Aporphines 7-substituted

Substituents are related to absolute configuration by the following simple rule Aporphines substituted at both C-10 and C-11, or at both C-9 and C-10, are usually dextrorotatory and belong to the L(5)-series. Aporphines unsubstituted or monosubstituted in ring D can belong either to the L(5)- or the i)(R)-series. 

A very large number of substituted phenanthrenes have been made from stilbenes by this photocydization method, as have more complex polycyclic aromatic compounds by related reactions involving a single cydizatlon (e.g. 3.64 for chrysenes) or two, or more, successive cydizations le.g. 3.65). The reaction can be nicely adapted to provide a route from 1-benzylidenetetra-hydroisoquinolines to alkaloids of the aporphine family (e.g. 3.66). 

The second illustration above is a phthalide THIQ, and these phenethylamines are sometimes referred to as secophthalide-isoquinolines. Here, the oxygen atom of the original isofuranone ring is substituted on the newly formed double bond. This structure can easily open up to the corresponding ketonic carboxylic acid. These seco-modifications of the attacked isoquinoline (first example, illustrated with an aporphine) and the simpler 1-substituted isoquinolines (second example, as illustrated by the isobenzofuranone) are the only ones included in this book. The standard phenethylamines that are commonly found in cacti, compounds which are not from these seco-mecha-nisms, have been tabulated in TIHKAL and will not be repeated here. 

Pronuciferine (1) has been synthesized by photocyclization of the brominated phenol (2).9a The light-induced rearrangement of proaporphines yields aporphines that are substituted at C-9 or at both C-8 and C-9.5 This topic is further discussed below, under the sections on aporphines and aporphine dimers. The known alkaloid N-methylcrotsparine has been found in Pachygone ovata.9b... 

Five of the eight alkaloids isolated from this plant are derivatives of aminoethylphenanthrene, open aprophines, chief of which is uvariopsine (168). The others of this type represent various 0- and A-substituted bases. The remaining new alkaloids proved to be oxo-aporphines in addition to which liriodenine and a methoxy and a dimethoxy derivative of it were present (168). 

Still another DA receptor model, based on the study of aporphines, takes chirality factors into consideration. This model suggested by Neumeyer (16, 96) postulates an obstruction or "obstacle" on the receptor that precludes appropriate interaction of aporphines in the 6aJ> configuration with the receptor. This model, in common with many others, also takes into account OH binding sites, conformational aspects, steric hindrance factors, and N-substitution with the observation as noted elsewhere (e.g., 97), that N-substitution with groups as large as propyl may provide supplemental binding to favor D-2 receptor interaction. As the asymmetric center of apomophine is located on the carbon ct to the N, whereas in I-III it is located on the ben-... 

A total of 41 aporphines sensu stricto have been isolated from 12 Guatteria species. These include aporphines, noraporphines, and (V-formylnoraporphines, differing by their substitution pattern on the two aromatic rings, but no quaternary aporphinium alkaloids have been reported. 

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... 

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... 

The structural assignment of thalixine is very doubtful. All natural aporphinoids are substituted at C-1 and C-2 (aporphine numbering). 

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). 

Ovigerine, obtained from Hernandia ovigera, crystallized only as the hydrochloride, CigHi504N-HCl (mp 300° decomp. [aj -P 177° in H2O). The UV-spectrum of this salt, 317, 270, 234 mp. (log e 3.77, 4.10, and 4.29), was suggestive of a 1,11-substituted aporphine. The NMR-spectrum of the free base showed no signals characteristic of either X-methyl or methoxyl, but complex signals characteristic of two superimposed methylenedioxy groups appeared centered at 4.12 and 3.99 t. 

Aporphines synthesized via benzyne intermediates obtained from treatment of appropriately substituted 6-methoxy-7-hydroxy-2 -halo-N-methyltetrahydro-benzylisoquinolines with KNH2 in liquid ammonia include N-methylcaaverine (1-hydroxy-2-methoxyaporphine), thaliporphine and domestidne. The upper limit on the yields by this route appears to be 24%, a by-product being the corresponding dibenzopyrrocoline salt resulting from cyclization on nitrogen. ... 

In addition a range of oxidised cularines matching that of the oxidised aporphines is also known. The bases limousamine (92) and 4-hydroxysarcocapnine (93) represent hydroxy substitution unknown in the benzylisoquinoline and.bisbenzylisoquinoline series (probably because of the ease with which such compounds can be converted into pavines and isopavines) but... 

The distinction between structures (72 R1 = R2 = H, R3 + R4 = CH2, R5 = OMe) and [75, R1 + R2 = CH2,R3 = R5 = H,R4 = OMe, C(7)-oxo] for oxoxylopine could not be made on the basis of its n.m.r. spectrum alone (both would show 1,2,4-proton pattern for ring d).105 However, it is known that the correspondingly substituted aporphines with reduced heterocyclic rings and lacking the C(7)-oxo function show different u.v. spectra. Therefore, oxoxylopine was reduced with zinc and hydrochloric acid to give a compound whose u.v. 

Owing to its low solubility, the free base was not amenable to NMR spectroscopy, but its 0-acetyl derivative showed methoxyl singlets at 8 3.91 and 4.11 and an acetyl methyl singlet at 8 2.50. The absence of a one-proton singlet near 8 7.1 indicated that 0-3 was substituted. Indeed, 0-methylation of moschatoline yielded 1,2,3-trimethoxyoxo-aporphine, which showed NMR methoxyl peaks at 8 4.06, 4.10, and 4.18, identical with authentic synthetic material. 

A study of several ethoxyl-trimethoxyl substituted 1,2,9,10-oxo-aporphines (24-26) showed that loss of a C-1 alkyl radical was greater than loss of a C-9 or C-10 alkyl radical (Table IV) 31). 

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). 

A potentially useful new synthetic route to the aporphines involves reducti of a properly substituted nitrotetrahydrobenzyllsoquinollne with zinc in a mixture of trifluoroacetic acid and trifluoromethanesulfonic acid. In this... 

The separation and tentative characterization of aporphine and related alkaloids present in Nandina domestica Thunb. has been achieved using t.l.c.-g.c. The intensities of i.r. bands of aporphines in the 1480—1630 cm region have been used to determine the substitution pattern at C-1 and C-11 for a variety of aporphines and dehydroaporphines. ... 

Substituted phenanthrenecarboxylic acids can be obtained in this way and yield the phenanthrene hydrocarbons on decarboxylation. Weisbach and his co-workers803 applied this reaction to synthesis of aporphine. 

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