Oxygen Atom Transfer in a Nucleophilic Epoxidation Process.

Transcription

1 Anti-Selective Epoxidation of Methyl α-methylene-β-tert-butyldimethylsilyloxycarboxylate Esters. Evidence for Stereospecific Oxygen Atom Transfer in a Nucleophilic Epoxidation Process. Jakub Švenda and Andrew G. Myers* Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts Supporting Information Table of Contents: General Experimental Procedures, Materials, and Instrumentation... S1 Preparation of Methyl α-methylene-β-tert-butyldimethylsilyloxycarboxylate Esters as Substrates for Epoxidation... S2 Anti-Selective Epoxidation of Methyl α-methylene-β-tert-butyldimethylsilyloxycarboxylate Esters... S6 Titanium-Catalyzed, Syn-Selective Epoxidation of Methyl α-methylene-β-hydroxycarboxylate Esters...S11 Preparation of Methyl trans-deuterio-α-methylene-β-tert-butyldimethylsilyloxycarboxylate Esters...S13 Stereospecific Epoxidation of Methyl trans-deuterio-α-methylene-β-tert-butyldimethylsilyloxycarboxylate Esters...S19 Stereospecific Epoxidation of Di-tert-Butyl Maleate...S21 Measurement of a Secondary Deuterium Isotope Effect By a Competition Experiment...S22 Measurement of 12 C/ 13 C Isotope Effects Using the Singleton Experiment...S24 General Experimental Procedures. All reactions were performed in round-bottom flasks fitted with rubber septa under a positive pressure of argon, unless otherwise noted. Air- and moisture-sensitive liquids were transferred by syringe or stainless steel cannula. Organic solutions were concentrated by rotary evaporation (house vacuum, ca Torr) at ambient temperature, unless otherwise noted. Analytical thin-layer chromatography (TLC) was performed using glass plates pre-coated with silica gel (0.25 mm, 60 Å pore-size, mesh, Merck KGA) impregnated with a fluorescent indicator (254 nm). TLC plates were visualized by exposure to ultraviolet light, then were stained by submersion in aqueous ceric ammonium molybdate (CAM) or potassium permanganate solutions followed by brief heating on a hot plate. Flash-column chromatography was performed as described by Still et al., 1 employing silica gel (60 Å, μm, standard grade, Dynamic Adsorbents, Inc.). Materials. Commercial solvents and reagents were used as received. Anhydrous solutions of tert-butyl hydroperoxide in benzene were prepared and stored according to Sharpless et al. 2 All transfers of tert-butyl hydroperoxide solutions were conducted using calibrated plastic pipettes. Solutions of potassium tertbutoxide in tetrahydrofuran (1.0 M) were prepared in vials fitted with a syringe valve ( Mininert ) and were stored at ambient temperature in a desiccator for no more than 7 d. 1 Still, W. C.; Khan, M.; Mitra, A. J. Org. Chem. 1978, 43, (a) Sharpless, K.B.; Verhoeven, T. R. Aldrichimica Acta 1979, 12, (b) Hill, J. G.; Rossiter, B. E.; Sharpless, K. B. J. Org. Chem. 1983, 48, S1

2 Instrumentation. Proton nuclear magnetic resonance ( 1 H NMR) spectra were recorded using Varian INOVA 500 (500 MHz) or Varian INOVA 600 (600 MHz) NMR spectrometers at 23 C. Proton chemical shifts are expressed in parts per million (ppm, δ scale) and are referenced to residual protium in the NMR solvent (CHCl 3, δ 7.26 ppm; C 6 D 5 H, δ 7.15 ppm). Data are represented as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet and/or multiple resonances), integration, coupling constant (J) in Hertz. Carbon nuclear magnetic resonance ( 13 C NMR) spectra were recorded using Varian Mercury 400 (100 MHz) or Varian INOVA 500 (125 MHz) NMR spectrometers at 23 C. Carbon chemical shifts are expressed in parts per million (ppm, δ scale) and are referenced to the carbon resonances of the NMR solvent (CDCl 3, δ 77.0, C 6 D 6, δ 128.0). Infrared (IR) spectra were obtained using a Shimadzu 8400S FT-IR spectrometer and were referenced to a polystyrene standard. Data are represented as follows: frequency of absorption (cm 1 ), intensity of absorption (vs = very strong, s = strong, m = medium, w = weak, br = broad). High-resolution mass spectra were obtained at the Harvard University Mass Spectrometry Facility. Melting points were measured using a Thomas Hoover uni-melt apparatus (6427F10). Preparation of Methyl α-methylene-β-tert-butyldimethylsilyloxycarboxylate Esters as Substrates for Epoxidation. Methyl 5-Benzyloxy-3-hydroxy-2-methylenepentanoate (26). 3-Quinuclidinol (136 mg, 1.07 mmol, 0.25 equiv) was added to a stirring solution of 3- benzyloxypropanal (24) 3 (700 mg, 4.26 mmol, 1 equiv), methyl acrylate (1.92 ml, mmol, 5.0 equiv), and methanol (96 μl, 2.98 mmol, 0.7 equiv) at 23 C. After stirring at 23 C for 14 h, the reaction mixture was concentrated and the residue was purified by flash-column chromatography (gradient elution with 10 40% ether in hexanes) to provide the allylic alcohol 26 as a colorless oil (504 mg, 47%). 1 H NMR (500 MHz, CDCl 3 ) δ: (m, 5H), 6.28 (dd, 1H, J = 1.0, 1.0 Hz), 5.93 (dd, 1H, J = 1.5, 0.5 Hz), (m, 1H), 4.52 (s, 2H), 3.76 (s, 3H), (m, 2H), 3.59 (d, 1H, J = 5.0 Hz), (m, 1H), (m, 1H). 13 C NMR (125 MHz, CDCl 3 ) δ: 166.7, 142.1, 137.8, 128.4, 127.8, 127.7, 125.1, 73.3, 70.2, 68.6, 51.7, FTIR (neat), cm 1 : 3497 (br), 2865 (m), 1717 (s), 1076 (vs). HRMS (ESI): Calcd for (C 14 H 18 O 4 +Na + ): , found: Methyl 3-Hydroxy-4,4-dimethoxy-2-methylenebutanoate (28). 3-Quinuclidinol (35 mg, 0.28 mmol, 0.25 equiv) was added to a stirring solution of 2,2- dimethoxyacetaldehyde (27) 4 (115 mg, 1.11 mmol, 1 equiv) in methyl acrylate (500 μl, 5.55 mmol, 5.0 equiv) at 23 C. After stirring at 23 C for 8 h, the reaction mixture was concentrated and the residue was 3 Nielsen, L.; Lindsay, K. B., Faber, J.; Nielsen, N. C.; Skrydstrup, T. J. Org. Chem. 2007, 72, The aqueous solution of 2,2-dimethoxyacetaldehyde (50 ml, 60% by weight, Aldrich) was extracted with dichloromethane (3 50 ml), organic extracts were combined and the combined solution was dried over anhydrous magnesium sulfate. The dried solution was filtered and concentrated to provide the anhydrous 2,2-dimethoxyacetaldehyde (27) as a colorless oil (17.1 g). S2

