Highly enantioselective chlorination of β-oxo esters and subsequent stereospecific substitution of tertiary chlorides are described. Enantioselective chlorination of β-keto esters and malonates was performed using a chiral Lewis acid catalyst prepared from Cu(OTf)(2) and the newly developed spirooxazoline ligand 2 to yield the desired α-chlorinated products with high enantioselectivity (up to 98% ee). Nucleophilic substitution of the resulting chlorides proceeded smoothly to afford a variety of chiral molecules such as α-amino, α-alkylthio, and α-fluoro esters, without loss of enantiopurity. The results of X-ray crystallographic analysis proved that Walden inversion occurs at the chlorinated tertiary carbon center. These results supported the fact that the substitution proceeds via an S(N)2 mechanism.
Highly enantioselective gem-chlorofluorination of active methylene compounds was carried out by using a copper(II) complex of a chiral spiro pyridyl monooxazoline ligand. This reaction yielded α-chloro-α-fluoro-β-keto esters and α-chloro-α-fluoro-β-keto phosphonates with up to 92% ee. The resulting dihalo β-keto ester was converted into various α-fluoro-α-heteroatom-substituted carbonyl compounds via nucleophilic substitution without loss of optical purity. A fully protected β-amino acid with a gem-chlorofluoromethylene function was also synthesized.
Highly enantioselective fluorination of α-alkyl-β-keto esters was performed using a chiral Lewis acid catalyst prepared from Cu(OTf) 2 and chiral spiro oxazoline ligands. The fluorination proceeded in a highly enantioselective manner both when cyclic and acyclic substrates were applied to the reaction. Fluorination of α-alkylmalonates was also performed to afford the corresponding products in good enantioselectivity.
Enantioselective gem-Chlorofluorination of Active Methylene Compounds Using a Chiral Spiro Oxazoline Ligand. -The reaction of phosphonates proceeds with a lower selectivity toward monochlorination and thus dichlorinated by-products are also formed. The dihalo-β-ketoester (IIa) is converted into fluorinated derivatives without loss of optical purity including a fully protected β-amino acid (XIX) with a α-chlorofluoromethylene function. -(SHIBATOMI*, K.; NARAYAMA, A.; SOGA, Y.; MUTO, T.; IWASA, S.; Org. Lett. 13 (2011) 11, 2944-2947, http://dx.doi.org/10.1021/ol201007e ; Dep. Environ. Life Sci., Toyohashi Univ. Technol., Toyohashi, Aichi 441, Japan; Eng.) -H. Simon
Lewis acid catalysts, generated in situ from Cu(O‐Tf)2 and axially chiral ligands (I), are successfully employed for various transformations which proceed with good enantioselectivities.
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