Supporting Information

Supporting Information A Convergent Synthesis of Enantiopure pen-chain, Cyclic and Fluorinated α-amino Acids Shi-Guang Li, Fernando Portela-Cubillo and Samir Z. Zard* Laboratoire de Synthése rganique, CNRS UMR 7652, Ecole Polytechnique, 91128 Palaiseau Cedex, France samir.zard@polytechnique.edu Contents: General Experimental Methods........S2 Experimental Procedures and Spectroscopic Data...S3-S44 Copies of 1 H and 13 C NMR Spectra.........S45-S117 S1

General Experimental Methods Purification procedures were in accordance with the instructions in D. D. Perrin and W. L. F. Armarego, Purification of Laboratory Chemicals, Fourth Edition, The Bath Press, Bath, 2002. All reactions were carried out under dry, oxygen free nitrogen. Flash chromatography was performed on silica gel (SDS, 60 Å C. C. 40-63 mm) as the stationary phase. Thin Layer Chromatography (TLC) was performed on alumina plates pre-coated with silica gel (Merck silica gel, 60 F254), which were visualized by the quenching of UV fluorescence when applicable (λmax = 254 nm and/or 366 nm) and/or by staining with vanillin or anisadehyde in acidic ethanol and/or KMn 4 in basic water followed by heating. Melting points were recorded by heating on Reichert plates under a microscope and are uncorrected. Infrared spectra were recorded as solutions in CCl 4 using CaF 2 cells or as solids in Nujol using KBr cells, on a Perkin-Elmer FT 1600. Absorption maxima (νmax) are reported in wavenumbers (cm -1 ) and only selected peaks are reported. Nuclear magnetic resonance spectra were recorded at ambient temperature on a Bruker Avance DPX 400 instrument. Proton magnetic resonance spectra ( 1 H NMR) were recorded at 400 MHz and coupling constants (J) are reported to ± 0.5 Hz. The following abbreviations were utilized to describe peak patterns when appropriate: br = broad, s = singlet, d = doublet, t = triplet, q = quartet and m = multiplet. Carbon magnetic resonance spectra ( 13 C NMR) were recorded at 100.6 MHz. Chemical shifts (δ H, δ C ) are quoted in parts per million (ppm) and are referenced to the residual solvent peak (CDCl 3 : δ H = 7.26 and δ C = 77.0; DMS: δ H = 2.50 and δ C = 39.43). Low-resolution mass spectra (m/z) were recorded by chemical ionization (CI/NH 3 ) on a Hewlett-Packard HP 5989B and only report molecular species ([M+H] +, [M+NH 4 ] + ) and other major fragments. High-resolution mass spectra were recorded by positive electron impact ionization (EI+) at 70 ev on a JEL JMS-GCmate II mass spectrometer. The quoted masses are accurate to ± 5 ppm. The names of the molecules that appear in the following pages were generated using either BeilsteinAutoNom 2000 (CAS) or ChemBioDraw Ultra 12.0 S2

Experimental Procedures and Spectroscopic Data General procedure A: A solution of xanthate (2.0 equiv) and olefin (1.0 equiv) in ethyl acetate (AcEt) (1 ml/mmol of xanthate) was refluxed for 15 min under a nitrogen flow. Dilauroyl peroxide (DLP) (10 mol %) was then added and additional DLP (5 mol %) was added every 90 min until total consumption of the starting xanthate or until no evolution could be detected by TLC analysis. The reaction mixture was then cooled to 20 C and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography on silica gel to yield the desired xanthate adduct. General procedure B: A solution of xanthate (1.0 equiv), triethylamine (5.5 equiv) and hypophosphorous acid (50% in water) (5.0 equiv) in dioxane (10 ml/mmol of xanthate) was refluxed under nitrogen for 15 minutes. AIBN (0.1 equiv) was then added to the solution, and reflux was kept for an additional 1 h under N 2 (if necessary, another 0.1 equiv of AIBN was added to the solution and kept reflux for another 1 h). The resulting mixture was partitioned between ethyl acetate and water. The organic layer was then washed with brine, dried over anhydrous MgS 4, filtered, and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography to afford the reduced product. General procedure C: A solution of xanthate (1.0 equiv) in propan-2-ol (10 ml/mmol of xanthate) was refluxed for 15 min under nitrogen. Dilauroyl peroxide was then added portionwise (20 mol% per hour) to the refluxing solution. When starting material was totally consumed (detected by TLC), the crude mixture was cooled to room temperature, concentrated under reduced pressure and purified by flash column chromatography to give reduced product. S3

(R)-methyl 2-(benzyloxycarbonylamino)-5-cyano-3-(ethoxycarbonothioylthio) pentanoate (6a). Following general procedure A, compound 6a was obtained in 82% yield (337 mg, Purified by flash chromatography with petroleum ether/ethyl acetate = 19/1) as yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ = 7.40 (m, 5 H, 5 CH), 5.64 (m, 1 H, NH) [d, 1 H, J = 8.3 Hz, NH], 5.16 (s, 2 H, CH 2 ), 4.82 (m, 1 H, CH), 4.68 (q, 2 H, J = 7.1 Hz, CH 2 ), 4.54 (m, 1 H, CH), 3.78 (s, 3 H, CH 3 ), 2.64 (m, 2 H, CH 2 ), 2.28 (m, 1 H, CHH), 2.07 (m, 1 H, CHH), 1.47 (t, 3 H, J = 7.1 Hz, CH 3 ). 13 C NMR (100 MHz, CDCl 3 ): δ = 210.9 (C), 170.0 (C), 156.4 (C), 135.7 (C), 128.7 (2 CH), 128.5 (CH), 128.2 (2 CH), 118.7 (C), 71.2 (CH 2 ), 67.7 (CH 2 ), 56.4 (CH), 53.1 (CH 3 ), 52.9 (CH 3 ), 40.1 (CH), 29.0 (CH 2 ), 15.1 (CH 3 ), 13.7 (CH 3 ). IR (CCl 4 ) (ν max/cm -1 ): 3443, 2952, 2251, 1774, 1728, 1540. HRMS: m/e calcd. For C 18 H 22 N 2 5 S 2 : 410.0970, Found 410.0966. (S)-methyl 2-(benzyloxycarbonylamino)-5-cyanopentanoate (7a). Following general procedure B, compound 7a was obtained in 80% yield (190 mg, Purified by flash chromatography with petroleum ether/ethyl acetate = 19/1) as yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ = 7.39 (m, 5 H, 5 CH), 5.49 (m, 1 H, NH), 5.15 (s, 2 H, CH 2 ), 4.44 (m, 1 H, CH), 3.80 (s, 3 H, CH 3 ), 2.47 (m, 2 H, CH 2 ), 2.06 (m, 1 H, CHH), 1.76 (m, 1 H, CHH), 1.78 (m, 2 H, CH 2 ). 13 C NMR (100 MHz, CDCl 3 ): δ = 172.3 (C), 156.0 (C), 136.1 (C), 128.6 (2 CH), 128.4 (CH), 128.2 (2 CH), 119.1 (C), 67.2 (CH 2 ), 53.0 (CH), 52.7 (CH 3 ), 31.8 (CH 2 ), 21.6 (CH 2 ), 16.8 (CH 2 ). IR (CCl 4 ) (ν max/cm -1 ): 3443, 2954, 2250, 1728, 1540. [α] 20 D = + 7.3 (c 1.6, CHCl 3 ). HRMS: m/e calcd. For C 15 H 18 N 2 4 : 290.1267, Found 290.1266. S4

(R)-methyl 2-(benzyloxycarbonylamino)-5-cyano-3-(ethoxycarbonothioylthio)- 5-methylhexanoate (6b). Following general procedure A, compound 6b was obtained in 54% yield (236 mg, Purified by flash chromatography with petroleum ether/ethyl acetate = 19/1) as yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ = 7.40 (m, 5 H, 5 CH), 5.64/5.59 (d, 1 H, J = 8.5 Hz, NH), 5.17 (s, 2 H, CH 2 ), 4.96/4.83 (dd, 1 H, J = 3.0 Hz, 8.2 Hz, CH), 4.68 (m, 2 H, CH 2 ), 4.64/4.50 (m, 1 H, CH), 3.85/3.77 (s, 3 H, CH 3 ), 2.20/1.94 (m, 2 H, CH 2 ), 1.46 (m, 3 H, CH 3 ), 1.48/1.47 (s, 6 H, 2 CH 3 ). 13 C NMR (100 MHz, CDCl 3 ): δ = 212.1/211.9 (C), 169.8 (C), 156.3 (C), 135.9 (C), 128.6 (2 CH), 128.3/128.2 (2 CH), 128.1 (CH), 124.2 (C), 71.0/70.8 (CH 2 ), 67.5 (CH 2 ), 58.0/57.8 (CH), 53.2/52.9 (CH 3 ), 50.1/49.4 (CH 2 ), 42.6 (CH 2 ), 31.8 (CH), 27.5 (2xCH 3 ), 26.9 (C) 13.7 (CH 3 ). IR (CCl 4 ) (ν max/cm -1 ): 3442, 2954, 2251, 1780, 1728, 1540. HRMS: m/e calcd. For C 20 H 26 N 2 5 S 2 : 438.1283, Found 438.1286. (S)-methyl 2-(benzyloxycarbonylamino)-5-cyano-5-methylhexanoate (7b). Following general procedure B, compound 7b was obtained in 70% yield (120 mg, Purified by flash chromatography with petroleum ether/ethyl acetate = 19/1) as yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ = 7.41 (m, 5 H, 5 CH), 5.40 (m, 1 H, NH), 5.16 (s, 2 H, CH 2 ), 4.46 (m, 1 H, CH), 3.81 (s, 3 H, CH 3 ), 2.13 (m, 1 H, CHH), 1.86 (m, 1 H, CHH), 1.61 (m, 2 H, CH 2 ), 1.37 (s, 6 H, 2 CH 3 ). 13 C NMR (100 MHz, CDCl 3 ): δ = 172.3 (C), 156.0 (C), 136.1 (C), 128.6 (2 CH), 128.3 (CH), 128.2 (2 CH), 119.2 (C), 67.2 (CH 2 ), 53.6 (CH), 52.7 (CH 3 ), 36.6 (CH 2 ), 32.1 (CH 2 ), 28.8 (CH 2 ), 26.7 (CH 3 ), 26.4 (CH 3 ). IR (CCl 4 ) (ν max/cm -1 ): 3442, 2954, 2251, 1728, 1540. [α] 20 D = + 6.9 (c S5