3 purified by flash-column chromatography (gradient elution with 20 30% ethyl acetate in hexanes) to provide the allylic alcohol 28 as a colorless oil (165 mg, 79%). 1 H NMR (500 MHz, CDCl 3 ) δ: 6.32 (s, 1H), 5.95 (s, 1H), 4.54 (dd, 1H, J = 5.3, 5.0 Hz), 4.42 (d, 1H, J = 5.0 Hz), 3.76 (s, 3H), 3.43 (s, 3H), 3.40 (s, 3H), 2.89 (d, 1H, J = 5.5 Hz). 13 C NMR (100 MHz, CDCl 3 ) δ: 166.7, 138.4, 127.1, 105.4, 71.1, 55.4, 55.0, FTIR (neat), cm 1 : 3493 (br), 2953 (m), 1721 (s), 1438 (m), 1125 (s), 1073 (vs). HRMS (ESI): Calcd for (C 8 H 14 O 5 +Na + ): , found: Methyl 3-Hydroxy-2-methylene-5,5-diphenylpent-4-enoate (30). 3-Quinuclidinol (122 mg, 0.96 mmol, 0.20 equiv) was added to a stirring solution of 3,3- diphenylacrolein (29) 5 (1.0 g, 4.80 mmol, 1 equiv), methyl acrylate (2.16 ml, mmol, 5.0 equiv), and methanol (136 μl, 3.36 mmol, 0.7 equiv) at 23 C. After stirring at 23 C for 60 h, the reaction mixture was concentrated and the residue was purified by flash-column chromatography (gradient elution with 5 20% ethyl acetate in hexanes) to provide the allylic alcohol 30 as a yellow oil (700 mg, 50%). 1 H NMR (500 MHz, C 6 D 6 ) δ: (m, 4H), (m, 6H), 6.32 (d, 1H, J = 9.5 Hz), 6.05 (d, 1H, J = 1.0 Hz), 5.48 (dd, 1H, J = 1.5, 1.0 Hz), 5.13 (dd, 1H, J = 9.5, 6.5 Hz), 3.18 (s, 3H), 2.74 (d, 1H, J = 6.5 Hz). 13 C NMR (125 MHz, CDCl 3 ) δ: 167.0, 144.8, 141.5, 141.3, 138.9, 129.6, 128.3, 128.2, 127.8, 127.6, 127.6, 127.5, 126.2, 69.8, FTIR (neat), cm 1 : 3435 (br), 1721 (s), 1441 (m), 1148 (s), 696 (vs). HRMS (ESI): Calcd for (C 19 H 18 O 3 +Na + ) , found: Methyl 4-Benzyloxy-3-tert-Butyldimethylsilyloxy-2-methylenebutanoate (32). tert-butyldimethylsilyl trifluoromethylsulfonate (1.07 ml, 4.66 mmol, 1.1 equiv) was added dropwise to a stirring solution of the allylic alcohol 31 6 (1.0 g, 4.23 mmol, 1 equiv) and N,Ndiisopropylethylamine (885 μl, 5.08 mmol, 1.2 equiv) in dichloromethane (40 ml) at 0 C. After stirring at 0 C for 4 h, a saturated aqueous solution of sodium bicarbonate was added (10 ml) and the resulting biphasic mixture was allowed to warm to 23 C. The phases were separated and the aqueous phase was extracted with dichloromethane (2 40 ml). The organic extracts were combined and the combined solution was dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue was purified by flash-column chromatography (gradient elution with 2 10% ethyl acetate in hexanes) to provide the tert-butyldimethylsilyl ether 32 as a colorless oil (1.43 g, 97%). 1 H NMR (500 MHz, CDCl 3 ) δ: (m, 5H), 6.33 (dd, 1H, J = 2.5, 2.0 Hz), 6.04 (dd, 1H, J = 2.5, 2.0 Hz), (m, 1H), 4.59 (d, 1H, J = 15.0 Hz), 4.54 (d, 1H, J = 15.0 Hz), 3.74 (s, 3H), 3.56 (dd, 1H, J = 12.0, 4.0 Hz), 3.41 (dd, 1H, J = 12.0, 8.0 Hz), 0.92 (s, 9H), 0.11 (s, 3H), 0.04 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ: 166.5, 141.1, 138.5, 128.2, 127.4, 127.3, 126.1, 74.9, 73.1, 70.3, 51.7, 25.8, 18.2, 4.9, 5.0. FTIR (neat), cm 1 : 2953 (m), 2930 (m), 2858 (m), 1721 (s), 1252 (s), 1098 (vs). HRMS (ESI): Calcd for (C 19 H 30 O 4 Si+Na + ): , found: Amorese, A.; Arcadi, A.; Bernocchi, E.; Cacchi, S.; Cerrini, S.; Fedeli, W. Ortar, G. Tetrahedron 1989, 45, Kamal, A.; Krishnaji, T.; Reddy, P. V. Tetrahedron Lett. 2007, 48, S3

4 Methyl 5-Benzyloxy-3-tert-butyldimethylsilyloxy-2-methylenepentanoate (33). tert-butyldimethylsilyl trifluoromethylsulfonate (1.62 ml, 7.05 mmol, 1.2 equiv) was added dropwise to a stirring solution of the allylic alcohol 26 (1.47 g, 5.87 mmol, 1 equiv) and N,Ndiisopropylethylamine (1.33 ml, 7.63 mmol, 1.3 equiv) in dichloromethane (58 ml) at 0 C. After stirring at 0 C for 1.5 h, a saturated aqueous solution of sodium bicarbonate was added (25 ml) and the resulting biphasic mixture was allowed to warm to 23 C. The phases were separated and the aqueous phase was extracted with dichloromethane (2 50 ml). The organic extracts were combined and the combined solution was dried over anhydrous magnesium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue was purified by flash-column chromatography (gradient elution with 5 20% ethyl acetate in hexanes) to provide the tert-butyldimethylsilyl ether 33 as a colorless oil (2.0 g, 93%). 1 H NMR (500 MHz, CDCl 3 ) δ: (m, 5H), 6.23 (dd, 1H, J = 1.0, 1.0 Hz), 5.91 (dd, 1H, J = 1.5, 1.0 Hz), 4.73 (dd, 1H, J = 7.0, 3.5 Hz), 4.47 (s, 2H), 3.74 (s, 3H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), 0.89 (s, 9H), 0.05 (s, 3H), 0.03 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ: 166.5, 144.0, 138.6, 128.3, 127.6, 127.4, 124.4, 72.7, 67.8, 66.6, 51.7, 37.7, 25.8, 18.1, 4.8, 5.2. FTIR (neat), cm 1 : 2954 (m), 2930 (m), 2857 (m), 1722 (s), 1256 (s), 1093 (s). HRMS (ESI): Calcd for (C 20 H 32 O 4 Si+H + ): , found: Methyl 3-tert-Butyldimethylsilyloxy-4,4-dimethoxy-2-methylenebutanoate (34). tert-butyldimethylsilyl chloride (1.07 g, 7.10 mmol, 1.5 equiv) was added in one portion to a stirring solution of the allylic alcohol 28 (900 mg, 4.73 mmol, 1 equiv) and imidazole (709 mg, mmol, 2.2 equiv) in dichloromethane (15 ml) at 23 C. After stirring at 23 C for 48 h, the reaction mixture was partitioned between dichloromethane (50 ml) and a saturated aqueous solution of ammonium chloride (10 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (30 ml). The organic extracts were combined and the combined solution was dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue was purified by flashcolumn chromatography (gradient elution with 5 15% ethyl acetate in hexanes) to provide the tertbutyldimethylsilyl ether 34 as a colorless oil (1.2 g, 83%). 1 H NMR (500 MHz, CDCl 3 ) δ: 6.22 (s, 1H), 5.89 (s, 1H), 4.65 (d, 1H, J = 5.0 Hz), 4.17 (d, 1H, J = 6.0 Hz), 3.76 (s, 3H), 3.44 (s, 3H), 3.34 (s, 3H), 0.89 (s, 9H), 0.10 (s, 3H), 0.02 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ: 166.9, 141.6, 125.1, 108.2, 71.5, 56.2, 55.6, 51.7, 25.7, 18.1, 5.0, 5.0. FTIR (neat), cm 1 : 2953 (m), 2932 (m), 2859 (m), 2359 (m), 2344 (m), 1730 (s), 1260 (s), 1107 (vs). HRMS (ESI): Calcd for (C 14 H 28 O 5 Si+Na + ): , found: Methyl 3-tert-Butyldimethylsilyloxy-3-cyclohexyl-2-methylenepropanoate (36). S4

