Protoberberine cyclization

Scheme 36. Acid-catalyzed cyclization of the Hofmann degradation products of dihydro-protoberberines. Reagents a, cone HC1 b, POCl3 c, H2S04 d, 10% HC1. 

Lead tetraacetate oxidation was applied to construct a benzo[c]-phenanthridine skeleton. The Hofmann degradation product 224 derived from the phenolic protoberberine 59a was oxidized with lead tetraacetate to afford the p-quinol acetate 225, which was cyclized to the benzo[c]-... 

Ring D inversion seems to be a crucial step in biogenetic transformations of protoberberines to related alkaloids such as rhoeadine, retroprotoberberine, spirobenzylisoquinoline, and indenobenzazepine alkaloids. 8,14-Cyclober-bin-13-ol 478 derived from berberine (15) was successively treated with ethyl chloroformate, silver nitrate, and pyridinium dichromate (PDC) in dimethyl-formamide to give the keto oxazolidinone 479 (Scheme 98). Heating of 479 with 10% aqueous sodium hydroxide in ethanol effected hydrolysis, retro-aldol reaction, cyclization, and dehydration to provide successfully the... 

Total synthesis of the representative protoberberines, (+)-xylopinine 151 (equation 71) and (+)-stylopine 152 (equation 72), have been achieved using silylarene-iminium salt photochemistry128. The photochemical routes appear to be superior to alternative ground-state methods involving dipolar cyclizations. 

The protoberberine alkaloid, xylopinine, has been synthesized in an optically active form by Kametani et al.22 ). A key reaction in this synthesis was the photochemical cyclization of the optically active amino acid derivative 1,2,3,4-tetrahydro-6,7-dimethoxy-3-methoxycarbonyl-1 -methylene-2-veratroylisoquinoline with 1,3... 

Reversed regioselectivity in aryl radical additions to enamides and enamines can also be observed with aryl substituents on the alkene [86]. This cyclization type has been successfully applied in the synthesis of protoberberines and the pavine alkaloids. Argemonine (39) was obtained from a 6-exo cyclization of 40 passing through a well-stabilized benzylic radical (Scheme 15). 

Disubstituted protoberberines have been synthesized in high yield by the photolysis of the related bromo-enamides (Scheme 3). The enamide (75) is converted into the enamide (76) in 80% yield by photolysis, and the cyclized base can... 

There are two types of enamides readily available for the simple synthesis of protoberberine alkaloids via the route involving photocyclization. One is the 2-acyl-1-benzylideneisoqui noline-type enamide that has a stilbene structure in the molecule and is known to undergo a six -electron conrota-tory electrocyclic cyclization to a dihydrophenanthrene and subsequent dehydrogenation (103), and thus provides a useful synthetic route to apor-phine alkaloids. The second is the 2-aroyl-l-methyleneisoqui noline-type enamide that gives the 8-oxoberbine in good yields on irradiation. 

The enamide 127 that is substituted in an ortho position of the benzyli-dene group was prepared to investigate regioselective cyclization under nonoxidative conditions. However, irradiation brought about an exclusive cyclization to the unsubstituted position to afford the 2,3,9,12-tetrameth-oxy-substituted protoberberine iodide 128 (Scheme 54). 

Recently, Castedo et al. (137) studied enamide photocyclization for aporphine synthesis and modified Cava s procedure (135 -137) after consideration of the reaction course and structural requirement for the exclusive formation of aporphine. Castedo s group concluded that an enamide should have a forced m-stilbene geometry, in order to avoid an undesired mode of cyclization leading to protoberberine-type compounds and also to avoid a facile conversion to oxoaporphines after cyclization. 

Coyle and Bryant have reported the efficient synthesis of a triazabicyclo[3.3.0]octane system by the photocyclization of hydantoin derivatives. Thus irradiation of (295), synthesized by standard Mannich procedures, afforded the bicyclooctanes (296) in moderate to good yields. The process, akin to Norrish Type II behaviour, is a 1,6-hydrogen transfer followed by bonding in the resultant biradical (297). The bis-Mannich base compound (298) also photocyclizes, yielding (299). Coyle and his co-workers have also successfully applied the known reactivity of phthalimides to yield polycyclic compounds. Thus irradiation of (300) affords the cyclized compound (301). This can be converted into the protoberberine alkaloid skeleton (302) by treatment with aqueous HCl. The crown ether analogues (303) and (304) have... 

Bradsher and co-workers have developed a general method for synthesizing the protoberberine ring system. It involves the condensation of a properly constituted 1-isoquinoline carboxaldehyde with the appropriately substituted benzyl bromide. Acid-catalyzed cyclization of the resulting quaternary salts affords the fully aromatic tetracyclic ring system which on catalytic reduction leads directly to the tetrahydro-protoberberine skeleton. Recent modifications 93) of this synthetic method involving the use of the oxime, or better, the ethylene acetal of the 1-isoquinoline carboxaldehyde, have permitted the use of less vigorous conditions for the production of the tetracyclic intermediate... 

When using the appropriate tetramethoxyisoquinolinium salt LXXXII (R = 0CH3), the protoberberine base norcoralydine (119) was obtained in 39% yield by this method. In contrast to the results obtained in the synthesis of 2,3-dimethoxyberbine, the intermediate isocarbostyril LXXXIII (R = 0CH3) was quite stable to acid and could be readily isolated. Attempts to induce the cyclization of this compound with acid were unsuccessful. The above method constitutes the most efficient synthetic route to the protoberberine alkaloids so far devised. 