1.0, CHCl 3 ). HRMS: m/e calcd. For C 17 H 22 N 2 4 : 318.1580, Found 318.1578. (R)-methyl 2-(benzyloxycarbonylamino)-3-(ethoxycarbonothioylthio)-5,5-di- methyl hexanoate (6c). Following general procedure A, compound 6c was obtained in 63% yield (269 mg, Purified by flash chromatography with petroleum ether/ethyl acetate = 19/1) as yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ = 7.39 (m, 5 H, 5 CH), 5.66 (d, 1 H, J = 9.2 Hz, NH), 5.16 (s, 2 H, CH 2 ), 4.92/4.69 (dd, 1 H, J = 3.1 Hz, 9.1 Hz, CH), 4.68 (m, 2 H, CH 2 ), 4.45/4.33 (m, 1 H, CH), 3.80/3.74 (s, 3 H, CH 3 ), 1.79/1.65 (m, 1 H, CHH), 1.54 (m, 1 H, CHH), 1.44 (m, 3 H, CH 3 ), 1.03/0.98 (s, 9 H, 3 CH 3 ). 13 C NMR (100 MHz, CDCl 3 ): δ = 212.6/213.0 (C), 170.6 (C), 156.2 (C), 136.2 (C), 128.6 (2 CH), 128.3 (CH), 128.2/128.1 (2 CH), 70.5/70.2 (CH 2 ), 67.2 (CH 2 ), 58.7/58.5 (CH), 52.6 (CH 3 ), 49.5/48.8 (CH 2 ), 45.2/42.4 (CH), 31.4/31.2 (C), 29.5/29.4 (3xCH 3 ), 13.8 (CH 3 ). IR (CCl 4 ) (ν max/cm -1 ): 3437, 3036, 1772, 1735, 1717. HRMS: m/e calcd. For C 20 H 29 N 5 S 2 : 427.1487, Found 427.1486. (S)-methyl 2-(benzyloxycarbonylamino)-5,5-dimethylhexanoate (7c). Following general procedure B, compound 7c was obtained in 75% yield (145 mg, Purified by flash chromatography with petroleum ether/ethyl acetate = 19/1) as yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ = 7.40 (m, 5 H, 5 CH), 5.36 (m, 1 H, NH), 5.16 (s, 2 H, CH 2 ), 4.40 (m, 1 H, CH), 3.78 (s, 3 H, CH 3 ), 1.85 (m, 1 H, CHH), 1.69 (m, 1 H, CHH), 1.23 (m, 2 H, CH 2 ), 0.85 (s, 9 H, 3 CH 3 ). 13 C NMR (100 MHz, CDCl 3 ): δ = 173.7 (C), 156.5 (C), 136.4 (C), 128.6 (2 CH), 128.2 (2 CH), 128.1 (CH), 67.1 (C), 54.5 (CH), 52.3 (CH 3 ), 39.2 (CH 2 ), 30.1 (C), 29.2 (3 CH 3 ), 27.9 (CH 2 ). IR (CCl 4 ) (ν S6

max/cm -1 ): 3437, 3036, 1735, 1719, 1550. [α] 20 D= + 13.6 (c 4.9, CHCl 3 ). HRMS: m/e calcd. For C 17 H 25 N 4 : 318.1580, Found 318.1583. (R)-dimethyl 2-(benzyloxycarbonylamino)-3-(ethoxycarbonothioylthio)- hexanedioate (6d). Following general procedure A, compound 6d was obtained in 81% yield (359 mg, Purified by flash chromatography with petroleum ether/ethyl acetate = 19/1) as yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ = 7.37 (m, 5 H, 5 CH), 5.64/5.67 (d, 1 H, J = 9.0 Hz, NH), 5.14 (s, 2 H, CH 2 ), 4.92/4.88 (dd, 1 H, J = 3.7 Hz, 9.0 Hz, CH), 4.67 (m, 2 H, CH 2 ), 4.47/4.32 (s, 3 H, CH 3 ), 3.70/3.69 (s, 3 H, CH 3 ), 2.55 (m, 2 H, CH 2 ), 2.23/2.11 (m, 1 H, CHH), 1.93 (m, 1 H, CHH), 1.42 (m, 3 H, CH 3 ). 13 C NMR (100 MHz, CDCl 3 ): δ = 212.6/212.2 (C), 172.9 (C), 170.3 (C), 156.0/ 156.2 (C), 136.0 (C), 128.6 (2 CH), 128.3 (C), 128.1 (2 CH), 70.7/70.8 (CH 2 ), 67.4/67.3 (CH 2 ), 57.0 (CH), 52.9/52.8 (CH 3 ), 52.6/51.8 (CH 3 ), 31.3/31.2 (CH 2 ), 27.7/25.8 (CH 2 ), 13.7 (CH 3 ). IR (CCl 4 ) (ν max/cm -1 ): 3432, 2955, 1750, 1733, 1550. HRMS: m/e calcd. For C 19 H 25 N 7 S 2 : 443.1072, Found 443.1070. (S)-dimethyl 2-(benzyloxycarbonylamino)hexanedioate (7d). Following general procedure B, compound 7d was obtained in 73% yield (191 mg, Purified by flash chromatography with petroleum ether/ethyl acetate = 19/1) as yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ = 7.38 (m, 5 H, 5 CH), 5.45 (m, 1 H, NH), 5.14 (m, 2 H, CH 2 ), 4.42 (m, 1 H, CH), 3.77 (m, 3 H, CH 3 ), 3.69 (m, 3 H, CH 3 ), 2.37 (m, 2 H, CH 2 ), 1.90 (m, 1 H, CHH), 1.73 (m, 1 H, CHH), 1.70 (m, 2 H, CH 2 ). 13 C NMR (100 MHz, CDCl 3 ): δ = 173.5 (C), 172.7 (C), 156.0 (C), 136.2 (C), 128.5 (2 CH), 128.2 S7

(2 CH), 128.1 (CH), 67.0 (CH 2 ), 53.7 (CH), 52.4 (CH 3 ), 51.5 (CH 3 ), 33.3 (CH 2 ), 31.9 (CH 2 ), 26.6 (CH 2 ). IR (CCl 4 ) (ν max/cm -1 ): 3441, 2954, 1741, 1728, 1547. [α] 20 D = + 8.6 (c 1.4, CHCl 3 ). HRMS: m/e calcd. For C 16 H 21 N 6 : 323.1369, Found 323.1366. (R)-methyl 2-(benzyloxycarbonylamino)-3-(ethoxycarbonothioylthio)-6- (methoxy(methyl)amino)-6-oxohexanoate (6e). Following general procedure A, compound 6e was obtained in 68% yield (321 mg, Purified by flash chromatography with petroleum ether/ethyl acetate = 19/1) as yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ = 7.87 (m, 5 H, 5 CH), 5.72 (t, 1 H, NH), 5.14 (s, 2 H, CH 2 ), 4.95/4.82 (dd, 1 H, J = 3.5 Hz, 9.0 Hz, CH), 4.65 (m, 2 H, CH 2 ), 4.44/4.32 (m, 1 H, CH), 3.80/3.74 (s, 3 H, CH 3 ), 3.68 (s, 3 H, CH 3 ), 3.18 (s, 3 H, CH 3 ), 2.64 (m, 2 H, CH 2 ), 2.22 (m, 1 H, CHH), 2.09 (m, 1 H, CHH), 1.96 (m, 2 H, CH 2 ), 1.45 (m, 3 H, CH 3 ). 13 C NMR (100 MHz, CDCl 3 ): δ = 212.8/212.4 (C), 170.5/170.4 (C), 156.2/156.1 (C), 136.1/136.0 (C), 128.6 (2 CH), 128.2/128.3 (CH), 128.1 (2 CH), 70.7/70.5 (CH 2 ), 67.3/67.2 (CH 2 ), 61.3 (CH 3 ), 57.0 (CH), 52.7/52.6 (CH 3 ), 32.3/29.3 (CH 2 ), 27.1/25.0 (CH 2 ), 13.7 (CH 3 ). IR (CCl 4 ) (ν max/cm -1 ): 3430, 3031, 1772, 1742, 1672, 1546, 1504. HRMS: m/e calcd. For C 20 H 28 N 2 7 S 2 : 472.1338, Found 4472.1335. (S)-methyl 2-(benzyloxycarbonylamino)-6-(methoxy(methyl)amino)-6- oxohexanoate (7e). Following general procedure B, compound 7e was obtained in 80% yield (192 mg, Purified by flash chromatography with petroleum ether/ethyl acetate = 19/1) as yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ = 7.40 (m, 5 H, 5 CH), 5.51 (m, 1 H, NH), 5.14 (s, 2 S8

H, CH 2 ), 4.41 (m, 1 H, CH), 3.77 (s, 3 H, CH 3 ), 3.69 (s, 3 H, CH 3 ), 3.20 (s, 3 H, CH 3 ), 2.49 (m, 2 H, CH 2 ), 1.92 (m, 3 H, CH 2 ), 1.74 (m, 2 H, CH 2 ). 13 C NMR (100 MHz, CDCl 3 ): δ = 172.9 (2xC), 156.0 (C), 136.3 (C), 128.6 (2 CH), 128.2 (2 CH), 128.1 (CH), 67.0 (CH 2 ), 61.3 (CH 3 ), 53.7 (CH), 52.5 (CH 3 ), 32.1 (CH 3 ), 31.1 (CH 2 ), 22.6 (CH 2 ), 20.2 (CH 2 ). IR (CCl 4 ) (ν max/cm -1 ): 3431, 3036, 2955, 1742, 1735, 1672, 1546, 1504. [α] 20 D = + 9.7 (c 1.8, CHCl 3 ). HRMS: m/e calcd. For C 17 H 24 N 2 6 : 352.1634, Found 352.1633. (R)-methyl 2-(benzyloxycarbonylamino)-3-(ethoxycarbonothioylthio)-7,7- dimethoxy-6-oxoheptanoate (6f). Following general procedure A, compound 6f was obtained in 73% yield (356 mg, Purified by flash chromatography with petroleum ether/ethyl acetate = 19/1) as yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ = 7.37 (m, 5 H, 5 CH), 5.63 (m, 1 H, NH), 5.14 (s, 2 H, CH 2 ), 4.92/4.80 (dd, 1 H, J = 3.3 Hz, 8.9 Hz, CH), 4.64 (m, 2 H, CH 2 ), 4.49/4.47 (s, 1 H, CH), 4.38/4.24 (m, 1 H, CH), 3.82/3.74 (s, 3 H, CH 3 ), 3.41 (s, 3 H, CH 3 ), 2.79 (m, 2 H, CH 2 ), 2.15/2.04 (m, 1 H, CHH), 1.92/1.85 (m, 1 H, CHH), 1.44 (m, 3 H, CH 3 ). 13 C NMR (100 MHz, CDCl 3 ): δ = 212.6/212.3 (C), 204.3 (C), 170.4 (C), 156.2 (C), 136.0 (C), 128.6 (2 CH), 128.3 (CH), 128.1 (2 CH), 103.9 (CH), 70.6 (CH 2 ), 67.4 (CH 2 ), 57.0 (CH), 54.8 (2xCH 3 ), 52.8/53.1 (CH 3 ), 34.7 (CH), 25.6 (CH 2 ), 23.6 (CH 2 ), 13.7 (CH 3 ). IR (CCl 4 ) (ν max/cm -1 ): 3430, 2958, 1745, 1727, 1548. HRMS: m/e calcd. For C 21 H 29 N 8 S 2 : 487.1335, Found 487.1334. (S)-methyl 2-(benzyloxycarbonylamino)-7,7-dimethoxy-6-oxoheptanoate (7f). Following general procedure B, compound 7f was obtained in 80% yield (214 mg, S9

