New Aporphine Alkaloids

Neolitsine is the first aporphine found to possess tw o methylenedioxy groups. It is present in NeoUtsea pulchella Merrill, from which it was isolated as crystals melting at 149°-150° ([ajj) -f-56.5° in CHCI3), and analyzing for C19H17NO4. The alkaloid gave a positive Labat test, and formed a picrate (mp 186° decomp.), a methiodide which crystallized 

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. 

From the bark and wood of Launis nobilis L. the new noraporphine launobine was obtained, C18H17O4N (mp 214°-215° decomp. [app +192.7° in CHCI3). The alkaloid has one methylenedioxy, one methoxyl, and one hydroxyl, and Clarke-Eschweiler A-methylation was found to give (+ )-bulbocapnine. Launobine is therefore norbulbocapnine (III) (3). 

Sparsiflorine was originally isolated as a white amorphous powder, C17H17O3N (mp 230°-232° decomp.), from the leaves of the shrub Croton sparsiflorus Morung (Euphorbiaceae) (4) hydrochloride (mp 283°-284° decomp.), hydrobromide (mp 276°-278° decomp.), oxalate (mp 265°-267° decomp.), and picrate (mp 225°). The alkaloid was found to contain one methoxyl, three active hydrogens, and no methylenedioxy or A -methyl group. 

After repeated attempts, sparsiflorine was crystallized as silky fine needles (from alcohol) (mp 228° decomp.). The free base suffers ready oxidation and decomposes on standing or upon heating in solution. The hydrochloride ([ajp -1-43° in H2O), exhibits 310, 275, 266, and 

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A record number of new aporphine alkaloids, sixteen, has been isolated and characterized during the year under review. Even better methods for the synthesis of aporphines in high yields have been developed,1-3 and an interesting relationship between aporphines, morphinandienones, neoproaporphines, and spirinedienones has been pointed out.1 A novel and unusual alkaloid is eupolauramine (70), which is structurally related to the aristolactams but which incorporates an additional nitrogen atom in ring A.4... 

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... 

New aporphine alkaloids are cabudine (11), from Thalictrum isopyroides, which is also the first aporphinoid to incorporate a hydroxymethyl substituent and liridinine (12), obtained from Liriodendron tulipifera L. tulipifera has also yielded N-acetylnornuciferine (13), as well as 7V-acetylasimilobine (14). Interestingly... 

The year under review has witnessed a particularly bountiful harvest of new aporphine alkaloids. These, with their botanical sources, are given below. 

New aporphine alkaloids and their sources are shown in Table 1. Of particular interest in this listing are leucoxylonine and ocoxylonine, which are the first aporphines with only one unsubstituted aromatic carbon atom. ... 

New Aporphine Alkaloids - A number of new aporphine alkaloids have been isolated from a variety of plant sources. Structures have been assigned most often on the basis of spectra (especially nmr) and sometimes also by conversion to previously known aporphines. The stereochemistry shown below was not always proven, but is assigned when possible by the reviewers on the apparently valid assumption that all levorotatory aporphines have the D (or R) configuration at the asymmetric carbon atom and that all dextrorotatory aporphines have the L (or S) configuration at this same carbon atom. ... 

A useful and timely supplementary listing of new aporphines, oxoaporphines, phenanthrenes, and 4,5-dioxoaporphines has appeared.1 The alkaloids of Glaucium species, which include several aporphines and oxoaporphines, have been tabulated2 and a general discussion of the chemistry and biogenesis of isoquinoline alkaloids, including the aporphines, has been presented.3... 

A careful investigation of the alkaloidal content of the Brazilian plant Ocotea minarum (Lauraceae) has led to five new aporphines, namely ocotominarine (3), ocominarine (4), norleucoxylonine (5), iso-oconovine (6), and 4-hydroxy-dicentrine (7).4... 

Microbial formation of plant isoquinolines became an attractive issue over recent years [116]. Magnoflorine was of particular interest thanks to its pharmacological activities. On one hand, it was found that this aporphine alkaloid protects human high density lipoprotein (HDL) against lipid peroxidation but it also exhibits anti-HIV activity [117-119]. New production strategies for this alkaloid will be vital in the future. 

