Enantioselective radical C-H amination for the synthesis of β-amino alcohols
Enantioselective radical C-H amination for the synthesis of β-amino alcohols
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DOI：
10.1038/s41557-020-0482-8
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发表时间：
2020-06-22
期刊：
影响因子：
21.8
通讯作者：
Nagib, David A.
中科院分区：
文献类型：
--
作者：
Nakafuku, Kohki M.;Zhang, Zuxiao;Nagib, David A.
不对称的自由基C-H官能化是解决现代合成挑战的罕见但强大的工具。具体地，醇的对映体和区域选择性C-H胺化以获得有药用价值的手性β-氨基醇仍然是难以捉摸的。为了解决这一挑战，设计了一种自由基中继分子伴侣策略，其中醇被瞬时转化为经历分子内H原子转移（HAT）的亚氨酸酯自由基。这种区域选择性的HAT也呈现对映选择性利用能量转移催化介导选择性自由基的产生和拦截的手性铜催化剂。这种多催化、不对称、自由基C-H胺化的成功开发使人们能够从多种含有烷基、烯丙基、苄基和炔丙基C-H键的醇中广泛获得手性β-氨基醇。机理实验表明，三重态能量敏化的Cu-结合自由基前体促进催化剂介导的HAT立体选择性，使几个重要类别的手性β-胺的合成通过对映选择性，自由基C-H amination.The合成手性氨基醇从简单的醇起始原料可以实现通过催化，不对称自由基接力。多种催化剂协同工作以利用H-原子转移机制来通过瞬态N-中心自由基实现对映体和区域选择性C-H胺化。
Asymmetric, radical C-H functionalizations are rare but powerful tools for solving modern synthetic challenges. Specifically, the enantio- and regioselective C-H amination of alcohols to access medicinally valuable chiral beta-amino alcohols remains elusive. To solve this challenge, a radical relay chaperone strategy was designed, wherein an alcohol was transiently converted to an imidate radical that underwent intramolecular H-atom transfer (HAT). This regioselective HAT was also rendered enantioselective by harnessing energy transfer catalysis to mediate selective radical generation and interception by a chiral copper catalyst. The successful development of this multi-catalytic, asymmetric, radical C-H amination enabled broad access to chiral beta-amino alcohols from a variety of alcohols containing alkyl, allyl, benzyl and propargyl C-H bonds. Mechanistic experiments revealed that triplet energy sensitization of a Cu-bound radical precursor facilitates catalyst-mediated HAT stereoselectivity, enabling the synthesis of several important classes of chiral beta-amines by enantioselective, radical C-H amination.The synthesis of chiral amino alcohols from simple alcohol starting materials can be achieved through a catalytic, asymmetric radical relay. Multiple catalysts work in concert to harness a H-atom transfer mechanism to enable enantio- and regioselective C-H amination by transient N-centred radicals.