Purified by flash chromatography with petroleum ether/ethyl acetate = 19/1) as yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ = 7.40 (m, 5 H, 5 CH), 5.38 (m, 1 H, NH), 5.14 (m, 2 H, CH 2 ), 4.49 (m, 2 H, CH 2 ), 3.80 (s, 3 H, CH 3 ), 3.43 (s, 6 H, 2 CH 3 ), 2.63 (m, 2 H, CH 2 ), 1.87 (m, 1 H, CHH), 1.73 (m, 1 H, CHH), 1.68 (m, 2 H, CH 2 ). 13 C NMR (100 MHz, CDCl 3 ): δ = 205.1 (C), 172.7 (C), 155.9 (C), 136.5 (C), 128.6 (2 CH), 128.2 (2 CH), 128.1 (CH), 104.0 (CH), 67.2 (CH 2 ), 54.9 (CH), 53.6 (2xCH 3 ), 52.6(CH 3 ), 36.4 (CH 2 ), 32.0 (CH 2 ), 18.5 (CH 2 ). IR (CCl 4 ) (ν max/cm -1 ): 3430, 2958, 1745, 1726, 1548. [α] 20 D = + 6.7 (c 1.0, CHCl 3 ). HRMS: m/e calcd. For C 18 H 25 N 7 : 367.1631, Found 367.1630. (R)-methyl 2-(benzyloxycarbonylamino)-7-chloro-3-(ethoxycarbonothioylthio)-6- oxoheptanoate (6g). Following general procedure A, compound 6g was obtained in 67% yield (309 mg, Purified by flash chromatography with petroleum ether/ethyl acetate = 19/1) as yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ = 7.39 (m, 5 H, 5 CH), 5.63 (m, 1 H, NH), 5.16 (s, 2 H, CH 2 ), 4.91/4.83 (dd, 1 H, J = 3.5 Hz, 8.8 Hz, CH), 4.67 (m, 2 H, CH 2 ), 4.44/4.29 (m, 1 H, CH), 4.11 (s, 2 H, CH 2 ), 3.85/3.76 (s, 3 H, CH 3 ), 2.86 (m, 2 H, CH 2 ), 2.25/2.13 (m, 1 H, CHH), 1.98/1.96 (m, 1 H, CHH), 1.45 (m, 3 H, CH 3 ). 13 C NMR (100 MHz, CDCl 3 ): δ = 212.4 (C), 201.3 (C), 170.2 (C), 156.2 (C), 136.0 (C), 128.6 (2 CH), 128.4 (CH), 128.2 (2 CH), 71.0 (CH 2 ), 67.5 (CH 2 ), 56.9 (CH), 53.3 (CH 3 ), 48.2 (CH 2 ), 36.7 (CH 2 ), 26.4 (CH 2 ), 13.9 (CH 3 ). IR (CCl 4 ) (ν max/cm -1 ): 3433, 2958, 1778, 1742, 1723. HRMS: m/e calcd. For C 19 H 24 ClN 6 S 2 : 461.0734, Found 461.0731. (S)-methyl 2-(benzyloxycarbonylamino)-7-chloro-6-oxoheptanoate (7g). S10

Following general procedure B, compound 7g was obtained in 79% yield (181 mg, Purified by flash chromatography with petroleum ether/ethyl acetate = 19/1) as yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ = 7.40 (m, 5 H, 5 CH), 5.40 (m, 1 H, NH), 5.15 (s, 2 H, CH 2 ), 4.43 (m, 1 H, CH), 4.09 (s, 2 H, CH 2 ), 3.80 (s, 3 H, CH 3 ), 2.69 (m, 2 H, CH 2 ), 1.90 (m, 1 H, CHH), 1.73 (m, 1 H, CHH), 1.71 (m, 2 H, CH 2 ). 13 C NMR (100 MHz, CDCl 3 ): δ = 202.1 (C), 172.6 (C), 156.0 (C), 136.2 (C), 128.6 (2 CH), 128.3 (CH), 128.2 (2 CH), 67.1 (CH 2 ), 53.3 (CH), 52.6 (CH 3 ), 48.2 (CH 2 ), 38.7 (CH 2 ), 31.9 (CH 2 ), 19.0 (CH 2 ). IR (CCl 4 ) (ν max/cm -1 ): 3433, 2958, 1743, 1724, 1548. [α] 20 D = + 9.3 (c 2.0, CHCl 3 ). HRMS: m/e calcd. For C 16 H 20 ClN 5 : 341.1030, Found 341.1032. (R)-methyl 2-(benzyloxycarbonylamino)-6-cyclopropyl-3-(ethoxycarbonothioyl- thio)-6-oxohexanoate (6h). Following general procedure A, compound 6h was obtained in 60% yield (272 mg, Purified by flash chromatography with petroleum ether/ethyl acetate = 19/1) as yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ = 7.39 (m, 5 H, 5 CH), 5.62 (m, 1 H, NH), 5.15 (s, 2 H, CH 2 ), 4.91/4.80 (dd, 1 H, J = 3.4 Hz, 8.8 Hz, CH), 4.66 (m, 2 H, CH 2 ), 4.40/4.27 (m, 1 H, CH), 3.82/3.75 (s, 3 H, CH 3 ), 2.81 (m, 2 H, CH 2 ), 2.20/1.94 (m, 3 H, CHH), 2.07/1.94 (m, 1 H, CHH), 1.92 (m, 2 H, CH 2 ), 1.44 (m, 3 H, CH 3 ), 1.05 (m, 2 H, CH 2 ), 0.89 (m, 2 H, CH 2 ). 13 C NMR (100 MHz, CDCl 3 ): δ = 212.8/212.4 (C), 209.4 (C), 170.5 (C), 156.2 (C), 136.1 (C), 128.6/128.5 (2xCH), 128.3/128.2 (CH), 128.1 (2 CH), 70.7/70.6 (CH 2 ), 67.4/67.3 (CH 2 ), 57.1/57.0 (CH), 53.3/52.9 (CH 3 ), 40.3/40.2 (CH), 26.4 (CH 2 ), 24.4 (CH), 20.7 (CH 2 ), 18.8 (CH 3 ), 11.0 (2xCH 2 ). IR (CCl 4 ) (ν max/cm -1 ): 3443, 2953, 1772, 1738, 1727, 1547. HRMS: m/e calcd. For S11

C 21 H 27 N 6 S 2 : 453.1280, Found 453.1279. (S)-methyl 2-(benzyloxycarbonylamino)-6-cyclopropyl-6-oxohexanoate (7h). Following general procedure B, compound 7h was obtained in 79% yield (158 mg, Purified by flash chromatography with petroleum ether/ethyl acetate = 19/1) as yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ = 7.39 (m, 5 H, 5 CH), 5.43 (m, 1 H, NH), 5.15 (s, 2 H, CH 2 ), 4.42 (m, 1 H, CH), 3.78 (s, 3 H, CH 3 ), 2.63 (m, 2 H, CH 2 ), 1.91 (m, 2 H, CH 2 ), 1.70 (m, 1 H, CHH), 1.69 (m, 1 H, CHH), 1.05 (m, 2 H, CH 2 ), 0.90 (m, 2 H, CH 2 ). 13 C NMR (100 MHz, CDCl 3 ): δ = 210.1 (C), 172.8 (C), 156.0 (C), 136.3 (C), 128.5 (2 CH), 128.1 (3 CH), 67.0 (CH 2 ), 57.7 (CH), 52.4 (CH 3 ), 42.4 (CH 2 ), 31.8 (CH 2 ), 20.5 (CH), 19.4 (CH 2 ), 10.7 (2 CH 2 ). IR (CCl 4 ) (ν max/cm -1 ): 3443, 2954, 1739, 1728, 1547. [α] 20 D = + 6.0 (c 1.0, CHCl 3 ). HRMS: m/e calcd. For C 18 H 23 N 5 : 333.1576, Found 333.1573. (R)-methyl 2-(benzyloxycarbonylamino)-7-(1,3-dioxoisoindolin-2-yl)-3-(ethoxy- carbonothioylthio) -6-oxoheptanoate (6i). Following general procedure A, compound 6i was obtained in 61% yield (349 mg, Purified by flash chromatography with petroleum ether/ethyl acetate = 4/1) as yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ = 7.91 (m, 2 H, 2 CH), 7.78 (m, 2 H, 2 CH), 7.38 (m, 5 H, 5 CH), 5.58 (m, 1 H, NH), 5.15 (s, 2 H, CH 2 ), 4.90/4.82 (dd, 1 H, J = 3.8 Hz, 8.8 Hz, CH), 4.67 (m, 2 H, CH 2 ), 4.51 (s, 2 H, CH 2 ), 4.44/4.32 (m, 1 H, CH), 3.82/3.75 (m, 1 H, CH), 3.82/3.75 (s, 3 H, CH 3 ), 2.80 (m, 2 H, CH 2 ), 2.26/2.16 (m, 1 H, CHH), 2.02/1.96 (m, 1 H, CHH), 1.44 (m, 3 H, CH 3 ). 13 C NMR (100 MHz, CDCl 3 ): δ = 212.0 (C), 200.7 (C), 170.2 (C), 167.6 (2xC), 136.0 (C), 134.2 (2xCH), S12