V-Formylnornantenine (54), a new amidic aporphine alkaloid, has been isolated from Cyclea atjehensis. Analysis of the NMR spectrum at... 

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. 

Thus, certain dopamine agonists especially dopaminergic aporphine alkaloids may represent new agents to prevent or treat duodenal ulcer disease. 

Aporphine Alkaloids.—A study on the biosynthesis of boldine previously published in preliminary form and reviewed73 is now available in full74 without the addition of essentially new information. 

The year under review has witnessed the isolation and structural elucidation of no less than nine new aporphines, as well as of five aporphine-benzylisoquinoline dimers. Two of these five aporphine-benzylisoquinolines, namely kalashine and khyberine, are the first such dimers known to be substituted at C-l 1 of the aporphine moiety. Thallium(m) trifluoroacetate is an oxidizing agent which effects the cyclization of tetrahydrobenzylisoquinolines to aporphines in satisfactory yields.1 A listing of aporphinoid alkaloids has appeared.2... 

A detailed study of the alkaloidal content of the Formosan Stephania sasakii (Menispermaceae) has led to four new aporphines stesakine (4), dehydrostesakine (5), dehydrocrebanine (6),11 and dehydrophanostenine (7).4 Additionally, dehydro-stephanine (8) has been isolated from S. kwangsiensis.12... 

Photocyclization of 1-benzylideneisoquinolines to the Aibexao[d,e,g -quinolines is a well-studied example of the above stilbene-phenanthrene cyclization and therefore has been extended to the development of new photochemical methods for the synthesis of aporphine alkaloids (11-14). In this section, photocyclization of 2-acyl-1 -benzylideneisoquinolines to dehy-droaporphines and their subsequent conversion to aporphines and oxo-aporphines are summarized. 

What is apparently a new aporphine (mp 183°-184°, [aJJJ +181° in chloroform), containing three methoxyls and a hydroxyl group, has been isolated from Corydalis gortschakovii Schrenk [44). Acetylation gave the 0,W-diacetyl derivative (mp 163.5°-164.5°) which was optically inactive. The 0-methyl derivative yielded a methiodide which was identical with the methiodide of 0-methyl corydine. The alkaloid exhibited A jax 304, 268, and 220 (log e 3.6, 3.98, and 4.4). 

A new aporphine found in Thalictrum fendleri is preocoteine (XCIII) (66). This alkaloid was obtained only in small amounts as an oil, but its UV-spectrum showing 312, 302, and 278 mp. (log e 4.22, 4.22, 4.16) is diagnostic of a 1,2,3,9,10-pentasubstituted aporphine, and is close to that of the well-characterized aporphine base ocoteine (XV) which has A , 314, 302, and 283 mp (log e 4.1, 4.2, and 4.2) and is also present in T. fendleri. Additionally, the UV-spectrum of preocoteine shows a bathochromic shift upon the addition of base, so that the molecule must be phenolic. 

Investigation of Xylopia descreta, a member of the Annonaceae family, has resulted in the isolation of four new protoberberine alkaloids— xylopinine, descretine, descretinine, and descretamine, in addition to the aporphine base, xylopine 49). 

Thalifaboramine is but one of over 16 new aporphine-benzylisoquinoline dimeric alkaloids that have been isolated from Thalictrum faberi Ulbr., and the crude basic fraction, as well as most of the new alkaloids, including thalifaboramine (79), have demonstrated cytotoxic effects against the P-388 carcinoma cell [133],... 

Preliminary biological testing of the new aporphine-pavine alkaloid EP-10, isolated from extracts of the whole plant of the Taiwanese Thalictrum fauriei Hayata in 1986, demonstrated that the alkaloid possessed weak in vitro activity, as compared with thalicarpine, in the lysis of Hela cells [35]. 

Several new aporphine and berberine alkaloids which were uncovered in the period of the last ten years or so are from plants of the Anixmaceae such as the 7-hydroxyaporphine, dasymachaline (9) from Desmosdasymachatus [27], the dioxoaporphine, l,2,3-trimethoxy-4,5-dioxo-6a,7-dehydroaporphine (10) from Pseuduvaria macrophylla [28], the tetrasubstituted... 

