Berberines synthesis

As observed in a different cell system (Coptis japonica cell suspension cultures), an alternative step in berberine synthesis is the formation of the methylendioxy group at the stage of tetrahydrocolumbamine [108]. The cytochrome P450 enzyme... 

RUEFFER, M., ZENK, M.H., Canadine synthase from Thalictrum tuberosum cell cultures catalyzes the formation of the methylenedioxy bridge in berberine synthesis. Phytochemistry, 1994, 36, 1219-1223. 

M. Rueffer and M.H. Zenk, Berberine synthase, the methylenedioxy group forming enzyme in berberine synthesis. Tetrahedron Lett. 26 (1985), 201-202. E. Galneder, M. Rueffer, G. Wanner, M. Tabata, and M.H. Zenk, Alternative final steps in berberine biosynthesis in Coptis Japonica cell cultures. 

Special Reactions of Papaverine. Papaverine undergoes a number of reactions, which are of interest as providing methods of synthesis for other alkaloids, of which examples will be found under laudanosine, laudanine, laudanidine, codamine (pp. 187-195), berberine (p. 331), corydaline (p. 284), and glaucine (p. 311). 

On treatment of N-methylpapaverine, formed by the lithium aluminum hydride reduction of papaverine methiodide with phosphoric acid, N-methylpavine is formed which is identical with the racemic alkaloid argemonine. This reaction was used for the synthesis of the alkaloid (-h)-coreximine (268) (174) and similar compounds containing the proto-berberine grouping in the molecule (269,270). 

The disproportionation reaction of isoquinolinium salts to 1,2-dihydro-isoquinolines and isocarbostyril derivatives (Scheme 16) was used by Brown and Dyke for the synthesis of berberine and 8-oxoberberine derivatives (277-279). 

The parent, unsubstituted isochromanone has been caused to react with a variety of aromatic amines to prepare Ar-substituted 1,4-dihydro-3(2.ff)-isoquinolones,4 and with amines to give amides.5 The 6,7-methylenedioxy-3-isochromanone was an intermediate in the synthesis of protopine and its allied alkaloids,6 and for the synthesis of the berberine ring system.7 The 6-methoxy analog was prepared as a potential intermediate in a camptothecin synthesis8 and 8-methoxy-4,5,6,7-tetramethyl-3-isochromanonc was an intermediate in the synthesis of sclerin.9 The compound herein described was the basis of a facile synthesis of ( l )-xylopmins,10 and its reaction with hydrazine has been reported.11... 

Scheme 16. Synthesis of polyberbine (66), polycarpine (67), and its analog from proto-berberines. Reagents a, MCPBA, NaHCQ3, CH2C12, -78°C b. MCPBA, NaH, THF.

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). 

A biomimetic synthesis of benzo[c]phenanthridine alkaloids from a protoberberine via the equivalent of a hypothetical aldehyde enamine intermediate has been developed (130,131). The enamide 230 derived from berberine (15) was subjected to hydroboration-oxidation to give alcohol 231, oxidation of which with pyridinium chlorochromate afforded directly oxyche-lerythrine (232) instead of the expected aldehyde enamide 233. However, the formation of oxychelerythrine can be rationalized in terms of the intermediacy of 233 as shown in Scheme 41. An alternative and more efficient... 

In conclusion, although the Stevens rearrangement of a tetrahydroproto-berberine metho salt readily afforded a spirobenzylisoquinoline skeleton, there exist no reports on synthesis of functionalized spirobenzylisoquinolines or related alkaloids using this method. 

The spirobenzylisoquinoline 171b derived from berberine (15) (Section IV,A,1) was oxidized with m-chloroperbenzoic acid to the /V-oxide 389, which was treated with trifluoroacetic anhydride to afford dehydrohydrastine (370) in 56% overall yield (Scheme 71) through the Polonovski reaction (187). Holland et al. (188,189) reported the reverse reaction from dehydrophthalides to spirobenzylisoquinolines, namely, 370 was reduced with diisobutylalu-minum hydride to give a mixture of two diastereoisomeric spirobenzylisoquinolines 320 and 348 via the enol aldehyde. This reaction was applied to synthesis of various spirobenzylisoquinoline alkaloids such as (+)-sibiricine (352), ( + )-corydaine (347), (+ )-raddeanone (354), ( )-yenhusomidine (359), (+ )-ochrobirine (343), and ( )-yenhusomine (323). 

Indenobenzazepines have been used as key intermediates for synthesis of rhoeadine, protopine, phthalideisoquinoline, and spirobenzylisoquinoline alkaloids. Several new alkaloids possessing an indenobenzazepine skeleton have been isolated, and they are presumably biosynthesized from proto-berberine alkaloids. 

Futhermore, the photocyclization of the donor-acceptor pair thioether-imide has already been applied to the synthesis of the berberine alkaloid chilinene as an a-key step [252]. 

Acylation of the keto acid (637) leads to the isobenzopyrylium salt (638) (77CHE1183). However, the isobenzopyrylium salt (639), a potential intermediate for the synthesis of analogues of berberine alkaloids, results from the formylation of the substituted ketone or the isochromanone (640) using dichloromethyl butyl ether (Scheme 251) (81CHE221). A second product, the 5-oxoniachrysene (641), is formed and this compound may also be obtained by reaction of the isobenzopyrylium salt with phosphorus pentachloride and then with triethylamine. The intermediacy of a cyclic vinyl ether is proposed. 

Elucidation of the enzymatic synthesis of berberine has thus been a longstanding goal (Fig. 17) [3, 106]. 

The isolation of the cDNAs encoding the enzymes involved in diverse isoquinoline alkaloid formation in plants and microorganisms allowed the first metabolic engineering routes to be developed and paved the way for new ways of future production of isoquinoline alkaloids. For instance, transgenic opium poppy plants were created in which codeinone reductase was suppressed by RNAi, resulting in the substitution of morphine synthesis with the non-narcotic precursor reticuline [110]. In a similar approach, RNAi suppression or overexpression of salutaridinol 1-0-acetyltransferase in opium poppy led to accumulation of salutaridine or increase of morphine, codeine and thebaine content [111], suppression of the BBE led to accumulation of berberine in California poppy cells [112],... 

This is the name given to an alkaloid (mp 200-201°) isomeric with protopine, isolated from Zanthoxylum conspersipunctum Merr. (146), whose structure (157) has been confirmed by a synthesis. The reaction sequence, beginning with the corresponding berberine, was essentially that described in the original protopine synthesis (147). 

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

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