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1 Enantioselective Organocatalytic Michael Addition of Malonates to α, β-unsaturated Ketones Pengfei Li, Shigang Wen, Feng Yu, Qiaoxia Liu, Wenjun Li, Yongcan Wang, Xinmiao Liang, * Jinxing Ye * Dalian Institute of Chemical Physics, Chinese Academy of Science, 457 Zhongshan Road, Dalian 11623, P. R. China. Engineering Research Center of Pharmaceutical Process Chemistry, Ministry of Education, School of Pharmacy, East China University of Science and Technology, 13 Meilong Road, Shanghai 2237, P. R. China. liangxm@dicp.ac.cn; yejx@ecust.edu.cn Supporting Information Contents A: General Information and Starting Materials S2 B: General Procedure for Asymmetric Michael Addition S2 C: Characterization Data of Addition Products S3 D: Copies of CSP-GC or CSP-HPLC Analysis of Addition Products S1 E: Copies of 1 H and 13 C NMR spectra of Adducts S33 F: References S56 S1

2 A: General Information and Starting Materials General. The 1 H-NMR and 13 C-NMR were recorded on a Bruke DRX 4 (4 MHz) instrument. (s = singlet, d = doublet, dd = double doublet, t = triplet, q = quartet, m = multiplet). Chromatography was carried out with silica gel (2-3 mesh) using mixtures of petroleum ether and ethyl acetate as eluent. High resolution mass spectrometry was carried out using an ACQUITY Ultra Performance Liquid Chromatography system (Waters, Milford MA) coupled TM with a Q-TOF premier (Waters MS Technologies, Manchester, U.K) by electrospray ionization (ESI). Optical rotations were measured on an Autopol III automatic polarimeter (Rudolph Research analytical); concentrations (c) are reported in g per 1 ml. Enantiomeric excess was detered by chiral HPLC using Agilent 12 Series or chiral GC using Agilent GC689 and GC 789. Chiralpak IA (.46cm x 25 cm), Chiralpak OD-H (.46cm x 25 cm), Chiralpak AS-H (.46cm x 25 cm) or Chirasil Dex CB (# CP 752). Materials. All solvent and inorganic reagents were of p.a. quality and used without purification. Both aromatic enones and heteroaromatic enone were prepared following the literature procedures. [1] Unless otherwise noted, materials were obtained from commercial sources and used without purification. B: General Procedure for Asymmetric Michael Addition To a solution of THF (2. ml) was added α, β-unsaturated ketone 8 or 11 (1. mmol), malonate 9 (3. mmol), catalyst (.5-.1 mmol). The reaction mixture was stirred at given temperature for the time indicated in Table 2 or Table 3 and then the solvent was removed under vacuum. The residue was purified by column chromatography on silica gel to yield the desired addition product. S2

