Protoberberines photocyclization

The phenanthridine skeleton is synthesized by photocyclization of the enamides prepared from cyclohexanonimines and benzoyl chlorides (17,18). The benzo[c]phenanthridine skeletons are formed from the enamides prepared from 2-tetralonimines and benzoyl chlorides (19,20). More conveniently, the skeletons of protoberberine alkaloids are readily synthesized from the enamides prepared by simple acylation of 1 -methyl-3,4-dihy-droisoquinolines with benzoyl chlorides (21-24). This berbine synthesis is one of the most typical examples of the application of enamide photocyclization to alkaloid synthesis and can be further extended to the facile synthesis of the skeletons of the yohimbine group of indole alkaloids (25,26). 

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. 

This nonoxidative photocyclization reaction was extended to the A-acetyl derivative 122, which was irradiated through a Vycor filter in the presence of iodine and hydriodic acid to give the product 123 in 42% yield (106). Lenz and Yang (106) have synthesized a protoberberine alkaloid, / -coralydine, by applying this type of photocyclization (Schemes 52 and 53). 

A similar photocyclization was reported on the corresponding formate 124, which exists in the Z configuration predominantly or sometimes exclusively (107). Irradiation in the presence of hydriodic acid afforded the protoberberine iodide 126 in good yields, which was further converted to ( )-xylopinine by sodium borohydride reduction. 

Total synthesis of protoberberine alkaloids via the route involving enamide photocyclization consists of nonoxidative photocyclization of the 2-aroyl-l-methylene-3,4-dihydroisoquinolines and the subsequent metal-hydride reduction of the photocyclized lactams. This simple combination of reactions for alkaloid synthesis provides one of the most convenient synthetic routes to this group of popular alkaloids. 

Xylopinine. Among many popular protoberberine alkaloids, xylopinine has been of interest to synthetic chemists because of its pharmacological activity (112). Three groups (21,23,29-32,44,107) have independently described total synthesis of this alkaloid Ninomiya et al. (16) and Kametani et al. (66) succeeded in the asymmetric synthesis of this alkaloid by enamide photocyclization. 

Ipecac Alkaloids. As an extension of the synthetic work of protoberberine alkaloids, Ninomiya et al. (116) reported that the 2-acryloyl-1-methylenete-trahydroisoquinolines (178) underwent ready photocyclization to yield the benzo[a]quinolizines (182). 

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... 

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. 

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). 

The enamide photocyclization reaction has been widely exploited for the synthesis of protoberberine and other alkaloids (see Vol. 4 of these Reports and ref. 7). It has now been found that enamides of the type (160 X = OMe) undergo photochemical elimination of methanol to produce in good yield protoberberine precursorsofthetype(161). Forexample,compounds(161 R = R = H, = OMe),2 2 (151. r4 H r2 1 3 OCHjO), and (161 ... 

Irradiation of the Z- or of a mixture of the E- and Z-isomers of the N-formyl enamides in the presence of hydriodic acid furnished the corresponding protoberberine salts in good yields. The photocyclization is regiospecific, forming 10,11-substituted protoberberine salts from 3, 4 -disubstituted benzyl-idene enamides. A suggested mechanism is ° ... 

Numerous other examples of the dienamide photocyclization reaction in the synthesis of berbine, protoberberine, benzophenanthridine, Amaryllidaceae, and indole alkaloids have been discussed elsewhere. ... 

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