The Woodward–Doering/Rabe–Kindler Total Synthesis of Quinine: Setting the Record Straight

Abstract

In 1918, Paul Rabe and Karl Kindler reported the three‐step conversion of d‐quinotoxine into quinine. In 1944 Robert B. Woodward and William von Eggers Doering reported the total synthesis of homomeroquinene and d‐quinotoxine from 7‐hydroxyisoquinoline. Based on the transformations by Rabe and Kindler, Woodward and Doering asserted the “Total Synthesis of Quinine” (the title of their 1944 and 1945 papers). In 2000 and 2001, Gilbert Stork concluded that the claim by Woodward and Doering is a “myth” because they had synthesized only homomeroquinene and d‐quinotoxine; no synthetic quinine had been made in Cambridge. In fact, Rabe and Kindler never published the experimental details of their conversion of d‐quinotoxine into quinine. This Review presents the results of a detailed examination of the synthesis of cinchona alkaloids, and previously unpublished material combined with unpublished material and numerous interviews give insight into the lives of the personalities in this nearly 100‐year saga.

Bonding Beyond Borders: The Nozoe Autograph Books and Other Collections

“…Stork's message to Prelog written in the author's travelling autograph book ( Figure 9) inquired if Prelog, or anyone known to Prelog, had repeated the Rabe and Kindler conversion of quinotoxine to quinine. The historical research by Seeman in 2007 [35] and the experimental studies by Smith and Williams in 2008 [54] confirmed Figure 11A]. It shows the conversion of hinokitiol to substituted 1,3-azulene dicarboxylic acids.…”

“…Koji was particularly playful as he often is when relaxing at restaurants that serve sake. But Gilbert asked a very serious question, a question whose meaning and substance I would only discover nearly ten years later when I was studying [35] the validity of Stork's claim [36][37][38][39] that the Woodward-Doering total synthesis of quinine [40,41] was a "myth." (Woodward received the Nobel Prize in 1965.)…”

Evolution and current status of the phytochemistry of nitrogenous compounds

“…It was through the effort of the alkaloid chemists Königs, Skraup and Rabe that this problem was solved, over a period of 30 years from 1880 to 1910. The synthesis of quinine was finally formally achieved by the Woodward-Doering/Rabe-Kindler synthesis, a matter of utmost interesting and exciting controversy, recommended reading to every phytochemist (Seeman, 2007). Interestingly, the first stereoselective and unambiguous total synthesis of quinine was reported by Stork et al in 2001, 181 years after the discovery of this alkaloid.…”

Ethics and Responsible Conduct of Research within the Chemical Community. Ideas and Experiences Worth Sharing

“…Sometimes, my lectures are part of the institution’s mandated RCR training program. Other times, I speak about my own research in RCR (House and Seeman, 2010; Seeman and House, 2010a,b) and history and sociology of chemistry as they relate to RCR (for example, see Seeman, 2007). While there are many valuable resources available for use in RCR educational programs, including a number of excellent texts (Beach, 1996; Committee on Assessing Integrity in Research Environments, 2002; Panel on Scientific Responsibility and the Conduct of Research, 1992; Panel on Scientific Responsibility and the Conduct of Research, 1993; Lock and Wells, 1996; Macrina, 2014; Resnik, 1998; Seebauer and Barry, 2001; Shamoo and Resnik, 2015; Steneck, 2007), there is only one that specifically focused on the chemical community—the book The Ethical Chemist: Professionalism and Ethics in Science (Kovac, 2004).…”