3 C: Characterization Data of Addition Products [2] diethyl 2-(3-oxocyclohexyl)malonate (1aa) Prepared according to general procedure. The product was obtained in 95% O yield, colorless oil. 1 H-NMR (4 MHz, CDCl 3 ): δ (ppm) (m, 6H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), COOEt (m, 2H), (m, 3H), 3.29 (d, J = 8. Hz, 1H), (m, 4H);. 13 C-NMR (4 MHz, CDCl 3 ): δ (ppm) 13.9, 24.4, 28.6, 37.9, 4.8, 44.9, COOEt 56.7, 61.3, 167.6, 167.7, [α] 25.5 D = (c = 1.7 in CHCl 3, 96% ee), literature value reported by Steven 2a for the R enantiomer [α] 2 D = (c = 1 in CHCl 3, 93% ee). HRMS: exact mass calculated for [M+Na] + (C 13 H 2 O 5 Na) requires m/z , found m/z The enantiomeric excess was detered by GC. [Chirasil-Dex CB column, 1 C/ from 7 C to 16 C then hold for 3 ]: (major), (or). dimethyl 2-(3-oxocyclohexyl)malonate (1ab) Prepared according to general procedure. The product was obtained in 83% O yield, white solid. 1 H-NMR (4 MHz, CDCl 3 ): δ (ppm) (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 2H), COOMe (m, 2H), (m, 1H), 3.35 (d, J = 8. Hz, 1H), 3.75 (s, 6H). 13 C-NMR (4 MHz, CDCl 3 ): δ (ppm) 24.5, 28.7, 38.1, 4.9, 45., 52.5, 56.5, COOMe 168.1, 168.2, [α] 25. D = (c = 1.4 in CHCl 3, 96% ee), literature value 2a-2c reported for the R enantiomer [α] 2 D = (c = 1 in CHCl 3, 83% ee). HRMS: exact mass calculated for [M+Na] + (C 11 H 16 O 5 Na) requires m/z , found m/z The enantiomeric excess was detered by GC. [Chirasil-Dex CB column, 1 C/ from 7 C to 16 C then hold for 25 ]: (major), 24.2 (or). diisopropyl 2-(3-oxocyclohexyl)malonate (1ac) O Prepared according to general procedure. The product was obtained in 95% yield, colorless oil. 1 H-NMR (4 MHz, CDCl 3 ): δ (ppm) (m, 12H), (m, 1H), (m, 1H), (m, 2H), COOi-Pr (m, 2H), (m, 3H), 3.22 (d, J = 7.6 Hz, 1H), (m, 2H). COOi-Pr 13 C-NMR (4 MHz, CDCl 3 ): δ (ppm) 21.6, 21.6, 24.5, 28.7, 37.9, 41., 45.1, 57.2, 69.1, 167.3, 167.4, [α] 26.1 D = (c = 1.3 in CHCl 3, 96% ee). HRMS: exact mass calculated for [M+Na] + (C 15 H 24 O 5 Na) requires m/z , found m/z The enantiomeric excess was detered by GC. [Chirasil-Dex CB column, 1 C/ from 7 C to 15 C then hold for 5 ]: (major), (or). diethyl 2-(3-oxocycloheptyl)malonate (1ba) O COOEt COOEt Prepared according to general procedure. The product was obtained in 83% yield, yellow oil. 1 H-NMR (4 MHz, CDCl 3 ): δ (ppm) 1.27 (t, J = 7.2 Hz, 6H), (m, 3H), (m, 3H), (m, 5H), 3.3 (d, J = 6.8 Hz, 1H), (m, 4H). 13 C-NMR (4 MHz, CDCl 3 ): δ (ppm) 14., 24.4, 28.7, 34.1, 35.6, 43.5, 47.1, 57.4, 61.4, 168., 168.1, [α] 26.7 D = (c = 1.2 in CHCl 3, 93% ee), literature value reported by Steven 2a for S3