5 tert-butyldimethylsilyl trifluoromethylsulfonate (7.8 ml, mmol, 1.1 equiv) was added dropwise to a stirring solution of the allylic alcohol 35 7 (6.12g, mmol, 1 equiv) and N,Ndiisopropylethylamine (6.45 ml, mmol, 1.2 equiv) in dichloromethane (200 ml) at 0 C. After stirring at 0 C for 1 h, a saturated aqueous solution of sodium bicarbonate was added (100 ml) and the resulting biphasic mixture was allowed to warm to 23 C. The phases were separated and the aqueous phase was extracted with dichloromethane (2 100 ml). The organic extracts were combined and the combined solution was dried over anhydrous magnesium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue was purified by flash-column chromatography (1% ethyl acetate in hexanes) to provide the tert-butyldimethylsilyl ether 36 as a colorless oil (9.3 g, 96%). 1 H NMR (500 MHz, CDCl 3 ) δ: 6.27 (d, 1H, J = 2.0 Hz), 5.82 (dd, 1H, J = 2.0, 1.5 Hz), 4.41 (d, 1H, J = 3.5 Hz), 3.75 (s, 3H), (m, 6H), (m, 5H), 0.91 (s, 9H), 0.04 (s, 3H), 0.07 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ: 167.0, 142.9, 125.3, 74.0, 51.7, 43.4, 30.3, 26.5, 26.5, 26.2, 26.2, 25.9, 18.1, 4.6, 5.1. FTIR (neat), cm 1 : 2928 (m), 2855 (m), 1721 (s), 1100 (s). HRMS (ESI): Calcd for (C 17 H 32 O 3 Si+H + ) , found: Methyl 3-tert-Butyldimethylsilyloxy-2-methylenepent-4-enoate (38). tert-butyldimethylsilyl chloride (350 mg, 2.32 mmol, 1.5 equiv) was added in one portion to a stirring solution of the allylic alcohol 37 8 (220 mg, 1.55 mmol, 1 equiv) and imidazole (232 mg, 3.41 mmol, 2.2 equiv) in dichloromethane (5 ml) at 23 C. After stirring at 23 C for 12 h, the reaction mixture was partitioned between dichloromethane (10 ml) and a saturated aqueous solution of ammonium chloride (10 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (2 40 ml). The organic extracts were combined and the combined solution was dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue was purified by flashcolumn chromatography (gradient elution with 1 3% ethyl acetate in hexanes) to provide the tertbutyldimethylsilyl ether 38 as a colorless oil (283 mg, 71%). 1 H NMR (500 MHz, CDCl 3 ) δ: 6.22 (dd, 1H, J = 1.5, 1.0 Hz), 5.97 (dd, 1H, J = 1.5, 1.5 Hz), (m, 1H), 5.29 (ddd, 1H, J = 17.0, 2.0, 1.5 Hz), (m, 2H), 3.76 (s, 3H), 0.91 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ: 166.4, 142.7, 139.2, 124.1, 114.4, 71.4, 51.7, 25.8, 18.3, 4.9, 5.1. FTIR (neat), cm 1 : 2955 (m), 2930 (m), 2859 (m), 1723 (s), 1258 (s), 1111 (s), 1084 (s). HRMS (ESI): Calcd for (C 13 H 24 O 3 Si+H + ): , found: Methyl 3-tert-Butyldimethylsilyloxy-2-methylene-5-phenylpent-4-enoate (40). tert-butyldimethylsilyl trifluoromethylsulfonate (4.05 ml, mmol, 1.1 equiv) was added dropwise to a stirring solution of the allylic alcohol 39 7 (3.5 g, mmol, 1 equiv) and N,Ndiisopropylethylamine (3.35 ml, mmol, 1.2 equiv) in dichloromethane (160 ml) at 0 C. After 7 (a) Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc. 1999, 121, (b) Aggarwal, V.; Emme, I.; Fulford, S. Y. J. Org. Chem. 2003, 68, Brand, M.; Drewes, S. E.; Roos, G. H. P. Synth. Commun. 1986, 16, S5

6 stirring at 0 C for 3 h, a saturated aqueous solution of sodium bicarbonate was added (40 ml) and the resulting biphasic mixture was allowed to warm to 23 C. The phases were separated and the aqueous phase was extracted with dichloromethane (2 100 ml). The organic extracts were combined and the combined solution was dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue was purified by flash-column chromatography (gradient elution with 1 3% ethyl acetate in hexanes) to provide the tert-butyldimethylsilyl ether 40 as a colorless oil (5.08 g, 95%). 1 H NMR (500 MHz, CDCl 3 ) δ: 7.36 (d, 2H, J = 8.0 Hz), 7.29 (t, 2H, J = 7.5 Hz), 7.22 (t, 1H, J = 7.5 Hz), 6.62 (d, 1H, J = 16.0 Hz), 6.25 (dd, 1H, J = 1.5, 1.0 Hz), 6.16 (dd, 1H, J = 15.5, 6.5 Hz), 6.03 (dd, 1H, J = 1.5, 1.5 Hz), 5.22 (d, 1H, J = 6.5 Hz), 3.76 (s, 3H), 0.93 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ: 166.3, 142.7, 136.9, 130.6, 129.7, 128.5, 127.5, 126.5, 124.2, 71.1, 51.7, 25.8, 18.3, 4.7, 5.0. FTIR (neat), cm 1 : 2953 (m), 2930 (m), 2857 (m), 1721 (s), 1254 (s), 1103 (s). HRMS (ESI): Calcd for (C 19 H 28 O 3 Si+Na + ): , found: Methyl 3-tert-Butyldimethylsilyloxy-2-methylene-5,5-diphenylpent-4-enoate (41). tert-butyldimethylsilyl chloride (230 mg, 1.53 mmol, 1.5 equiv) was added in one portion to a stirring solution of the allylic alcohol 30 (300 mg, 1.02 mmol, 1 equiv) and imidazole (153 mg, 2.24 mmol, 2.2 equiv) in dichloromethane (2 ml) at 23 C. After stirring at 23 C for 19 h, the reaction mixture was partitioned between dichloromethane (100 ml) and a saturated aqueous solution of ammonium chloride (30 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (50 ml). The organic extracts were combined and the combined solution was dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue was purified by flash-column chromatography (gradient elution with 1 2% ethyl acetate in hexanes) to provide the tertbutyldimethylsilyl ether 41 as a white solid (369 mg, 88%). 1 H NMR (500 MHz, CDCl 3 ) δ: (m, 10H), 6.23 (s, 1H), 6.12 (d, 1H, J = 10.0 Hz), 5.89 (s, 1H), 5.17 (d, 1H, J = 10.0 Hz), 3.74 (s, 3H), 0.87 (s, 9H), 0.04 (s, 3H), 0.15 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ: 166.7, 143.9, 142.5, 142.1, 139.1, 129.8, 129.5, 128.2, 128.0, 127.7, 127.5, 124.7, 68.7, 51.6, 25.8, 18.0, 4.6, 5.1. FTIR (neat), cm 1 : 2954 (m), 2930 (m), 2858 (m), 1727 (s), 1057 (s). HRMS (ESI): Calcd for (C 25 H 32 O 3 Si+Na + ): , found: Anti-Selective Epoxidation of Methyl α-methylene-β-tert-butyldimethylsilyloxycarboxylate Esters. Methyl 3-tert-Butyldimethylsilyloxy-2-epoxypentanoate (1) (anti diastereomer). Solid anhydrous potassium tert-butoxide was added in five equal portions (9 mg, 0.08 mmol, 0.05 equiv each portion) over 4 h (one portion each hour after the initial addition at time 0) to a stirring solution of substrate 42 9 (400 mg, 1.55 mmol, 1 equiv, racemic) and tert-butyl hydroperoxide (4.5 M solution in benzene, 689 μl, 3.10 mmol, 2.0 equiv) in tetrahydrofuran (15 ml) at 0 C. After stirring at 0 C for 1.5 h, solid sodium sulfite (976 mg, 7.74 mmol, 5.0 equiv) was added in one portion. The resulting mixture was 9 Perlmutter, P.; Tabone, M. J. Org. Chem. 1995, 60, S6

