The First Total Synthesis of Cocaine

Key words

cocaine - tropinone - total synthesis - Hofmann elimination

Significance

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 S_N2 to form the tropane skeleton (Chem. Ber. 1901, 34, 129).

Comment

Cycloheptanone was elaborated to allylic bromide A, which was reductively aminated to afford the precursor B to the tropane skeleton. The key intramolecular transannular S_N2 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.