4 the R enantiomer [α] 2 D = (c =.1 in CHCl 3, 89% ee). HRMS: exact mass calculated for [M+Na] + (C 14 H 22 O 5 Na) requires m/z , found m/z The enantiomeric excess was detered by HPLC. [AS-H column, 22 nm, hexane: IPA = 9:1,.8 ml/]: (major), (or). diethyl 2-(3-oxocyclopentyl)malonate (1ca) Prepared according to general procedure. The product was obtained in 64% O yield, colorless oil. 1 H-NMR (4 MHz, CDCl 3 ): δ (ppm) (m, 6H), (m, 1H), (m, 1H), (m, 2H), (m, 1H), COOEt (m, 1H), (m, 1H), 3.32 (d, J = 9.2 Hz, 1H), (m, COOEt 4H). 13 C-NMR (4 MHz, CDCl 3 ): δ (ppm) 14., 27.4, 36.3, 38.1, 42.8, 56.4, 61.5, 168., 168.1, [α] 27.5 D = (c = 1.7 in CHCl 3, 63% ee), literature value reported by Steven 2a for the R enantiomer [α] 2 D = (c =.9 in CHCl 3, 3% ee). HRMS: exact mass calculated for [M+Na] + (C 12 H 18 O 5 Na) requires m/z , found m/z The enantiomeric excess was detered by HPLC. [AS-H column, 22 nm, hexane: IPA = 4:1,.8 ml/]: (or), (major). diethyl 2-(2,2-dimethyl-5-oxocyclohexyl)malonate (1da) O Prepared according to general procedure. The product was obtained in 77% yield, colorless oil. 1 H-NMR (4 MHz, CDCl 3 ): δ (ppm) 1.6 (s, 6H), (m, 6H), (m, 2H), (m, 3H), (m, 1H), COOEt (m, 1H), 3.57 (d, J = 4.8 Hz, 1H ), (m, 4H). 13 C-NMR (4 MHz, CDCl 3 ): δ (ppm) 13.9, 2.1, 28.7, 33.1, 37.7, 4., 4.4, 45.1, 52.2, COOEt 61.4, 61.7, 168.6, 168.7, 21.. [α] 27.7 D = (c = 1.3 in CHCl 3, 91% ee). HRMS: exact mass calculated for [M+Na] + (C 15 H 24 O 5 Na) requires m/z , found m/z The enantiomeric excess was detered by HPLC. [IA column, 22 nm, hexane: IPA = 2:1,.8 ml/]: (major), (or). diethyl 2-(3-oxo-1-phenylbutyl)malonate (12aa) EtOOC Prepared according to general procedure. The product was obtained in 92% yield, colorless oil. 1 H-NMR (4 MHz, CDCl 3 ): δ (ppm) 1.1 (t, J = 7.2 Hz, 3H), 1.25 (t, J = 7.2 Hz, 3H), 2.2 (s, 3H), (m, 2H), 3.69 (d, J = 1. Hz, 1H), (m, 3H), 4.19 (q, J = 7.2 Hz, 2H), (m, 5H). 13 C-NMR (4 MHz, CDCl 3 ): δ (ppm) 14., 14.3, 3.5, 4.7, 47.7, 57.7, 61.6, 61.9, 127.5, 128.4, 128.7, 14.7, 167.9, 168.5, [α] 28.2 D = (c = 1.2 in CHCl 3, 96% ee), literature value reported by Steven 2a for the S enantiomer [α] 2 D = (c = 1.1 in CHCl 3, 87% ee). HRMS: exact mass calculated for [M+Na] + (C 17 H 22 O 5 Na) requires m/z , found m/z The enantiomeric excess was detered by HPLC. [AS-H column, 254 nm, hexane: IPA = 9:1,.8 ml/]: (major), (or). dimethyl 2-(3-oxo-1-phenylbutyl)malonate (12ab) MeOOC COOEt O COOMe O Prepared according to general procedure. The product was obtained in 92% yield, yellow oil. 1 H-NMR (4 MHz, CDCl 3 ): δ (ppm) 2.5 (s, 3H), (m, 2H), 3.52 (s, 3H), (m, 4H), (m, 1H), (m, 5H). 