Centre of Biomedical Research, Sanjay Gandhi Post-Graduate Institute of Medical Sciences Campus, Raebareli Road, Lucknow, 226014, India.
Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur, 721302, India.
Chemistry. 2019 Nov 18;25(64):14688-14693. doi: 10.1002/chem.201903512. Epub 2019 Oct 16.
Mukaiyama-Mannich reactions of ester enolate equivalents with aldimines have been elegantly used for the asymmetric synthesis of β-amino acids; nevertheless, the corresponding asymmetric reaction employing ketimines are unexplored. Herein, the first organocatalytic enantioselective Mukaiyama-Mannich reaction employing isatin-derived ketimines with unsubstituted silyl ketene acetals is disclosed towards the scalable synthesis of 2-oxoindolinyl-β -amino acid esters at room temperature with excellent enantioselectivities (ee >99.5 %). Ultra-low catalyst loadings (as low as 250 ppm) could be used for the quantitative product formation with high enantiopurity. The synthetic utility of this protocol has been showcased in the short formal synthesis of pharmaceutically demanded (+)-AG-041R, a potent gastrin/CCK-B receptor antagonist.
Mukaiyama-Mannich 反应的酯烯醇醚等价物与亚胺的反应被巧妙地用于β-氨基酸的不对称合成；然而，相应的使用酮亚胺的不对称反应尚未被探索。在此，首次报道了使用靛红衍生的酮亚胺与未取代的硅基酮烯醇缩醛的有机催化对映选择性 Mukaiyama-Mannich 反应，可在室温下以优异的对映选择性（ee>99.5%）实现 2-氧代吲哚啉基-β-氨基酸酯的规模化合成。超低的催化剂负载量（低至 250ppm）可用于高对映纯度的定量产物形成。该方法的合成实用性已在具有高需求的 (+)-AG-041R 的短形式合成中得到展示，（+)-AG-041R 是一种有效的胃泌素/CCK-B 受体拮抗剂。
