Catalytic Asymmetric 1,3‐Dipolar Cycloaddition of β‐Fluoroalkylated α,β‐Unsaturated 2‐Pyridylsulfones with Nitrones for Chiral Fluoroalkylated Isoxazolidines and γ‐Amino Alcohols

Abstract

2-Pyridylsulfone- and fluoroalkylated group-activated olefins underwent highly efficient diastereo- and enantioselective 1,3-dipolar cycloadditions across various aromatic and aliphatic nitrones in the presence of a chiral Ni /bis(oxazoline) catalyst. The process was tuned by 4 Å molecular sieves, chiral bis(oxazoline) ligands, reaction solvents, and temperature. A wide array of optically pure fluoroalkylated isoxazolidines were obtained, thus facilitating the asymmetric synthesis of an enantioenriched α-trifluoromethylated γ-amino alcohol in gram-scale and a trifluoromethylated derivative of 1,3-oxazinan-2-one with potential pharmaceutical interest. A stereochemical model, based on the absolute configuration of one adduct and some control experiments, was postulated to account for the observed endo- and enantioselectivity.

Catalytic Asymmetric 1,3‐Dipolar Cycloaddition of β‐Fluoroalkylated α,β‐Unsaturated 2‐Pyridylsulfones with Nitrones for Chiral Fluoroalkylated Isoxazolidines and γ‐Amino Alcohols

“…Zuschriften 1534 www.angewandte.de (controlled by the substituents of two substrates) of the reaction (entry 4), which is different from previous reports. [20] Founded on the above experimental results and the X-ray crystal structure of the catalytic adduct 3ap (Supporting Information), [21] ap ossible transition state was proposed to clarify the origin of the stereoselectivity.A si llustrated in Figure 2, the tridentate (S,S)-Ph-dbfox ligand L1 and olefin substrate (1)coordinate with the nickel(II) ion without crystal water to form at rigonal bipyramid structure.T he use of 2pyridylsulfonyl moiety is the key controlling unit. Due to the face shielding from the top phenyl ring of ligand L1,t he Noxide of nitrone (2)c an only approach the activated olefin from the Si-face in favor of the endo-product.…”

“…Zuschriften fused aromatic-ring-containing nitrones 2t and 2u were investigated. 2-Naphthyl-substituted nitrone showed abetter reactivity than the 1-naphthyl-substituted case for steric hindrance effects,w hereas it provided the same level of enantioselectivity (entries [20][21]. Fort he challenging aliphatic nitrone substrates 2v, 2w,a nd 2x with aP ho rb enzyl (Bn) N-protecting group,g ood results were obtained by performing the reaction at À20, À10, and 0 8 8Cr espectively (entries [22][23][24].…”

Advances in Synthesis of Enantioenriched Chiral Sulfones by Enantioselective Conjugate Addition Reactions

“…In 2016, Huang and co‐workers presented an efficient enantio‐ and diastereoselective 1,3‐dipolar cycloaddition reaction between α,β‐unsaturated 2‐pyridylsulfone 207 and nitrones 208 , which was catalyzed by chiral Ni−(ClO 4 ) 2 /( S,S )‐Ph‐dbfox complex to obtain chiral isoxazolidine heterocycles compounds 210 (Scheme 54). [73] Moreover, the results of the substrate scopes showed all substrates were furnished the β‐sulfonyl isoxazolidine heterocycles 210 in moderate to excellent yields as single diastereomers with good to excellent enantioselectivities (75–99% ee). Based on the experimental results and the X‐ray crystal structure, the authors proposed a plausible transition state structure for the reaction wherein the nickel(II) ion coordinates with ligand and olefin substrates to form a trigonal bipyramid structure, and then affected by the shielding effect from the phenyl ring of ligand, nitrones attack the olefins only from the Si ‐face and obtained the endo‐adducts.…”

Experimental and Computational Studies on the 1,3‐Dipolar Cycloaddition between Enantiomerically Pure 2,3‐Dihydrothiazoles and Nitrones

“…Moreover, isoxazolidines have also demonstrated to be synthetic intermediates of a great utility that can be converted, among other compounds, into 1,3‐amino alcohols . A substantial amount of successful catalytic asymmetric nitrone cycloadditions, including metal‐catalyzed and organocatalyzed reactions have been reported. However, the use of diastereoselective approaches using optically pure substrates that provide completely enantiomerically pure products still remains a valuable methodology .…”