7 allowed to warm to 23 C, then was stirred at this temperature for 30 min. The crude product mixture was filtered through Celite eluting with ether and the filtrate was concentrated. 1 H NMR analysis of the residue revealed that the product comprised a 16:1 mixture of anti and syn epoxides, respectively. The mixture was separated by flash-column chromatography (gradient elution with 1 2% ethyl acetate in hexanes) to provide the pure anti diastereomer 1 as a colorless oil (264 mg, 62%). 1 H NMR (500 MHz, CDCl 3 ) δ: 3.99 (dd, 1H, J = 7.5, 5.0 Hz), 3.76 (s, 3H), 2.98 (d, 1H, J = 6.5 Hz), 2.93 (d, 1H, J = 5.5 Hz), (m, 1H), (m, 1H), 0.93 (t, 3H, J = 8.0 Hz), 0.89 (s, 9H), 0.08 (s, 6H). 13 C NMR (125 MHz, CDCl 3 ) δ: 169.8, 72.7, 60.5, 52.4, 49.8, 27.5, 25.8, 18.1, 10.3, 4.8, 4.9. FTIR (neat), cm 1 : 2955 (m), 2930 (m), 2859 (m), 1738 (s), 1254 (s), 1094 (vs), 1065 (s). HRMS (ESI): Calcd for (C 13 H 26 O 4 Si+Na + ): , found: Methyl 4-Benzyloxy-3-tert-butyldimethylsilyloxy-2-epoxypropanoate (2) (anti diastereomer). Solid anhydrous potassium tert-butoxide (1.6 mg, 0.01 mmol, 0.05 equiv) was added to a stirring solution of substrate 32 (100 mg, 0.29 mmol, 1 equiv, racemic) and tert-butyl hydroperoxide (4.5 M solution in benzene, 127 μl, 0.57 mmol, 2.0 equiv) in tetrahydrofuran (2.8 ml) at 0 C. After 1 h, a second portion of solid anhydrous potassium tert-butoxide (1.6 mg, 0.01 mmol, 0.05 equiv) was added. After a total reaction period of 2 h, solid sodium sulfite (163 mg, 1.29 mmol, 5.0 equiv) was added in one portion. The resulting mixture was allowed to warm to 23 C, then was stirred at this temperature for 30 min. The crude product mixture was filtered through Celite eluting with ether and the filtrate was concentrated. 1 H NMR analysis of the residue revealed that the product comprised a 10:1 mixture of anti and syn epoxides, respectively. The mixture was separated by flash-column chromatography (gradient elution with 1 5% ethyl acetate in hexanes) to provide the pure anti diastereomer 2 (82 mg, 78%). 1 H NMR (500 MHz, C 6 D 6 ) δ: 7.25 (d, 2H, J = 7.5 Hz), (m, 2H), 7.07 (t, 1H, J = 7.0 Hz), 4.52 (t, 1H, J = 6.5 Hz), 4.33 (d, 1H, J = 12.0 Hz), 4.30 (d, 1H, J = 12.5 Hz), 3.81 (dd, 1H, J = 9.0, 6.5 Hz), 3.67 (dd, 1H, J = 9.0, 6.5 Hz), 3.27 (s, 3H), 2.82 (d, 1H, J = 6.5 Hz), 2.63 (d, 1H, J = 6.5 Hz), 0.93 (s, 9H), 0.12 (s, 3H), 0.09 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ: 169.6, 138.0, 128.3, 127.5, 127.5, 73.5, 71.8, 69.6, 59.3, 52.3, 49.6, 25.7, 18.1, 4.9, 5.1. FTIR (neat), cm 1 : 2955 (m), 2929 (m), 2858 (m), 1739 (s), 1254 (s), 1100 (vs). HRMS (ESI): Calcd for (C 19 H 30 O 5 Si+H + ): , found: Methyl 5-Benzyloxy-3-tert-butyldimethylsilyloxy-2-epoxypentanoate (3) (anti diastereomer). A solution of potassium tert-butoxide in tetrahydrofuran was added in six equal portions (1.0 M, 17 μl, 0.02 mmol, 0.05 equiv each portion) over 10 h (one portion each 2 h after the initial addition at time 0) to a stirring solution of substrate 33 (120 mg, 0.33 mmol, 1 equiv, racemic) and tert-butyl hydroperoxide (3.2 M solution in benzene, 206 μl, 0.66 mmol, 2.0 equiv) in tetrahydrofuran (3.0 ml) at 0 C. After stirring at 0 C for 1 h, solid sodium sulfite (207 mg, 1.65 mmol, 5.0 equiv) was added in one portion. The resulting mixture was allowed to warm to 23 C, then was stirred at this temperature for 30 min. The crude product mixture was filtered through Celite eluting with ether and the filtrate was concentrated. 1 H NMR analysis of the residue revealed that the product comprised a 14:1 mixture of anti and syn epoxides, respectively. The mixture was separated by flash-column chromatography (gradient elution with 2 10% ethyl acetate in hexanes) to provide the pure anti diastereomer 3 as a colorless oil (80 mg, 64%). 1 H NMR S7

8 (500 MHz, C 6 D 6 ) δ: 7.27 (d, 2H, J = 8.0 Hz), 7.16 (t, 2H, J = 7.0 Hz), 7.08 (t, 1H, J = 7.0 Hz), 4.29 (d, 1H, J = 12.0 Hz), 4.25 (d, 1H, J = 13.0 Hz), 4.23 (t, 1H, J = 4.5 Hz), (m, 1H), (m, 1H), 3.27 (s, 3H), 2.59 (d, 1H, J = 6.5 Hz), 2.55 (d, 1H, J = 6.5 Hz), (m, 1H), (m, 1H), 0.97 (s, 9H), 0.20 (s, 3H), 0.12 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ: 169.4, 138.3, 128.3, 127.6, 127.5, 72.8, 69.7, 66.3, 60.4, 52.3, 49.8, 34.8, 25.7, 18.0, 4.8, 5.2. FTIR (neat), cm 1 : 2953 (m), 2930 (m), 2857 (m), 1740 (s), 1096 (vs). HRMS (ESI): Calcd for (C 20 H 32 O 5 Si+Na + ): , found: Methyl 3-tert-Butyldimethylsilyloxy-2-epoxy-4,4-dimethoxybutanoate (4) (anti diastereomer). A solution of potassium tert-butoxide in tetrahydrofuran (1.0 M, 276 μl, 0.28 mmol, 0.05 equiv) was added to a stirring solution of substrate 34 (1.68 g, 5.52 mmol, 1 equiv, racemic) and tert-butyl hydroperoxide (3.2 M solution in benzene, 3.45 ml, mmol, 2.0 equiv) in tetrahydrofuran (55 ml) at 0 C. After 1.5 h, a second portion of the potassium tert-butoxide solution in tetrahydrofuran (1.0 M, 276 μl, 0.28 mmol, 0.05 equiv) was added. After a total reaction period of 3 h, solid sodium sulfite (3.48 g, mmol, 5.0 equiv) was added in one portion. The resulting mixture was allowed to warm to 23 C, then was stirred at this temperature for 30 min. The crude product mixture was filtered through Celite eluting with ether and the filtrate was concentrated. 1 H NMR analysis of the residue revealed that the product comprised a 13:1 mixture of anti and syn epoxides, respectively. The mixture was separated by flash-column chromatography (gradient elution with 10 15% ether in hexanes) to provide the pure anti diastereomer 4 as a colorless oil (1.55 g, 88%). A pure sample of the syn diastereomer 43 was also obtained for spectroscopic analysis and comparison. Anti diastereomer 4: 1 H NMR (500 MHz, CDCl 3 ) δ: 4.40 (d, 1H, J = 6.5 Hz), 4.07 (d, 1H, J = 7.5 Hz), 3.76 (s, 3H), 3.48 (s, 3H), 3.46 (s, 3H), 3.09 (d, 1H, J = 6.5 Hz), 2.88 (d, 1H, J = 6.0 Hz), 0.88 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ: 169.5, 107.4, 72.6, 59.2, 57.1, 56.9, 52.4, 50.1, 25.7, 18.2, 4.8, 5.0. FTIR (neat), cm 1 : 2953 (m), 2929 (m), 1740 (s), 1254 (s), 1105 (s). HRMS (ESI): Calcd for (C 14 H 28 O 6 Si+K + ) , found: Syn diastereomer 43: 1 H NMR (500 MHz, CDCl 3 ) δ: 4.34 (d, 1H, J = 6.0 Hz), 4.19 (d, 1H, J = 6.5 Hz), 3.74 (s, 3H), 3.43 (s, 3H), 3.40 (s, 3H), 3.13 (d, 1H, J = 6.0 Hz), 2.95 (d, 1H, J = 6.5 Hz), 0.87 (s, 9H), 0.10 (s, 3H), 0.07 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ: 169.1, 106.4, 70.5, 57.4, 55.8, 55.6, 52.3, 47.3, 25.7, 18.3, 4.9, 5.0. FTIR (neat), cm 1 : 2953 (m), 2929 (m), 1748 (s), 1251 (s), 1117 (s). HRMS (ESI): Calcd for (C 14 H 28 O 6 Si+K + ) , found: Methyl 3-tert-Butyldimethylsilyloxy-3-cyclohexyl-2-epoxypropanoate (5) (anti diastereomer). A solution of potassium tert-butoxide in tetrahydrofuran was added in five equal portions (1.0 M, 19 μl, 0.02 mmol, 0.05 equiv each portion) over 6 h (one portion each 1.5 h after the initial addition at time 0) to a stirring solution of substrate 36 (120 mg, 0.38 mmol, 1 equiv, racemic) and tert-butyl hydroperoxide (3.2 M solution in benzene, 240 μl, 0.77 mmol, 2.0 equiv) in tetrahydrofuran (3.5 ml) at 0 C. After stirring at 0 C for 4.5 h, solid sodium sulfite (240 mg, 1.90 mmol, 5.0 equiv) was added in one portion. The resulting mixture was allowed to warm to 23 C, then was stirred at this temperature for 30 min. The crude product mixture was filtered through Celite eluting with ether and the filtrate was concentrated. 1 H NMR analysis of the residue revealed that the product comprised a 18:1 mixture of anti and syn epoxides, respectively. The mixture was separated by flash-column chromatography (gradient S8

