Total Syntheses of Colchicine in Comparison: A Journey through 50 Years of Synthetic Organic Chemistry

• Published in: Angewandte Chemie International Edition 2004-06, Vol.43 (25), p.3230-3256
• Main Authors: Graening, Timm, Schmalz, Hans-Günther
• Format: Article
• Language: English
• Subjects: alkaloids; Chemistry, Organic - methods; Colchicine - chemical synthesis; Colchicine - chemistry; cycloaddition; Models, Molecular; Molecular Conformation; natural products; Protein Binding; Structure-Activity Relationship; synthesis design; total synthesis; Tubulin - chemistry
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.200300615

Colchicine, the major alkaloid of the meadow saffron, is one of the most prominent natural products and, like other tubulin‐binding natural products (e.g. taxol and the epothilones), exhibits great pharmaceutical potential. The first syntheses in the late 1950s were milestones in natural product synthesis. But even today this structurally supposedly simple molecule poses a challenge to synthetic chemists. Only in the last years have syntheses been developed that are efficient enough to provide novel structurally modified colchicine analogues. The comparative examination of all known colchicine total syntheses undertaken in this Review not only reveals the tremendous progress in synthetic organic methodology over the past decades, but also shows how the unique synthetic problems posed by this molecule can be solved in an exceptionally creative manner. Only a few target molecules have been synthesized in such multifaceted ways. The tubulin‐binding alkaloid colchicine (1), isolated from the meadow saffron, is an antimitotic agent with a great pharmaceutical potential. Only a few other natural products have proved to be such a challenge to synthetic chemists for half a century. The comparative analysis of the often fascinating synthetic strategies reveals why this seemingly simple structure still belongs to the “difficult targets”.