13 C-NMR (4 MHz, CDCl 3 ): δ (ppm) 3.2, 4.4, 47.1, 52.3, 52.6, 57.1, 127.2, 128., 128.5, 14.4, 168., 168.5, [α] 29.2 D = (c = 1.1 in CHCl 3, 94% ee), literature value reported by Steven 2a for the S enantiomer [α] 2 D = (c = 1 in CHCl 3, 89% ee). HRMS: exact mass calculated for [M+Na] + (C 15 H 18 O 5 Na) S4

5 requires m/z , found m/z The enantiomeric excess was detered by HPLC. [AS-H column, 22 nm, hexane: IPA = 4:1,.8 ml/]: (major), (or). diisopropyl 2-(3-oxo-1-phenylbutyl)malonate (12ac) Prepared according to general procedure. The product was obtained in 9% i-prooc COOi-Pr O yield, yellowy oil. 1 H-NMR (4 MHz, CDCl 3 ): δ (ppm).98 (d, J = 6.4 Hz, 3H), 1.5 (d, J = 6. Hz, 3H), 1.25 (dd, J =2., 6.4 Hz, 6H), 2.3 (s, 3H), (m, 2H), 3.65 (d, J = 1.4 Hz, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 5H). 13 C-NMR (4 MHz, CDCl 3 ): δ (ppm) 21.2, 21.3, 21.5, 21.6, 3.3, 4.4, 47.7, 57.7, 68.8, 69.2, 127.1, 128.2, 128.4, 14.5, 167.1, 167.8, [α] 29.1 D = (c = 1.2 in CHCl 3, 96% ee). HRMS: exact mass calculated for [M+Na] + (C 19 H 26 O 5 Na) requires m/z , found m/z The enantiomeric excess was detered by HPLC. [AS-H column, 254 nm, hexane: IPA = 9:1,.8 ml/]: (major), (or). diethyl 2-(1-(4-chlorophenyl)-3-oxobutyl)malonate (12ba) Cl Prepared according to general procedure. The product was obtained in 95% yield, colorless oil. 1 H-NMR (4 MHz, CDCl 3 ): δ (ppm) 1.5 (t, J = 7.2 Hz, 3H), 1.25 (t, J = 7. Hz, 3H), 2.3 (s, 3H), (m, 2H), 3.66 (d, J = 9.6 Hz, 1H), (m, 3H), (m, 2H), (m, 4H). 13 C-NMR (4 MHz, CDCl 3 ): δ (ppm) 13.8, 14., 3.3, 39.7, 47.1, 57.1, 61.4, 61.7, 128.6, 129.6, 132.9, 139.1, 167.4, 168., [α] 29.3 D = (c = 1.1 in CHCl 3, 93% ee), literature value reported by Steven 2a for the S enantiomer [α] 2 D = (c = 1.2 in CHCl 3, 83% ee). HRMS: exact mass calculated for [M+Na] + (C 17 H 21 ClO 5 Na) requires m/z , found m/z The enantiomeric excess was detered by HPLC. [AS-H column, 254 nm, hexane: IPA = 9:1,.8 ml/]: 12.4 (major), (or). diethyl 2-(1-(2-bromophenyl)-3-oxobutyl)malonate (12ca) EtOOC EtOOC Br COOEt O COOEt O Prepared according to general procedure. The product was obtained in 94% yield, colorless oil. 1 H-NMR (4 MHz, CDCl 3 ): δ (ppm) 1.11 (t, J = 7.2 Hz, 3H), 1.22 (t, J = 7. Hz, 3H), 2.9 (s, 3H), 3.6 (d, J = 7.2 Hz, 2H), 3.95 (d, J = 8.8 Hz, 1H), 4.5 (q, J = 7.2 Hz, 2H), (m, 2H), 4.46 (dd, J = 7., 15. Hz, 1H), 7.5 (m, 1H), (m, 2H), 7.55 (d, J = 8. Hz, 1H). 