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The First Total Synthesis of Cocaine
In 1901, Richard Willstätter and Adolf Bode reported one of the first vollständige Synthese (complete or total synthesis) of a complex natural product. In this seminal work, the authors began their synthesis from cycloheptanone and, in 23 linear steps, completed the synthesis of (±)-cocaine. The key step is a bromination followed by an intramolecular transannular SN2 to form the tropane skeleton (Chem. Ber. 1901, 34, 129).
Cycloheptanone was elaborated to allylic bromide A, which was reductively aminated to afford the precursor B to the tropane skeleton. The key intramolecular transannular SN2 reaction was achieved upon exposure to Br2 and the resulting salt C was further manipulated to complete the synthesis of tropinone. Finally, an α-carboxylation, dissolving metal reduction, Fischer esterification, and a benzoylation afforded (±)-cocaine, to complete one of the first examples of a total synthesis.
20 April 2021 (online)
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