Woodward and Doering

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. 

Returning to quinine, the synthesis was not accomplished until 1945, by Woodward and Doering [7] at Harvard University, and it is a moot point whether or not they attempted to collect the 4000 francs prize offered by the French Pharmaceutical Society almost one hundred years earlier. 

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... 

Quinine (2) is the major active principle of cinchona, which was isolated by Pelletier and Caventou in 1820 [16] however, its structure could only be established after 100 years [17]. The total synthesis of quinine was accomplished by Woodward and Doering [18] and others [19] but none of the synthetic methods are economical and, therefore, can not compete with the natural production of quinine the bark of the cinchona tree is still the only source of the drug. In addition to quinine (2), three more antimalarial components, quinidine (3), cinchonidine (4) and cinchonine (5) are present in the bark. 

Apart from the classical papers describing the total synthesis of quinine by Woodward and Doering [77,78], several ingenious routes to the total synthesis of... 

The classic work in the synthesis of Cinchona alkaloids, which was initiated in the 1920s by Rabe and his co-workers and completed in the 1940s by Woodward and Doering, is described fully in a previous chapter (9). After a dormant period of more than 20 years in this field, interest was renewed in these alkaloids because of their antimalarial properties. Shortages of the Cinchona alkaloids from natural sources led to new efforts at total synthesis. 

Woodward was always attracted to molecules with novel structures or interesting biological activities. He attacked the synthesis of steroids during his years at MIT, and with American chemist Bill Doering in 1944, he published the paper that described the fulfillment of his boyhood dreams the synthesis of quinine. What Woodward and Doering actually reported was the twenty-step synthesis of a qtiinotoxine, a molecule whose conversion into quinine had been reported by the German chemist Paul Rabe in 1918. Rabe s reported synthesis of quinine was later discredited, but that in no way diminished the impact of Woodward s beautifully planned synthesis of quinotoxine. 

The cinchona bark was in scarce supply in World War 11. The plantations had been captured by Germany and Japan, which caused thousands of Allied soldiers fighting in Africa and the Pacific to die after contracting malaria. This prompted the need for a synthetic source. In 1944, Woodward and Doering reported the total synthesis of quinine, which is an alkaloid that was later claimed to be the dmg to have relieved more human suffering than any other in history. ... 

Scheme 4. General retrosynthetic plan utilized by Woodward and Doering in their formal total synthesis of quinine (1).

Scheme 5. Woodward and Doering s synthesis of advanoed intermediate 19.

Scheme 6. Woodward and Doering s opening of cyclic template 19 to provide advanced intermediate 25.

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