Highly Enantioselective Organocatalytic Oxidative Kinetic Resolution of Secondary Alcohols Using Chiral Alkoxyamines as Precatalysts: Catalyst Structure, Active Species, and Substrate Scope

The
development and characterization of enantioselective organocatalytic
oxidative kinetic resolution (OKR) of racemic secondary alcohols using
chiral alkoxyamines as precatalysts are described. A number of chiral
alkoxyamines have been synthesized, and their structure–enantioselectivity
correlation study in OKR has led us to identify a promising precatalyst,
namely, 7-benzyl-3-n-butyl-4-oxa-5-azahomoadamantane,
which affords various chiral aliphatic secondary alcohols (ee up to
>99%, krel up to 296). In a mechanistic
study, chlorine-containing oxoammonium species were identified as
the active species generated in situ from the alkoxyamine precatalyst,
and it was revealed that the chlorine atom is crucial for high reactivity
and enantioselectivity. The present OKR is the first successful example
applicable to various unactivated aliphatic secondary alcohols, including
heterocyclic alcohols with high enantioselectivity, the synthetic
application of which is demonstrated by the synthesis of a bioactive
compound.

本研究报道了以手性烷氧基胺作为预催化剂，对外消旋二级醇开展对映选择性有机催化氧化动力学拆分（oxidative kinetic resolution, OKR）的方法开发与性能表征工作。研究团队合成了多款手性烷氧基胺，并通过在OKR体系中开展结构-对映选择性关联研究，筛选得到一款性能优异的预催化剂——7-苄基-3-正丁基-4-氧杂-5-氮杂高金刚烷。该催化剂可高效制备多种手性脂肪族二级醇，其对映体过量值（enantiomeric excess, ee）最高可达99%以上，相对反应速率常数（relative rate constant, krel）最高可达296。机理研究表明，含氯氧鎓物种是由烷氧基胺预催化剂原位生成的活性中间体，且氯原子对实现高反应活性与高对映选择性至关重要。本OKR体系是首款可适用于多种未活化脂肪族二级醇（包括杂环醇）的高对映选择性拆分方法，其合成应用价值通过一款生物活性化合物的全合成得到了验证。