ChemInform Abstract: Alkyne Phosphonites for Sequential Azide—Azide Couplings.

Abstract

Modern research often demands the modular conjugation of molecular systems with functional modules including fluorophores, purification tags, solubility enhancers, isotopic labels, or biologically active ligands, which enable their functional analysis, tracking in complex environments, and aids in several medicinal and pharmaceutical applications. Such molecular systems span several orders of size and complexity and range from small molecules and natural products to polymers, particles, or surfaces in material research and to even whole living organisms in the life sciences. A common way to achieve the functionalization of these systems relies on the incorporation of highly reactive functional groups, which can be easily introduced either by synthetic or biochemical methods. Ideally, these groups are chemically inert to other given functionalities, while still displaying a high level of intrinsic reactivity. Furthermore, these functional groups should be able to form reliably new chemical bonds in high yields as defined for click reactions and with excellent chemoselectivity. Among many reactive functional groups that meet these criteria, azides have certainly been the most popular, as they can be reacted either with alkynes to form triazoles by 1,3dipolar cycloaddition or with P reagents by Staudinger reactions. The development of copper-catalyzed (CuAAC) and strain-promoted azide–alkyne cycloaddition as well as the use of phosphines and phosphites in Staudinger ligations led to numerous labeling and conjugation applications. Azide groups can be introduced easily into small molecules, polymers, and materials by organic synthesis. Along those lines, the high tolerance of azides towards a number of other organic transformations whilst still offering a high reactivity to ensure efficient conversions leads to the ubiquitous application of CuAAC and the commercial availability of many azide-containing functional building blocks. Herein, we introduce a reagent which allows the sequential coupling of two different azido compounds in polar, unpolar, and aqueous solvents by a short reaction sequence. This approach allows the modular coupling of readily available azido-containing functional building blocks by a final metal-free conjugation step. To achieve this formal azide–azide, coupling we wanted to combine the CuAAC with the metal-free Staudinger phosphonite reaction recently advanced in our laboratory. Our proposal led to the design of an alkyne directly attached to borane-protected phosphonite (Scheme 1). The borane protecting group fulfills several purposes, as it ensures that no homo-coupling occurs during