LA JOLLA, Calif.—Natural products are attractive to drug developers because they generally offer a chemical diversity that is unheralded in the synthetic chemistry world. This same diversity makes these products problematic, however, as they can be incredibly difficult to synthesize. The need for chemical protecting groups complicates these syntheses, so researchers at The Scripps Research Institute recently tried to develop "smarter" protocols that didn't rely on protecting groups.
As they report in Nature, the researchers looked to clues in the natural biosynthetic pathways of indole production in cyanobacteria. They then harnessed "the natural reactivity of specific functional groups in a complex setting" to generate a series of compounds and intermediates in fewer steps than would be required under traditional methods. For example, they generated ambiguine H and related compounds in 7-10 steps rather than 20-25, and were able to achieve gram instead of milligram quantities. In the process, the researchers devised a general 8-step guideline for synthesis planning that they suggest is a culmination of common but disparate knowledge.
In a related News & Views item about the paper, Dr. John Porco, Jr., of Boston University said the work "will inspire new chemistry by exposing the intrinsic reactivity of chemical reagents and reactive intermediates. Further work on chemical synthesis using 'undressed' molecules should lead to many more advances and innovative developments in organic synthesis."