13 C-NMR (4 MHz, CDCl 3 ): δ (ppm) 13.8, 13.9, 3., 39.1, 45.6, 55.2, 61.4, 61.5, 124.7, 127.5, 128.7, 129., 133.4, 139.6, 167.6, 168., [α] 28.8 D = (c =.99 in CHCl 3, 94% ee), literature value reported by Steven 2a for the S enantiomer [α] 2 D = (c =.5 in CHCl 3, 6% ee). HRMS: exact mass calculated for [M+Na] + (C 17 H 21 BrO 5 Na) requires m/z 47.47, found m/z The enantiomeric excess was detered by HPLC. [AS-H column, 22 nm, hexane: IPA = 9:1,.8 ml/.]: (major), (or). diethyl 2-(1-(4-bromophenyl)-3-oxobutyl)malonate (12da) Prepared according to general procedure. The product was obtained in 94% yield, colorless oil. S5

6 Br 1 H-NMR (4 MHz, CDCl 3 ): δ (ppm) 1.6 (t, J = 7.2 Hz, 3H), 1.26 (t, J = 7. Hz, 3H), 2.4 (s, 3H), (m, 2H), 3.66 (d, J = 1. Hz, 1H), (m, 3H), (m, 2H), (m, 4H). 13 C-NMR (4 MHz, CDCl 3 ): δ (ppm) 13.8, 14., 3.3, 39.7, 47.1, 57., 61.4, 61.7, 121., 13., 131.5, 139.6, 167.4, 167.9, [α] 28.8 D = (c = 1.5 in CHCl 3, 94% ee), literature value reported by Steven 2a for the S enantiomer [α] 2 D = (c = 1.1 in CHCl 3, 85% ee). HRMS: exact mass calculated for [M+Na] + (C 17 H 21 BrO 5 Na) requires m/z 47.47, found m/z The enantiomeric excess was detered by HPLC. [AS-H column, 22 nm, hexane: IPA = 4:1,.8 ml/.]: (major), (or). diethyl 2-(1-(2-nitrophenyl)-3-oxobutyl)malonate (12ea) Prepared according to general procedure. The product was obtained in 97% EtOOC COOEt O yield, orange oil. 1 H-NMR (4 MHz, CDCl 3 ): δ (ppm) 1.1 (t, J = 7.2 Hz, 3H), 1.24 (t, J = 7.2 Hz, 3H), 2.11 (s, 3H), (m, 2H), (m, 3H), (m, 2H), (m, 1H), (m, 1H), (m, NO 2H), (d, J = 8.4 Hz, 1H) C-NMR (4 MHz, CDCl 3 ): δ (ppm) 13.7, 13.9, 29.9, 34.6, 46.1, 55.7, 61.6, 61.7, 124.6, 127.9, 129.2, 132.6, 135.4, 15.3, 167.4, 168., [α] 29.4 D = (c = 1.4 in CHCl 3, 94% ee). HRMS: exact mass calculated for [M+Na] + (C 17 H 21 NO 7 Na) requires m/z , found m/z The enantiomeric excess was detered by HPLC. [AS-H column, 254 nm, hexane:ipa =9:1,.8 ml/.]: (major), (or). diethyl 2-(1-(4-nitrophenyl)-3-oxobutyl)malonate (12fa) O 2 N EtOOC EtOOC COOEt O COOEt O Prepared according to general procedure. The product was obtained in 9% yield, yellow oil. 1 H-NMR (4 MHz, CDCl 3 ): δ (ppm) 1.6 (t, J = 7.2 Hz, 3H), 1.26 (t, J = 7. Hz, 3H), 2.6 (s, 3H), (m, 2H), 3.73 (d, J = 9.6 Hz, 1H), (m, 2H), (m, 1H), (m, 2H), 7.45 (d, J = 8.8 Hz, 2H), 8.13 (d, J = 8.4 Hz, 2H). 