132.2 (CH), 128.6 (2 CH), 128.3 (2xC), 128.2 (2 CH), 123.6 (2xCH), 70.9 (CH 2 ), 67.5 (CH 2 ), 59.2 (CH), 53.9 (CH 3 ), 52.8 (CH), 46.5 (CH 2 ), 37.0/36.9 (CH), 35.3 (CH 2 ), 24.2 (CH 2 ) 13.7 (CH 3 ); IR (CCl 4 ) (ν max/cm -1 ): 3352, 2926, 1777, 1729, 1455, 1046. HRMS: m/e calcd. For C 27 H 28 N 2 8 S 2 : 572.1287, Found 572.128. (S)-methyl 2-(benzyloxycarbonylamino)-7-(1,3-dioxoisoindolin-2-yl)-6-oxohep- tanoate (7i). Following general procedure B, compound 7i was obtained in 73% yield (201 mg, Purified by flash chromatography with petroleum ether/ethyl acetate = 4/1) as yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ = 7.92 (m, 2 H, 2 CH), 7.78 (m, 2 H, 2 CH), 7.39 (m, 5 H, 5 CH), 5.45 (m, 1 H, NH), 5.14 (s, 2 H, CH 2 ), 4.49 (s, 2 H, CH 2 ), 4.42 (m, 1 H, CH), 3.78 (s, 3 H, CH 3 ), 2.60 (m, 2 H, CH 2 ), 1.93 (m, 1 H, CHH), 1.75 (m, 1 H, CHH), 1.74 (m, 2 H, CH 2 ). 13 C NMR (100 MHz, CDCl 3 ): δ = 201.7 (C), 172.7 (C), 167.7 (2xC), 156.0 (C), 136.3 (C), 134.1 (2 CH), 132.0 (CH), 128.6 (2 CH), 128.2 (2xC), 128.1 (2 CH), 123.5 (2xCH), 66.5 (CH 2 ), 54.0 (CH), 52.0 (CH 3 ), 46.1 (CH 2 ), 38.6 (CH 2 ), 32.0 (CH 2 ), 19.3 (CH 2 ). IR (CCl 4 ) (ν max/cm -1 ): 3353, 2926, 1778, 1731, 1455, 1046. [α] 20 D = + 13 (c 1.0, CHCl 3 ). HRMS: m/e calcd. For C 24 H 24 N 2 7 : 452.1584, Found 452.1581. (R)-methyl 2-(benzyloxycarbonylamino)-5-(1,3-dioxoisoindolin-2-yl)-3-(ethoxy- carbonothioylthio)pentanoate (6j). Following general procedure A, compound 6j was obtained in 68% yield (179 mg, Purified by flash chromatography with petroleum ether/ethyl acetate = 4/1) as yellow oil. S13

1 H NMR (400 MHz, CDCl 3 ): δ = 7.87 (m, 2 H, 2 CH), 7.75 (m, 2 H, CH), 7.37 (m, 5 H, 5 CH), 5.62 (m, 1 H, NH), 5.14 (s, 2 H, CH 2 ), 5.00/4.94 (s, 1 H, CH), 4.63 (m, 2 H, CH 2 ), 4.42/4.32 (m, 1 H, CH), 4.00/3.90 (m, 2 H, CH 2 ), 3.78/3.74 (s, 3 H, CH 3 ), 2.27/2.17 (m, 1 H, CHH), 2.02/1.86 (m, 1 H, CHH), 1.41 (m, 3 H, CH 3 ). 13 C NMR (100 MHz, CDCl 3 ): δ = 212.3 (C), 170.2/170.1 (C), 168.2/168.0 (2xC), 136.0 (C), 134.3 (2xCH), 132.1/132.0 (CH), 128.6 (2 CH), 128.3 (2xC), 128.2/128.1 (2xCH), 123.3 (2 CH), 70.8/70.7 (CH 2 ), 67.5/67.3 (CH 2 ), 56.9 (CH) 52.9 (CH 3 ), 51.7/50.5 (CH 3 ), 35.7 (CH 2 ), 35.5 (CH 2 ), 31.6/29.5 (CH 2 ), 13.7 (CH 3 ). IR (CCl 4 ) (ν max/cm -1 ): 3431, 3350, 2943, 1773, 1755, 1717, 1546, 1396. HRMS: m/e calcd. For C 25 H 26 N 2 7 S 2 : 530.6131, Found 530.6129. (S)-methyl 2-(benzyloxycarbonylamino)-5-(1,3-dioxoisoindolin-2-yl)pentanoate (7j). Following general procedure B, compound 7j was obtained in 83% (115 mg, Purified by flash chromatography with petroleum ether/ethyl acetate = 4/1 to 2/1) yield as white solid (mp: 97-99 C). 1 H NMR (400 MHz, CDCl 3 ): δ = 7.86 (m, 2 H, 2 CH), 7.74 (m, 2 H, 2 CH), 7.37 (m, 5 H, 5 CH), 5.49 (m, 1 H, NH), 5.12 (s, 2 H, CH 2 ), 4.44 (m, 1 H, CH), 3.76 (s, 5 H, CH 3, CH 2 ), 1.92 (m, 1 H, CHH), 1.79 (m, 3 H, CHH, CH 2 ). 13 C NMR (100 MHz, CDCl 3 ): δ = 172.5 (C), 168.4 (2xC), 155.7 (C), 136.2 (C), 134.0 (2 CH), 132.0 (CH), 128.6 (2xCH), 128.2 (2xC), 128.1 (2xCH), 123.4 (2xCH), 66.9 (CH 2 ), 52.8 (CH), 52.6 (CH 3 ), 37.6 (CH 2 ), 30.0 (CH 2 ), 24.7 (CH 2 ). IR (CCl 4 ) (ν max/cm -1 ): 3431, 3350, 2943, 1773, 1757, 1717, 1546, 1396. [α] 20 D = + 12.8 (c 4.3, CHCl 3 ). HRMS: m/e calcd. For C 22 H 22 N 2 6 : 410.1478, Found 410.1479. (2S)-methyl 5-(1,3-dioxoisoindolin-2-yl)-2-(3,3,3-trifluoro-2-methoxy-2-phenyl- propanamido)pentanoate (10). S14

A round-bottomed flask containing compound 7j (20 mg, 0.048 mmol) and 10% Pd/C (40 mg) was stopped with a septum and an inert atmosphere was generated. Under vacuo, a hydrogen balloon was connected to the flask and immediately MeH (1.0 ml) was added. After only 30 min of reaction it was stopped by filtration over celite, the bed was washed with ether and the solvents were removed in the rotator evaporator. The crude product 9 was used immediately and without further purification in the next step to avoid any racemization and decomposition. To a solution of crude compound 9 in THF (1 ml) was added (S)-Mosher s Acid (0.05 mmol, 12 mg), DCC (0.058 mmol, 12 mg) and DMAP (1 mg). The solution was stirred at room temperature overnight. The solution was filtered and the solvent was removed under reduced pressure, to which the mixture was purified by flash chromatography (ether/petroleum ether = 1:1) to yield Mosher s amide 10 (15.2 mg) in 64% yield over two steps as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ): δ = 7.84 (dd, 2 H, J = 3.0, 5.5 Hz, 2x=CH), 7.72 (dd, 2 H, J = 3.0, 5.5 Hz, 2x=CH), 7.54 (d, 2 H, J = 7.6 Hz, 2x=CH), 7.42 7.34 (m, 3 H, 3x=CH), 7.20 (d, 1 H, J = 8.3 Hz, NH), 4.70 (dt, 1 H, J = 5.2, 7.6 Hz, NCH), 3.76 (s, 3 H, CH 3 ), 3.62 (dd, 2 H, J = 6.5, 13.2 Hz, CH), 3.51 (d, 3 H, J = 1.6 Hz, Me), 1.98 1.62 (m, 4 H, 2xCH 2 ). 13 C NMR (100 MHz, CDCl 3 ): δ = 171.9 (C), 168.2 (C), 166.4 (C), 134.0 (2x=CH), 132.7 (C), 132.0 (C), 129.5 (2x=CH), 128.6 (2x=CH), 127.3 (=CH), 123.3 (2x=CH), 123.5 (q, J = 289.6 Hz, CF 3 ), 84.0 (q, J = 26.6 Hz, CCF 3 ), 55.2 (CH 3 ), 52.6 (CH 3 ), 51.7 (CHN), 37.2 (CH 2 N), 29.5 (CH 2 ), 24.7 (CH 2 ). IR (CCl 4 ) (ν max/cm -1 ): 2928, 1775, 1746, 1718, 1558, 1438, 1396, 1364, 1190, 1169, 1037, 908. HRMS: Calcd. for C 24 H 23 F 3 N 2 6 : 492.1508; Found: 492.1508. S-4-cyano-1-((3R,7aR)-1-oxo-3-(trichloromethyl)hexahydropyrrolo[1,2-c]oxazol- 7a-yl)butan-2-yl -ethyl carbonodithioate (13a). S15

Following general procedure A, compound 13a was obtained in 86% yield (383 mg, Purified by flash chromatography with petroleum ether/ethyl acetate = 19/1) as orange oil. 1 H NMR (400 MHz, CDCl 3 ): δ = 5.06/5.02 (s, 1 H, CH), 4.66 (m, 2 H, CH 2 ), 4.04 (m, 1 H, CH), 3.30 (m, 2 H, CH 2 ), 2.70-1.60 (m, 10 H, CH 2 ), 144/1.43 (t, 3 H, J = 7.1 Hz, CH 3 ). 13 C NMR (100 MHz, CDCl 3 ): δ = 212.3/212.0 (C), 175.9/175.1 (C), 119.2 (C), 102.6 (C), 101.9/100.1 (C), 71.3 (C), 70.4 (CH 2 ), 58.0/57.6 (CH 2 ), 45.7/45.0 (CH 2 ), 40.8/40.5 (CH 2 ), 35.9 (CH), 32.0/30.2 (CH 2 ), 25.0 (CH 2 ), 15.0/14.9 (CH 2 ), 13.8 (CH 3 ). IR (CCl 4 ) (ν max/cm -1 ): 2961, 2250, 1807, 1711, 1550. HRMS: m/e calcd. For C 15 H 19 Cl 3 N 2 3 S 2 : 443.9903, Found 443.9900. 5-((3R,7aS)-1-oxo-3-(trichloromethyl)hexahydropyrrolo[1,2-c]oxazol-7a-yl)penta nenitrile (14a). Following general procedure B, compound 14a was obtained in 76% yield (213 mg, Purified by flash chromatography with petroleum ether/ethyl acetate = 19/1) as yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ = 5.01 (s, 1 H, CH), 3.28 (m, 2 H, CH 2 ), 2.41 (t, 2 H, J = 6.7 Hz, CH 2 ), 2.25 (m, 1 H, CHH), 2.08-1.58 (m, 9 H, 4 CH 2, CHH). 13 C NMR (100 MHz, CDCl 3 ): δ = 176.1 (C), 119.4 (C), 102.2 (CH), 100.4 (C), 71.6 (C), 58.2 (CH 2 ), 36.7 (CH 2 ), 35.9 (CH 2 ), 25.4 (CH 2 ), 25.2 (CH 2 ), 22.8 (CH 2 ), 17.1 (CH 2 ). IR (CCl 4 ) (ν max/cm -1 ): 2961, 2928, 2250, 1711, 1550. [α] 20 D = + 8.4 (c 1.4, CHCl 3 ). HRMS: m/e calcd. For C 12 H 15 Cl 3 N 2 2 : 324.0199, Found 324.0198. Methyl 4-(ethoxycarbonothioylthio)-5-((3R,7aR)-1-oxo-3-(trichloromethyl) hexahydropyrrolo[1,2-c]oxazol-7a-yl)pentanoate (13b). S16

