Enantioselective Friedel−Crafts Reaction of β-Trifluoromethylated Acrylates with Pyrroles and Its Application to the Synthesis of Trifluorinated Heliotridane

Abstract

Table of Contents General Methods S1-S2 Synthesis of β-CF 3 Acrylates (1) S2 General Catalytic Procedure for the Asymmetric Friedel-Crafts Reactions S2 Characterization Data of the Asymmetric FC Reaction Products (3a-3o) S3-S10 Synthesis of Optically Active Trifluoromethylated Heliotridane S10-S12 Absolute Stereochemistry Determination S13-S14 1 H, 13 C, and 19 F NMR Spectra S15-S84 HPLC Charts S85-S92 General MethodsAll reactions were performed in oven-dried glassware under a nitrogen atmosphere, except where noted. Chemicals and solvents were purchased from commercial suppliers and used as received, excepting as follows. Dichloromethane, THF, ether, and toluene were dried by passing through an activated column. All reactions were monitored by TLC, or 19 F NMR. TLC analysis was performed by illumination with a UV lamp (254 nm), S2 staining with I 2 , or PMA [phosphomolybdic acid (5 g) in ethanol (100 ml)] and heating. All flash chromatography was packed with silica-gel (60 N spherical neutral size 63-210 µm) as the stationary phase. 1 H NMR (600 MHz) spectra were recorded on a Bruker Avance 600 instrument in CDCl 3 (7.26), or CD 2 Cl 2 (5.24), and chemical shifts were measured relative to residual solvent peak. Chemical shifts (δ) are expressed in ppm downfield from internal TMS. Data are reported as follows: Chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublet, dt = doublet of triplet, dq = doublet of quartet, m = multiplet, br = broad), coupling constant(s) and integration. 13 C NMR (150.9 MHz) spectra were recorded on a Bruker Avance 600 instrument. Chemical shifts are reported in parts per million (ppm) down field from TMS, using the middle resonance of CDCl 3 (77.23), or CD 2 Cl 2 (53.73) as an internal standard. 19 F NMR (188 MHz) was recorded on a Varian Mercury 200 instrument using CFCl 3 (0) as an internal standard. HPLC analysis were performed on a JASCO U-2080 plus using 4.6 x 250 mm CHIRALPAK OD-H or CHIRALCEL AD-H column. Optical rotations were measured on a HORIBA SEPA-300. Infrared spectra were recorded on a JASCO FT/IR-200 spectrometer. Mass spectra were recorded on a SHIMADZU GCMS-QP5050A or SHIMADZU LCMS-2010EV. High resolution mass spectra (HRMS)

Stereoselective Construction of an Asymmetric Carbon Center Possessing a Trifluoromethyl Group

“…Very recently, the first chiral Lewis acid catalyzed enantioselective Friedel-Crafts alkylation of pyrroles 220 with -trifluoromethyl acrylimide 221 has been reported by Shibata et al (Scheme 62) [137]. Thus, treatment of -trifluoromethyl acrylimide 221 with various pyrroles 220 in the presence of a catalytic amount of (R,R)-Ph-dbfox 222 and Zn(NTf 2 ) 2 in CH 2 Cl 2 at -75 to -20 °C for 24 -48 h gives the corresponding Friedel-Crafts adducts 223 in a highly enantioselective manner.…”