Enantiocontrol with a Hydrogen-bond Directing Pyrrolidinylsilanol Catalyst

Abstract

Dichloromethane (DCM), hexane, ethyl acetate (EtOAc), and diethyl ether (Et 2 O) were obtained from EMD Chemicals. Toluene (PhMe), methanol (MeOH), and tetrahydrofuran (THF) were obtained from Fisher Scientific. Palladium on carbon (5 wt% and 10 wt%), anhydrous magnesium sulfate, (-)-sparteine, acetaldehyde, and 2-mesitylmagnesium bromide solution (1.0 M in Et 2 O) were acquired from Sigma Aldrich. Dimethoxyethane, trichlorosilane, secbutyllithium (1.3 M in cyclohexane/hexanes (98/2)), and ytterbium (III) triflate hydrate were purchased from Acros Organics.tert-butyl-1-pyrrolidine-carboxylate, ammonium hexafluorosilicate, amberlyst-A21, 1-methylisatin, and 1-phenylisatin were purchased from Alfa-Aesar. Diphenylchlorosilane was obtained from Gelest. 4-chloroisatin was obtained from TCI America. Commercially available reagents were purchased and used without further purification unless otherwise indicated. sec-Butyllithium was titrated before use with diphenylacetic acid to obtain accurate concentration for reactions.Reactions were analyzed by thin layer chromatography (TLC) on EMD glass plates that were pre-coated with silica gel 60 F254, and the reactions were purified by column chromatography using Acros silica gel 60 Å (0.035-0.070 mm) or Sigma Aldrich silica gel 150 Å grade 62 (60-200 mesh). The following abbreviations are used throughout: ethyl acetate (EtOAc), acetonitrile (MeCN), dichloromethane (DCM), isopropanol (IPA), methanol (MeOH), enantiomeric excess (ee), triethylamine (Et 3 N). All aldol reactions were performed in glass vials with Teflon caps and exposure to atmospheric conditions.All 1 H and 13 C NMR spectra were recorded at ambient temperature at 300, 400, and 600 MHz or 75, 100, and 150 MHz, respectively. 19 F NMR spectra were recorded at ambient temperature at 282 MHz. 29 Si NMR spectra were recorded at ambient temperature at 119 MHz. The 1 H spectral data are reported as follows: chemical shift in parts per million downfield from tetramethylsilane on the δ scale, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; s, septet; m, multiplet; dd, doublet of doublets, and b, broadened), coupling constant (Hz), and integration. Carbon NMR chemical shifts are reported in ppm from tetramethylsilane with the solvent reference employed as the internal standard (deuterochloroform (CDCl 3 )) at 77.16 ppm. Unless otherwise indicated, all chiral stationary phase HPLC analyses were performed with a Daicel CHIRALCEL OD-H column (4.6 x 250mm, 5 µm), CHIRALPAK AD-H column (4.6 x 250 mm, 5 µm), or CHIRALPAK AS-H column (4.6 x 250 mm, 5 µm), with corresponding guard columns, with a flow rate of 0.5 -1.0 mL/min (2-propanol/hexanes isocratic system) using a photodiode array detector and at various column oven temperature. Compounds were analyzed by HRMS on an orbitrap spectrometer using electrospray ionization in the positive ion mode at >60000 resolutions and using typical ESI source values. These settings result in mass accuracies <5 ppm. Some compounds were analyzed by LRMS in the positive ion mode o...

Molecular Structures of Enantiomerically-Pure (S)-2-(Triphenylsilyl)- and (S)-2-(Methyldiphenylsilyl)pyrrolidinium Salts

“…Compound (S)-2·HClO 4 crystallized in the monoclinic crystal system, space group P2 1 , as colorless plates ( Figure 4 and Table 1). The asymmetric unit of compound (S)-2·HClO 4 Figures 2 and 4). The C-Si-C angles are in both independent molecules very close to the ideal tetrahedral angle (Figure 4).…”

“…The perchlorate salts (S)-1·HClO 4 and (S)-2·HClO 4 were prepared by treatment of (S)-1·HCl and (S)-2·HCl, respectively, with excess perchloric acid (60 wt %). Colorless single-crystals were formed overnight under normal atmosphere at room temperature within the remaining solvent.…”

“…Since then, some impressive developments in the catalyst design have been achieved, overcoming synthetic challenges and introducing pyrrolidinylsilanols as bifunctional hydrogen bond-directing organocatalysts [3,4]. The stereochemical information of 2-substituted silylpyrrolidines was introduced by asymmetric deprotonation of N-(tert-butoxycarbonyl)pyrrolidine (N-Boc-pyrrolidine) with sec-butyllithium in the presence of (-)-sparteine [5,6], followed by a substitution reaction with a silyl halide or methoxide as the electrophile.…”

“…Recently, a detailed structural and kinetic investigation gave new insight into the structure-reactivity relation in enamines and iminium ions derived from 2-tritylpyrrolidine [7] and 2-(triphenylsilyl)pyrrolidine [8]. 4 ], which were obtained from the respective optically-pure chloride salts [1] by treatment with perchloric acid.…”

Kinetic and Binding Studies Reveal Cooperativity and Off‐Cycle Competition for H‐Bonding Catalysis with Silsesquioxane Silanols

“…Our group and others have demonstrated that activity of organic, silanol‐containing hydrogen‐bond donor (HBD) catalysts can be tuned by silanol arrangement and acidity (e.g. 4 – 6 , Figure ) . Silanols display higher acidities compared with alcohols, which is attributed to hyperconjugation effects between the oxygen and silicon .…”