Aporphine alkaloids synthesis

Although several oxidative C—C bond cleavages have been observed, the only method useful for transformation is C-8—C-8a bond cleavage. Treatment of berberine (15) with m-chloroperbenzoic acid in dichloromethane in the presence of sodium bicarbonate at - 78°C gave polyberbine (66) and N-formylnoroxyhydrastinine (69, R1 + R2 = CH2) in 20 and 15% yield, respectively (Scheme 16) (54). Similar treatment of palmatine (64) and coptisine (65) led to polycarpine (67) and the enamide 68, respectively, in 40-50% yield (55). The yield of polyberbine was improved to 76% when.the oxidation was carried out in tetrahydrofuran in the presence of sodium hydride however, the yields of 67 and 68 could not be improved under the, same reaction conditions (56). The products were used for synthesis of tetrahydroprotoberberine (Section V,I,5) and aporphine alkaloids (Section V,J,3). 

Scheme 105. Synthesis of the aporphine alkaloids rugosinone (501) and ledecorine (502). Reagents a, MeOH b, NaOH, EtOH c, LAH d, NaBH e, HCHO then NaBH4.

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). 

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... 

Photocyclization of the former type of enamides for the synthesis of aporphine alkaloids will be summarized in the following section. 

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. 

Corunnine, Nandazurine, ( )-Caaverine, ( )-Isoboldine, ( )-Thalicmi-dine, and ( )-Domesticine. Relative to the aporphine synthesis by enamide photocyclization, Kupchan and O Brien (141) have developed the oxidative photochemical synthesis of aporphine alkaloids. 

These domino reactions have also been employed by us for the total synthesis of pharmacologically important [50,51] aporphine alkaloids namely dehydronomuciferine (1) and ( ) N-nomuciferine (2)(Scheme 1), and biologically active [52] phenanthrene alkaloids namely N-noratherosperminine (3) and atherosperminine (4)(Scheme 2). Incidentally, phenanthrene alkaloids are related to the aporphines, from which they can be obtained by degradative procedures [37],... 

Because benzylisoquinolines have been available synthetically (in racemic form) for decades, there is quite a bit of chemistry known regarding their use as key intermediates in the synthesis of a number of more complex isoquinoline alkaloids. The asymmetric synthesis of benzylisoquinolines has been used to complete total synthesis of representative members of several of these alkaloid classes. As shown in Figure 6, the protoberberine alkaloid norcoralydine, the aporphine alkaloid ocoteine, the isopavine alkaloid reframoline and the morphinan 0-methylflavinantine have been made available in optically active form for the first time (except by isolation or resolution) using this approach. 

Some years ago a general synthetic method 52) for the morphinan-dienone-type alkaloids was discovered by modifying the Pschorr reaction which had been used widely for the synthesis of the aporphine alkaloids and this method was applied to a synthesis of the homo-morphinandienone-type compounds. 

The aporphine alkaloids have been previously reviewed in this series and there has also been published a summarizing report (450). Therefore, only a tabulation (Table VI) of those bases which were isolated from the Papaveraceae and their photochemical synthesis, the characteristic Pellagri reaction, the physicochemical data, and the biosynthesis are given. 

Further studies of the synthesis of the aporphine alkaloids were carried out to find simpler procedures and to increase the yields. The most frequently applied methods are the Bischler-Napieralski reaction (91, 408, 408a, 449, 450), the Pschorr cyclization (451, 452), and the photocy-clization of various benzylisoquinoline precursors (416a, 453,454) (Scheme 10). 

Scheme 11. Synthesis of the aporphine alkaloids (24) via the p-quinol acetate route (413).

R = H) in 20% yield. Compound (111 R = OMe, R == H) has also been synthesized by a conventional Pschorr cyclization route.The photochemical oxidation of glaucine to 7-oxoglaucine has been reported. Photochemical synthesis of the unusual aporphine alkaloid thalphenine (113 N-Mel) has been achieved. Irradiation of (114) under basic conditions gave directly (113), presumably via the intermediate quinone methide (115), which results from the initially formed aporphine precursor by elimination of the elements of methanol. Quaternization of (113) provided ( )-thalphenine (113 A/-Mel), whose Hofmann elimination gave the alkaloid thaliglucine (93 R = H2). 

The metabolism of apocodeine to apomorphine and norapomorphine was shown to occur in rats. The clinical application of apomorphine has been discussed. The synthesis and pharmacological testing of several aporphine alkaloid analogues have been reported. The pharmacology of liriodenine, thalicminine, corydine, and isocorydine hydrochloride has been investigated. The synthesis of tritium- and deuterium-labelled apomorphine has been reported. " Under controlled conditions, exclusive introduction of label into the catechol ring of the molecule was achieved. 

This aryl coupling reaction has been shown to be useful for nonphenolic oxidative coupling for synthesis of alkaloids for example, the aporphine alkaloid ( + )-ocoteine (2) can be obtained in 46 %, yield by reaction of 1 with TTFA.°... 

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. 

An intramolecular SrnI reaction was used as key step in the synthesis of the alkaloid 0-demethyleupoularamine 3. The intermediately formed SrnI product is readily transformed by photochemical oxidative biaryl formation and subsequent methylation to the target compound 3 in good yield (Equation 13.7) [23]. The SrnI cyclization of l-(2-bromobenzyl)-l,2,3,4-tetrahydroisoquinolin-7-ol derivatives 4 was recently applied to the synthesis of aporphine alkaloids 5 (Equation 13.8) [24] and, by using the same approach, homoaporphine alkaloids can also be synthesized. 

Like carbanions and anions from aryl amines, the anions from phenols have been used in intramolecular to obtain heterocycles by C—C bond formation [87]. One example of this approach is the photostimulated reaction of the phenoxide ion linked with a pendant bromoarene by Al-substi-tuted tetrahydroisoquinoline bridge such as 122. Under this reaction condition, aporphine alkaloid derivatives 123a,b (n=1) were obtained in good yields (Eq. 10.42). This approach was extended for the first time to the synthesis of a homoaporphine alkaloid 123c (w=2) [88]. 

With substituted halogenobenzenes, the amide ion might be expected to add preferentially to one or other end of the triple bond and so lead to rearranged amines or mixtures of amines. The occurrence of such cine substitution has obvious attractions for the synthetic chemist in providing useful routes to various amines which might otherwise be difficult to obtain. An example is provided by the synthesis of 2-amino-4-methoxybiphenyl from 3-bromo-4-methoxybi-phenyl (reaction 61). A similar rearrangement is exploited in a recent synthesis of the aporphine alkaloid, laureline. ... 

Introduction - Interest in the aporphine alkaloids continues at a rather high level, and a number of developments have been reported since the appearance of the last review (April, 1966) on this class of compounds-More than thirty new aporphines of varied structure have been isolated from natural sources the structures of a few members have been confirmed by total synthesis. The synthesis of aporphines by methods other than the classical Pschorr method continues to be e3q>lored, and some new ring systems related to the aporphines have been synthesized. Some new pharmacological studies employing aporphines have been reported. 

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