Quinine total synthesis

Excellent reviews about quinine total synthesis with historical background ... 

For a short discussion of this topic and some of R. B. Woodward s other contributions, see G. Stork, Nature 1980, 284, 383. An additional source of excellent information on Woodward, including aspects of the quinine total synthesis, can be found in the text Robert Burns Woodward Architect and Artist in the World of Molecules (Eds. O. T. Benfey, PJ. T. Morris), Chemical Heritage Foundation, Philadelphia, 2001, p. 470. 

FIGURE 10.2 Target bond reaction profiles for various published quinine total synthesis plans. 

The initial observation that menthone reacts with amyl nitrite in the presence of base to give a good yield of an open-chain oximino ester was not expanded for synthetic purposes until Woodward almost forty years later utilized this reaction for the cleavage of a 7-keto-decahydroisoquinoline in the course of his total synthesis of quinine. 

Woodward achieved his first signal success of a lifetime devoted to the preparation of increasingly complex natural products by total synthesis by the successful preparation of quinine. Despite its elegance, this synthesis did not provide a commercially viable alternative to isolation of the drug from chincona bark. A rather short synthesis for this drug from readily available starting materials has been only recently developed by the group at Hoffmann-LaRoche. (The economics of this synthesis are,... 

Scheme 8.22 Intramolecular Sn2 reaction in the catalytic asymmetric total synthesis of quinine.

The synthesis of quinine is considered the quintessential classic in the art of total synthesis. Figure 4.59 summarizes the starting materials for four routes beginning with the historical Woodward-Doering-Rabe plan to the racemic mixture and including three recent modern... 

Woodward, R.B. Doering, W.E. (1945) The Total Synthesis of Quinine. Journal of the American Chemical Society, 67, 860-874. 

Scheme 6.103 Intramolecular SN2 reaction in the total synthesis of quinine.

Another microwave-mediated intramolecular SN2 reaction forms one of the key steps in a recent catalytic asymmetric synthesis of the cinchona alkaloid quinine by Jacobsen and coworkers [209]. The strategy to construct the crucial quinudidine core of the natural product relies on an intramolecular SN2 reaction/epoxide ringopening (Scheme 6.103). After removal of the benzyl carbamate (Cbz) protecting group with diethylaluminum chloride/thioanisole, microwave heating of the acetonitrile solution at 200 °C for 2 min provided a 68% isolated yield of the natural product as the final transformation in a 16-step total synthesis. 

Initially approved in the 1930s as antimalarial drug, quinacrine (2) became one of the first potential substitutes to quinine. The total synthesis of quinacrine would be achieved in 1931 by German scientists at Bayer,and it would be subsequently marketed as Mepacrine or Atebrine. However, quinacrine would soon be replaced by another synthetic and more efficient antimalarial drug, chloroquine (3). 

The Cinchona tree remains the only economically practical source of quinine. Although the development of synthetic quinine is considered a milestone in organic chemistry, it has never been produced industrially as a substitute for naturally occurring quinine. Nevertheless, the implications of the total synthesis of quinine in new strategies for the development of safer and more efficient antimalarial drugs, as we will show in the course of the next paragraphs, is priceless. But, let us discuss this total synthesis first. 

The history of the total synthesis of quinine is quite a story with many twists and controversies. It is actually a cumulative effort of several great chemists over one and a half century period. This effort started just a few years after the isolation of quinine by Pelletier and Caventou. In 1853, the very famous French chemist and bacteriologist Louis Pasteur managed to obtain quinotoxine (quinicine in older literature) by acid-catalyzed isomerization of quinine (cf. Scheme 1) ... 

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... 

Woodward RB, Doering WE. (1944) Total synthesis of quinine. J Amer Chem Soc 66 849. 

Seeman Jl. (2007) The Woodward-Doering/Rabe-Kindler total synthesis of quinine Setting the record straight. Angewante Chem Int Ed 46 1378-1413. 

