Catalytic asymmetric α C(sp3)-H addition of benzylamines to aldehydes
Catalytic asymmetric α C(sp3)-H addition of benzylamines to aldehydes
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DOI：
10.1038/s41929-022-00875-3
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发表时间：
2022-11-01
期刊：
影响因子：
37.8
通讯作者：
Zhao, Baoguo
中科院分区：
文献类型：
--
作者：
Hou, Chengkang;Peng, Bingfei;Zhao, Baoguo
羰基催化主要限于强活化的伯胺。近年来，手性双功能吡哆醛有机催化剂的发展，使未被NH_2保护的苄胺的惰性α-C（sp（3））-H键活化，得到具有高非对映体和对映体选择性的手性β-氨基醇，由于其固有的原子经济性和起始原料转化的效率，惰性C-H键的功能化受到了极大的关注。与过渡金属催化的C-H活化相比，有机催化不太常用于惰性C-H键的直接官能化。由于极低的布朗斯台德酸性，NH 2-未保护的苄胺的α C（sp（3））-H键在大多数反应中通常是惰性的。在这里，我们利用一个手性吡哆醛轴承作为双官能羰基催化剂的四酰胺侧链活化的α C（sp（3））-H键的NH 2-未保护的苄胺，使其酸性足以在温和的条件下去质子化。基于羰基催化策略，我们发展了一种苄胺与醛的直接不对称α-C-H加成反应，为合成具有优良的非对映体和对映体选择性的手性β-氨基醇提供了一种最直接的方法。
Carbonyl catalysis is mainly limited to strongly activated primary amines. Now, a chiral bifunctional pyridoxal organocatalyst is developed that enables the activation of the inert alpha C(sp(3))-H bond of NH2-unprotected benzylamines affording chiral beta-aminoalcohols with high diastereo- and enantioselectivities.Functionalization of inert C-H bonds has received tremendous attention due to the inherent atom economy and efficiency of the transformations of the starting materials. As compared to transition-metal-catalysed C-H activation, organocatalysis is much less commonly applied for direct functionalization of inert C-H bonds. The alpha C(sp(3))-H bonds of NH2-unprotected benzylamines usually are inert in most reactions due to the extremely low Bronsted acidity. Here we utilize a chiral pyridoxal bearing a quaramide side chain as a bifunctional carbonyl catalyst to activate the alpha C(sp(3))-H bond of NH2-unprotected benzylamines, making it acidic enough to be deprotonated under mild conditions. Based on the carbonyl catalysis strategy, we develop a direct asymmetric alpha C-H addition of benzylamines to aldehydes, providing one of the most straightforward methods for the synthesis of chiral beta-aminoalcohols with excellent diastereo- and enantioselectivities.