Berbine synthesis

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). 

Successful berbine synthesis summarized in Section IV,C prompted Nin-omiya s group (25,26,117,118) to extend enamide photocyclization to har-malane, therefore giving rise to a novel and facile synthesis of polycyclic heterocycles such as the yohimbine group of compounds. Before reductive photocyclization was introduced, the use of nonoxidative photocyclization with indole alkaloids was limited to simple systems and those possessing a large degree of aromaticity. 

Nucleophilic intramolecular addition of a carbon-silicon bond onto a carbon-nitrogen iminium ion is the key step of a berbine synthesis <82CC769,83H(20)417>. Thus, treatment of the isoquinolinium salt (235) with caesium fluoride in ethanol afforded (+)-xylopinine (237), presumably via the betaine (236) (Scheme 45). A silicon-directed intramolecular cyclization of a A-acyliminium ion (238) was also the key step of Speckamp s synthesis of (+)-epilupinine as shown in Scheme 46 <85JOC40I4>. 

Dibenzo[a,g]quinolizinium ion is the prototype of a series of compounds initially prepared as intermediates for the synthesis of berbine alkaloids but which, as a class, have recently attracted medicinal interest per se (Scheme 99, Table 11). 

Pd(OAc)2] in the presence of PPh3 was used as catalyst. The use of vinyl bromides in lactam formation has also been reported.498 Imides were obtained from aryl bromides. The method has further been applied to the synthesis of diazepam and 1,4-benzodiazepines499 and to a-methylene lactams and lactones.S00 501 In connection with the synthesis of natural products, the reaction has been employed in the preparation of hexadehydrohimbane,502 anthramycin503 and berbine derivatives.504 The catalyst was prepared in situ from [Pd(OAc)2] (106) and PPh3 in all cases. The mechanism of lactam formation is analogous to that for amides (Scheme 42). 

This substitution method has been extended to an annelation reaction which is applicable to the synthesis of berbine (berberine) type alkaloids 55. 

These thermal cyclizations offer a promising route for the synthesis of berbine compounds with electron-withdrawing groups in ring D (Scheme 59). 

The arylenamide photocyclisation protocol continues to provide convenient access to intermediates of interest in alkaloid synthesis. Spirocyclic 5-lactam (55) has been prepared from cycloalkylenamide (54) and irradiation of enones (56) yields the corresponding spiroketones (57). Analogous photocyclisations have led to nitro-substituted berbine derivatives. The piperidine arylenamides (59) are efficiently photocyclised to the corresponding benzo[b]quinolizine-6-ones (60), providing convenient access to benzoquinolizidine derivatives. In contrast,... 

A, few isochroman-3-ones occurs in nature The importance of isochroman-3-ones however is because they are valuable intermediates for the synthesis of isoquinolines. A most interesting use of isochroman-3-ones is that they provide benzocyclobutenes which are valuable synthons for berbines, spiro-benzylisoquinolines, 3-aryl isoquinoline, benzophenanthridines, benzocarbazoles, yohimbin, tetracycline, steroids etc. 

Homophthalic anhydrides are valuable synthons for the synthesis of isocoumarins, isoquinolones and particularly for several berbine alkaloids. 

Several 13-unsubstituted and 13-methyl-berbine alkaloids have been synthesised by reacting homophthalic anhydride with 3,4-dihydroisoquinolines followed by a sequence of reaction. Synthesis of (+) corydaline (57) involves the following steps... 

Scheme 28. Synthesis of berbine bases (80 and 81) according to Meise and Zymalkowski (625, 626).

Brown etal. reported the synthesis of many berbine derivatives, isopavine alkaloids, and amurensinine (56f) (581, 629). They describe some rearrangements of those alkaloids. 3-Hydroxy-2-methoxy-9,10-methylene-dioxyberbine (59d) and 3-hydroxy-2-methoxy-10,ll-methylenedioxy-berbine (60h) were synthesized through the N-formyl derivatives of... 

Vinylogous urethane (248) was employed in a radical-mediated synthesis of epilupinine (Scheme 48), where its cyclization was induced by treatment with tributyltin hydride-AIBN <89T5269>. In another radical process, a very efficient synthesis of berbine was achieved by photolysis of compound (249), which induced a diradical cyclization process promoted by an excited-state electron-transfer desilylation (Scheme 49) <85TL5867>. 

A very common method for the synthesis of berbine alkaloids is based on the one-pot double cyclization of iV-(phenylethyl)benzeneacetamide derivatives (e.g. 305) in the presence of phosphorus pentachloride or phosphorus oxychloride (Scheme 67) <81H(16)449,81S818,85AP(318)168,85IJC(B)360>. 

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

These optimized conditions were used to perform the preparative transformation on a 0.5 g scale, demonstrating the applicability of the BBE-catalyzed kinetic resolution of different benzylisoquinoline and berbine alkaloids. An impressive example employing the described enzymatic oxidative intramolecular C—C bond formation by the BBE can be found in the first asymmetric total synthesis of the natural product (S)-scoulerine, a sedative and muscle-relaxing agent, which was obtained in 7.4% yield over nine linear steps [166]. 

Schrittwieser JH, Resch V, Wallner S, Lienhart W-D, Sattler JH, Resch J, Macheroux P, Rroutil W. Biocatal ftic organic synthesis of optically pure (S)-scoulerine and berbine and benzylisoquinoline alkaloids. J. Org. Chem. 2011 76 6703 6714. 

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