Diversity Linker Units for Solid‐Phase Organic Synthesis

Abstract

In recent years an ever‐increasing number of traditional solution‐phase reactions have been adapted for solid‐phase organic synthesis (SPOS) because of the ease of application of solid‐phase techniques to combinatorial chemistry and high‐throughput screening. To accommodate the growing number of reactions being attempted on solid supports, new linker units continue to be reported in the literature. Linker units are typically grouped according to the functionality left at the “cleavage site” in the target molecule, and are normally classified as traditional (polar functionality remains following cleavage) or traceless (hydrogen residue left after cleavage) linkers. As the field continues to expand, however, more advanced linker units have been reported, which utilise the cleavage step in SPOS to incorporate additional diversity into target libraries. These linker units have been termed “diversity” or “multifunctional” linker units, and in this microreview we introduce this aspect of the field, giving representative examples indicating key stages of development including the linker units recently designed in our laboratory. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

The development of a ‘safety‐catch’ arylgermane for biaryl synthesis by palladium‐catalysed germyl‐stille cross‐coupling

“…66 They can be divided into two types: those constituting phase-tagged electrophiles and those constituting phase-tagged nucleophiles (cf. our envisaged linker).…”

From Polymer to Small Organic Molecules: A Tight Relationship between Radical Chemistry and Solid-Phase Organic Synthesis

“…Beside light-sensitive linkers, a number of studies have treated innovative linkages based on cleavage under radical conditions. Radical cleavage of linker units usually enables the introduction of either a hydrogen atom at the cleavage site (traceless linker [ 11 ]), or, which is of even more relevance in the context of diversity oriented synthesis [ 12 ], of an additional diversity element (diversity linker unit [ 13 ]). In this section of the review, the attention will be shifted among the “key” atom in the linker.…”

General Overview

“…Resin-bound fluorinated alkylsulfonate esters, for example, aryltriflates, can undergo palladium catalyzed transfer hydrogenolysis as a means to induce traceless cleavage or, conversely, undergo Suzuki coupling to arylate upon cleavage (Figure 1.8). [24,25] [26,27] To accommodate the burgeoning traditional chemistry that would be adapted to solid-phase organic synthesis, the composition and fate of the so-called linker group garnered great interest for several reasons. Since attachment of the organic substrate constitutes the first chemical reaction within the synthesis, the linker group needs to form a covalent bond with the organic substrate readily and efficiently.…”