13 C-NMR (4 MHz, CDCl 3 ): δ (ppm) 13.8, 14., 3.2, 39.8, 46.7, 56.5, 61.6, 61.9, 129.3, 129.6, 147., 148.5, 167.2, 167.6, [α] 28.7 D = (c = 1.2 in CHCl 3, 93% ee). HRMS: exact mass calculated for [M+Na] + (C 17 H 21 NO 7 Na) requires m/z , found m/z The enantiomeric excess was detered by HPLC. [AS-H column, 254 nm, hexane: IPA = 9:1,.8 ml/.]: (major), (or). diethyl 2-(3-oxo-1-o-tolylbutyl)malonate (12ga) EtOOC COOEt O Prepared according to general procedure. The product was obtained in 92% yield, colorless oil. 1 H-NMR (4 MHz, CDCl 3 ): δ (ppm).99 (t, J = 7. Hz, 3H), 1.27 (t, J = 7. Hz, 3H), 2. (s, 3H), 2.48 (s, 3H), (m, 2H), 3.7 (d, J = 9.6 Hz, 1H), (m, 2H), (m, 3H), (m, 4H). 13 C-NMR (4 MHz, CDCl 3 ): δ (ppm) 13.6, 14., 19.7, 3.4, 35.2, 47.7, 57.1, 61.2, 61.6, 126., 126.1, 126.8, 13.7, 136.9, 139.1, 167.7, 168.3, 26.. [α] 28.9 D = (c = 1.2 in CHCl 3, 93% ee). HRMS: exact mass calculated for [M+Na] + (C 18 H 24 O 5 Na) requires m/z , found m/z The enantiomeric excess was detered by HPLC. [AS-H column, 22 nm, hexane: IPA = 9:1,.8 ml/.]: 8.79 (major), (or). S6

7 diethyl 2-(3-oxo-1-m-tolylbutyl)malonate (12ha) EtOOC Prepared according to general procedure. The product was obtained in 86% yield, colorless oil. 1 H-NMR (4 MHz, CDCl 3 ): δ (ppm) 1.3 (t, J = 7. Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H), 2.3 (s, 3H), 2.31 (s, 3H), (m, 2H), 3.68 (d, J = 1. Hz, 1H), (m, 3H), (m, 2H), (m, 3H), 7.15 (t, J = 7.2 Hz, 1H). 13 C-NMR (4 MHz, CDCl 3 ): δ (ppm) 13.7, 14., 21.4, 3.2, 4.4, 47.4, 57.4, 61.2, 61.5, 125., 127.9, 128.3, 128.9, 137.9, 14.3, 167.6, 168.2, [α] 29. D = (c = 1.2 in CHCl 3, 94% ee). HRMS: exact mass calculated for [M+Na] + (C 18 H 24 O 5 Na) requires m/z , found m/z The enantiomeric excess was detered by HPLC. [AS-H column, 22 nm, hexane: IPA = 9:1,.8 ml/.]: (major), (or). diethyl 2-(3-oxo-1-p-tolylbutyl)malonate (12ia) EtOOC COOEt O Prepared according to general procedure. The product was obtained in 91% yield, colorless oil. 1 H-NMR (4 MHz, CDCl 3 ): δ (ppm) 1.4 (t, J = 7.2 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H), 2.2 (s, 3H), 2.29 (s, 3H), (m, 2H), 3.68 (d, J = 1 Hz, 1H), (m, 3H), (m, 2H), 7.7 (d, J = 8. Hz, 2H), 7.13 (d, J = 8. Hz, 2H). 