The Path To Synthesis

Retrosynthetic Analysis

Retrosynthetic analysis of taxol
      Once you have identified the target molecule you are trying to build, how do you know where to begin? One way to approach building a complex molecule is through retrosynthetic analysis. This method requires a thorough knowledge of chemical reactions but also an equally well-developed, intuitive grasp of chemistry.

      Retrosynthesis works backwards from the target molecule, ultimately ending with a simpler (and preferably commercially available) starting molecule. The synthesis will then proceed by transforming this starting material through chemical reactions and the addition of functional groups.

      Taxol, with its complex tetracycline skeleton, has an obvious disconnection point at the side chain. The two synthons (the term used for an idealized molecular fragment) are then each analysed retrosynthetically to step back to the starting products. A synthesis that proceeds in this way, by creating multiple intermediate pieces individually and then combining them at the end, is called a convergent synthesis. An alternate approach builds on the starting molecule in a single, linear pathway. Known as a consecutive synthesis, it is akin to climbing a ladder one step at a time.

      The semisynthesis of Taxol that we will follow involves building two key intermediates. The tetracycline skeleton is made by transforming 10-deacetylbaccatin-III (10-DAB) which is isolated from yew needles. The side chain is formed by a β-lactam which is itself formed from two starting molecules, an imine and an acyl chloride. The first five steps of our synthetic pathway involve building the β-lactam, the next three steps involve acetylzing 10-DAB and preparing the tetracycline skeleton to react with the β-lactam in step nine. The final step is remove the protecting groups to leave the hydroxyl groups necessary for anti-tumor activity.

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© 2009 Matthew Radcliff and Dr. Joseph Fox
Created with funding provided by
the Camille & Henry Dreyfus Foundation Special Grant Program in the Chemical Sciences
and the National Science Foundation