It is noteworthy that protosinomenine (XCVIII), despite being so similar to reticuline, and possessing the necessary C-8 hydroxyl group (protoberberine numbering) to permit cyclization, is not incorporated into berberine in H. canadensis. 

Cutter, P. S., Miller, R. B., Schore, N. E. Synthesis of protoberberines using a silyl-directed Pictet-Spengler cyclization. Tetrahedron 2002, 58,1471-1478. 

Photoinduced itniniutn ion-benzylsilane cydizations have also been employed to construct the protoberberine and spiro benzylisoquinoline alkaloid skeletons. For example, the spiro benzylisoqui-noline (138) can be accessed in 50% yield by the photocyclization of isoquinolinium salt (137). Photo-cyclization of the electron rich isoquinolinium salt (118) gave a 70% yield of ( )-xylopinine (Scheme 45). This photocyclization is claimed to proceed more cleanly and with higher efficiency than the corresponding fluoride-promoted ground state cyclization. 

CycUzations. Bromoarenes form radicals that can be exploited in synthesis, including cyclization routes to aporphines-indolo[2,l-a]isoquinolines, and protoberberine-pavine alkaloids. ... 

Furthermore, the following compounds were synthetically prepared racemic cheilanthifoline (58c) (47), kikemanine (58d) (129), canadine (58e), berberine (59a) (590, 614), tetrahydropalmatine (58g) (475), sinac-tine (58h), cavidine (68d) (616,617), nandinine (58i) (590, 614, 615), capaurine (58p) (618), capaurimine (58o) (128, 618a), xylopinine (60c) (610, 615, 619), O-methylcaseanadine (62b) (70, 620), thalictricavine (68b), and corydaline (68h) (615). Xylopinine (60c) and some other alkaloids were synthesized by benzoylation of 1-alkyl-3,4-dihydroisoquinolines followed by photocyclization. This method provides a useful route to the synthesis of other protoberberine alkaloids (619). It is also applicable to the synthesis of cularine (51) and spirobenzyltetrahydroisoquinoline alkaloids (188). Xylopinine was also synthesized from the corresponding enamide under benzyne reaction conditions (615). Kametani etal. summarized their findings on the synthesis of these alkaloids and described the formation of protoberberines by debenzylation and photolysis of tetrahydroisoquinolines (622, 623). The total stereospecific synthesis of racemic ophiocarpine (70a) from the 3,4-dihydroisoquinoline derivative by Mannich cyclization was also described (624). 

Similarly, acid-catalyzed deprotection and cyclization of tetrahydroisoquinoline acetal (186) afforded protoberberines (187) (Equation (20)) <88T203>. 

Among the most prominent is the synthesis of ( )-xylopinine [63] (56), a protoberberine alkaloid, and the alkaloids possessing an erythrane ring [64] (59), by the intramolecular PET cyclization of 55 and 57, respectively (Scheme 13). 

A general synthesis of protoberberines has been achieved from amino-acids of the type (77) by regiospecific decarbonylation, using phosphorus oxychloride, to iminium salts of the type (79), followed by acid cyclization. This method of preparation of the iminium salts has certain advantages over other routes. Amino-acids with the orientation of substituents shown in (77) are relatively easy to obtain from dihydroxyphenylalanine (80), but the more common orientation of substituents found in the protoberberines necessitates more lengthy methods of synthesis, which have been developed. This synthetic route has been further... 

Details of an alternative synthesis of 13-methyl-protoberberines have been published. The starting point is an N-phenethyl-homophthalimide of the type (83), and monomethylation is achieved by its Michael addition to methyl vinyl ketone to give the ketone (84 R = H), followed by methylation of this to the intermediate (84 R = M). Conversion of this into the ethylene ketal, followed by reduction with sodium borohydride and heating with toluene-p-sulphonic acid, results in the unsaturated lactam (85), and cyclization of this compound yields the lactam (86), which can be reduced to the 13-methyl-tetrahydroberberine. ... 

A patent that covers the synthesis of 13-hydroxy-protoberberines by conventional Mannich cyclization of benzylisoquinolines with formaldehyde has been published. ""... 

The benzophenanthridine skeleton is encountered in approximately 30 alkaloids, principally of the family Papaveraceae (Cordell, 1978a). In contrast to the biosynthesis of protopine alkaloids, phenanthridine alkaloids are synthesized in the cytoplasm (Hartmann, 1991). This type of system arises from a protoberberine precursor by fission of the C-6-N bond and recyclization. The biogenetic sequence leading to chelidonine (80) biosynthesis in Chelidonium majus has been supported by feeding experiments with multiply-labeled (-t-)-reticuline [(5)-reticuline] (20) and with labeled stylopine (79) (Fig. 32.25) (Hutchinson, 1986 Sim ek, 1985 Tanahashi and Zenk, 1988). (5)-Z-V-Methylstylopine and protopine (60) have been shown to be metabolites in this pathway. Reticuline is oxidatively cyclized to ( —)-scoulerine (72). Formation of two methylenedioxy groups results in the formation of stylopine (79) (Hartmann, 1991). 

An interesting approach to protoberberines has been reported which utilizes the ortho hydroxymethylation of phenols with boronic acids to generate the 3-lactone 9 in over 80% yield. Subsequent 0-methylation and condensation with a phenethylamine supplied an amidoalcohol which upon Bischler-Napieralski cyclization and borohydride reduction afforded the desired tetrahydroprotoberberine 10 in 65% overall yield (see Scheme 19.3). For a related conversion of an isoquinolone to a protoberberine lactam, see Sec. 3.3. 

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