α-Amino acids are essential building blocks for protein synthesis, and are also widely useful as components of medicinally active molecules and chiral catalysts.1,2,3,4,5 Efficient chemo-enzymatic methods for the synthesis of enantioenriched α-amino acids have been devised, but the scope of these methods for the synthesis of unnatural amino acids is limited.6,7 Alkene hydrogenation is broadly useful for enantioselective catalytic synthesis of many classes of amino acids,8,9 but this approach is not applicable to the synthesis of α-amino acids bearing aryl or quaternary alkyl α-substituents. The Strecker synthesis—the reaction of an imine or imine equivalent with hydrogen cyanide, followed by nitrile hydrolysis—is an especially versatile chemical method for the synthesis of racemic α-amino acids (Fig. 1).10,11 Asymmetric Strecker syntheses using stoichiometric chiral reagents have been applied successfully on gram-to-multi-kilogram scales to the preparation of enantiomerically enriched α-amino acids.12,13,14 In principle, Strecker syntheses employing sub-stoichiometric quantities of a chiral reagent provide a practical alternative to these approaches, but the reported catalytic asymmetric methods have seen only limited use on preparative scales (e.g., > 1 gram).15,16 The limited use of existing catalytic methodologies may be ascribed to several important practical drawbacks, including the relatively complex and precious nature of the catalysts, and the requisite use of hazardous cyanide sources. Herein we report a new catalytic asymmetric method for the syntheses of highly enantiomerically enriched non-proteinogenic amino acids using a simple chiral amido-thiourea catalyst to control the key hydrocyanation step. Because this catalyst is robust and lacks sensitive functional groups, it is compatible with safely handled aqueous cyanide salts, and is thus adaptable to large-scale synthesis. This new methodology can be applied to the efficient syntheses of amino acids that are not readily prepared by enzymatic methods or by chemical hydrogenation.

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Dual activation: The bifunctional primary amine thiourea catalyst 1 promotes the highly enantioselective direct conjugate addition of α‐branched aldehydes to nitroalkenes (see scheme). Cooperative activation of both the nucleophile and electrophile allows the use of mild reaction conditions and provides access to a wide variety of adducts with vicinal quaternary and tertiary stereogenic centers (>90 % ee).

A highly enantio- and diastereoselective synthesis of indolo- and benzoquinolizidine compounds has been developed through the formal aza-Diels–Alder reaction of enones with cyclic imines. This transformation is catalyzed by a new bifunctional primary aminothiourea that achieves simultaneous activation of both the enone and imine reaction components.

General Information: All reactions were performed under a nitrogen atmosphere in oven-dried round-bottomed flasks fitted with rubber septa or yellow polyethylene stoppers. Liquid reagents were transferred with stainless steel syringes. Flash Chromatography was performed with EM Science silica gel 60 (230-400 mesh). Materials:Dichloromethane was distilled from CaH 2 at 760 Torr. Commercially available aldehydes were purified by distillation from anhydrous calcium sulfate and/or column chromatography prior to use. Commercially available nitroalkenes were used as received.trans -β-nitrostyrene, trans-4-methoxy-β-nitrostyrene, trans-2-(2-nitrovinyl)thiophene, trans-2-(2-nitrovinyl)furan, trans-4-bromo-β-nitrostyrene, trans-β-nitro-2-(trifluoromethyl)styrene, 2-phenylpropionaldehyde, 2-methylpentanal, 2,6-dimethyl-5-heptenal, 2-methyl-3-(3,4-methylenedioxyphenyl)propanal were purchased from Aldrich. 3-(2-nitroethenyl)pyridine was purchased from TCI America. 4-fluoro-β-nitrostyrene was purchased from Fluka. (R)-3,3-dimethyl-2-butylamine was purchased from Lancaster. (E)-1-nitroprop-1-ene, [1] (E)-1-nitrohex-1-ene, [1] (E)-3-(benzyloxy)-1-nitroprop-1-ene, [1] trans -3,3,3-trifluoro-1-nitroprop-1-ene, [2] 3-(tertbutyldimethylsilyloxy)-2-methylpropanal, [3] 2-(4-methoxybenzyloxy)propanal, [4] thiourea catalysts [5] 1-2 were prepared according to previously published procedures.Instrumentation: Proton nuclear magnetic resonance ( 1 H NMR) spectra and carbon nuclear magnetic resonance ( 13 C NMR) spectra were recorded on a Varian Mercury-400 (400 MHz) NMR spectrometer. Chemical shifts for protons are reported in parts per million downfield from tetramethylsilane and are referenced to the solvent residual peak (CHCl 3 : δ 7.26). Chemical shifts for carbon are reported in parts per million downfield from tetramethylsilane and are referenced to the carbon resonances of the solvent (CDCl 3 : δ 77.0). Data are represented as follows: chemical shift, integration, multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), and coupling constants in Hertz (Hz). Infrared (IR) spectra were obtained using a Mattson Galaxy Series FTIR 3000 spectrophotometer referenced to a polystyrene standard. Data are represented as follows: frequency of absorption (cm -1 ), intensity of absorption (s = strong, m = medium, w = weak). Optical rotations were measured using a 2.0 mL cell (2S,3R)-2,3-dimethyl-4-nitro-2-phenylbutanal (6): Under a positive pressure of nitrogen at room temperature, thiourea catalyst 1 (75.3 mg, 0.20 mmol, 20 mol%) was loaded into an oven-dried 25 mL round-bottomed flask, equipped with a magnetic stir bar, rubber septum, and nitrogen inlet. The catalyst was dissolved in dichloromethane (6.7 mL). Water (90.1 µL, 5.0 mmol, 5.0 equiv.) and 2-phenylpropionaldehyde (265.4 µL, 2.0 mmol, 2.0 equiv.) were subsequently added via syringe. The resulting clear colorless solution was stirred for approximately two minutes. 1-nitropropene (87.1 mg, 1.0 mmol, 1.0 equiv.) was added via syringe re...