute configuration of this and related alkaloids. Enzyme specificity in the C— coupling reaction was demonstrated with similar oxidation of (/ )-(—)-laudanosoline methiodide, which afforded an aporphine converted by O-meth-ylation to (R)-(-)-glaucine. 

Aporphines may be prepared through a similar ring closure. N-Methyl-l-(2 -iodobenzyl)isoquinolinium salts (69) can be reduced in acetonitrile126 at a potential more negative than the second peak, according to Eq. (57). The electron consumption is 2.0 Fmol-1, and two hydrogen atoms are expelled during the reaction, so that the net uptake of electrons is 0. Catalytic reduction of 70 produces aporphine. 

The readily available reagent diphenyl selenoxide has been used as a mild and selective oxidant in the synthesis of aporphines (and homoaporphines). When the benzylisoquinoline (13) was treated with one equivalent of the reagent at room temperature in methanol, and the product was O- methylated with diazomethane, the aporphine (14) was obtained in 80% yield. The alternative use of chloranil, which is a commonly used oxidant for catechols, yielded less than 10% of (14).20... 

Photolysis of the hydrochloride of (71) gave the corresponding oxoaporphine O-methylatheroline, in 38% yield, which was converted into the aporphine glau-cine by successive methylation and reduction with zinc in hydrochloric acid.49... 

Several groups have examined the 13C spectra of the aporphine alkaloids (6, 7, 38-40) examples are found in Fig. 10. The chemical shift assignments (Table X) for the aliphatic carbon atoms of rings B and C were made by comparison to laudanosine (28) (6) and to the reduced proaporphines (41). In the case of caaverine (49) a comparison with (+)-lirmidine (50) revealed the P deshielding effect of the TV-methyl group on C-5 and C-6a and the shielding of C-7 by a y effect. 

The effect of nitrogen quaternization on the chemical shifts of several aporphine alkaloids was studied by Marsaioli et al. (39). The conversion of dicentrine (59) to its methiodide salt (60) caused deshielding of C-5 and C-6a whereas C-3a, C-4, C-7, C-7a, and C-llc were all shielded. The shielding of the aromatic carbon atoms may be caused by the electric field effect similar to that observed in nitrogen protonation (8, 12). C-4 and C-7 were most likely experiencing the y steric effect of the new methyl group. 

The pharmacological properties of the natural and synthetic aporphines such as apomorphine (119, 120) have ensured the thorough investigation of the in vivo mammalian metabolism of this class of compounds. Reported reactions include glucuronidation (121), O-methylation (91,122) O-demeth-ylation (123), and N-demethylation (123). Studies in vitro with enzyme preparations and in vivo with microorganisms reveal a similar pattern of metabolism. 

Belemine (125), from G. schomburgkiana (50, 51), is the oldest example of a 6a,7-didehydro-7-methylaporphine. Its mass spectrum suggested the molecular formula C, Hl7N03, and its UV spectrum was typical of a 6a,7-didehydro-aporphine. Its H-NMR spectrum was characterized by two methyl singlets at 2.57 and 2.78 ppm which were assigned to the C-7 methyl and (V-methyl... 

Full experimental details have appeared on the synthesis of bracteoline, isoboldine, N-methyl-laurotetanine, and related aporphines, through oxidation with... 

The new aporphine alkaloid oliveroline (13) exhibits antiparkinsonian activity, while oliveridine (AT-methyl-14) and oliverine (N-deoxy-18) cause a dose-dependent hypotension in normal rats followed by a secondary hypertension. In the isolated rabbit ear, oliveridine has a vasodilating effect comparable to that of papaverine.55 Cabudine, which corresponds to l,2-methylenedioxy-3-hydroxy-methyl-9-methoxydehydroaporphine, possesses adrenolytic activity.56... 

The conversion of (—)-apomorphine into (+)-apomorphine has been achieved.56 The O-dealkylation of 10,11-dimethoxyaporphine, using sodium thioethoxide in dimethylformamide, has been reported.57 The reactions of the enamine dehydro-nuciferine with dimethyl acetylenedicarboxylate, methyl propiolate, methyl acrylate, and diethyl azodicarboxylate have been investigated, and have resulted in the preparation of a novel series of 7-substituted aporphines.58... 

Isothebaine (= 1-Hydroxy-2,1 1-dimethoxyaporphine) (aporphine isoquinoline) Laudanosine (= Laudanine methyl ether) (benzylisoquinoline)... 

Hoffmann degradation is a classic way to transform aporphines into phe-nanthrene alkaloids. This transformation involves the thermolysis of the quaternary ammonium hydroxide formed by sequential treatment of an aporphine with an alkylating agent and silver oxide. This degradation was extensively used in initial degradative studies of the structure of aporphines. The alkylations are usually done with methyl iodide (20,30,45,60,85,86,88) or dimethyl sulfate... 

We may safely assume that phenanthrene alkaloids with a 2-dimethylamino side chain derive from quaternary aporphinium salts by in vivo Hoffmann elimination. These phenanthrene alkaloids may later be oxidized to the corresponding A -oxides or methylated to give trimethyl 2-(l-phenanthryl)ethylammonium salts. Far more intriguing is the biosynthesis of phenanthrene alkaloids with a 2-monomethylaminoethyl side chain, for which we have four examples A -nor-atherosperminine (13), noruvariopsine (14), secoglaucine (15), and secophoebine (16). One possibility would be direct elimination after protonation of the nitrogen of an aporphine. This transformation would have some similarity to the formation of 167 by acid treatment of 166 18). 

Apomorphine was the most potent of the protein kinase inhibitors (IC50 for PKA-catalytic subunit 1 pM). However, the methylated aporphine alkaloid analogues of apomorphine such as bulbocapnine, isocorydine, glaucine and (+)-boldine were either inactive or poor inhibitors of this en2 yme. 

The UV-spectrum of the alkaloid in ethanol showed maxima at 310 and 284 m/x (log 4.11 and 3.9) characteristic of a 1,2,9,10-tetrasub-stituted aporphine. The NMR-spectrum exhibited one i -methyl group at 7.53 r. A methylenedioxy group appeared as two doublets centered at 4.04 T and 4.17 t characteristic of C-1,2 disubstitution, while another methylenedioxy group was represented by a singlet at 4.05 t and was therefore assigned the C-9,10 position. Neolitsine must thus be represented by II. 

Mecambroline was isolated from Meconopsis carnbrica Vig. (Papaver-aceae), and the elemental data indicated the value C18H17O3N. The alkaloid melts at 145°, and exhibits [aj +76° (in CHCI3). A hydrochloride salt was obtained (inp 264°-266°) as well as a picrate (mp 179°-180°). Color tests showed the presence of a methylenedioxy and a phenolic group. The UV-spectrum had 308 and 275 mp, (log e 4.0 and 4.2), with a shoulder at 269 mp (log e 4.1), typical of a 1,2,10-tri-substituted aporphine. 0-Methylation with diazomethane gave a base (mp 111°-112°) 6). 

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