9 elution with 1 3% ethyl acetate in hexanes) to provide the pure anti diastereomer 5 as a colorless oil (90 mg, 72%). A pure sample of the syn diastereomer 44 was also obtained for spectroscopic analysis and comparison. Anti diastereomer 5: 1 H NMR (500 MHz, CDCl 3 ) δ: 3.76 (s, 3H), 3.65 (d, 1H, J = 8.5 Hz), 3.00 (d, 1H, J = 6.5 Hz), 2.93 (d, 1H, J = 6.5 Hz), 1.99 (d, 1H, J = 13.0 Hz), (m, 5H), (m, 3H), (m, 2H), 0.89 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ: 170.0, 76.7, 59.8, 52.4, 50.9, 42.0, 30.1, 29.2, 26.4, 26.1, 26.0, 25.9, 18.1, 4.5, 4.9. FTIR (neat), cm 1 : 2926 (s), 2852 (s), 1738 (s), 1256 (s), 1067 (s). HRMS (ESI): Calcd for (C 17 H 32 O 4 Si+H + ) , found: Syn diastereomer 44: 1 H NMR (500 MHz, CDCl 3 ) δ: 3.98 (d, 1H, J = 3.0 Hz), 3.75 (s, 3H), 3.13 (d, 1H, J = 6.5 Hz), 2.94 (d, 1H, J = 6.5 Hz), (m, 5H), (m, 6H), 0.88 (s, 9H), 0.05 (s, 6H). 13 C NMR (125 MHz, CDCl 3 ) δ: 169.8, 72.3, 57.9, 52.4, 47.5, 41.5, 30.8, 29.7, 26.6, 26.5, 26.4, 26.2, 26.0, 18.4, 4.3, 4.8. FTIR (neat), cm 1 : 2930 (s), 2854 (s), 1739 (s), 1256 (s), 1103 (s). HRMS (ESI): Calcd for (C 17 H 32 O 4 Si+H + ) , found: Methyl 3-tert-Butyldimethylsilyloxy-2-epoxy-3-phenylpropanoate (6) (anti diastereomer) and Methyl 3- tert-butyldimethylsilyloxy-2-epoxy-3-phenylpropanoate (46) (syn diastereomer). A solution of potassium tert-butoxide in tetrahydrofuran was added in three equal portions (1.0 M, 30 μl, 0.03 mmol, 0.05 equiv each portion) over 3 h (one portion each 1.5 h after the initial addition at time 0) to a stirring solution of substrate 45 9 (183 mg, 0.60 mmol, 1 equiv, racemic) and tert-butyl hydroperoxide (3.2 M solution in benzene, 373 μl, 1.19 mmol, 2.0 equiv) in tetrahydrofuran (5.0 ml) at 0 C. After stirring at 0 C for 3 h, solid sodium sulfite (376 mg, 2.99 mmol, 5.0 equiv) was added in one portion. The resulting mixture was allowed to warm to 23 C, then was stirred at this temperature for 30 min. The crude product mixture was filtered through Celite eluting with ether and the filtrate was concentrated. 1 H NMR analysis of the residue revealed that the product comprised a 2:1 mixture of anti and syn epoxides, respectively. The residue was purified by flash-column chromatography (2% ethyl acetate in hexanes) to provide the inseparable mixture of anti (6) and syn (46) diastereomers as a colorless oil (142 mg, 74%). 1 H NMR (asterisk denotes resonances corresponding to the syn diastereomer 46, 500 MHz, CDCl 3 ) δ: 7.40 (d, 2H, J = 6.5 Hz), (m, 3H), * (m, 5H), 5.46* (s, 1H), 5.39 (s, 1H), 3.75* (s, 3H), 3.68 (s, 3H), 3.17 (d, 1H, J = 6.0 Hz), 2.98 (d, 1H, J = 7.0 Hz), 2.84* (d, 1H, J = 5.5 Hz), 2.38* (d, 1H, J = 6.0 Hz), 0.86 (s, 9H), 0.83* (s, 9H), 0.05 (s, 3H), 0.05* (s, 3H), 0.16 (s, 3H), 0.17* (s, 3H). 13 C NMR (asterisk denotes resonances corresponding to the syn diastereomer 46, 125 MHz, CDCl 3 ) δ: 169.8*, 169.5, 139.7, 138.4*, 128.2*, 128.0*, 128.0, 127.9*, 127.9, 127.5, 72.6*, 71.3, 60.9, 60.3*, 52.4*, 52.3, 49.7, 48.3*, 25.7, 25.6*, 18.1, 18.1*, 4.8, 4.8*, 5.2, 5.3*. FTIR (neat), cm 1 : 2955 (m), 2930 (m), 2859 (m), 1736 (s), 1252 (s), 1090 (vs), 1071 (vs). HRMS (ESI): Calcd for (C 17 H 26 O 4 Si+Na + ): , found: Methyl 3-tert-Butyldimethylsilyloxy-2-epoxypent-4-enoate (7) (anti diastereomer). A solution of potassium tert-butoxide in tetrahydrofuran was added in three equal portions (1.0 M, 49 μl, 0.05 mmol, 0.05 equiv each portion) over 3 h (one portion each 1.5 h after the initial addition at time 0) to a stirring solution of substrate 38 (250 mg, 0.98 mmol, 1 equiv, racemic) and tert-butyl S9

