Metho-salts

Both des-bases yield mono- and di-metho-salts, and the latter ( digestion with sodium methoxide in methyl alcohol give the better yiel... 

Roylance showed that pilocarpidine on -methylation yielded two products, pilocarpine and neopilocarpine (see below), thus confirming Hamack s suggestion that pilocarpidine is the imino-base corresponding to pilocarpine, Spath and Kunz showed that pilocarpidine, on treatment with alcoholic sodium ethoxide, is converted into isopilocarpidine (nitrate, m.p. 109-111°), which, on quaternary methylation, yields isopilocarpine metho-salts (methopicrate, m.p. 119-120°). The confirmation of these observations by the synthesis of pilocarpidine and isopilocarpidine and their conversion into pilocarpine and isopilocarpine has been described already. 

This compound was prepared by Allen et who found it to be monobasic and to form a simple methiodide. Attempted Hofmann degradation of this methiodide failed to give any information. The dimer was found to be perfectly stable to hot aqueous sulfuric acid. With the foregoing data, and by analogy with the alkyl pyrrole dimers, they proposed structure (9) for the dimer. Later work confirmed this structure by conversion via the methiodide into base (10) which was synthesized by way of the metho salt (11), isomeric with... 

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

Another biomimetic transformation was reported by Nalliah et al. (155). 13-Oxotetrahydroberberine (ophiocarpinone) metho salt (291), derived from berberinephenolbetaine (121), was irradiated in methanol in the presence of sodium hydride to afford the spirobenzylisoquinoline 294 in 45% yield... 

Wu et al. (156) found that photolysis of 13-substituted dihydroprotober-berine metho salts 296 in methanol similarly afforded the corresponding spirobenzylisoquinolines 297 in 23-54% yields via the quinodimethides (Scheme 53). On the other hand, 13-unsubstituted metho salts 298 furnished, on irradiation, the imino ketones 299 (Scheme 54) instead of spirobenzylisoquinolines through N-demethylation and oxidation via the quinodimethide... 

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. 

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. 

Scheme 74. Synthesis of 13-oxoallocryptopine (402) from ophiocarpinone metho salt (291) by oxidation. Reagents a, air, NaH, KI, (MeOCH2)2 b, Zn, AcOH.

Labeled muramine (395) was synthesized for biosynthetic studies from tetrahydropalmatine (27) in 35% overall yield via the von Braun reaction product 30c (Section II,A,2) and the alcohol 403 (Scheme 76) (42). Labeled 13-oxygenated muramines 405a and 405b were obtained by oxidation of dihydropalmatine metho salt (404) with osmium tetroxide (42). 

Another photochemical method was reported by Kessar et al. (157). l-o-Toluyl-3,4-dihydroisoquinoline 299a, derived from dihydroberberine metho salt (298a), was irradiated and then reduced with sodium boro-hydride to provide the ring D-inverted 11,12-oxygenated protoberberine 482 (Scheme 100). 

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. 

The enol lactones were synthesized by Hofmann degradation of metho salts of classic phthalideisoquinoline alkaloids. The biogenetically relevant transformations were highly stereospecific. In this way aobamidine (96) was obtained from the methiodide of (erythro) bicuculline (88) (2), and ad-lumidiceine enol lactone (97) was produced from both (threo) isomeric adlumidiceine (89) and capnoidine (90) methiodides (14,15,91-93). (Z)- (98) and ( )-N-methylhydrastine (99) were obtained from / - (91, erythro) and a-N-methylhydrastinium (92, threo) iodides (5,87,91,96-98), respectively, as were (Z)- (101) and (JE)-narceine enol lactones (102) synthesized from a- (94, erythro) and /J-narcotine (95, threo) quaternary N-metho salts (87,90), respectively. In a similar process /J-hydrastine (91) JV-oxide heated in chloroform yielded enol lactone 124 of Z configuration (99) however, a-narcotine (94) N-oxide was transformed to benzoxazocine 125 (99). ... 

Secophthalideisoquinoline keto acids are postulated to be biosynthesized from phthalideisoquinoline metho salts via enol lactones. Such transformations occur easily in laboratory experiments (Section III,B,1). There are... 

B. CORYNANTHE ALKALOIDS 1. Antirhine and Antirhine jVb-Metho Salts... 

The other antirhine iVb-metho salt, namely, antirhine Ab-(3-methochloride (13) has been isolated from Amsonia elliptica Roem. and Schult. (27). Demethylation... 

Since the previous reviews on the pavine group in Vol. 4, 10, 12, and 17 of this treatise, which cover references prior to 1976, five new alkaloids of the pavine series have been discovered. These alkaloids are (—)-2,3-methylene-dioxy-4,8,9-trimethoxypavinane (3), thalipoline, (—)-caryachine Af-metho salt (16), (-)-eschscholtzidine Af-metho salt (17), and (-)-eschscholtzine A -oxide (20a). 

The new quaternary pavine base (-)-caryachine A-metho salt was isolated from Cryptocarya chinensis (29), previously shown to yield both the levorotato-ry and racemic forms of caryachine (7) (30,31). The structure 16 was derived... 

The structure proof of the second new quaternary base, (—)-eschscholtzidine Al-metho salt (17), isolated as its chloride from the fruits of Thalictrum revo-lutum, was provided by spectral analyses and direct comparison of the compound with the N-metho salt prepared from authentic (—)-eschscholtzidine (8), also present in the plant (32). 

It is a general feature of alkaloid chemistry that less is known about the quaternary alkaloidal components than the tertiary bases due to the difficulties encountered in handling the isolation and analyses of these highly polar compounds. It is interesting to note, however, that in the pavine series, 5 naturally occurring A -metho salts as against a total of 15 tertiary pavine alkaloids have been recognized. 

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