Quinine partial synthesis

Babe s general formula (p. 443) for the cinchona alkaloids was published in 1908 and a partial synthesis of quinine was effected by Babe and Kindler in 1918, but a complete synthesis of this alkaloid did not become available until 1945 when Woodward and Doering described their ingenious process. 

Scheme 5. Formal synthesis of quinine by Woodward-Doering. Conditions (i) PhCOCl, K2CO3 (ii) NaOEt (iii) HCl (6N), heat (iv) Rabe-Kindler partial synthesis.

Looking at Schemes 4 and 5, it is obvious that Woodward-Doering s synthetic route suffered from the lack of stereocontrol, which led to the production of their precursors of homomeroquinene target compound as a mixture of stereoisomers. The fact that the yield of such a transformation was not clearly determined, in addition to the anticipated difficult separation of the four isomers obtained at the end of the reaction (cf. Rabe-Kindler reaction), rendered this reaction commercially unpractical. Moreover, it is well accepted that Woodward and Doering never physically produced any quinine in their lab, and the success of their method is based on the assumption that Rabe and Kindler partial synthesis was a fact. This would be the center of the controversy when Stork later characterized what he called the quasi-universal impression that Woodward and Doering achieved the total synthesis of quinine as a widely believed myth . The whole story is very juicy and interested readers should refer to the amazing review published in Angewandte Chemie by Seeman in 2007. Nevertheless, in 2008, Smith and Williams successfully revisited the Rabe-Kindler conversion... 

Rabe P, Kindler K. (1918) Cinchona alkaloids. XIX. Partial synthesis of quinine. Ber Dtsh Chem Ges 51 466-467. 

CLXXXIII). The same series of reactions was subsequently applied to ethyl quininate (205), which fumiehed dihydroquinotoxine. Some twenty-five years later partial synthesis of quinotoxine itself was achieved in like manner by ProStenik and Prelog (90), who condensed ethyl quininate with -benzoylhomomeroquinene ethyl ester, derived by Beckmann rearrangement from iV-benzoylcinchotoxine oxime. 

As the absolute configuration of quinine was still unknown and stereochemical analysis did not exist, Rabe s ultimate objective was unfortunately far in advance of the realm of possibility. Even if he had successfully achieved the synthesis of the molecular structure of quinine, he would have conceivably produced sixteen different products, of which quinine would have required selective isolation from the other fifteen stereoisomers. Despite these overarching challenges, Rabe was able to effect a partial synthesis of quinine (1) from Pasteur s degradation product quinotoxine (3, cf. Scheme 2). This remarkable achievement is documented in Scheme 3 wherein, following bromination of the free amine in the piperidine ring of 3... 

A partial synthesis of quinine and quinidine has also been reported.33... 

A nice complement to the Haller-Bauer reaction (Section II.B) is the decarbonylation of aldehydes with (Ph3P)3RhCl (Wilkinson s catalyst) A recent example comes from the work of Baldwin and Barden and is shown in Figure 5. Interestingly, partial optical resolution was achieved in this synthesis by use of an optically active copper catalyst for the preparation of the labeled phenylcyclopropane carboxylic acid. The resolution to optical purity was then accomplished by recrystallization of the quinine salt of the acid. 

The chemistry of natural products encompasses their isolation, structure elucidation, partial and total synthesis, elucidation of their biogenesis, and the biomi-metic synthesis of N. p. Major breakthroughs in analysis were, e.g., the structural clarifications of morphine, lignin, insulin, estrones, and cholesterol as well as the elucidation of the biosyntheses of terpenoids, morphine, penicillin, chlorophyll, and vitamin B 2. Major advances in synthetic chemistry were, e.g., the total syntheses of camphor, hemin, quinine, saccharose, tropine, stryehnine, chlorophyll, vitamin B 2, erythromycin, taxol and palytoxin. Numerous N. p. of the so-ealled ehiral pool are used as starting materials for the synthesis of optically active compounds or serve (in the form of their derivatives) as catalysts for enantioselective syntheses. 

This is an intermediary substance in the synthesis of chloroquine and other quinine derivatives. Several workers involved in their production process presented with an allergic (partially airborne) rash on the face, hands, and wrists when in contact with 4,7-dichloro-quinoline. The exposure time varied from 3 weeks to 3 months (Pickering and Ive 1982). 

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