Organocatalytic Asymmetric Synthesis of Chiral Dioxazinanes and Dioxazepanes with in Situ Generated Nitrones via a Tandem Reaction Pathway Using a Cooperative Cation Binding Catalyst

Abstract

Heterocyclic skeletons play major roles in pharmaceuticals and biological processes. Cycloaddition reactions are most suitable synthetic tools to efficiently construct chemically diverse sets of heterocycles with great structural complexity owing to the simultaneous or sequential formation of two or more bonds, often with a high degree of selectivity. Herein, we report an unprecedented formal cycloaddition of N-Boc-N-hydroxy amido sulfones as the nitrone precursors with terminal-hydroxy α,β-unsaturated carbonyls in the presence of Song's chiral oligoethylene glycol as a cation-binding catalyst and KF as a base to afford a wide range of highly enantio- and diastereo-enriched six-membered dioxazinane and seven-membered dioxazepane heterocycles. In this process, nitrones as well as terminal-hydroxy α,β-unsaturated carbonyls serve as "amphiphilic" building units, and the reaction proceeds through a tandem pathway sequence of oxa-Mannich reaction/oxa-Michael reaction/tautomerization/protonation. The cation-binding catalysis in a densely confined chiral space in situ formed by the incorporation of potassium salt is the key to this successful catalysis. This strategy opens a new pathway for the asymmetric synthesis of diverse heterocyclic skeletons of great complexity.

Asymmetric Cation‐Binding Catalysis

“…The availability of variousa lkali metal cations andc ounter anions will allow the investigation of an umber of different organic transformations, taking advantage of this unprecedented mode of action. [27] Scheme12. Proposed mechanism of catalyst regeneration using KF and polymeric proton sourceCG50.…”

Synthesis of Isoxazolines by the Electrophilic Chalcogenation of β,γ-Unsaturated Oximes: Fishing Novel Anti-Inflammatory Agents

“…Data were collected in the m / z range of 50–1200 at a rate of two sweeps per second. The starting oximes 1a-I were prepared as previously described in the literature. ,− …”

Asymmetric Aminalization via Cation‐Binding Catalysis

“…Moreover, the terminal phenol groups are capable of simultaneously activating electrophiles by hydrogen bonding interactions. The resulted self‐assembled transition state leads to excellent stereoinduction in asymmetric reactions; for example, in desilylative kinetic resolution of silyl‐protected secondary alcohols, asymmetric Strecker reaction using potassium cyanide, kinetic resolution of β‐sulfonyl ketones through enantioselective β‐elimination, organocatalytic asymmetric synthesis of chiral dioxazinanes and dioxazepanes with in situ generated nitrones, enantioselective synthesis of anti ‐ syn ‐trihalides and anti ‐ syn ‐ anti ‐tetrahalides via asymmetric β‐elimination, and enantioselective glyoxalase I mimic catalytic isomerization of in situ generated hemithioacetals . The vast application potential of this catalytic system stimulated us to explore other challenging asymmetric transformations with nucleophilic anions .…”