Woodward, rest in peace

Readers may remember the fascinating story of the synthesis of quinine and questions about Woodward's synthesis of the molecule in 1945 that were discussed insightfully by Jeff Seeman in a review in Angewandte Chemie last year. I had an opportunity to take Dr. Seeman out to lunch and we had a great time discussing his article among other things. Clearly, the single most important question was; did Woodward actually synthesize quinine, considering that he had only synthesized quinotoxine, which was one step away from quinine? Woodward assumed that since Paul Rabe had already synthesized quinine from quinotoxine in 1918, the total synthesis of quinine had been achieved (strictly by today's standards, it should have been called a formal synthesis). This question was really amplified by Gilbert Stork, when in his elegant 2001 synthesis of quinine, he questioned the Woodward (and the Rabe) synthesis.

The whole story is exceedingly fascinating and classic detective story-like. When we were discussing this stuff with Dr. Seeman, there was even talk of people trying to unearth 80 year old samples of quinine (?) and then analysing them. Paramount to the resolution of the problem was one central question; can one convert quinotoxine to quinine using the conditions that Rabe used? If so, both Rabe and Woodward would be saved from history and vindicated.

At that time, Dr. Seeman said that a as-yet-undisclosed chemist was trying to reproduce the conversion. Now we know that that chemist is Robert Williams from Colorado State. And he has saved Rabe and Woodward by converting quinotoxine to quinine using primitive conditions that Rabe must have used, without any modern, sophisticated methodology. Interestingly in their conversion, impure Al powder worked better than pure Al powder, in one of those classic quirks of chemistry! But finally, they cinch the deal.

"Finally, the conclusions reached by Seeman on the validity of the Rabe–Kindler work now have firm experimental support which vanquishes any resilient doubts initially raised by Stork in a letter to Woodward in 1944 (apparently unanswered), in which he queried whether the Rabe–Kindler procedure had been repeated at Harvard; these concerns were then made more visible in his series of publications in 2000 and 2001 questioning the 1918 Rabe– Kindler publication[2] and the ensuing Woodward–Doering (formal) total synthesis. The Woodward and Doering paper concludes unambiguously: “In view of the established conversion of quinotoxine to quinine, with the synthesis of quinotoxine (emphasis ours) the total synthesis of quinine was complete.” The experimental facts reported herein reaffirm that assertion. Our validation of the formal total synthesis of quinine as originally reported by Woodward and Doering in 1944 should serve to remove the blemish asserted on the reputations of Rabe and Kindler as well as those of Woodward and Doering. The Supporting Information to the present work provides the complete experimental details to the chemical literature of the Rabe– Kindler d-quinotoxine into quinine conversion in both a modern experimental setting as well as a pre-1944 setting; may Paul Rabe and Karl Kindler requiescant in pacis.

Requiescant in pacis indeed! One lingering question that I have that remains unanswered is; why didn't the intrepid and meticulous Woodward not carry out this last step just to clinch the final product and convince himself that he indeed had quinine with Rabe's conditions? I guess the price we may pay for answering a major question of history is perhaps to let this relatively minor but intriguing question to go unanswered.