Tailored Functionalization of Calixarenes

Macrocyclic oligomers such as cyclodextrins, cucurbiturils, resorcinarenes, pillararenes and calixarenes are widely used as molecular platforms in supramolecular chemistry and in particular for the design of sensors, catalysts, multivalent systems, biomimetic receptors, etc. In general, the synthesis of such supramolecular systems requires the controlled introduction of functional groups on the precursor platform. However, the development of efficient methods for selective modification of macrocyclic oligomers remains extremely challenging. Indeed, in addition to the control of the classical chemo-, regio- and stereoselectivities, the reaction of a defined number of identical functional groups is a key issue that must be solved. By analogy with iterative processes, we propose to name “iteroselectivity” such a selectivity that concerns the formation of products (i.e. iteromers) differing by the number of repeating chemical transformations they underwent. High iteroselectivity is often crucial for the functionalization of large oligomers since numerous iteromers can otherwise be formed and their separation by traditional techniques may be precluded. This work describes a unique, general and rational methodology for the iteroselective functionalization of polyphenolic platforms by N-tert-butyl-aminocarbonyl (Bac) groups. The methodology consists of reacting the platform with tert-butylisocyanate (tBuNCO) and an inorganic base in an apolar solvent. This simple procedure has been applied to calix[4, 5, 6, 8]arenes and, in all cases, calixarenes with a single leftover phenolic moiety were isolated in high yields. Interestingly, this "all-but-one" methodology gives an easy access to inherently chiral calixarenes. It is also shown that the Bac group can be used as a protective group. Thus, the methodology has been used for the efficient monofunctionalization of a key calixarene, illustrating its huge potential for the tailored synthesis of macrocyclic oligomers.0