A catalytic asymmetric N-nitroso aldol reaction of γ,δ-didehydro-δ-lactones with nitrosoarenes was achieved using chiral tin dibromide as the chiral precatalyst and sodium ethoxide as the base precatalyst in the presence of ethanol. Optically active α-hydroxyamino ketones with up to 99% ee were regioselectively obtained in moderate to high yields from various δ-aryl-substituted γ,δ-didehydro-δ-valerolactones and o-substituted nitrosoarenes.
A s y m m e t r i c C y c l o a d d i t i o n o f A l k e n y l T r i c h l o r o a c e t a t e s w i t h N i t r o n e sAbstract: A catalytic enantioselective cycloaddition reaction of alkenyl trichloroacetates with nitrones was achieved using an (S)-BINOL-derived chiral tin dibromide possessing a 4-trifluoromethylphenyl group at 3-and 3¢-positions as the chiral precatalyst in the presence of sodium ethoxide, sodium iodide, and ethanol. Optically active isoxazolidines with up to 95% ee were diastereoselectively obtained in high yields even from aliphatic aldehyde derived nitrones under the influence of the in situ generated chiral tin ethoxide iodide.Asymmetric 1,3-dipolar cycloaddition is a convenient method for preparing nonracemic heterocyclic compounds. 1 A representative example is the reaction between nitrones and alkenes to provide chiral isoxazolidines, which can be further transformed by reductive N-O bond cleavage into optically active g-amino alcohols that serve as useful synthetic intermediates for natural products or pharmaceuticals. Since the first report of the catalytic enantioselective 1,3-dipolar cycloaddition of nitrones by Gothelf and Jørgensen in 1994, 2 various chiral catalysts, including chiral Lewis acid catalysts 3-5 and chiral organocatalysts, 6 have been developed for the asymmetric transformation; however, most of those protocols use electrondeficient olefins as dipolarophiles and as far as we know, there have been only very few examples on the catalytic reaction of electron-rich alkenes to give nonracemic isoxazolidines. 7 We report here a novel example of the enantioselective cycloaddition reaction between alkenyl trichloroacetates and nitrones catalyzed by a chiral tin ethoxide iodide (Scheme 1).We have previously reported an asymmetric Mannichtype reaction 8 of imines with alkenyl trichloroacetates, which are converted into chiral tin enolates in the presence of a catalytic amount of a chiral tin alkoxide. The chiral tin catalyst is efficiently recycled with the assistance of an alcohol. This addition reaction gives the corresponding optically active b-amino carbonyl compounds with syn-selectivity. We envisioned that if a nitrone was used instead of an imine, the electrophile would also undergo the aforementioned chiral tin catalyzed syn-selective asymmetric Mannich-type reaction to provide enantiomerically enriched b-hydroxyamino carbonyl compounds. Thus, we attempted to react cyclohexanonederived alkenyl trichloroacetate 1a with nitrone 2a employing chiral tin dibromide 4d and sodium ethoxide as catalysts and as a result, unanticipated cycloadduct 3aa was obtained with significant asymmetric induction. For example, when a mixture of 1a (2 equiv) and 2a (1 equiv) was treated with chiral tin dibromide 4d (5 mol%) and NaOEt (5 mol%) in the presence of EtOH (10 equiv) in THF at 60 °C for 30 minutes, a 71:29 diastereomeric mixture of 3aa was obtained in 32% yield (Table 1, entry 1). The major diastereomer of 3aa had 77% ee. Then, we tested some additives and as a result, found that ...
Experimental SectionGeneral Methods. Infrared (IR) spectra were recorded on a JASCO FT/IR-4100 using ATR. NMR spectra were recorded on a JEOL JNM LA-400 (400 MHz for 1 H NMR and 100 MHz for 13 C NMR) or LA-500 spectrometer (500 MHz for 1 H NMR and 125.65MHz for 13 C NMR). Chemical shifts were reported in ppm on the scale relative to Me 4 Si ( = 0 for 1 H NMR) or CDCl 3 ( = 77.0 for 13 C NMR) as an internal reference. ESI mass spectra were measured on a Thermo Scientific Exactive. Optical rotations were measured on a JASCO P-1020 polarimeter. Column chromatography was conducted with silica gel 60 N (KANTO CHEMICAL, spherical, neutral, 63-230 m). The enantiomeric excesses were determined by HPLC. HPLC analysis was performed on JASCO HPLC systems containing of the following instruments: pump, PU-2080; detector, UV-2075, measured at 254 nm; column, Daicel Chiralcel OD-H or Daicel Chiralpak AD-H, AD-3, or IA. All experiments were carried out under atmosphere of standard grade argon gas. THF was freshly distilled over sodium benzophenone ketyl under argon gas. Alkenyl trichloroacetates were prepared by treatment of the p 2 N General Experimental Procedure for Asymmetric Aldol Reaction of Alkenyl Esters and Isatins Catalyzed by Chiral Tin Dibromide 4a (Table 1-4) 4a in MeOH (10 μL, 0.01 mmol) and MeOH (0.58 mL) at room temperature. The resulting mixture was stirred for 30 min. Then, isatin derivative 2 1a' 1b-1d 1a 1e 1i(1.0 mmol) were added to the mixture at 0 ˚C. After being stirred for the specified time at 0 ˚C, the reaction mixture was treated with MeOH (1 mL), brine (1 mL), and solid KF (0.5 g) at ambient temperature for 10 min. The resulting precipitate was filtered off and the filtrate was dried over Na 2 SO 4 followed by concentration in vacuo. The residual crude product was purified by column chromatography on silica gel to give aldol product 3. The diastereomeric ratio was determined by 1 H NMR analysis.
Go catalytic! A catalytic enantioselective protonation of alkenyl trifluoroacetates was achieved by using an in situ generated chiral tin bromide methoxide as the chiral catalyst in the presence of methanol. Optically active ketones containing a tertiary stereogenic center at the α-position were obtained with enantioselectivities of up to 94 % ee.
N N R R' Ir Cl Ir complex 8dz (0.01 mol%) R = 2,4,6-tricyclohexylphenyl R' = bis(4-(trifluoromethyl)phenyl)methyl Me O Me OH t-BuOK (0.1 mol%) i-PrOH, 70 °C, 1 h 97% ee 4,500 h -1 TOF
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