The First Total Synthesis of Ingenol By J. D. Winkler et al., Journal of the American Chemical Society, 2002, Vol. 124, 9726.

Editorial Comments

One of the most active areas in research for organic chemists is in the area of synthesis. Synthetic chemistry lies at the heart of many disciplines, since it is important to be able to make molecules that have valuable properties such as therapeutic activity or interesting material uses. Natural products, compounds produced by living organisms, perhaps provide the greatest challenges to synthetic chemists and many research groups are actively involved in “total synthesis” of natural products. These compounds can be extremely difficult to make, since they often have many asymmetric centers, rings, and functional groups. Certain molecules such as vitamin B₁₂, taxol, and morphine have provided great challenges over the years to synthetic organic chemists.

Another molecule that has really challenged the creativity of synthetic chemists is the naturally occurring compound ingenol. This unusual compound has been the subject of intense interest because of its unique chemical structure and potent biological activity. Ingenol is a potent activator of an enzyme known as protein kinase C (PKC), an enzyme that regulates growth and development of cells. The overactivation of PKC by ingenol can lead to the development of cancer, and as such, ingenol is a useful molecule for studying the development of cancer.

From a structural point of view, ingenol represents a serious challenge due to the high degree of oxygen, a quaternary carbon, and a very unusual trans-fused bridged ring system that introduces a great deal of strain into the molecule. This molecule has intrigued many researchers over the past 20 years, and recently, researchers at the University of Pennsylvania were successful in synthesizing the natural product.