Following general procedure A, compound 13b was obtained in 77% yield (368 mg, Purified by flash chromatography with petroleum ether/ethyl acetate = 19/1) as yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ = 5.04/5.01 (s, 1 H, CH), 4.65 (m, 2 H, CH 2 ), 4.03 (m, 1 H, CH), 3.66 (s, 3 H, CH 3 ), 3.42-3.22 (m, 2 H, CH 2 ), 2.59-1.62 (m, 10 H, CH 2 ), 1.44/1.43 (t, 3 H, J = 7.1 Hz, CH 3 ). 13 C NMR (100 MHz, CDCl 3 ): δ = 213.4/213.1 (C), 176.2/175.4 (C), 173.2 (C), 102.7 (C), 102.2/100.2 (C), 71.5/71.3 (C), 70.1/70.0 (CH 2 ), 58.8/57.9 (CH 2 ), 51.7 (CH 3 ), 46.6/45.5 (CH 2 ), 41.0/40.7 (CH 2 ), 35.8/35.6 (CH), 31.6/31.2 (CH 2 ), 31.2/29.2 (CH 2 ), 25.2/25.0 (CH 2 ), 13.8 (CH 3 ). IR (CCl 4 ) (ν max/cm -1 ): 2987, 1807, 1690, 1586, 1550. HRMS: m/e calcd. For C 16 H 22 Cl 3 N 5 S 2 : 477.0005, Found 477.0003. Methyl5-((3R,7aS)-1-oxo-3-(trichloromethyl)hexahydropyrrolo[1,2-c]oxazol-7ayl )pentanoate (14b). Following general procedure B, compound 14b was obtained in 70% yield (193 mg, Purified by flash chromatography with petroleum ether/ethyl acetate = 19/1) as yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ = 4.98 (s, 1 H, CH), 3.70 (s, 3 H, CH 3 ), 3.25 (m, 2 H, CH 2 ), 2.35 (m, 2 H, CH 2 ), 2.20 (m, 1 H, CHH), 2.03-1.42 (m, 9 H, 4 CH 2, CHH). 13 C NMR (100 MHz, CDCl 3 ): δ = 176.3 (C), 173.9 (C), 102.1 (CH), 100.4 (C), 71.7 (C), 58.1 (CH 2 ), 51.6 (CH 3 ), 37.2 (CH 2 ), 35.9 (CH 2 ), 33.8 (CH 2 ), 25.2 (CH 2 ), 25.0 (CH 2 ), 23.0 (CH 2 ). IR (CCl 4 ) (ν max/cm -1 ): 2980, 2927, 1740, 1711. [α] 20 D = + 11.2 (c 2.0, CHCl 3 ). HRMS: m/e calcd. For C 13 H 18 Cl 3 N 4 : 357.0301, Found 357.0301. -ethyl S-5-oxo-1-((3R,7aR)-1-oxo-3-(trichloromethyl)hexahydropyrrolo[1,2-c]- S17

oxazol-7a-yl)hexan-2-yl carbonodithioate (13c). Following general procedure A, compound 13c was obtained in 79% yield (366 mg, Purified by flash chromatography with petroleum ether/ethyl acetate = 19/1) as orange oil. 1 H NMR (400 MHz, CDCl 3 ): δ = 5.04/5.01 (s, 1 H, CH), 4.66 (m, 2 H, CH 2 ), 4.02 (m, 1 H, CH), 3.52 3.28 (m, 2 H, CH 2 ), 2.70 1.65 (m, s, 13 H, CH 2, CH 3 ), 1.44 (t, 3 H, J = 7.1 Hz, CH 3 ). 13 C NMR (100 MHz, CDCl 3 ): δ = 213.7/213.3 (C), 207.7 (C), 176.3/175.4 (C), 102.8 (C), 102.3/100.2 (C), 71.6/71.3 (C), 70.2/70.0 (CH 2 ), 58.8/58.0 (CH 2 ), 46.7/45.7 (CH 2 ), 41.2/41.1 (CH 2 ), 40.6/40.4 (CH 2 ), 35.7/35.6 (CH), 30.3/30.1 (CH 2 ), 30.1/27.8 (CH 3 ), 25.1/25.0 (CH 2 ), 13.8 (CH 3 ). IR (CCl 4 ) (ν max/cm -1 ): 2983, 1804, 1699, 1584, 1550. HRMS: m/e calcd. For C 16 H 22 Cl 3 N 4 S 2 : 461.0056, Found 461.0052. (3R,7aS)-7a-(5-oxohexyl)-3-(trichloromethyl)tetrahydropyrrolo[1,2-c]oxazol-1(3 H)-one (14c). Following general procedure B, compound 14c was obtained in 77% yield (208 mg, Purified by flash chromatography with petroleum ether/ethyl acetate = 19/1) as yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ = 4.98 (s, 1 H, CH), 3.25 (m, 2 H, CH 2 ), 2.47 (t, 2 H, J = 7.1 Hz, CH 2 ), 2.21 (m, 1 H, CHH), 2.16 (s, 3 H, CH 3 ), 2.02-1.40 (m, 9 H, 4 CH 2, CHH). 13 C NMR (100 MHz, CDCl 3 ): δ = 208.8 (C), 176.4 (C), 102.1 (CH), 100.5 (C), 71.7 (C), 58.1 (CH 2 ), 43.4 (CH 2 ), 37.4 (CH 2 ), 35.8 (CH 3 ), 30.0 (CH 2 ), 25.2 (CH 2 ), 23.8 (CH 2 ), 23.1 (CH 2 ). IR (CCl 4 ) (ν max/cm -1 ): 2980, 2928, 1711, 1693. [α] 20 D = + 13.8 (c 2.0, CHCl 3 ). HRMS: m/e calcd. For C 13 H 18 Cl 3 N 3 : 341.0352, Found S18

341.0354. -ethyl S-5-(4-methoxyphenyl)-5-oxo-1-((3R,7aR)-1-oxo-3-(trichloromethyl) hexahydropyrrolo[1,2-c]oxazol-7a-yl)pentan-2-yl carbonodithioate (13d). Following general procedure A, compound 13d was obtained in 80% yield (444 mg, Purified by flash chromatography with petroleum ether/ethyl acetate = 19/1) as orange oil. 1 H NMR (400 MHz, CDCl 3 ): δ = 7.94 (d, 2 H, J = 8.9 Hz, CH), 6.95 (d, 2 H, J = 8.9 Hz, CH), 5.04/5.02 (s, 1 H, CH) 4.61 (m, 2 H, CH 2 ) 4.13 (m, 1 H, CH), 3.88 (s, 3 H, CH 3 ) 3.60-3.00 (m, 4 H, CH 2 ), 2.70-1.67 (m, 8 H, CH 2 ), 1.42/1.40 (t, 3 H, J = 6.1 Hz, CH 3 ). 13 C NMR (100 MHz, CDCl 3 ): δ = 213.6/213.1 (C), 197.6 (C), 176.1/175.5 (C), 163.5 (C), 130.3 (2xCH), 129.8 (CH), 113.7 (2xCH), 102.8 (C), 102.3/100.26 (C), 71.6/71.5 (C), 70.1/70.0 (CH 2 ), 58.9/58.0 (CH 3 ), 55.5 (CH 2 ), 46.9/45.9 (CH 2 ), 41.2/41.1 (CH 2 ), 35.7 (CH 2 ), 35.3 (CH), 31.2/28.6 (CH 2 ), 25.1 (CH 2 ), 13.8 (CH 3 ). IR (CCl 4 ) (ν max/cm -1 ): 2984, 1806, 1691, 1586, 1550. HRMS: m/e calcd. For C 22 H 26 Cl 3 N 5 S 2 : 553.0318, Found 553.0316. (3R,7aS)-7a-(5-(4-methoxyphenyl)-5-oxopentyl)-3-(trichloromethyl) tetrahydropyrrolo[1,2-c]oxazol-1(3h)-one (14d). Following general procedure B, compound 14d was obtained in 73% yield (254 mg, Purified by flash chromatography with petroleum ether/ethyl acetate = 19/1) as yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ = 7.97 (d, 2 H, J = 8.9 Hz, 2 CH), 6.98 (d, 2 H, J = 8.9 Hz, 2 CH), 4.99 (s, 1 H, CH), 3.88 (s, 3 H, CH 3 ), 3.25 (m, 2 H, CH 2 ), 2.97 (t, 2 H, S19

