Solid-Phase Synthesis of β-Amino Ketones Via DNA-Compatible Organocatalytic Mannich Reactions

Abstract

One-bead-one-compound (OBOC) libraries constructed by solid-phase split-and-pool synthesis are a valuable source of protein ligands. Most OBOC libraries are comprised of oligoamides, particularly peptides, peptoids, and peptoid-inspired molecules. Further diversification of the chemical space covered by OBOC libraries is desirable. Toward this end, we report here the efficient proline-catalyzed asymmetric Mannich reaction between immobilized aldehydes and soluble ketones and anilines. The reaction conditions do not compromise the amplification of DNA by the PCR. Thus, this chemistry will likely be useful for the construction of novel DNA-encoded libraries by solid-phase synthesis.

Keywords: DNA-encoded libraries; Mannich reaction; one-bead-one-compound libraries; organocatalysis; solid-phase synthesis.

Figure 1.

Mannich reaction on TentaGel microsphere, with disulfide-containing linker for cleavage using TCEP. Note that the addition of 4-formylbenzoic acid and subsequent Mannich couplings likely occurs on the secondary amine in the linker as well. Since this material is never released from the bead and analyzed, it is abbreviated as “R”.