10 hydroperoxide (3.2 M solution in benzene, 609 μl, 1.95 mmol, 2.0 equiv) in tetrahydrofuran (9.0 ml) at 0 C. After stirring at 0 C for 2 h, solid sodium sulfite (615 mg, 4.88 mmol, 5.0 equiv) was added in one portion. The resulting mixture was allowed to warm to 23 C, then was stirred at this temperature for 30 min. The crude product mixture was filtered through Celite eluting with ether and the filtrate was concentrated. 1 H NMR analysis of the residue revealed that the product comprised a 7:1 mixture of anti and syn epoxides, respectively. The mixture was separated by flash-column chromatography (gradient elution with 2 4% ether in hexanes) to provide the pure anti diastereomer 7 as a colorless oil (175 mg, 66%). A pure sample of the syn diastereomer 47 was also obtained for spectroscopic analysis and comparison. Anti diastereomer 7: 1 H NMR (500 MHz, CDCl 3 ) δ: (m, 1H), 5.31 (dt, 1H, J = 17.0, 1.5 Hz), 5.20 (dt, 1H, J = 10.5, 1.0 Hz), 4.67 (dt, 1H, J = 6.5, 1.5 Hz), 3.76 (s, 3H), 3.04 (d, 1H, J = 6.5 Hz), 2.97 (d, 1H, J = 6.0 Hz), 0.88 (s, 9H), 0.09 (s, 3H), 0.06 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ: 169.4, 136.2, 117.2, 71.9, 60.3, 52.4, 49.2, 25.7, 18.2, 4.5, 5.1. FTIR (neat), cm 1 : 2955 (m), 2930 (m), 2859 (m), 1742 (s), 1256 (s), 1092 (s). HRMS (ESI): Calcd for (C 13 H 24 O 4 Si+Na + ): , found: Syn diastereomer 47: 1 H NMR (500 MHz, CDCl 3 ) δ: (m, 1H), 5.30 (dt, 1H, J = 17.5, 1.5 Hz), 5.21 (dt, 1H, J = 10.0, 1.0 Hz), 4.81 (d, 1H, J = 7.0 Hz), 3.76 (s, 3H), 2.93 (d, 1H, J = 6.0 Hz), 2.80 (d, 1H, J = 6.0 Hz), 0.87 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ: 169.6, 135.8, 118.2, 71.4, 59.5, 52.4, 48.0, 25.7, 18.2, 4.6, 5.1. FTIR (neat), cm 1 : 2955 (m), 2930 (m), 2859 (m), 1740 (s), 1256 (s), 1105 (s). HRMS (ESI): Calcd for (C 13 H 24 O 4 Si+Na + ): , found: Methyl 3-tert-Butyldimethylsilyloxy-2-epoxy-5-phenylpent-4-enoate (8) (anti diastereomer). A solution of potassium tert-butoxide in tetrahydrofuran (1.0 M, 44 μl, 0.04 mmol, 0.05 equiv) was added to a stirring solution of substrate 40 (294 mg, 0.88 mmol, 1 equiv, racemic) and tert-butyl hydroperoxide (3.2 M solution in benzene, 553 μl, 1.77 mmol, 2.0 equiv) in tetrahydrofuran (8 ml) at 0 C. After 1 h, a second portion of the potassium tert-butoxide solution in tetrahydrofuran (1.0 M, 44 μl, 0.04 mmol, 0.05 equiv) was added. After a total reaction period of 2 h, solid sodium sulfite (557 mg, 4.42 mmol, 5.0 equiv) was added in one portion. The resulting mixture was allowed to warm to 23 C, then was stirred at this temperature for 30 min. The crude product mixture was filtered through Celite eluting with ether and the filtrate was concentrated. 1 H NMR analysis of the residue revealed that the product comprised a 8:1 mixture of anti and syn epoxides, respectively. The residue was purified by radial chromatography (2.0 mm rotor, 1% ethyl acetate in hexanes) to provide the pure anti diastereomer 8 (218 mg, 71%) as a colorless oil. 1 H NMR (500 MHz, CDCl 3 ) δ: 7.39 (d, 2H, J = 7.5 Hz), 7.32 (t, 2H, J = 7.5 Hz), 7.25 (t, 1H, J = 7.0 Hz), 6.62 (d, 1H, J = 16.0 Hz), 6.27 (dd, 1H, J = 15.5, 6.5 Hz), 4.86 (d, 1H, J = 7.0 Hz), 3.75 (s, 3H), 3.11 (d, 1H, J = 6.5 Hz), 3.00 (d, 1H, J = 6.5 Hz), 0.90 (s, 9H), 0.11 (s, 3H), 0.07 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ: 169.4, 136.4, 132.3, 128.5, 127.8, 127.3, 126.6, 71.7, 60.5, 52.4, 49.4, 25.7, 18.2, 4.3, 5.0. FTIR (neat), cm 1 : 2955 (m), 2930 (m), 2857 (m), 1740 (s), 1252 (s), 1099 (s), 1078 (s), 1067 (s). HRMS (ESI): Calcd for (C 19 H 28 O 4 Si+Na + ): , found: Methyl 3-tert-Butyldimethylsilyloxy-2-epoxy-5,5-diphenylpent-4-enoate (9) (anti diastereomer) and Methyl 3-tert-Butyldimethylsilyloxy-2-epoxy-5,5-diphenylpent-4-enoate (48) (syn diastereomer). S10

11 Solid anhydrous potassium tert-butoxide (2 mg, 0.02 mmol, 0.05 equiv) was added to a stirring solution of substrate 41 (150 mg, 0.37 mmol, 1 equiv, racemic) and tert-butyl hydroperoxide (4.5 M solution in benzene, 163 μl, 0.73 mmol, 2.0 equiv) in tetrahydrofuran (3.6 ml) at 0 C. After 1 h, a second portion of solid anhydrous potassium tert-butoxide (2 mg, 0.02 mmol, 0.05 equiv) was added. After a total reaction period of 3.5 h, solid sodium sulfite (231 mg, 1.84 mmol, 5.0 equiv) was added in one portion. The resulting mixture was allowed to warm to 23 C, then was stirred at this temperature for 30 min. The crude product mixture was filtered through Celite eluting with ether and the filtrate was concentrated. 1 H NMR analysis of the residue revealed that the product comprised a 3:1 mixture of anti and syn epoxides, respectively. The mixture was separated by flash-column chromatography (gradient elution with 1 4% ethyl acetate in hexanes) to provide the pure anti diastereomer 9 (82 mg, 53%) as a colorless oil, followed by the pure syn diastereomer 48 (27 mg, 17%) as a white solid. Anti diastereomer 9: 1 H NMR (500 MHz, CDCl 3 ) δ: (m, 4H), (m, 4H), (m, 2H), 6.21 (d, 1H, J = 9.0 Hz), 4.61 (d, 1H, J = 9.0 Hz), 3.75 (s, 3H), 2.99 (d, 1H, J = 5.5 Hz), 2.79 (d, 1H, J = 6.0 Hz), 0.85 (s, 9H), 0.03 (s, 3H), 0.11 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ: 169.2, 143.8, 141.6, 139.0, 129.7, 128.3, 128.2, 127.7, 127.6, 126.6, 70.3, 60.4, 52.4, 49.2, 25.7, 18.0, 4.4, 5.1. FTIR (neat), cm 1 : 2953 (m), 2930 (m), 2858 (m), 1744 (s), 1250 (s), 1063 (vs). HRMS (ESI): Calcd for (C 25 H 32 O 4 Si+Na + ): , found: Syn diastereomer 48: 1 H NMR (400 MHz, CDCl 3 ) δ: (m, 3H), (m, 5H), (m, 2H), 5.93 (d, 1H, J = 8.0 Hz), 5.09 (d, 1H, J = 8.0 Hz), 3.73 (s, 3H), 2.98 (d, 1H, J = 8.0 Hz), 2.95 (d, 1H, J = 8.0 Hz), 0.83 (s, 9H), 0.06 (s, 3H), 0.21 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ: 169.6, 144.9, 141.6, 138.7, 129.6, 128.3, 128.2, 127.9, 127.9, 127.8, 125.0, 68.8, 60.6, 52.4, 49.6, 25.7, 18.0, 4.3, 5.5. FTIR (neat), cm 1 : 2953 (m), 2928 (m), 2857 (m), 1742 (s), 1250 (s), 1094 (s), 1061 (vs). HRMS (ESI): Calcd for (C 25 H 32 O 4 Si+Na + ): , found: Titanium-Catalyzed, Syn-Selective Epoxidation of Methyl α-methylene-β-hydroxycarboxylate Esters. Methyl 3-tert-Butyldimethylsilyloxy-3-cyclohexyl-2-epoxypropanoate (44) (syn diastereomer). Titanium (IV) isopropoxide (22 μl, 0.08 mmol, 0.2 equiv) was added dropwise to a stirring solution of the allylic alcohol 35 7 (75 mg, 0.38 mmol, 1 equiv, racemic) in dichloromethane (3.8 ml) at 20 C containing suspended activated 4Å molecular sieves (50 mg, powdered). After stirring at 20 C for 20 min, a solution of tert-butyl hydroperoxide in benzene (2.9 M, 261 μl, 0.76 mmol, 2.0 equiv) was added dropwise. The reaction mixture was allowed to warm to 15 C, then was stirred at this temperature for 14 h. Water (1.0 ml) was added and the resulting biphasic mixture was allowed to warm to 23 C. After vigorous stirring for 30 min, the phases were separated and the aqueous phase was extracted with dichloromethane (2 10 ml). The organic extracts were combined and the combined solution was dried over anhydrous magnesium sulfate. The dried solution was filtered and the filtrate was concentrated. 1 H NMR analysis of the residue revealed that the crude epoxy alcohol (73 mg) was formed with 20:1 syn selectivity. The crude epoxy alcohol was redissolved in dichloromethane (3.0 ml) and the resulting solution was cooled to 0 C, whereupon N,N-diisopropylethylamine (71 μl, 0.41 mmol, 1.1 equiv) and tert-butyldimethylsilyl trifluoromethylsulfonate (87 μl, 0.38 mmol, 1.0 equiv) were added sequentially. After stirring at 0 C for 2 h, a saturated aqueous solution of sodium bicarbonate (5 ml) was added and the biphasic mixture was allowed to warm to 23 C. The phases were separated and the aqueous phase was extracted with dichloromethane (2 20 ml). The organic extracts were combined and the combined solution was dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was S11

