Selective functionalization: Shields for small molecules.

P rotecting groups have a long history in synthetic chemistry 1. A protecting group is covalently attached to one functional group to block its reactivity while a second functional group undergoes a chemical transformation, after which the protecting group is then removed (Fig. 1a). The use of protecting groups requires both protection and deprotection steps, so efficiency considerations dictate that their use should be avoided whenever possible. Indeed, many research groups have sought to develop highly selective synthetic reactions that obviate the need for them 2. Nevertheless, many situations warrant judicious use of protecting groups, often because the selective chemical methods to circumvent their employment have yet to be discovered. In this context, a report by Andreas Herrmann and co-workers in Nature Chemistry 3 describes an intriguing new strategy in which nucleic acid aptamers are employed as noncovalent protecting groups in the form of 'aptameric protective groups' , or APGs, for use with otherwise-unprotected complex small-molecule compounds. What is the motivation for developing APGs? Structurally complex natural products often display numerous chemically equivalent (or nearly so) functional groups that are challenging to differentiate using small-molecule reagents. For example, the aminoglycoside antibiotic neomycin B has six primary NH 2 groups (Fig. 1b), all of which can react with acylating reagents. Preparing site-specifically acylated analogues of neomycin B by direct reaction with acylating reagents is generally intractable. Herrmann and co-workers reasoned that complexing neomycin B with a macromolecule that shields most of the NH 2 groups would allow a remaining, unshielded NH 2 group to react preferentially, thereby enabling efficient synthesis of various site-specifically modified analogues of neomycin B without resorting to total synthesis or other approaches. A schematic depiction of the APG strategy is shown in Fig. 1c. For this approach to work, an appropriate macromolecule must be identified to serve as a noncovalent protecting group. Supramolecular complexes have been used for this purpose 4–6 , but without any clear path to generalize their application. Fortunately, there is another way. In the early 1980s, the discovery of naturally occurring catalytic ribonucleic acid (RNA), or ribozymes, established experimentally that nucleic acids can do more than store genetic information 7. Soon thereafter, artificial RNA aptamers that bind various small-molecule compounds (and later proteins) were identified by in vitro selection 8. The more recent discovery of gene-regulating 'riboswitches' 9 showed that nature also uses RNA for important binding functions. Both binding and catalysis require …