J = 7.2 Hz, CH 2 ), 2.25-1.36 (m, 10 H, 5 CH 2 ). 13 C NMR (100 MHz, CDCl 3 ): δ = 198.7 (C), 176.3 (C), 163.4 (C), 130.3 (2 CH), 130.0 (C), 113.7 (2 CH), 102.1 (CH), 100.4 (C), 71.7 (CH 2 ), 58.1 (CH 2 ), 55.5 (CH 3 ), 37.9 (CH 2 ), 37.4 (CH 2 ), 36.0 (CH 2 ), 25.1 (CH 2 ), 24.5 (CH 2 ), 23.1 (CH 2 ). IR (CCl 4 ) (ν max/cm -1 ): 2980, 2927, 1711, 1694. [α] 20 D = + 7.5 (c 2.2, CHCl 3 ). HRMS: m/e calcd. For C 19 H 22 Cl 3 N 4 : 433.0614, Found 433.0613. S-5-(4-bromophenyl)-5-oxo-1-((3R,7aR)-1-oxo-3-(trichloromethyl) hexahydro- pyrrolo [1,2-c]oxazol-7a-yl)pentan-2-yl -ethyl carbonodithioate (13e). Following general procedure A, compound 13e was obtained in 91% yield (549 mg, Purified by flash chromatography with petroleum ether/ethyl acetate = 19/1) as yellow solid (mp: 120-122 C). 1 H NMR (400 MHz, CDCl 3 ): δ = 7.83 (d, 2 H, J = 8.6 Hz, CH), 7.63 (d, 2 H, J = 8.6 Hz, CH), 5.05/5.02 (s, 1 H, CH), 4.63 (m, 2 H, CH 2 ), 4.11 (m, 1 H, CH), 3.52-3.00 (m, 4 H, CH 2 ), 2.74-1.62 (m, 8 H, CH 2 ), 1.43 (m, 3 H, CH 3 ). 13 C NMR (100 MHz, CDCl 3 ): δ = 213.6/213.1 (C), 198.0 (C), 176.2/175.5 (C), 135.4 (C), 131.9 (2xCH), 129.6 (2xCH), 128.3 (C), 102.8 (C), 102.3/100.2 (C), 71.6/71.4 (C), 58.9/58.0 (CH 2 ), 46.8/45.8 (CH 2 ), 41.2 (CH 2 ), 35.8 (CH), 30.0 (CH 2 ), 28.4 (CH 2 ), 25.1 (CH 2 ), 13.8 (CH 3 ). IR (CCl 4 ) (ν max/cm -1 ): 2986, 1805, 1691, 1584, 1550. HRMS: m/e calcd. For C 21 H 23 BrCl 3 N 4 S 2 : 600.9317, Found 600.9315. (3R,7aS)-7a-(5-(4-bromophenyl)-5-oxopentyl)-3-(trichloromethyl)tetrahydropyrr olo[1,2-c]oxazol-1(3h)-one (14e). Following general procedure B, compound 14e was obtained in 72% yield (317 mg, S20

Purified by flash chromatography with petroleum ether/ethyl acetate = 19/1) as yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ = 7.85 (d, 2 H, J = 8.5 Hz, 2 CH), 7.64 (d, 2 H, J = 8.5 Hz, 2 CH), 4.99 (s, 1 H, CH), 3.27 (m, 2 H, CH 2 ), 2.99 (t, 2 H, J = 7.2 Hz, CH 2 ), 2.24 (m, 1 H, CHH), 2.08-1.48 (m, 9 H, 4 CH 2, CHH). 13 C NMR (100 MHz, CDCl 3 ): δ = 198.9 (C), 176.3 (C), 135.7 (C), 131.9 (2 CH), 129.6 (2 CH), 128.2 (C), 102.1 (CH), 100.5 (C), 71.8 (C), 58.1 (CH 2 ), 38.2 (CH 2 ), 37.4 (CH 2 ), 35.9 (CH 2 ), 25.2 (CH 2 ), 24.1 (CH 2 ), 23.3 (CH 2 ). IR (CCl 4 ) (ν max/cm -1 ): 2981, 2927, 1711, 1691. [α] 20 D = + 3.8 (c 1.8, CHCl 3 ). HRMS: m/e calcd. For C 18 H 19 BrCl 3 N 3 : 480.9614, Found 480.9613. (S)-methyl 2-(5-(4-methoxyphenyl)-5-oxopentyl)pyrrolidine-2-carboxylate hydrochloride (16). Compound 14d (177 mg, 0.5 mmol) was dissolved in MeH (10 ml) under argon. Small chunks of sodium (7 mg, 0.3 mmol) were added portion-wise over 30 minutes and the reaction mixture was stirred for an additional 30 min once no more of the starting material is observed by TLC (petroleum ether/ethyl acetate 1:1). The reaction vessel is cooled in an ice/water bath and AcCl (0.789 ml, 10 mmol) was added dropwise into the reaction mixture over 1 h. The resulting milky brown solution is heated to reflux until no more of the intermediate N-formyl ester remains by TLC (petroleum ether/ethyl acetate 1:1). The precipitated NaCl is removed via filtration. The filtrate is concentrated under reduced pressure to afford brown oil. Purification of the crude hydrochloride salt is achieved using flash silica gel chromatography eluting with a gradient of 95:5-90:10 CH 2 Cl 2 : MeH to afford the amine salt 16 (62% yield, 110 mg) as an oil, which crystallizes upon standing under reduced pressure. 1 H NMR (400 MHz, CDCl 3 ): δ = 7.96 (d, 2 H, J = 8.9 Hz, CH), 6.97 (d, 2 H, J = 8.9 Hz, CH), 3.91 (s, 3 H, CH 3 ), 3.76 (s, 3 H, CH 3 ), 3.04 (t, 2 H, J = 6.6 Hz, CH 2 ), S21

2.94/2.93 (t, 3 H, J = 7.2 Hz, CH 2 ), 2.50 (s, 1 H, NH), 2.20-1.47 (m, 10 H, CH 2 ). 13 C NMR (100 MHz, CDCl 3 ): δ = 198.6 (C), 177.4 (C), 163.3 (C), 130.3 (2xCH), 130.1 (C), 113.7 (2xCH), 69.5 (C), 55.4 (CH 3 ), 52.3 (CH 3 ), 40.5 (CH 2 ), 39.8 (CH 2 ), 38.1 (CH 2 ), 36.0 (CH 2 ), 25.1 (CH 2 ), 24.9 (CH 2 ), 24.7 (CH 2 ). IR (CCl 4 ) (ν max/cm -1 ): 2986, 1732, 1698, 1582, 1550. [α] 20 D = + 15.3 (c 1.6, CHCl 3 ). HRMS: m/e calcd. For C 18 H 28 ClN 4 : 355.1550, Found 355.1548. (R)-1-tert-butyl 2-methyl 2-(4-cyano-2-(ethoxycarbonothioylthio)butyl)- pyrrolidine-1,2-dicarboxylate (19a). Following general procedure A, compound 19a was obtained in 84% yield (362 mg, Purified by flash chromatography with petroleum ether/ethyl acetate = 19/1) as yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ = 4.68 (m, 2 H, CH 2 ), 3.92/3.79 (m, 1 H, CH), 3.74/3.73 (s, 3 H, CH 3 ), 3.66/3.51 (m, 2 H, CH 2 ), 2.73-1.89 (m, 10 H, 5 CH 2 ), 1.51-1.42 (m, 12 H, 4 CH 3 ). 13 C NMR (100 MHz, CDCl 3 ): δ = 212.9 (C), 174.2 (C), 154.8 (C), 119.3 (C), 80.32 (C), 70.43 (C), 67.3 (CH 2 ), 52.4 (CH 3 ), 48.7 (CH 2 ), 44.8 (CH 2 ), 38.6/37.9 (CH 2 ), 36.6 (CH 2 ), 32.5 (CH 2 ), 28.4 (3 CH 3 ), 23.4 (CH 2 ), 14.8 (CH 2 ), 13.8 (CH 3 ). IR (CCl 4 ) (ν max/cm -1 ): 2980, 2250, 1744, 1696, 1549, 1052. HRMS: m/e calcd. For C 19 H 30 N 2 5 S 2 : 430.1596, Found 430.1594. (S)-1-tert-butyl 2-methyl 2-(5-methoxy-5-oxopentyl)pyrrolidine- 1,2-dicarboxylate (20a). Following general procedure B, compound 20a was obtained in 78% yield (203 mg, Purified by flash chromatography with petroleum ether/ethyl acetate = 19/1) as yellow oil. S22

1 H NMR (400 MHz, CDCl 3 ): δ = 3.74/3.73 (s, 3 H, CH 3 ), 3.60/3.46 (m, 2 H, CH 2 ), 2.41 (m, 2 H, CH 2 ), 2.20/1.51 (m, 8 H, 5 CH 2 ), 1.47/1.43 (s, 9 H, 3 CH 3 ), 1.38 (m, 2 H, CH 2 ). 13 C NMR (100 MHz, CDCl 3 ): δ = 175.3/175.0 (C), 154.2/153.7 (C), 119.7/119.5 (C), 80.2/79.7 (C), 67.8/67.2 (C), 52.2 (CH 3 ), 48.6 (CH 2 ), 37.5/36.2 (CH 2 ), 34.5/32.3 (CH 2 ), 28.4 (3 CH 3 ), 25.8/ 25.5 (CH 2 ), 23.2/22.8 (CH 2 ), 17.1 (CH 2 ). IR (CCl 4 ) (ν max/cm -1 ): 2980, 2250, 1744, 1696, 1549. [α] 20 D = + 29.5 (c 1.8, CHCl 3 ). HRMS: m/e calcd. For C 16 H 26 N 2 4 : 310.1893, Found 310.1892. (R)-1-tert-butyl 2-methyl 2-(2-(ethoxycarbonothioylthio)-5-methoxy-5-oxopentyl) pyrrolidine-1,2-dicarboxylate (19b). Following general procedure A, compound 19b was obtained in 80% yield (371 mg, Purified by flash chromatography with petroleum ether/ethyl acetate = 19/1) as yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ = 4.67 (m, 2 H, CH 2 ), 3.83 (m, 1 H, CHH), 3.73-3.66 (m, 6 H, 2 CH 3 ), 3.58-3.50 (m, 1 H, CHH), 2.82-1.86 (m, 11 H, 5 CH 2, CH), 1.47-1.40 (m, 12 H, 4 CH 3 ). 13 C NMR (100 MHz, CDCl 3 ): δ = 213.7 (C), 175.1 (C), 173.3 (C), 154.1 (C), 80.4 (C), 69.8 (C), 67.7 (CH 2 ), 52.6 (CH 3 ), 51.6 (CH 3 ), 48.3 (CH 2 ), 45.9 (CH 2 ), 38.4 (CH 2 ), 35.9 (CH), 31.1 (CH 2 ), 27.9 (3 CH 3 ), 23.0 (CH 2 ), 13.8 (CH 3 ). IR (CCl 4 ) (ν max/cm -1 ): 2979, 1743, 1699, 1052. HRMS: m/e calcd. For C 20 H 33 N 7 S 2 : 463.1698, Found 463.1695. (S)-1-tert-butyl 2-methyl 2-(5-methoxy-5-oxopentyl)pyrrolidine-1,2- dicarboxylate (20b). Following general procedure B, compound 20b was obtained in 81% yield (222 mg, Purified by flash chromatography with petroleum ether/ethyl acetate = 19/1) as yellow S23

