Formal synthesis of quinine

Scheme 5. Formal synthesis of quinine by Woodward-Doering. Conditions (i) PhCOCl, K2CO3 (ii) NaOEt (iii) HCl (6N), heat (iv) Rabe-Kindler partial synthesis.

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. 

Thanks to quinicine 3 and cinchonicine 4 Pasteur achieved the first separation of racemic tartaric acid. This resolution is considered a milestone in organic chemistry. Conversely, the transformation of quinotoxine 3 into quinine in three steps is part of the (formal) Rabe-Kindler/Woodward-Doering synthesis of quinine as has recently been reaffirmed by R.M. Williams and his group (cf. Section 11.5.3). Meroquinene ester 7 is a 3,4-disubstituted piperidine formed from quininone 5 (cinchoninone) and base in the presence of 302. In this reaction, an activated bridgehead lactam is a key intermediate that is opened by KOBu1. Three stereocenters are lost and only two stereocenters survive in the course of this transformation (Scheme 12.3) [4]. 

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

As indicated in Scheme 7, these objectives were met with the formation of 11 over several steps, via 28, in 40 % yield. Following the reaction of this compound (11) in a Dieckmann condensation with the readily synthesized quinoline 10, subsequent treatment of the resultant product with hot 6 n HCl then completed the synthesis of quinotoxine (3), which was obtained as its natural epimer following selective crystallization. As such, the first total synthesis of quinine (1) was formally complete. ... 

With Woodward, synthesis assumed a sophistication previously unknown, and targets such as quinine (5, with von E. Doering and co-workers), cortisone (6), strychnine (7), and reserpine (8) were synthesized (along with many other molecules). Over these years, the structural and stereochemical features of the targets increased in complexity. As more complex structures were targeted, the newly acquired ability to control stereochemical features and chiral centers led to greater synthetic achievements. Corey formalized the... 

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