Effective and Practical Stereoselective Synthesis of Nutlins Precursors by Immobilization of Privileged Chiral Mono-Amidine Catalyst

Abstract

A strategy for the immobilization of Johnston's Mono(AMidine) catalyst (MAM) onto polystyrene, silica and hybrid silica-polystyrene nanoparticles is presented. The catalyst activity was evaluated in the stereoselective aza-Henry reaction leading to the pivotal β-amino nitroalkane precursors of the anti-cancer agents Nutlins (with Nutlin-3a as the most active drug). The effect of the support and the linker on the catalytic performance was investigated, observing an interesting match/mismatch effect when using a chiral linker. The polystyrene-supported 3-pyrrolidinol-linked PS-(S)-Pyr-MAM organocatalyst showed the best activity among the tested catalysts, behaving very similarly to the homogeneous counterpart in the synthesis of a library of Nutlins precursors: yield up to 95%, ee up to 99%, and dr up to >99:1. The catalyst recyclability was also assessed through simple filtration, yielding a satisfactory 93% ee after 5 cycles, showing only a moderate decrease in conversion efficiency (ca. 5% after each cycle), which resulted in an accumulated turnover number (TON) of 69.7.