Tetrahydroprotoberberines

Reagents a. Pb(OAc)4, Cu(OAc)2, AcOH, Me2NCHO b. LiAlH4, AICI3, Et2O 

In the case of tetrahydro-/3-carboline alkaloids, a remarkable solvent effect is observed. Namely, LTA oxidation in AcOH causes tetra-dehydrogenation, whereas in CH2CI2 the acetoxyindolenine is produced. 

3-epi-a-yohimbine (249) gave a tetradehydro compound 250, sodium borohydride reduction of which effected the partial inversion to give a-yohimbine (rauwolscine) (251). Similarly, deserpidinediol (252) and reserpinediol (253) were transformed to 3-isodeserpidinediol (254) and 

Reagents a. PbfOAcij, AcOH b. CH2CI2, room temp. 

Reagents a. Pb(OCOH CjBr-m), CHjCIj b. NaOMe, MeOH, A c. PblOAct,, CHjCIj 

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Tetrahydroprotoberberines (59) having a phenolic hydroxyl group were heated in trifluoroacetic anhydride in a sealed tube to afford the indene derivatives (60) after treatment with methanol (Scheme 14) (57). The products formed through both C-14—N and C-8—N bond cleavage followed by ring closure. 

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). 

Kano et al. (161,162) also investigated the Stevens rearrangement of tetrahydroprotoberberine metho salts 302 with dimsylsodium and obtained the spirobenzylisoquinolines 303 in high yield (Scheme 56). Similarly C-homoprotoberberine 304 gave the new spiro compound 305, whereas B-homoprotoberberine 306 afforded only the Hofmann degradation product 307. 

Scheme 73. Synthesis of protopine alkaloids from tetrahydroprotoberberine JV-oxides. Reagents a, K2Cr07 b, Mel.

Bentley and Murray (201) reported another method for synthesis of protopine alkaloids allocryptopine (392) and cryptopalmatine (395) from tetrahydroprotoberberine /V-oxides (35a and 400) through oxidative rearrangement with potassium chromate (Scheme 73). 

Kametani et al. (37-40) reported an abnormal Hofmann degradation of tetrahydroprotoberberine metho salts which resulted in secoberbines. From a synthetic point of view, however, this method appeared to be of little importance since other degradation products were formed as well. Furthermore, it was applicable only to derivatives with phenolic hydroxy groups at C-9 and/or C-l. 

This enzyme [EC 1.5.3.9], also called reticuline oxidase and tetrahydroprotoberberine synthase, catalyzes the re-... 

These reactions have been used in the synthesis of aikaioids such as corydalic acid methyi ester 502 (Scheme i95). Isoiated from Corydalis incisa, 502 is derived from a proposed biosynthetic intermediate in the route to the tetrahydroprotoberberine aikaioids. The 1,2,3,4-tetrasubstituted ring of 502 demands control by an ortholithiation strategy, and the synthetic route proposed by Clark and Jahangir employs a lateral lithiation of 503 and addition to an imine as the key disconnection at the centre of the molecule. 

The tetrahydroprotoberberines may exist in solution as an equilibrium mixture of the trans-fused conformation [75] and two m-fused conformations [76] and [77] interconvertible by nitrogen inversion [75] [76] and by ring inversion [76] [77]. 

Before the advent of 13C NMR spectroscopy the conformational analysis of the tetrahydroprotoberberines rested in part on the chemical shift of the angular 13a-proton (to low frequency of 8 3 8 in trans-fused derivatives and to high frequency of S 3-8 in cis-fused derivatives). (63) In spectra run in CDC13 solution the 13a-proton signals may be hidden by those arising from methoxyl group protons but have been found to be visible in spectra recorded in deuteriotoluene solutions. Thus [85] and [86] are shown to adopt the cis-fused conformation and [87] and [88]... 

In the spectra of the tetrahydroprotoberberines the chemical shift difference between the C(8) methylene protons is greater in trans-fused than in cis-fused conformations but in both cases is enhanced by the presence of a C(9) substituent. Both effects are illustrated by the spectra of [85]—[88], (60) of corydalidzine [91], (65) and of 13/1-hydroxystylopine [92]. (66) [The spectrum of the acetate of 13/1-... 

The chemical shifts of the aromatic protons in 2,3,9,10-tetra-substituted tetrahydroprotoberberines of the type [93]—[96] show... 

The tetrahydroprotoberberine alkaloids have a tetracyclic ring structure which is based on the dibenzo[a,g]quinolizidine system (Fig. 12). Carbon-13 NMR has been used extensively to study the quinolizidine conformation... 

Reaction of l-(3,4-dimethoxybenzyl)-9-hydroxy-l,2,3,4-tetrahydro-8//-pyrido[l,2-a]pyrazin-8-one with 37% formaldehyde solution gave a tetracyclic tetrahydroprotoberberine analogue in a Mannich-type reaction (78AJC187). Reactions of 2,3,4,4a,5,6-hexahydro-l//-pyrazino[l,2-a]-quinolines with 1 W-pyrrolo[2,3-h]pyridine in the presence of 37% aqueous CH20 and AcONa in AcOH, and with 3-dimethylaminomethyl-l //-pyrrolo[2,3-h]pyridine afforded 3-[(l//-pyrrolo[2,3-h]pyridin-3-yl)methyl] derivatives (94MIP6 96USP5576319). 

MUEMMLER, S., RUEFFER, M., NAGAKURA, N ZENK, M.H., S-Adenosyl-L-methionine (S)-scoulerine 9-O-methyItransferase, a highly stereo- and regio-specific enzyme in tetrahydroprotoberberine biosynthesis. Plant Cell Rep., 1985, 4, 36-39. 

Some modifications of the previous processes (23,36,72) were also reported (78,79) for the preparation of the ( )- and (—)-ethyl esters 29 and the corresponding ( )-methyl ester 30, another emetine precursor (34,37,61,72). The latter ( )-precursor 30 was alternatively synthesized by Takano et al. (80) who utilized cleavage of an a-diketone monothioketal intermediate. Birch reduction of the starting ( )-tetrahydroprotoberberine... 

Tetrahydroprotoberberines, A novel entr into this ring synthesis involves the cobalt-catalyzed cocyclization of a tetrahydroisoquinolinc such as 1 with trimethylsilyl-methoxyethyne (2). The reaction proceeds regioscicctively in favor of the more hindered isomer (3). In the absence of the trimethylsilyl group of 1, the condensation results in two isomers in a 1 1 ratio. 

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