Several new alkaloids of these groups have been reported. The new aporphines are steporphine (54) from Stephania sasakii, lanuginosine (55), from Michelia... 

Srilankine, C20H23NO5, [a]D +122°, a new 4-hydroxylated aporphine alkaloid isolated from the endemic species Alseodaphne semicarpifolia Nees... 

Proaporphines, which are biosynthetic precursors of aporphine alkaloids, have been isolated from two Sri Lankan plants of the family Menisperma-ceae. Investigation of Diploclisia glaucescens (BL) Diels, (syn Cocculus macrocarpus Wight and Am.) has afforded a new alkaloid, glucescine (40) (43), and stepharine (41) (44). Stepharine (41) was also found to occur in Anamirta cocculus (44-46). 

On reductive cleavage (JOO) with sodium in liquid ammonia the proaporphine alkaloids with dienone structure are converted into benzyl-isoquinoline bases (IV I XIV XIII). By treatment with W-hydro-chloric acid the dienone alkaloids are transformed (69, 349) into the aporphine alkaloids (Schemes 1 and 2) by dienone-phenol rearrangement (IV -> II XIV -5- XV, XVI, and XVII). Substitution of the proaporphine base at C-9 by a methoxyl function involves rearrangement which gives rise to two isomers, i.e., XV and XVI. On the other hand, by reduction of dienone with sodium borohydride (formation of two dienols) and following treatment with hydrochloric acid these dienols are converted (65,66, 68, 69, 349) into the aporphine alkaloids with formation of a new aromatic ring (VI and VII III XVIII XIX and XX). 

The alkaloids in the leaves of this plant consisted largely of isocrydine and two new aporphines, namely, 10-hydroxy-l,2-(methylenedioxy)-aporphine and 2,ll-dihydroxy-l,10-dimethoxyaporphine. The bark yielded predominantly laurolitsine (160a). 

Thalidoxine (208 R = H) is a new aporphine-benzylisoquinoline alkaloid isolated from Thalictrum dioicum. Methylation with diazomethane gave the known thalicarpine (208 R = Me). The site of the phenolic OH was established at C-4" rather than at C-5" by n.m.r. studies of the acetate (208 R = Ac). The... 

New investigation of bisbenzylisoquinoline biosynthesis is welcome (see ref. 32 also this Report, p. 16). Although aporphine alkaloids are the simplest developments of the benzylisoquinoline skeleton, their biosynthesis need not, as several examples show, be simple. It has, however, been found that the biosynthesis of boldine and isocorydine is straightforward. Further detail has been repor-ted on the biosynthesis of Erythrina alkaloids, which were established to be modified benzylisoquinolines some time ago. Further detail on the biosynthesis of morphine (23) and related alkaloids continues to be published. Of particular R. B. Herbert, in ref. 9, p. 11. 

New aporphine-benzylisoquinoline dimers are ( + )-thalirevolutine (38), (-1-)-thalirevoline (39), (-H )-thalilutidine (40), and (-H )-thalilutine (41), all present in Thalictrum revolutum (Ranunculaceae) while (-I- )-thaliadanine (42) is found in Thalictrum minus Race B. Another new alkaloid is thaliadine (43), also located in T. minus Race Thaliadine must be an oxidation product of an aporphine-benzylisoquinoline alkaloid. 

Chen JJ, Ishikawa T, Duh C-Y, Tsai I-L, Chen I-S. New dimeric aporphine alkaloids and cytotoxic constituents of Hernandia nymphaeifolia. Planta Med 1996 62 528-33. 

A number of aporphine alkaloids have been isolated in this laboratory in such small quantities that their structure could at first only be stablished on the basis of their spectroscopic characteristics (Ref. 1). The need to confirm the structures of these new alkaloids and to obtain them in quantities sufficient to allow investigation of their pharmacological properties led us to attempt their synthesis by classical methods, but the problems encountered in some cases forced us to try modified or radically different approaches. As a result, we have developed a new synthetic procedure that is applicable to a variety of different kinds of isoquinoline alkaloids. 

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