Selenium-Linking Strategy for Traceless Solid-Phase Synthesis: Direct Loading, Aliphatic C−H Bond Formation upon Cleavage and Reaction Monitoring by Gradient MAS NMR Spectroscopy

Abstract

The development of a novel traceless linking strategy for the solid-phase synthesis of small non-peptide compounds by the use of resin-bound selenium is described. Compounds were attached by direct loading without the requirement of an auxiliary spacer. We demonstrate the synthesis of a small [2 × 3]-sized library of single alkyl aryl ethers with two points of diversity by the Mitsunobu reaction. The selenium−alkyl bond that attaches the alkyl aryl ethers to the resin was smoothly cleaved under radical conditions by homolysis with tributylstannane and catalytic amount of AIBN to generate an aliphatic C−H bond in the liberated ethers. The selenium atom remains immobilized during the entire synthesis, and in the cleavage step, tributylstannyl phenyl selenide is scavenged on the resin. Reaction monitoring was facilitated by the use of gradient high-resolution magic angle spinning 2D-NMR. This new linking method can be applied to solid-phase synthesis of many classes of organic compounds under a broad variation of reaction conditions.