Heterocycles containing a trifluoromethyl group are representatives of a major structure type in agricultural and medicinal chemistry, and thus the development of a simple and flexible method to generate a novel trifluoromethylated heterocyclic system has received much attention.[1] Trifluoromethyl-substituted 2-isoxazolines are amongst an important class of heterocyclic compounds with remarkable biological activities, and they make interesting synthetic targets.[2] Since the first discovery of the structurally unique 3,5-diaryl-5-(trifluoromethyl)-2-isoxazoline derivatives 1 (Figure 1) as pest control agents in 2004, [3a] the search for new agrochemicals and veterinary medicines has focused largely on this skeleton, [3] despite their diverse structural variants.[2] Thus far, more than 20 000 compounds have been synthesized and patented in the past 5 years (the results of substructure searching using 1 with Scifinder), and many promising drug candidates have been disclosed including an antiparasiticide compound of either type A or B (Figure 1).[3] More interestingly, recent biological evaluation of the optically active type B compound (X 6 = CONHCH 2 COCH 2 CF 3 ), obtained by HPLC methods using a chiral stationary phase, revealed that the R enantiomer of B is inactive and the S enantiomer is the active component.[3b] Once the importance of the optical purity of these compounds was verified, the next challenge was to control the stereochemistry at a quaternary carbon center bearing a CF 3 group. As part of our ongoing research programs directed to the development of efficient methods for the asymmetric synthesis of organofluorine compounds, [4] we disclose herein the synthesis of trifluoromethyl-substituted 2-isoxazolines by a cinchona alkaloid catalyzed asymmetric hydroxylamine/enone cascade reaction consisting of a conjugate addition/cyclization/dehydration sequence (Scheme 1).Optically active 2-isoxazolines are mostly constructed by the asymmetric 1,3-dipolar cycloaddition of nitrile oxides to olefins, [5a-h] the asymmetric cyclization of b,g-unsaturated oximes, [5i] stereoselective ring-closure reaction through oximes of chiral Michael adducts of thiophenol to chalcones, [5j] and proline-catalyzed conjugate addition/oxime-transfer reactions of unsaturated aldehydes.[5k] These methods, however, were not applicable to the synthesis of 1 because of the limitations in substrate specificity, and indeed, the catalytic enantioselective synthesis of trifluoromethyl-substituted 2-isoxazolines 1 has not been reported. We therefore started to investigate the asymmetric version of the nonchiral 2-isoxazoline-formation reaction.[3c] We first examined the reaction of (E)-4,4,4-trifluoro-1,3-diphenylbut-2-en-1-one (2 a) with hydroxylamine in the presence of NaOH and a catalytic amount of N-3,5-bis(trifluoromethylbenzyl) quinidinium bromide (3 a) as a chiral phase-transfer catalyst in toluene at À30 8C (Table 1). The trifluoromethylated 2-isoxazoline (R)-1 a was formed in 89 % ee, although the yield was 24 % (Table 1, ...