Smith AC, Wilhams RM. (2008) Rabe rest in peace Confirmation of the Rabe-Kindler conversion of d-quinotoxine into quinine Experimental affirmation of the Woodward-Doering formal total synthesis of quinine. Angewante Chem Int Ed 47 1736-1740. 

Stork Q Niu D, Fujimoto A, Koft ER, Balkovec JM, Tata JR, Dake GR. (2001) The first stereoselective total synthesis of quinine. J Amer Chem Soc 123 3239-3242. 

Lebold and Kerr reported the total synthesis of the eustifolines-A (172), -B (173), -C (93),-D (227), and glycomaurrol (92) starting from the readily available quinine imine 1574 and diene 1575 (899). This methodology uses the Diels-Alder reaction of a quinone monoimine 1574 and subsequent Plieninger indolization of the adduct 1576 for the synthesis of the key tetrahydrocarbazole framework. 

The total synthesis of quinine by Woodward and Doering18 in 1944 and synthesis of cinchonamine made in 1958 by Chen et al,1B are among the main achievements in research on the natural quinuclidine... 

Roush WR, Hall SE (1981) Studies on the total synthesis of chlorothricol-ide stereochemical aspects of the intramolecular Diels-Alder reactions of methyl undeca-2,8,10-trienoates. J Am Chem Soc 103 5200-5211 Rudler H, Denise B, Xu Y, Parlier A, Vaissermann J (2005) Bis(trimethylsilyl)-ketene acetals as C,0-dinucleophiles one-pot formation of polycyclic y-and 8-lactones from pyridines and pyrazines. Eur J Org Chem 3724-2744 Sekino E, Kumamoto T, Tanaka T, Ikeda T, Ishikawa T (2004) Concise synthesis of anti-HIV-1 Active (+)-inophyllum B and (+)-calanolide A by application of (-)-quinine-catalyzed intramolecular oxo-michael addition. J Org Chem 69 2760-2767... 

Ishikawa et al. reported that ( )-quinine-catalyzed asymmetric intramolecular oxo-Michael addition (IMA) of 7-hydroxy-8-tigloylcoumarin gave cis-2,3-dimethyl-4-chromanone systems with high enantioselectivity and moderate diaster-eoselectivity, especially when chlorobenzene was used as a solvent. " Therefore, total synthesis of (+)-calanolide A (1) was achieved by application of the (—)-quinine-catalyzed asymmetric IMA. However, the synthetic route starting from 1,3,5- trimethoxybenzene was too long (13 steps with 3.5% overall yield) to practice. Finally, the authors improved and shortened the original synthetic route by application of Mgl2-assisted demethylation. 

Tanaka, T. Kumanoto, T. Ishikawa, T. Enantioselective total synthesis of anti HIV-1 active (+)-calanolide A through a quinine-catalyzed asymmetric intromolecular oxo-Michael addition. Tetrahedron Lett., 2000, 41 10229-10232. 

The chemical techniques available to chemists in the period 1820-1920, although improving rapidly, did not allow a structure to be proposed for quinine with any confidence the first completely correct proposal (211) came in 1922 and was finally confirmed by total synthesis (212) as late as 1945. However, part structures were known, such as the 6-me-thoxyquinoline moiety, from long before, and were sufficient to allow the synthesis of mimics. The first clinically successful mimics were the 8-aminoquinolines. 

In addition to dimethylcuprates, various alternate cuprate reagents can be used. As shown in Scheme 11.12, a divinylcuprate was used in a 1,4-addition employed in the total synthesis of meroquinene 42 (Scheme 11.12), a degradation product of cinchonine and also an intermediate en route to cinchona alkaloids such as quinine [52,53]. As illustrated, enone 36, available via acetoxyglucal 35 (Scheme 11.11), was treated with divinylcuprate to exclusively afford the axially substituted 4-vinyl derivative 38. Trapping of this intermediate with methyl bromoacetate gave a mixture of C3 epimers readily equilibrated to 39 in the presence of triethylamine. Further manipulations of 39 gave the 2-deoxy derivative 40 and, in turn, the dialdehyde 41. Cyclization of the latter to enantiomerically pure meroquinene 42 proceeded uneventfully. 

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