Seiko Fujii, a member of Professer Marty Burke's research group, has made a major advance in small molecule synthesis which will be celebrated next month on the cover of Angewandte Chemie, one of the top chemistry journals in the world.

Seiko has discovered a powerfully simple new strategy that enables chemists to more efficiently make complex molecules for a wide range of applications in science and medicine. The breakthrough makes it possible for a previously developed “iterative cross-coupling” (ICC) approach for chemical synthesis to be optimally matched to the overall electronic structure of a small molecule target (S. Fujii et al. Angew. Chem. Int. Ed. 2011, Early View doi/10.1002/anie.201104526). This new strategy has been dubbed “reversed-polarity iterative cross-coupling” (RP-ICC).

 The power of this new strategy was harnessed to achieve the first total synthesis of the complex natural product synechoxanthin from simple and readily accessible building blocks. First isolated in 2008 from a bacterium that thrives in the presence of extreme oxidative stress, synechoxanthin has the potential to serve as a powerful antioxidant in human beings, possibly replacing the function of antioxidant proteins whose deficiencies have been linked to a wide range of human diseases such as atherosclerosis, neurodegenerative disorders, and cancer. To make this molecule in the laboratory, three readily-available, highly-stable, and non-toxic building blocks were assembled in a highly convergent fashion using only one reaction iteratively. As a result of the new RP-ICC strategy, all intermediates along the synthetic pathway were easily-activated coupling partners leading to maximized yields. The inherent simplicity, efficiency, and flexibility of this building block-based approach now stands to enable systematic study and optimization of the antioxidant functions of this complex natural product.

 More than 75 of the Burke group’s previously developed “MIDA boronate” building blocks for iterative cross-coupling are already commercially available. This new breakthrough promises to stimulate a large expansion of this collection of highly versatile reagents that are already being utilized in many academic and industrial laboratories worldwide to speed the discovery of new medicines.