Cincholoiponic acid

The isomeric substance, cinchotenidine, similarly obtained from cinchonidine, crystallises in needles, m.p. 256°, [ajo — 201-4° or — 207° (iV-H2S04), and, like cinchotenine, gives by further oxidation cinchoninic and cincholoiponic acids. 

The isomeride quiienidine, similarly produced by the oxidation of quinidine, crystallises in prisms, m.p. 246°, [a]f ° -(- 258° (A -H jS04), and, like quitenine, gives quininic and cincholoiponic acids by further oxidation. 

Cincholoiponic acid, CgH4g04N. HgO, results from oxidation of einehotenine, einehotenidine, quitenine, quitenidine, meroquinenine cincholoipon, and, aceording to Skraup, is also formed directly by th oxidation of each of the foiu" parent alkaloids. It crystallises from watd in prisms, m.p. 126° or 221-2° (dry), is insoluble in alcohol or ether, solnblil... 

It has already been shown that both the laevorotatory and dextrorotatory cinchona alkaloids on degradation yield scission products from the quinuclidine nucleus, which are structurally and optically identical, for example, meroquinenine, [a] -f- 27 6° d-/3-cincholoiponic acid. 

Chondrodendron polyanthum, 371 Chondrodendron tomentosum, 363, 371, 373, 377, 391 alkaloids, 376 Chondrodine, 363, 364 Chondrofoline, 364, 365 Chrycentrine, 172, 313 Chiysanthemine, 773 Chrysanthemum cineraricefoHum, 773 Chuchuara, 781 Chuehuhuasha, 781 Cicuta virosa, 13 Cinchamidine, 419, 429 Cinchene, 439 Cinchenine, 438, 439, 440 apoCinchenine, 440, 441 Cincholoipon, 438 Cincholoiponic acid, 438, 443 Cinchomeronic acid, 183 Cinchona alkaloid structure, synthesis, 457 Cinchona alkaloids, bactericidal action of some derivatives, 478 centres of asymmetry, 445 constitution, 435 formulae and characters of transformation products, 449, 451 general formula, 443 hydroxydihydro-bases, 448, 452-4 melting-points and specific rotations, 446... 

None the less the expressions (XIII), (XIV) and (XV) had gained general acceptance shortly after the turn of the century, and were finally shown conclusively to be correct through the s3mthesis of cincholoiponic acid by an unambiguous route (68, 69). 

From the alkaloids, by more extensive degradation (60,147), or from meroquinene (64, 148), d-/3-cincholoiponic acid (CV) is obtainable. This acid is unstable with respect to a stereoisomer, d-a-cincholoiponic acid, into which it is transformed when it is heated with aqueous potash (65). This result suggests that the /3-acid, and thence, the alkaloids themselves, possess the cis orientation of the groups attached to the piperidine ring. The conclusion is strengthened by consideration of the synthesis of the a- and /3-cincholoiponic acids (c/. Section IV, 2). When malonic ester was added to the nitrile CVI, a reaction mixture was obtained from... 

Cincholoiponic acid was the first of the degradation products of the cinchona alkaloids to be synthesized. The synthesis followed the course illustrated in the accompanying chart. The mixture of racemic a- and 3-cincholoiponic acids (cf. Section III, 1) obtained in this way was separated, and resolved by crystallization of the brucine salts. The d-/3-cincholoiponic acid proved to be identical with the acid from cinchonine (68, 69). 

Meroquinenine, CgHjjOaN (meroquinene), formed by the oxidation of all four alkaloids and of cinchoninone or quininone and by the hydrolysis of quinenine or cinchenine (p. 489), crystallises from methyl alcohol in needles, m.p. 223-4° (dee.), [ajp -f- 27-5° (H2O). It gives a nitrosoamine, m.p. 67°, and a monoacetyl derivative, m.p. 110°, and can be esterified the ethyl ester hydrochloride has m.p. 165°. When oxidised by chromic acid it yields formic and cincboloiponic acids. On reduction with zinc dust and hydriodic acid, it adds on two atoms of hydrogen forming cincholoipon, CgH jOaN, and when heated with hydrochloric acid at 250-60° gives 3-ethyl-4-methylpyridine ()3-collidine). 

The synthesis of (-)-alangimarckine (114) from the tricyclic amino-acid (113), which had previously been prepared from cincholoipon ethyl ester (112), confirms the structure and relative stereochemistry recently deduced, " and also proves that the absolute stereochemistry is as given in (114) (Scheme 15). 

Alangicine (132) has been synthesized from the acid derived from (129) by reduction and hydrolysis. This, with the appropriate /3-phenethylamine, gives the amide (131). The absolute stereochemistry of alangicine has been confirmed by its synthesis from ethyl cincholoiponate via the lactam acid (133). ... 

These results indicate that quinine and quinidine differ in structure from cinchonine and cinchonidine in containing a methoxyl group in position 6 in a quinoline nucleus. The identity of the other oxidation products, meroquinenine, cincholoiponic and loiponic acids, in all four cases indicates that the second half of the molecule has the same structure in all four alkaloids. Further, this second half must be joined to the quinoline nucleus at position 4 by a group capable of conversion into carboxyl. 

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