12 concentrated. The residue was purified by flash-column chromatography (2% ethyl acetate in hexanes) to provide the pure syn diastereomer 44 (81mg, 65% over 2 steps). Methyl 2-Epoxy-3-hydroxy-3-phenylpropanoate (50) (syn diastereomer). Titanium (IV) isopropoxide (31 μl, 0.10 mmol, 0.2 equiv) was added dropwise to a stirring solution of the allylic alcohol (100 mg, 0.52 mmol, 1 equiv, racemic) in dichloromethane (5 ml) at 20 C containing activated 4Å molecular sieves (60 mg, powdered). After stirring at 20 C for 20 min, a solution of tert-butyl hydroperoxide in benzene (2.9 M, 359 μl, 1.04 mmol, 2.0 equiv) was added dropwise. Reaction mixture was allowed to warm to 15 C, then was stirred at this temperature for 18 h. Titanium (IV) isopropoxide (31 μl, 0.10 mmol, 0.2 equiv) was added to above reaction mixture at 15 C. After stirring at 15 C for 20 min, a solution of tert-butyl hydroperoxide in benzene (2.9 M, 359 μl, 1.04 mmol, 2.0 equiv) was added dropwise. After stirring at 15 C for 10 h, water (2.0 ml) was added. The resulting biphasic mixture was allowed to warm to 23 C, then was stirred vigorously at this temperature for 30 min. The phases were separated and the aqueous phase was extracted with dichloromethane (2 35 ml). The organic extracts were combined and dried over anhydrous magnesium sulfate. The dried solution was filtered and the filtrate was concentrated. 1 H NMR analysis of the residue indicated that the crude epoxy alcohol 50 was formed with 20:1 syn selectivity. Residue was purified by flash-column chromatography (gradient elution with 10 20% ethyl acetate in hexanes) to provide the pure syn diastereomer of the epoxy alcohol 50 as a colorless oil (66 mg, 61%). 1 H NMR (500 MHz, CDCl 3 ) δ: 7.43 (d, 2H, J = 7.5 Hz), (m, 3H), 5.18 (d, 1H, J = 6.0 Hz), 3.74 (s, 3H), 3.14 (d, 1H, J = 5.5 Hz), 2.90 (d, 1H, J = 5.5 Hz), 2.89 (d, 1H, J = 5.5 Hz). 13 C NMR (125 MHz, CDCl 3 ), δ: 170.0, 138.4, 128.4, 128.3, 127.0, 71.8, 58.9, 52.7, FTIR (neat), cm 1 : 3501 (br), 2955 (m), 2926 (m), 2866 (m), 1738 (s), 1252 (s), 1123 (s), 1046 (s). HRMS (ESI): Calcd for (C 11 H 12 O 4 +Na + ) , found: Methyl 3-tert-Butyldimethylsilyloxy-2-epoxy-3-phenylpropanoate (46) (syn diastereomer). tert-butyldimethylsilyl trifluoromethylsulfonate (27 μl, 0.12 mmol, 1.1 equiv) was added dropwise to a stirring solution of the epoxy alcohol 50 (22 mg, 0.11 mmol, 1 equiv) and N,Ndiisopropylethylamine (22 μl, 0.13 mmol, 1.2 equiv) in dichloromethane (1.0 ml) at 0 C. After stirring at 0 C for 50 min, the saturated solution of aqueous sodium bicarbonate was added (2.0 ml) and the resulting biphasic mixture was allowed to warm to 23 C. The phases were separated and the aqueous phase was extracted with dichloromethane (2 30 ml). The organic extracts were combined and dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue was purified by flash-column chromatography (2% ethyl acetate in hexanes) to provide the pure syn diastereomer 46 as a colorless oil (26 mg, 77%). 1 H NMR (500 MHz, CDCl 3 ) δ: (m, 5H), 5.46 (s, 1H), 3.75 (s, 3H), 2.84 (d, 1H, J = 5.5 Hz), 2.38 (d, 1H, J = 6.0 Hz), 0.83 (s, 9H), 0.05 (s, 3H), 0.17 (s, 10 Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc. 1999, 121, S12

13 3H). 13 C NMR (125 MHz, CDCl 3 ), δ: 169.8, 138.4, 128.2, 128.0, 127.9, 72.6, 60.3, 52.4, 48.3, 25.6, 18.1, 4.8, 5.3. FTIR (neat), cm 1 : 2955 (m), 2930 (m), 2857 (m), 1740 (s), 1250 (s), 1090 (s), 1067 (s). HRMS (ESI): Calcd for (C 17 H 26 O 4 Si+Na + ): , found: Preparation of Methyl trans-deuterio-α-methylene-β-tert-butyldimethylsilyloxycarboxylate Esters. Methyl 3-Deuteriopropiolate (11). 11 Methyl propiolate (2 ml, mmol, 1 equiv) was added to a vigorously stirring biphasic mixture of deuterium oxide (3.4 ml), anhydrous potassium carbonate (55 mg, 0.40 mmol, 1.8 mol%) and tetra-n-butylammonium iodide (100 mg, 0.27 mmol, 1.2 mol%) in dichloromethane (5 ml) at 23 C. After stirring at 23 C for 3 h, the organic phase was separated, then added to a vigorously stirring solution of anhydrous potassium carbonate (55 mg, 0.40 mmol, 1.8 mol%) in deuterium oxide (3.4 ml) at 23 C. After stirring at 23 C for 3 h, the phases were separated and the aqueous phase was extracted with dichloromethane (5 ml). The organic extracts were combined and the combined solution was dried over anhydrous magnesium sulfate. The dried solution was filtered, providing a clear, yellow solution of methyl 3-deuteriopropiolate (11) in dichloromethane (~2.0 M, 10 ml; 90% incorporation of deuterium, as determined by 1 H NMR spectroscopy). Methyl (Z)-3-Cyclohexyl-3-hydroxy-2-(deuterio(iodo)methylene)propanoate (52). Cyclohexanecarboxaldehyde (466 μl, 3.85 mmol, 1 equiv) was added to a stirring suspension of anhydrous magnesium iodide (1.28 g, 4.62 mmol, 1.2 equiv) in dichloromethane (25 ml) at 0 C and the resulting light-yellow mixture was stirred at 0 C for 5 min. Then, the solution of methyl 3- deuteriopropiolate in dichloromethane (~2.0 M, 2.5 ml, 5.00 mmol, 1.3 equiv) prepared above was added. The reaction mixture was allowed to warm to 23 C and was stirred for 23 h. Then, the reaction mixture was partitioned between a saturated aqueous solution of sodium bicarbonate (40 ml) and dichloromethane (40 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (2 50 ml). The organic extracts were combined and the combined solution was dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was concentrated. 1 H NMR analysis of the residue revealed a 9:1 mixture of Z and E isomers, respectively. The mixture was separated by flash-column chromatography (gradient elution with 5 10% ethyl acetate in hexanes) to provide the pure Z-isomer 52 as a colorless, light-sensitive oil (620 mg, 50%). 1 H NMR (500 MHz, CDCl 3 ) δ: 4.09 (t, 1H, J = 7.0 Hz), 3.84 (s, 3H), 2.44 (d, 1H, J = 7.0 Hz), 1.90 (d, 1H, J = 12.5 Hz), (m, 2H), (m, 1H), (m, 2H), (m, 3H), (m, 2H). 13 C NMR (125 MHz, CDCl 3 ) δ: 167.0, 145.8, 84.6 (t, J = 28.8 Hz), 80.1, 52.0, 42.3, 29.5, 28.1, 26.2, 26.0, FTIR (neat), cm 1 : 3476 (br), 2925 (s), 2851 (m), 1714 (s), 1263 (s). HRMS (ESI): Calcd for (C 11 H 16 DIO 3 +Na + ): , found: (a) Labuschange, A. J. H.; Schneider, D. F. Tetrahedron Lett. 1983, 24, (b) Schwier, T.; Gevorgyan, V. Org. Lett. 2005, 7, S13

