Tetrahydropalmatine. synthesis

Constitution. Comparison of the empirical formula of the three alkaloids, and the fact that jatrorrhizine and columbamine each stands to palmatine in the relation of a monohydric phenol to its methyl ether, makes it clear that the only difference between jatrorrhizine and columbamine must be in the position of the free hydroxyl group. The method by which this point was settled is described in dealing with the two tetrahydro-derivatives of these alkaloids (p. 291). The constitution of palmatine (XXV R = R = Me) is dealt with under tetrahydropalmatine, but it is still necessary to describe the complete synthesis of this alkaloid via oxypalmatine (XXVII) and tetrahydropalmatine. 

Cavidine. As in the case of the synthesis of tetrahydropalmatine (23) and sinactine (22,23), the 13-methylprotoberberine alkaloid cavidine (170) was synthesized via the dehydrolactam 169, which was readily prepared from the enamide 136 on irradiation (22,24). Since cavidine (170) had been converted (114) to thalictrifoline, this synthesis formally completed the first total synthesis of thalictrifoline (171) (Scheme 68). 

Electron chains. The respiratory chain and ATP synthesis in mitochondria demand the controlled flux of electrons. This target seems to be attacked by ellipticine, pseudane, pseudene, alpinigenine, sanguinarine, tetrahydropalmatine, CH3-(CH2)i4-2,6-methyl-piperidines, capsaicin, the hydroxamic acid DIMBOA, and solenopsine. As mentioned before, however, only a few alkaloids have been evaluated in this context (Table V). 

The yield of the lithiation, in case of benzylamine, is again good only when the amine is tertiary. This then leads to the quaternary salt in the cyclisation reaction. The dehydrogenation of quaternary salt does not proceed in synthetically useful yield. For this reason the method is not suitable for the synthesis of isoquinolines themselves. However, when the desired product is a tetrahydroisoquinoline the method can be of some value as in a synthesis of tetrahydropalmatine (vide infra). 

The isolation of the alkaloids of the protoberberine type (102) and the synthesis of columbamine from berberine (101) have been reported. The synthesis of coreximine, scoulerine, and tetrahydropalmatine have been described (59, 235, 236). The synthesis of alkaloids having a protoberberine skeleton has been reviewed (374). 

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). 

Structure and Synthesis. In addition to the proof of the structure of tetrahydropalmatine by virtue of its preparation from palmatine and the reverse oxidation, the resolution of the dZ-base was accomplished by means of d- and Z-tartaric acids in succession, the d-base d-tartrate and the Z-base Z-tartrate being the forms of least solubility (225). The d- and Z-bases had [a]n +291° (ethanol) and —294° (ethanol), respectively, the natural d-base having [a] +292.5° (58). Spath and Mosettig (226) have also related tetrahydropalmatine directly to tetrahydroberberine, that is to canadine. The d-, Z-, and dZ-forms of canadine were demethylenated by means of phloroglucinol and sulfuric acid yielding the base XXX in its three possible forms, the d-form having +307° (ethanol). These when... 

Still another synthesis was achieved by Spath and Kruta (227), who showed that tetrahydropapaveroline (XXXI) on condensation with formaldehyde yielded two products which on complete 0-methylation gave a separable mixture of tetrahydropalmatine (XXXII) and norcoralydine (analogous to XXVII). It is to be noted that in the former case the condensation took place in a position ortho to a hydroxyl group. In the latter... 

Akiyama et al. described a Sc(OTQ3-catalyzed reaction to access isoquinoUne skeleton 222 (Scheme 85) [141]. The tosyl imine formed in situ and benzylic methylene worked as hydride acceptor and donor, respectively. Sc(OTf)3 played dual roles, one of which was to promote the condensation of benzaldehyde 221 and tosylamide. Because the hydride donor in the reaction was inactive benzylic methylene, electron-withdrawing tosyl group was indispensable to increase the electrophilicity of C=N bond, additionally Sc(OTf)3 could further activate the imine. The methodology was elegantly elaborated in the formal synthesis of ( )-tetrahydropalmatine 225. 

An alkaloid, D, with virtually identical properties was isolated from Argemone munita and its identity with muramine seemed probable. A comparison of the two specimens confirmed this identity. In the meantime a repeat synthesis from tetrahydropalmatine has confirmed the... 

The conversion of tetrahydroberberine into tetrahydropalmatine, first achieved by Spath and Lang, is described elsewhere (p. 292). By demethylenating berberine sulphate Sp th and Quietensky obtained the dihydric phenolic base (XXV R = R = H), which on complete 0-methylation yielded palmatine (XXV R = R = Me), and on partial methylation gave jatrorrhizine (XXV R = H R = Me), the latter being isolated and identified as di-tetrahydrojatrorrhizine (p. 291). Columbamine is represented by (XXV R = Me R = H). A complete synthesis of palmatine was effected by Haworth, Koepfli and Perkin, who condensed 3 4-dimethoxyAomophthalic anhydride with 8-veratryl-ethylamine to -j8-veratrylethyl-3 4-dimethoxy omophthalamic acid, the methyl ester (XXVI) of which was converted by treatment with phosphorus oxychloride into oxypalinatine (XXVII), CjiHjiO N, buff-coloured prisms, m.p. 183°. This behaves like oxyberberine (XXII, p. 335), and on electrolytic reduction yields dZ-tetrahydropalmatine, m.p. 147°, which on oxidation with iodine in alcohol furnished palmatine (XXV R = R = Me) in the form of the iodide, m.p. 241° (dec.). 

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