oil. 1 H NMR (400 MHz, CDCl 3 ): δ = 3.71 (s, 3 H, CH 3 ), 3.68/3.66 (s, 3 H, CH 3 ), 3.70/3.41 (m, 2 H, CH 2 ), 2.35 (t, 2 H, J = 7.3 Hz, CH 2 ), 2.33-1.57 (m, 8 H, CH 2 ), 1.45/1.41 (s, 9 H, CH 3 ), 1.38 (m, 2 H, CH 2 ). 13 C NMR (100 MHz, CDCl 3 ): δ = 175.5 (C), 174.1 (C), 153.8 (C), 80.0/79.5 (C), 67.8/67.3 (C), 52.1 (CH 3 ), 51.5 (CH 3 ), 48.5 (CH 2 ), 37.5/36.1 (CH 2 ), 34.8 (CH 2 ), 33.9/33.7 (CH 2 ), 28.4 (3xCH 3 ), 25.2/25.0 (CH 2 ), 23.1 (CH 2 ), 22.7 (CH 2 ). IR (CCl 4 ) (ν max/cm -1 ): 2979, 1743, 1699. [α] 20 D = + 18.8 (c 2.8, CHCl 3 ). HRMS: m/e calcd. For C 17 H 29 N 6 : 343.1995, Found 343.1995. (R)-1-tert-butyl 2-methyl 2-(2-(ethoxycarbonothioylthio)-5-(methoxy(methyl)- amino)-5-oxopentyl)pyrrolidine-1,2-dicarboxylate (19c). Following general procedure A, compound 19c was obtained in 80% yield (394 mg, Purified by flash chromatography with petroleum ether/ethyl acetate = 19/1) as yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ = 4.64 (m, 2 H, CH 2 ), 3.90/3.80 (m, 1 H, CH), 3.69/3.67 (s, 3 H, CH 3 ), 3.62/3.50 (m, 2 H, CH 2 ), 3.19/3.18/3.16/3.15 (s, 3 H, CH 3 ), 2.78-1.89 (m, 10 H, 5 CH 2 ), 1.45-1.39 (m, 12 H, 4 CH 3 ). 13 C NMR (100 MHz, CDCl 3 ): δ = 213.5 (C), 174.7 (2 C), 153.0 (C), 80.0 (C), 69.8 (C), 67.2 (CH 2 ), 61.2 (CH 3 ), 52.1 (CH 3 ), 48.8 (CH 2 ), 46.2 (CH 2 ), 38.6 (CH 2 ), 37.5 (CH 2 ), 35.4 (CH), 32.2 (CH 3 ), 30.7 (CH 2 ), 28.4 (3 CH 3 ), 22.7 (CH 2 ), 13.8 (CH 3 ). IR (CCl 4 ) (ν max/cm -1 ): 2980, 1744, 1698, 1671, 1052. HRMS: m/e calcd. For C 21 H 36 N 2 7 S 2 : 492.1964, Found 492.1964. (S)-1-tert-butyl 2-methyl 2-(5-(methoxy(methyl)amino)-5-oxopentyl)pyrrolidine- 1,2-dicarboxylate (20c). S24

Following general procedure B, compound 20c was obtained in 73% yield (217 mg, Purified by flash chromatography with petroleum ether/ethyl acetate = 19/1) as yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ = 3.69 (s, 6 H, CH 3 ), 3.68/3.40 (m, 2 H, CH 2 ), 3.16 (s, 3 H, CH 3 ), 2.44 (m, 2 H, CH 2 ), 2.22-1.45 (m, 8 H, CH 2 ), 1.43/1.41 (s, 9 H, CH 3 ). 13 C NMR (100 MHz, CDCl 3 ): δ = 175.5 (2xC), 154/153.8 (C), 79.9/79.3 (C), 67.4 (C), 61.2 (CH 3 ), 52.1 (2xCH 3 ), 48.6 (CH 2 ), 37.4/36.1 (CH 2 ), 34.8/33.7 (CH 2 ), 31.8 (CH 2 ), 28.4 (3xCH 3 ), 24.8 (CH 2 ), 23.3 (CH 2 ), 22.7 (CH 2 ). IR (CCl 4 ) (ν max/cm -1 ): 2980, 1744, 1698, 1671. [α] 20 D = +19.4 (c 1.6, CHCl 3 ). HRMS: m/e calcd. For C 18 H 32 N 2 6 : 372.2260, Found 372.2257. (R)-1-tert-butyl 2-methyl 2-(2-(ethoxycarbonothioylthio)-6,6-dimethoxy-5- oxohexyl) pyrrolidine-1,2-dicarboxylate (19d). Following general procedure A, compound 19d was obtained in 77% yield (391 mg, Purified by flash chromatography with petroleum ether/ethyl acetate = 19/1) as yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ = 4.65 (m, 2 H, CH 2 ), 4.52/4.51/4.48 (s, 1 H, CH), 3.81 (m, 2 H, CH 2 ), 3.73/3.72 (s, 3 H, CH 3 ), 3.63-3.53 (m, 2 H, CH 2 ), 3.49-3.48 (m, 6 H, 2 CH 3 ), 2.83-1.92 (m, 9 H, 4 CH 2, CH), 1.53-1.37 (m, 12 H, 4 CH 3 ). 13 C NMR (100 MHz, CDCl 3 ): δ = 213.3 (C), 204.9 (C), 175.1 (C), 153.9 (C), 103.6 (CH), 80.2 (C), 70.3 (C), 67.4 (CH 2 ), 54.7 (2 CH 3 ), 52.2 (CH 3 ), 48.9 (CH 2 ), 46.1 (CH 2 ), 41.1 (CH 2 ), 37.6 (CH 2 ), 36.4 (CH), 34.4 (CH 2 ), 28.0 (3 CH 3 ), 22.3 (CH 2 ), 13.6 (CH 3 ). IR (CCl 4 ) (ν max/cm -1 ): 2979, 1743, 1714, 1699, 1052. HRMS: m/e calcd. For S25

C 22 H 37 N 8 S 2 : 507.1961, Found 507.1964. (S)-1-tert-butyl 2-methyl 2-(6,6-dimethoxy-5-oxohexyl)pyrrolidine-1,2- dicarboxylate (20d). Following general procedure B, compound 20d was obtained in 76% yield (227 mg, Purified by flash chromatography with petroleum ether/ethyl acetate = 19/1) as yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ = 4.49/4.48 (s, 1 H, CH), 3.78 (s, 3 H, CH 3 ), 3.70-3.40 (m, 2 H, CH 2 ), 3.43/3.42 (s, 6 H, CH 3 ), 2.60 (m, 2 H, CH 2 ), 2.34-1.59 (m, 8 H, CH 2 ), 1.46/1.43 (s, 9 H, CH 3 ), 1.38 (m, 2 H, CH 2 ). 13 C NMR (100 MHz, CDCl 3 ): δ = 205.5 (C), 175.3 (C), 154.0 (C), 104.1 (CH), 80.0 (C), 67.4 (C), 54.8 (2xCH 3 ), 52.1 (CH 3 ), 48.5 (CH 2 ), 37.5 (CH 2 ), 37.3 (CH 2 ), 35.0 (CH 2 ), 28.4 (3xCH 3 ), 23.2 (CH 2 ), 23.1 (CH 2 ), 22.8 (CH 2 ). IR (CCl 4 ) (ν max/cm -1 ): 2979, 1743, 1714, 1699. [α] 20 D = + 16.7 (c 1.5, CHCl 3 ). HRMS: m/e calcd. For C 19 H 33 N 7 : 387.2257, Found 387.2259. (R)-1-tert-butyl 2-methyl 2-(4-(1,3-dioxoisoindolin-2-yl)-2-(ethoxycarbonothioylthio) butyl)pyrrolidine-1,2-dicarboxylate (19e). Following general procedure A, compound 19e was obtained in 78% yield (429 mg, Purified by flash chromatography with petroleum ether/ethyl acetate = 9/1) as yellow solid (mp: 109-111 C). 1 H NMR (400 MHz, CDCl 3 ): δ = 7.84 (m, 2 H, 2 CH), 7.72 (m, 2 H, 2 CH), 4.65/4.54 (m, 2 H, CH 2 ), 3.83/3.81 (m, 3 H, CH 2, CH), 3.71 (s, 3 H, CH 3 ), 3.51 (m, 2 H, CH 2 ), 2.69-1.75 (m, 8 H, 4 CH 2 ), 1.44/1.42 (s, 12 H, 4 CH 3 ). 13 C NMR (100 S26

MHz, CDCl 3 ): δ = 213.2 (C), 174.7 (C), 167.9 (2 C), 153.7 (C), 133.3 (2 CH), 132.0 (2xC), 123.3 (2 CH), 80.7/79.9 (C), 69.8 (C), 67.7 (CH 2 ), 52.5 (CH 3 ), 48.5 (CH 2 ), 44.4 (CH 2 ), 37.7 (CH 2 ), 36.5 (CH 2 ), 35.5 (CH 2 ), 34.7 (CH), 28.3 (3 CH 3 ), 22.8 (CH 2 ), 13.8 (CH 3 ). IR (CCl 4 ) (ν max/cm -1 ): 2979, 1745, 1719, 1698, 1550, 1052. HRMS: m/e calcd. For C 26 H 34 N 2 7 S 2 : 550.1807, Found 550.1806. (S)-1-tert-butyl 2-methyl 2-(4-(1,3-dioxoisoindolin-2-yl) butyl)pyrrolidine- 1,2-dicarboxylate (20e). Following general procedure B, compound 20e was obtained in 79% yield (265 mg, Purified by flash chromatography with petroleum ether/ethyl acetate = 9/1) as yellow solid (mp: 126-128 C). 1 H NMR (400 MHz, CDCl 3 ): δ = 7.83 (m, 2 H, CH), 7.72 (m, 2 H, CH), 3.69 (s, 3 H, CH 3 ), 3.68 (m, 2 H, CH 2 ), 3.65/3.41 (m, 2 H, CH 2 ), 2.30-1.56 (m, 8 H, CH 2 ), 1.41/1.38 (s, 9 H, CH 3 ), 1.32 (m, 2 H, CH 2 ). 13 C NMR (100 MHz, CDCl 3 ): δ = 175 (C), 168.4 (2xC), 157.7 (C), 133.9(2xCH), 132.1 (2xC), 123.1 (2xCH), 80.0/79.4 (C), 67.9/67.4 (C), 52.1 (CH 3 ), 48.5 (CH 2 ), 38.0/37.9 (CH 2 ), 37.4/36.2 (CH 2 ), 34.8/33.7 (CH 2 ), 28.9 (CH 2 ), 28.3 (3xCH 3 ), 23.3/22.7 (CH 2 ), 21.2/21.0 (CH 2 ). IR (CCl 4 ) (ν max/cm -1 ): 2979, 1745, 1719, 1698, 1550. [α] 20 D = + 13.6 (c 2.4, CHCl 3 ). HRMS: m/e calcd. For C 23 H 30 N 2 6 : 430.2104, Found 430.2101. (R)-1-tert-butyl 2-methyl 2-(5-(4-bromophenyl)-2-(ethoxycarbonothioylthio)-5- oxopentyl) pyrrolidine-1,2-dicarboxylate (19f). Following general procedure A, compound 19f was obtained in 88% yield (518 mg, S27

