Phase-Switch Synthesis with Boronic Acids as Productive Tags

摘要

Progress in chemical biology and medicinal chemistry relies extensively on the availability of large libraries of novel small molecules of high purity. In response to these demands, new techniques and strategies are needed to accelerate and facilitate the synthesis and purification of novel organic compounds. Phase-switching strategies are very attractive because they combine the respective advantages of solution and solid-phase synthesis techniques. In phase-switch chemistry, reactions take place conveniently under homogeneous conditions, and product separation is facilitated by precipitation or a "catch-and-release" filtration operation. Phase trafficking is possible through functionalization of the substrate or reagents with a phase "tag". Several ingenious phase-switching strategies were developed and employ various tags such as perfluoroalkyl groups, polyethylene glycol chains,metal chelators, hydrogen-bonding receptors, polymerizable norbornene groups, polyaromatics, and others. While many of these strategies have been used only for tagging reagents or catalysts, a few were employed for tagging substrates and allow multistep syntheses to be performed. In all of these methods, however, the requirement for a phase-switch tag creates two chemically unproductive steps: attachment of the tag to the substrate and detagging of the product at the end. The latter operation often leaves an undesired remnant (or "trace") of the phase-switch tag. Although traceless fluorous syntheses have been reported, the required tags are complex and still need to be attached to the substrate. Herein, we describe a new phase-switching strategy involving the simple boronic acid functionality as a productively convertible tag. Rather than cleaving the extraneous tag at the end, as in other phase-switch systems, we can use the wide range of selective transformations known for this class of compound to productively derivatize the boronic acid tag. Because of the large number of commercially available boronic acids that can serve as potential substrates toward many synthetic applications, this phase-switch system can also circumvent the tag-attachment step.