\u201cYou can really simplify synthesis in a big way\u201d with this new reaction, Koh says. His overarching research goal is to come up with creative ways to make complex synthesis easier, which is one of the main reasons he joined the growing cadre of chemists working on atom swapping<\/a>. While other groups focus on editing aromatic scaffolds, he and his team turned their attention to saturated rings<\/a>.<\/p>\n The first step in the researchers\u2019 new atom-swap process is to remove the oxygen atom. To do this, they adapted a light-driven method developed by\u00a0Corey Stephenson\u2019s lab<\/a> (Nat. Chem. 2011, DOI: 10.1038\/nchem.949) to crack open the ring and turn its two carbon-oxygen bonds into carbon-bromine bonds.<\/p>\n The team then react the partially deconstructed, brominated intermediate in a classic substitution reaction with a nucleophile to rebuild the ring around a different atom. Adding an amine and base, for example, creates an azetidine. Or adding sodium sulfide slides in a sulfur atom to give thietane rings\u2014valuable pharmaceutical building blocks that are more challenging to make and much more expensive to buy than oxetane.<\/p>\n The researchers designed the reaction to play nicely with a variety of common organic functional groups, including other ethers. The starting material just can\u2019t have any exposed hydroxy groups, because those will be susceptible to the bromination reaction.<\/p>\n To show off their reaction\u2019s capabilities, the researchers used it to edit a variety of complex molecules, including turning an oxetane-containing anti-inflammatory molecule into a more potent thietane analog in a single operation. They also showed some examples in which starting from a commercially available oxetane and then swapping in a sulfur or nitrogen atom significantly cut the number of steps needed to create a key building block for a drug molecule.<\/p>\n Yoonsu Park<\/a> of the Korea Advanced Institute of Science and Technology, who works on atom swapping<\/a> but was not involved with the research, calls the paper \u201csimply groundbreaking\u201d work that \u201coffers a powerful simplified logic\u201d for constructing complex molecular fragments under mild conditions.<\/p>\n \u201cWe have these huge libraries of oxetanes . . . and the ability to kind of quickly diversify those, I think, will be really attractive,\u201d says Zachary Wickens<\/a>, an organic chemist at the University of Wisconsin\u2013Madison who also was not involved with the work. \u201cMy guess is that people will try this almost right away.\u201d<\/p>\n
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