13 C-NMR (4 MHz, CDCl 3 ): δ (ppm) 13.7, 14., 2.9, 3.2, 4.1, 47.4, 57.5, 61.2, 61.5, 128., 129.1, 136.6, 137.3, 167.6, 168.2, [α] 29.1 D = (c = 1.3 in CHCl 3, 94% ee), literature value reported by Steven 2a for the S enantiomer [α] 2 D = (c = 1.1 in CHCl 3, 88% ee). HRMS: exact mass calculated for [M+Na] + (C 18 H 24 O 5 Na) requires m/z , found m/z The enantiomeric excess was detered by HPLC. [AS-H column, 22 nm, hexane: IPA = 9:1,.8 ml/.]: 11.2 (major), (or). diethyl 2-(1-(2-methoxyphenyl)-3-oxobutyl)malonate (12ja) EtOOC COOEt O COOEt O Prepared according to general procedure. The product was obtained in 71% yield, yellow oil. 1 H-NMR (4 MHz, CDCl 3 ): δ (ppm) 1. (t, J = 7. Hz, 3H), 1.25 (t, J = 7. Hz, 3H), 2.5 (s, 3H), 2.91 (dd, J = 4.4, 16.4 Hz, 1H), 3.7 (dd, J = 9.2, 16.4 Hz, 1H), 3.87 (s, 3H), 3.93 (q, J = 7.1 Hz, 2H), 4.5 (d, J = 1. Hz, 1H), (m, 3H), (m, 2H), (m, 2H). OMe 13 C-NMR (4 MHz, CDCl 3 ): δ (ppm) 13.7, 14., 29.9, 37.3, 45.7, 55., 55.3, 61., 61.3, 11.9, 12.4, 127.8, 128.4, 13.4, 157.4, 168., 168.6, [α] 29.4 D = (c = 1.1 in CHCl 3, 97% ee). HRMS: exact mass calculated for [M+Na] + (C 18 H 24 O 6 Na) requires m/z , found m/z The enantiomeric excess was detered by HPLC. [AS-H column, 254 nm, hexane: IPA = 9:1,.8 ml/]: (major), (or). dimethyl 2-(1-(2-nitrophenyl)-3-oxobutyl)malonate (12eb) MeOOC COOMe Prepared according to general procedure. The product was obtained in 93% O yield, orange oil. 1 H-NMR (4 MHz, CDCl 3 ): δ (ppm) 2.1 (s, 3H), (m, 2H), 3.6 (s, 3H), 3.71 (s, 3H), 4.3 (d, J = 8.4 Hz, 1H), (m, 1H), (m, 3H), (dd, J = 1.2, 8. Hz, 1H). NO 13 2 C-NMR (4 MHz, CDCl 3 ): δ (ppm) 29.9, 34.5, 45.9, 52.6, 53.5, 55.5, 124.6, 128., 128.9, 132.7, 135.2, 15.2, 167.8, 168.3, [α] 29.4 D = (c =.99 in CHCl 3, S7

8 93% ee). HRMS: exact mass calculated for [M+Na] + (C 15 H 17 NO 7 Na) requires m/z , found m/z The enantiomeric excess was detered by HPLC. [AS-H column, 254 nm, hexane: IPA = 9:1,.8 ml/]: (major), (or). diethyl 2-(3-oxo-1-(thiophen-2-yl)butyl)malonate (12ka) EtOOC S Prepared according to general procedure. The product was obtained in 83% yield, yellow oil. 1 H-NMR (4 MHz, CDCl 3 ): δ (ppm) 1.14 (t, J = 7. Hz, 3H), 1.26 (t, J = 7. Hz, 3H), 2.1 (s, 3H), 3.1 (d, J = 6.4 Hz, 2H), 3.75 (d, J = 8.8 Hz, 1H), 4.6 (m, 2H), (m, 2H), (m, 1H), (m, 2H), (d, J = 3.2 Hz, 1H). 13 C-NMR (4 MHz, CDCl 3 ): δ (ppm) 13.8, 14., 3.2, 35.7, 47.9, 57.7, 61.5, 61.6, 124.2, 125.7, 126.6, 143.6, 167.5, 167.9, [α] 29.4 D = (c = 1.5 in CHCl 3, 9% ee), literature value reported by Steven 2a for the S enantiomer [α] 2 D = (c = 1. in CHCl 3, 88% ee). HRMS: exact mass calculated for [M+Na] + (C 15 H 2 SO 5 Na) requires m/z , found m/z The enantiomeric excess was detered by HPLC. [AS-H column, 254 nm, hexane: IPA = 9:1,.8 ml/]: (major), (or). diethyl 2-(2-oxoheptan-4-yl)malonate (12la) EtOOC COOEt O COOEt O Prepared according to general procedure. The product was obtained in 91% yield, colorless oil. 1 H-NMR (4 MHz, CDCl 3 ): δ (ppm).89 (t, J = 6.8 Hz, 3H), (m, 1H), 2.14 (s, 3H), 2.51 (dd, J = 6., 8.4 Hz,1H), (m, 2H), 3.52 (d, J = 5.6 Hz, 1H), 4.17 (m, 4H). 