14 Methyl (Z)-3-Hydroxy-2-(deuterio(iodo)methylene)-3-phenylpropanoate (54). Benzaldehyde (312 μl, 3.07 mmol, 1 equiv) was added to a stirring suspension of anhydrous magnesium iodide (1.03 g, 3.69 mmol, 1.2 equiv) in dichloromethane (25 ml) at 23 C. The resulting yellow-brown mixture was stirred at 23 C for 25 min. The mixture was then cooled to 0 C and the solution of methyl 3-deuteriopropiolate in dichloromethane (~2.0 M, 2.0 ml, 4.00 mmol, 1.3 equiv) prepared above was added. After stirring at 0 C for 2.5 h, the reaction mixture was allowed to warm to 23 C, then was partitioned between a saturated aqueous solution of sodium bicarbonate (30 ml) and dichloromethane (60 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (60 ml). The organic extracts were combined and the combined solution was dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was concentrated. 1 H NMR analysis of the residue revealed a 20:1 mixture of Z and E isomers, respectively. The mixture was separated by flash-column chromatography (gradient elution with 5 10% ethyl acetate in hexanes) to provide the pure Z-isomer 54 as a colorless, light-sensitive oil (562 mg, 57%). 1 H NMR (500 MHz, CDCl 3 ) δ: (m, 5H), 5.56 (d, 1H, J = 4.5 Hz), 3.73 (s, 3H), 2.81 (d, 1H, J = 5.0 Hz). 13 C NMR (125 MHz, CDCl 3 ) δ: 166.3, 145.0, 140.0, 128.7, 128.3, 126.5, 87.0 (t, J = 28.7 Hz), 76.0, FTIR (neat), cm 1 : 3471 (br), 1713 (s), 1245 (s) 1038 (s), 1024 (s). HRMS (ESI): Calcd for (C 11 H 10 DIO 3 +Na + ) , found: Methyl (Z)-3-Hydroxy-2-(deuterio(iodo)methylene)-3-(4-methoxyphenyl)propanoate (56). 4-Methoxybenzaldehyde (467 μl, 3.84 mmol, 1 equiv) was added to a stirring suspension of anhydrous magnesium iodide (1.28 g, 4.60 mmol, 1.2 equiv) in dichloromethane (25 ml) at 0 C. Then, the solution of methyl 3-deuteriopropiolate in dichloromethane (~2.0 M, 2.5 ml, 4.99 mmol, 1.3 equiv) prepared above was added. After stirring at 0 C for 14 h, the reaction mixture was allowed to warm to 23 C, then was partitioned between a saturated aqueous solution of sodium bicarbonate (25 ml) and dichloromethane (25 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (2 30 ml). The organic extracts were combined and the combined solution was dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was concentrated. 1 H NMR analysis of the residue revealed a 20:1 mixture of Z and E isomers, respectively. The mixture was separated by flash-column chromatography (gradient elution with 5 15% ethyl acetate in hexanes) to provide the pure Z-isomer 56 as a colorless, light-sensitive oil (1.0 g, 75%). 1 H NMR (500 MHz, CDCl 3 ) δ: 7.25 (d, 2H, J = 9.0 Hz), 6.88 (d, 2H, J = 8.5 Hz), 5.51 (d, 1H, J = 5.5 Hz), 3.80 (s, 3H), 3.73 (s, 3H), 2.64 (d, 1H, J = 5.0 Hz). 13 C NMR (125 MHz, CDCl 3 ) δ: 166.4, 159.5, 145.4, 132.2, 127.9, 114.0, 86.1 (t, J = 28.3 Hz), 75.5, 55.3, FTIR (neat), cm 1 : 3466 (br), 1715 (s), 1510 (s), 1244 (vs), 1028 (s). HRMS (ESI): Calcd for (C 12 H 12 DIO 4 +Na + ): , found: S14

15 Methyl (Z)-3-Hydroxy-2-(deuterio(iodo)methylene)-3-(4-cyanophenyl)propanoate (58). 4-Cyanobenzaldehyde (757 mg, 5.77 mmol, 1 equiv) was added to a stirring suspension of anhydrous magnesium iodide (1.93 g, 6.93 mmol, 1.2 equiv) in dichloromethane (38 ml) at 0 C and the resulting yellow mixture was stirred at 0 C for 5 min. Then, the solution of methyl 3-deuteriopropiolate in dichloromethane (~2.0 M, 3.8 ml, 7.51 mmol, 1.3 equiv) prepared above was added. The reaction mixture was allowed to warm to 23 C and was stirred for 37 h. The reaction mixture was partitioned between a saturated aqueous solution of sodium bicarbonate (50 ml) and dichloromethane (50 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (2 70 ml). The organic extracts were combined and the combined solution was dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was concentrated. 1 H NMR analysis of the residue revealed a 12:1 mixture of Z and E isomers, respectively. The mixture was separated by flash-column chromatography (gradient elution with 10 20% ethyl acetate in hexanes) to provide the pure Z-isomer 58 as a colorless, light-sensitive oil (1.05 g, 53%). 1 H NMR (500 MHz, CDCl 3 ) δ: 7.65 (d, 2H, J = 8.5 Hz), 7.47 (d, 2H, J = 8.0 Hz), 5.59 (d, 1H, J = 5.5 Hz), 3.75 (s, 3H), 3.12 (d, 1H, J = 5.5 Hz). 13 C NMR (125 MHz, CDCl 3 ) δ: 165.8, 145.5, 143.9, 132.4, 127.1, 118.5, 111.8, 88.6 (t, J = 28.1 Hz), 75.3, FTIR (neat), cm 1 : 3475 (br), 2229 (m), 1710 (s), 1245 (s), 1044 (s). HRMS (ESI): Calcd for (C 12 H 9 DINO 3 +NH 4 + ): , found: Methyl (Z)-3-tert-Butyldimethylsilyloxy-3-cyclohexyl-2-(deuterio(iodo)methylene)propanoate (12). tert-butyldimethylsilyl trifluoromethylsulfonate (280 μl, 1.22 mmol, 1.1 equiv) was added dropwise to a stirring solution of the allylic alcohol 52 (360 mg, 1.11 mmol, 1 equiv) and N,Ndiisopropylethylamine (231 μl, 1.33 mmol, 1.2 equiv) in dichloromethane (10 ml) at 0 C. After stirring at 0 C for 20 min, a saturated aqueous solution of sodium bicarbonate was added (5 ml) and the resulting biphasic mixture was allowed to warm to 23 C. The phases were separated and the aqueous phase was extracted with dichloromethane (2 50 ml). The organic extracts were combined and the combined solution was dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue was purified by flash-column chromatography (gradient elution with 2 5% ethyl acetate in hexanes) to provide the tert-butyldimethylsilyl ether 12 as a colorless oil (444 mg, 91%). 1 H NMR (500 MHz, CDCl 3 ) δ: 4.26 (d, 1H, J = 4.5 Hz), 3.81 (s, 3H), (m, 5H), (m, 1H), (m, 5H), 0.90 (s, 9H), 0.05 (s, 3H), 0.02 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ: 166.7, 146.9, 82.8 (t, J = 28.6 Hz), 78.6, 51.6, 43.1, 29.6, 26.8, 26.3, 26.2, 26.0, 25.7, 18.0, 4.9, 5.3. FTIR (neat), cm 1 : 2949 (m), 2928 (m), 2854 (m), 1732 (s), 1252 (s). HRMS (ESI): Calcd for (C 17 H 30 DIO 3 Si+Na + ): , found: S15