Abstract
Catalytic kinetic resolution of amines represents a longstanding challenge in chemical synthesis. Here, we described a kinetic resolution of secondary amines through oxygenation to produce enantiopure hydroxylamines involving N–O bond formation. The economic and practical titanium-catalyzed asymmetric oxygenation with environmentally benign hydrogen peroxide as oxidant is applicable to a range of racemic indolines with multiple stereocenters and diverse substituent patterns in high efficiency with efficient chemoselectivity and enantio-discrimination. Late-stage asymmetric oxygenation of bioactive molecules that are otherwise difficult to synthesize was also explored.
Highlights
Catalytic kinetic resolution of amines represents a longstanding challenge in chemical synthesis
The current nonenzymatic kinetic resolution (KR) of secondary amines predominantly relies on asymmetric N-acylation strategy involving N–C bond formation, which typically requires the use of stoichiometric pre-prepared acylating agents involving lengthy reagent synthesis (Fig. 1a)[12,13,14,15,16,17,18]
We envisioned that asymmetric Oxygen atom transfer (OAT) to secondary amines to produce enantiopure hydroxylamines involving N–O bond formation would be an ideal template for KR design based on economical and environmental factors (Fig. 1b)
Summary
Catalytic kinetic resolution of amines represents a longstanding challenge in chemical synthesis. Asymmetric oxygenation of racemic indoline 1a was selected as a reference reaction using aqueous H2O2 as the oxo-transfer agent to search for a suitable chiral catalyst (Table 1). Di-μ-oxo titanium(salen) C2 effected the expected asymmetric oxygenation, though poor chiral recognition and notable over-oxidation were observed (entry 2).
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