Purified by flash chromatography with petroleum ether/ethyl acetate = 19/1) as yellow solid (mp: 132-134 C). 1 H NMR (400 MHz, CDCl 3 ): δ = 7.80 (m, 2 H, 2 CH), 7.97 (m, 2 H, 2 CH), 4.62 (m, 2 H, CH 2 ), 3.95 (m, 1 H, CH), 3.70 (s, 3 H, CH 3 ), 3.57 (m, 2 H, CH 2 ), 3.18-3.04 (m, 2 H, CH 2 ), 2.70-1.87 (m, 8 H, 4 CH 2 ), 1.43/1.42 (s, 9 H, CH 3 ), 1.40 (m, 3 H, CH 3 ). 13 C NMR (100 MHz, CDCl 3 ): δ = 213.7 (C), 198.1 (C), 174.8 (C), 153.8 (C), 135.1 (C), 131.2 (2 CH), 129.6 (2 CH), 127.8 (C), 80.9/79.9 (C), 69.9/67.9 (C), 52.2 (CH 3 ), 48.5/46.2 (CH 2 ), 38.9/38.6 (CH 2 ), 37.8/37.6 (CH 2 ), 36.3/35.9 (CH 2 ), 35.2 (CH), 30.4 (CH 2 ), 28.4 (3 CH 3 ), 22.7/22.5 (CH 2 ), 13.8 (CH 3 ). IR (CCl 4 ) (ν max/cm -1 ): 2979, 1744, 1695, 1586, 1052. HRMS: m/e calcd. For C 25 H 34 BrN 6 S 2 : 587.1011, Found 587.1010. (S)-1-tert-butyl 2-methyl 2-(5-(4-bromophenyl)-5-oxopentyl) pyrrolidine-1,2- dicarboxylate (20f). Following general procedure B, compound 20f was obtained in 75% yield (309 mg, Purified by flash chromatography with petroleum ether/ethyl acetate = 19/1) as yellow solid (mp: 138-140 C). 1 H NMR (400 MHz, CDCl 3 ): δ = 7.84 (d, 2 H, J = 8.3 Hz, CH 2 ), 7.64 (d, 2 H, J = 8.3 Hz, CH 2 ), 3.73 (s, 3 H, CH 3 ), 3.70/3.41 (m, 2 H, CH 2 ), 2.99 (t, 2 H, J = 7.2 Hz, CH 2 ), 2.40-1.71 (m, 8 H, CH 2 ), 1.45/1.42 (s, 9 H, CH 3 ), 1.31 (m, 2 H, CH 2 ). 13 C NMR (100 MHz, CDCl 3 ): δ = 199 (C), 175.6 (C), 153.8 (C), 135.7 (C), 131.9 (2xCH), 129.6 (2xCH), 128.14 (C), 80.0/79.5 (C), 67.9/67.4 (C), 52.1 (CH 3 ), 67.9/67.4 (C), 52.12 (CH 3 ), 48.6 (CH 2 ), 38.4 (CH 2 ), 37.5/36.2 (CH 2 ), 35.1/33.7 (CH 2 ), 28.4(3xCH 3 ), 24.3/24.1 (CH 2 ), 23.2 (CH 2 ), 22.7 (CH 2 ). IR (CCl 4 ) (ν max/cm -1 ): 2979, 1744, 1695, 1586. [α] 20 D = + 15.7 (c 1.0, CHCl 3 ). HRMS: m/e calcd. For C 22 H 30 BrN 5 : 467.1307, Found 467.1309. (2R)-1-tert-butyl 2-methyl 2-(4-(benzoyloxy)-4-cyano-2-(ethoxycarbonothioylthio) S28

butyl)pyrrolidine-1,2-dicarboxylate (19g). Following general procedure A, compound 19g was obtained in 76% yield (418 mg, Purified by flash chromatography with petroleum ether/ethyl acetate = 19/1) as yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ = 8.12 (m, 2 H, 2 CH), 7.64 (m, 1 H, CH), 7.51 (m, 2 H, 2 CH), 5.72/4.63 (m, 1 H, CH), 4.62 (m, 2 H, CH 2 ), 4.10 (m, 1 H, CH), 3.73/3.72 (s, 3 H, CH 3 ), 3.56 (m, 2 H, CH 2 ), 2.94-1.78 (m, 8 H, 4 CH 2 ), 1.53-1.36 (m, 12 H, 4 CH 3 ). 13 C NMR (100 MHz, CDCl 3 ): δ = 212.3 (C), 174.4 (C), 164.5 (C), 154.6 (C), 134.0 (C), 130.1 (2 CH), 128.8 (C), 128.6 (2 CH), 116.6 (C), 80.3 (C), 70.6 (C), 67.2 (CH),52.5 (CH 3 ), 48.3 (CH 2 ), 42.1 (CH 2 ), 40.3 (CH 2 ), 38.6 (CH 2 ), 36.6 (CH 2 ), 28.2 (3 CH 3 ), 22.7 (CH 2 ), 22.6 (CH), 13.7 (CH 3 ). IR (CCl 4 ) (ν max/cm -1 ): 2980, 1743, 1719, 1697, 1052. HRMS: m/e calcd. For C 26 H 34 N 2 7 S 2 : 518.2087, Found 518.2086. (2S)-1-tert-butyl 2-methyl 2-(4-(benzoyloxy)-4-cyanobutyl)pyrrolidine- 1,2-dicarboxylate (20g). Following general procedure B, compound 20g was obtained in 72% yield (235 mg, Purified by flash chromatography with petroleum ether/ethyl acetate = 19/1) as orange oil. 1 H NMR (400 MHz, CDCl 3 ): δ = 8.10 (m, 2 H, CH), 7.66 (t, 1 H, J = 7.4 Hz, CH), 7.51 (m, 2 H, CH), 5.63 (m, 1 H, CH), 3.74 (s, 3 H, CH 3 ), 3.7/3.42 (m, 2 H, CH 2 ), 2.39-1.43 (m, 10 H, CH 2 ), 1.46/1.45/1.44 (s, 9 H, CH 3 ). 13 C NMR (100 MHz, CDCl 3 ): δ = 175 (C), 164.8 (C), 153.7 (C), 134.1 (C), 130.0 (3xCH), 128.7 (2xCH), 80.2/79.7 (C), 67.7/67.6 (C), 61.5 (CH), 52.3 (CH 3 ), 48.7 (CH 2 ), 37.6/36.2 (CH 2 ), S29

34.8/33.6 (CH 2 ), 32.9/32.6 (CH 2 ), 28.4 (3xCH 3 ), 22.7 (CH 2 ), 19.2 (CH 2 ). IR (CCl 4 ) (ν max/cm -1 ): 2980, 1743, 1719, 1697. [α] 20 D = +19.7 (c 2.1, CHCl 3 ). HRMS: m/e calcd. For C 23 H 30 N 2 6 : 430.2104, Found 430.2105. (2R)-methyl 2-(((benzyloxy)carbonyl)amino)-5,5,5-trifluoro-3-(((octadecyloxy)- carbonthioyl)thio)pentanoate (25). Following general procedure A, compound 25 was obtained in 72% yield (239 mg, dr = 1:0.7, Purified by flash chromatography with petroleum ether/ethyl acetate = 9/1) as a colorless oil. Major product: 1 H NMR (400 MHz, CDCl 3 ): δ = 7.40 7.31 (m, 5 H, Ph), 5.50 (d, 1 H, J = 7.2 Hz, NH), 5.14 (d, 2 H, J = 1.7 Hz, PhCH 2 ), 4.87 (d, 1 H, J =6.6 Hz, CHN), 4.71 (br, 1 H, CHS), 4.57 (dt, 2 H, J = 2.7 Hz, J = 6.7 Hz, CH 2 CH 2 ), 3.75 (s, 3 H, CH 3 ), 2.85 2.74 (m, 1 H, CHaHbCF 3 ), 2.59 2.46 (m, 1 H, CHaHbCF 3 ), 1.82 1.75 (m, 2 H, CH 2 CH 2 CH 2 ), 1.26 (s, 30 H, (CH 2 ) 15 ), 0.88 (t, 3 H, J = 6.8 Hz, CH 2 CH 3 ). 13 C NMR (100 MHz, CDCl 3 ): δ =209.8 (C=S), 169.4 (C 2 Me), 156.3 (CNH), 135.6 (C), 128.6 (=CH), 128.4 (=CH), 128.2 (=CH), 125.5 (q, J = 278.1 Hz, CF 3 ) 75.2 (CH 2 CH 2 ), 67.7 (PhCH 2 ), 56.7 (CHN), 53.1 (CH 3 ), 46.8 (CHS), 37.14 (q, J =29.5Hz, CH 2 CF 3 ), 31.9 (CH 2 ), 29.7 (CH 2 ), 29.5 (CH 2 ), 29.4 (CH 2 ), 29.3 (CH 2 ), 29.2 (CH 2 ), 28.0 (CH 2 ), 25.8 (CH 2 ), 22.7 (CH 2 ), 14.1 (CH 3 ). IR (CCl 4 ) (ν max/cm -1 ): 3415, 2927, 2855, 1733, 1500, 1338, 1252, 1145, 1111, 1049, 908. HRMS: Calcd. for C 33 H 52 F 3 N 5 S 2 : 663.3239, -Xa C 14 H 15 F 3 N 4 : 318.0953; Found: 318.0953. Minor product: 1 H NMR (400 MHz, CDCl 3 ): δ = 7.37 7.32 (m, 5 H, Ph), 5.50 (d, 1 H, J = 8.0 Hz, NH), 5.13 (s, 2 H, PhCH 2 ), 4.92 (dd, 1H, J = 3.0 Hz, J = 8.0 Hz, CHN), 4.57 4.52 (m, 3 H), 3.80 (s, 3 H, CH 3 ), 2.80 2.54 (m, 2 H, CH 2 CF 3 ), 1.79 1.74 (m, 2 H, CH 2 ), 1.26 (s, 30 H, (CH 2 ) 15 ), 0.88 (t, 3 H, J = 6.8 Hz, CH 3 ). 13 C NMR (100 MHz, S30