Cryptopine synthesis

This formula was confirmed hy Haworth and Perkin s synthesis of a-flZZocryptopine from herherine, the first application of a process, of which examples have heen given already in the syntheses of cryptopine (p. 298) and protopine (p. 301) hy the same authors. Anhydrotetrahydromethyl-herherine (I cf. hase (a), p. 346) in dry chloroform was added to a solution of perhenzoic acid in ether cooled helow 5°. The amine oxide, C21H23O5N (II), separated as an oil, which after shaking with sodium hydroxide solution, solidified and was crystallised from water in slender prisms, m.p. 135°. It was dissolved in acetic acid, hydrochloric acid added, the mixture heated in boiling water for an hour and the hase precipitated hy addition of potassium hydroxide. The precipitate was dissolved in methyl alcohol, ether added, the alcohol washed out with water and the ethereal... 

The synthesis of the parent ring-system of the protopine alkaloids using Perkin s method has been described.224 The preparation of examples of the indeno[l,2-c]isoquinoline ring system (219), exhibited by a rearrangement product of cryptopine, has been described.225 The transformation of protopine to benzophenanthridine alkaloids will be described in Section 3 J. 

Oxyberberine (XVIII) is the first product of the oxidation of berberine. It may be reduced to tetrahydroberberiiie at a lead cathode in alcoholic sulfuric acid (215). Its synthesis is therefore a synthesis of berberine. The general procedure for the synthesis of this type of compound is described in connection with the synthesis of cryptopine, and oxyberberine itself was prepared by this procedure. Another synthesis of oxyberberine was achieved by Perkin, Ray, and Robinson (216). The 8-piperonyl-ethylimide of meconinecarboxylic acid (XX) was heated with phosphoryl chloride to yield an uncharacterized isoquinoline derivative, presumably XXI, which when reduced with zinc in acetic acid suffered reduction of the doubl bond, opening of the lactone ring, lactam formation, and dehydration to yield oxyberberine. This ready elimination of water was later observed in ophiocarpine (6). 

Structure and Synthesis. When Buck and Perkin (228) attempted to apply the Pictet and Gams synthesis (220) of berberine to epiberberine they obtained an isomer, tetrahydro- -epiberberine (XXXIII). Subsequently, Haworth and Perkin achieved a total synthesis which is detailed in connection with the synthesis of cryptopine. Oxidation of sinactine with iodine in boiling alcohol yields epiberberinium iodide, from which the chloride was prepared by treatment with silver chloride, and this was identical with epiberberinium chloride prepared from cryptopine (235). Finaly, Spath and Mosettig (236) resolved the dZ-tetrahydroepiberberine (m.p. 170°) (XLIII) from cryptopine by means of d- and Z-tartaric acids in succession and showed that the Z-form, [a] —302° (chloroform), was identical with the natural alkaloid. The cZ-form had the same numerical value for its optical rotation and melted at 178-179°. 

The synthesis of the homophthalic acid was a rather involved one, requiring as primary starting material /3-veratrylbutyric acid. It was necessary to block the 6-position with a bromine atom, ring-close to the corresponding 4-bromo-6,7-dimethoxy-3-methyl-l-indanone, and then treat the isonitroso derivative of this with p-toluenesulfonyl chloride in the presence of alkali. The resulting carboxy nitrile on hydrolysis and de-bromination with sodium amalgam afforded the desired acid. Similar syntheses are described in greater detail in the chapter on protopine and cryptopine. 

The correctness of the nuclear structure of cryptopine received final verification in a synthesis achieved by Haworth and Perkin (29). The first stage consisted in the condensation of 3,4-methylenedioxyhomo-phthalic acid with 8-veratrylethylamine to yield the imide, which on partial... 

The synthesis of protopine (31) was achieved in a manner strictly analogous to that used for cryptopine. The intermediate analogous to XXVIIA (methylenedioxy group replacing two methoxyls) was obtained from 9-3,4-methylenedioxyphenethylamine by condensation with 3,4-methylenedioxyhomophthalic acid and partial hydrolysis of the imide thus formed. The subsequent steps followed those already outlined. Here too, yields in the ultimate step are not recorded and the possibility of forming a cryptocavine analog are not to be overlooked. 

The synthesis of allocryptopine by Haworth and Perkin (82) was the first application of the process already outlined for cryptopine and protopine. This choice was made because the starting material, tetrahydro-berberine ((XXIX) with the methylenedioxy and the methoxy groups interchanged) was readily available. Furthermore, Pyman (18) had already made a full investigation of the decomposition of the methohydroxide to... 

The synthesis of cryptopine was efiTected by Haworth and Perkin by a process first used by the same authors in the preparation of a-aUo-crj ptopine 03-homochelidonine) (p. 301). 8 4-MethylenedioxyAomo-... 

As one outcome of an investigation into methods for the synthesis of the berberine type of alkaloid by Perkin and his collaborators, in the course of which an extensive series of bases related to, or associated with berberine, including the interesting linear berberine paraberine), were prepared, Haworth, Perkin and Pink devised a general method for such syntheses, of which examples are given under protopine (p. 299) and cryptopine (p. 295), and which was applied by Haworth, Koepfli and Perkin to oxyberberine and palmatine (p. 342). For these two alkaloids it involved the preparation of 3 4-dimethoxyfeonjophthalic anhydride, which was condensed with )S-piperonylethylamine and the resulting phlhalamic acid (XXIII), as the methjd ester, boiled with phosphorus oxychloride, which converted it into oxyberberine (XXH). 

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