Synfacts 2021; 17(05): 0577
DOI: 10.1055/s-0040-1719805
Chemistry in Medicine and Biology

The First Total Synthesis of Cocaine

Contributor(s):
Dirk Trauner
,
Matthew McLarney DiCairano
Willstätter R, *, Bode A. Ludwig Maximilian University of Munich, Germany
Ueberführung von Tropinon in r-Cocaïn.

Chem. Ber. 1901;
34: 1457-1461
DOI: 10.1002/cber.19010340220.
 

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 SN2 to form the tropane skeleton (Chem. Ber. 1901, 34, 129).


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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 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.


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Publication History

Publication Date:
20 April 2021 (online)

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