Tetrahydroberberines

Shortly afterwards Spath and Kruta taking advantage of the fact that although alkyloxy bases of the type (XIX) condense with formaldehyde to give products of type (XX) and are therefore unsuitable for the synthesis of tetrahydroberberines, the non-alkylated tetrahydropapavero-lines (XIX R = R = OH) condense with formaldehyde at positions 2 or 6 to give products, which on alkylation furnish equal amounts of types (XX, R = R = OMe) and (XXI, R = R = OMe). 

Gadamer by fractional crystallisation of dZ-tetrahydroberberine bromocamphorsulphonate, isolated a laevorotatory alkaloid identical... 

It is of interest in this connection to note that the conversion of tetrahydroberberine into an anhydro-base of type E (p. 337) represents transformation from the berberine to the cryptopine type (p. 295), and that a-canadine methochloride occurs in Zanthoxylum brachyacanihum with its cryptopine analogue, y-homochelidonine ( -aiiocryptopine, p. 301). 

The Hofmann degradation is the most well-known C—N bond cleavage reaction, and its value to structural elucidation of alkaloids has been demonstrated (76). Hofmann degradation of tetrahydroberberine methohy-droxide (1) led to two products base A (2), the C-14—N bond cleavage product, and base B (3), the C-6—N bond cleavage product (Scheme 2) (17,18). The former was the major product when 1 was heated under reduced pressure, but the latter, the thermodynamically controlled product, predominated when the reaction was carried out at atmospheric pressure or in an alkaline medium because base A recyclized back to the starting quaternary base through the transannular reaction. In fact, 2 was heated in aqueous alcohol to afford 1. The mechanism of this recyclization reaction was discussed by Kirby et al. (19). 

This recyclization reaction has been skillfully utilized for stereospecific labeling at C-13 of tetrahydroberberine with tritium or deuterium for biosynthetic studies of ophiocarpine (20). Base A- and B-type products have... 

Scheme 2. Hofmann degradation of tetrahydroberberine metho salt (1).

The von Braun reaction (Scheme 6) is another basic reaction for C—N bond cleavage 32). Tetrahydroberberine (26) was heated under reflux with cyanogen bromide in benzene to afford the bromocyanide (28) and the unsaturated cyanide (29) through C-6—N and C-14—N bond cleavage, respectively. The C-8—N bond cleavage product was not obtained because of the steric hindrance of the methoxyl group at C-9 in SN2-type reactions 33). The... 

Prior et al. (44) found that 13-methylprotoberberine (44) gave the C-14—N bond cleavage product 45, and Hanaoka et al. (45) also detected the C-14—N bond cleavage product 47 as a minor product along with 40b and 46 in the reaction of tetrahydroberberine (26) (Scheme 10). Finally, the C-8—N bond cleavage reaction was applied to synthesis of benzocycloheptaquinoline 23 (46) and 6 -methyl-l-benzylisoquinoline 50 via 49 (Scheme 11) (47). The bond cleavage was found to proceed smoothly in ethanol-free chloroform under reflux (46). 

Treatment of tetrahydroberberine (26) with sodium benzenethiolate (48) or -selenolate (49) in the presence of ruthenium catalyst afforded the C-14—N bond cleavage products 51 or 52 with a phenylthio or phenylseleno group at C-14 (Scheme 12). The latter was converted to the 10-membered amino olefin 53 on treatment with m-chloroperbenzoic acid. 

Boron tribromide cleaved a methoxyl group (e.g., 79 - 80) (Scheme 19) (65) as well as a methylenedioxy group (66). Tetrahydroberberine (26) was converted to tetrahydrocoptisine (82) by treatment with boron tribromide and subsequent methylenation (67). 

Using ethyl chloroformate as a reagent for C-8—N bond cleavage (Section II,A,4), synthesis of ( )-canadaline (272) from tetrahydroberberine (26) was independently achieved by Ronsch (40) and Hanaoka et al. (41,45). Bond-cleaved iodide 40a or chloride 40b was converted to the acetate 280 or the alcohol 281, both of which were easily derivatized to 272 through reduction of the urethane and oxidation of the alcohol 274 (Scheme 48). 

Irradiation of tetrahydroberberine methiodide (1) in aqueous methanol in a stream of oxygen in the presence of Rose Bengal afforded in one step... 

Scheme 75. One-step synthesis of allocryptopine (392) from tetrahydroberberine methiodide (1) by photooxygenation. Reagents a, h, 02, Rose Bengal, MeOH. 

Reduction of berberinephenolbetaine (121) with zinc in acetic acid afforded tetrahydroberberine (26) and its isomer. The structure of the latter was shown to be the isoindolobenzazepine 458, commonly referred to as Schopf s base VI, and its formation mechanism was also postulated (Scheme 93) (224). Recently 458 was isolated and named as chilenamine. 

The degradation of a-aminocarboxylic acids has proven to be a useful method for the preparation of iminium salts. For example, treatment of N- methylpipecolic acid (97) with phosphorus oxychloride gave 94% of the iminium salt (98) (Scheme 7) (76JA7448). The synthetic utility of this approach is illustrated by the synthesis of tetrahydroberberine (Scheme 8) (78JOC2115). The advantage of this method for the preparation of iminium salts is that the position of the carbon-nitrogen double bond can be controlled. 

Of these bases, (-)-ophiocarpine AT-oxide is a new natural product,71 (+)-10-desmethylxylopine is a new alkaloid that is isomeric with govanine,72 and staudine is a new base that has been shown to have the bridged tetrahydroberberine structure (38) by spectroscopic studies and an X-ray crystallographic examination.74... 

An alternative approach to synthesis of this ring system involves insertion of CO into the brominated secondary base (43), by treatment with carbon monoxide, lead tetra-acetate, and triphenylphosphine in tributylamine, the product being the amide (44), reduction of which affords the amine.81 Govadine (42 R1 = R4 = OMe, R2 = R5 = OH, R3 = H) has been synthesized by the conventional ring-closure, with formaldehyde, of the diphenolic base (45), or of its dibenzyl ether, in acid solution.82 Tetrahydroberberines, together with N-benzyltetrahydroisoquinolines, have also been obtained by the electrolytic reduction of 3,4-dihydroisoquinolines of structure (46).83... 

In addition to the preparation of a- and /3-hydrastine described above from the betaine (64), another conversion of a tetrahydroberberine into hydrastine has been reported. Acetylophiocarpine, on treatment with ethyl chloroformate, gives the acetoxy-derivative of (88), which can be hydrolysed to the hydroxymethyl compound and then oxidized to the aldehyde by pyridinium perchlorate. Hydrolysis of the acetoxyl group afforded the hemi-acetal (93 R = H), conversion of which into the mixed acetal (93 R = Et) protected the aldehyde system during reduction of N—C02Et to NMe by lithium aluminium hydride. Hydrolysis of the acetal, followed by oxidation, then gave a-hydrastine, and a similar sequence of reactions starting from O-acetyl-13-epi-ophiocarpine afforded / -hydrastine.119 Methods of synthesis of alkaloids of this group have been reviewed.120... 

CYP719A1 (canadine synthase) [109] is responsible for (S)-tetrahydroberberine production, which is then enzymatically oxidised to berberine. 

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