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

Abstract

Dedicated to Professor William von Eggers Doering on the occasion of his 90th birthdayRobert Burns Woodward and William von Eggers Doering of Harvard University published a communication in 1944 and a full paper in 1945 in the Journal of the American Chemical Society both entitled "The Total Synthesis of Quinine".[1] This now famous full paper has been the subject of much attention over the years, particularly recently. It is now well-understood, that the Woodward-Doering "total synthesis" was actually a "formal" total synthesis of quinine (1) that relied on a seminal 1918 publication by Paul Rabe and Karl Kindler, wherein d-quinotoxine (2), the final synthetic substance in the Woodward-Doering work, was converted into quinine by a three-step sequence (Scheme 1).[2] This sequence involved: 1) oxidation of d-quinotoxine with sodium hypobromite to produce "N-bromoquinotoxine" (3); 2) base-mediated cyclization of 3 to produce "quininone" (4); and 3) aluminumpowder reduction of "quininone" to produce quinine (1) and quinidine (6, as a minor product). The 1918 paper, termed a "preliminary notice" by the authors, provided only a terse summary of this three-step process. This paper referenced Rabes 1911 conversion of cinchotoxine into cinchoninone and cinchonidinone (employing the analogous reactions for the quinotoxine to quininone and quinidinone conversion) [3] but subsequently in 1932, complete experimental details for the reduction protocol were published. [4] Despite the significant fanfare accompanying the publication of the Woodward-Doering paper during World War II, and the ensuing rich history of quinine and the Cinchona alkaloids in modern medicine, [5] it is surprising that apparently no one has reported efforts to simply attempt to repeat the Rabe-Kindler conversion of d-quinotoxine into quinine. This is particularly significant since concomitant with their relatively recent total synthesis of quinine, [6] Gilbert Stork and co-workers raised some possible doubts about the validity of this conversion, referring to Woodward and Doerings "total synthesis" as a "widely believed myth." [7] Consequently, the Woodward-Doering claim for a "total synthesis" albeit as a "formal" total synthesis by relay through d-quinotoxine based on the Rabe-Kindler sequence, has been besmirched. [7] This fascinating saga, spanning more than eighty years, was meticulously researched very recently by Seeman whose 2007 publication entitled: "The Woodward-Doering/RabeKindler Total Synthesis of Quinine: Setting the Record Straight", [8] helped kindle our own interest in this story. In his analysis of all the available data in the literature and in archival materials, Dr. Seeman stated: "I conclude that Paul Rabe and Karl Kindler did convert d-quinotoxine into quinine Scheme 1. Conversion of d-quinotoxine (2) to quinine (1). a) NaOBr, NaOH, HCl (aq), Et 2 O, 55 % yield of crude product; b) NaOEt, EtOH, 88 % yield of crude product; c) aluminum powder, NaOEt, EtOH, 5 % yield (as the tartrate salt).

Natural Product Synthesis: Changes over Time

“…Yet, the claim of a total synthesis of quinine remained under dispute [12] until the conversion of quinotoxine to quinine, originally reported by Rabe, [13] had been successfully repeated. [15] These impressive syntheses in the early phase of natural product synthesis remain as benchmarks today. Nevertheless, .…”

Naturstoffsynthese im Wandel der Zeit

“…B. deutlich bei der von der Fachwelt und den Medien viel beachteten [11] "Erstsynthese von Chinin" [12] durch Woodward und Doering. [15] Diese eindrucksvollen Synthesen aus der Frühphase der Naturstoffsynthese haben auch heute noch Bestand. Diese erste Naturstoffsynthese von Woodward (Schema 3) zeigt mit der Wahl eines Hydroxychinolins 3 als Ausgangspunkt bereits die Brillanz dieses Forschers auf, da 3 bereits alle Gerüstatome des Zwischenziels 2 aufweist.…”

“…Allerdings konnte bei der Hydrierung von 4 nicht die sicherlich erhoffte cis-Anordnung der Wasserstoffatome an der Ringverknüpfung erreicht werden, so- Dennoch blieb der Rang einer Totalsynthese von Chinin lange umstritten, [11] bis die seinerzeit von Rabe und Kindler beschriebene Umwandlung von Chinotoxin in Chinin [13] nachgearbeitet werden konnte. [15] Diese eindrucksvollen Synthesen aus der Frühphase der Naturstoffsynthese haben auch heute noch Bestand. Dennoch hatte die Vorgehensweise in dieser Phase der Naturstoffsynthese ihre Schwächen, beispielsweise bei den Bemühungen um die Synthese von Penicillin (Schema 4), [16] bei der über tausend Chemiker in weltweit 39 Laboratorien über Jahre nicht den Durchbruch schafften.…”

2,3,8-Trisubstituted Quinolines with Antimalarial Activity

“…During World War II, demand for quinine (1) increased substantially, mainly after Java, a big supplier of quinine, fell under the control of the Japanese army and exports were stopped. In addition, synthetic efforts to prepare quinine (1), described initially by Rabe (Rabe and Kindler 1918), followed by Proštenik (Proštenik and Prelog 1943) and finally by Woodward Doering 1944, 1945), which was claimed to be the first formal synthesis (Smith and Williams 2008, Seeman 2007, Kaufman and Rúveda 2005, Stork et al 2001 were not economically viable. As a result, pressure to develop alternative drugs with antimalarial activity increased.…”