13 C-NMR (4 MHz, CDCl 3 ): δ (ppm) 13.9, 14., 2., 3.2, 33.2, 34.4, 45.2, 54., 61.1, 61.2, 168.6, 168.9, [α] 27.9 D = (c = 1.5 in CHCl 3, 96% ee). HRMS: exact mass calculated for [M+Na] + (C 14 H 24 O 5 Na) requires m/z , found m/z The enantiomeric excess was detered by HPLC. [OD-H column, 22 nm, hexane: IPA = 2:1,.8 ml/]: (major), (or). diethyl 2-(2-oxooctan-4-yl)malonate (12ma) Prepared according to general procedure. The product was obtained in EtOOC COOEt O 9% yield, colorless oil. 1 H-NMR (4 MHz, CDCl 3 ): δ (ppm).87 (t, J = 7. Hz, 3H), (m, 12H), 2.14 (s, 3H), (m, 1H), (m, 1H), (m, 1H), 3.52 (d, J = 5.6 Hz, 1H), (m, 4H). 13 C-NMR (4 MHz, CDCl 3 ): δ (ppm) 13.8, 14., 22.5, 29., 3.2, 31.8, 33.4, 45.2, 54., 61.1, 61.2, 168.6, 168.9, [α] 28.1 D = (c = 1.5 in CHCl 3, 97% ee). HRMS: exact mass calculated for [M+Na] + (C 15 H 26 O 5 Na) requires m/z , found m/z The enantiomeric excess was detered by HPLC. [OD-H column, 22 nm, hexane: IPA = 2:1,.8 ml/]: 6.15 (major), (or). diethyl 2-(3-oxo-1-phenylpentyl)malonate (12na) EtOOC COOEt O Prepared according to general procedure. The product was obtained in 8% yield, colorless oil. 1 H-NMR (4 MHz, CDCl 3 ): δ (ppm).93 (t, J = 7.2 Hz, 3H), 1.2 (t, J = 7.2 Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H), (m, 2H), 2.91 (m, J = 7.2 Hz, 2H), 3.72 (d, J = 1. Hz, 1H), 3.92 (m, 3H), 4.2 (q, J = 7.2 Hz, 2H), (m, 5H). 13 C-NMR (4 MHz, CDCl 3 ): S8

9 δ (ppm) 7.5, 13.7, 14., 36.4, 4.5, 46.2, 57.4, 61.3, 61.6, 127.2, 128.1, 128.4, 14.5, 167.7, 168.3, [α] 13.4 D = (c = 1.1 in CHCl 3, 83% ee). HRMS: exact mass calculated for [M+Na] + (C 18 H 24 O 5 Na) requires m/z , found m/z The enantiomeric excess was detered by HPLC. [AS-H column, 254 nm, hexane: IPA = 9:1,.8 ml/]: 1.81 (major), (or). S9

10 D: CSP-HPLC or CSP-GC Analysis of Addition Products diethyl 2-(3-oxocyclohexyl)malonate (1aa) pa FID1 A, 前部信号 (D:\CHEM32\1\DATA\LIPF\81128\ 环己烯酮 - 丙二酸酯.D 峰面积峰面积 : 381 : Racemic adduct (sample in CH 2 Cl 2 ) pa 1 8 FID1 A, 前部信号 (D:\CHEM32\1\DATA\LIPF\81128\ 环己烯酮 - 丙二酸酯 1.D 峰面积 : 峰面积 : Asymmetric adduct (sample in CH 2 Cl 2 ) S1

11 dimethyl 2-(3-oxocyclohexyl)malonate (1ab) pa FID1 A, 前部信号 (D:\CHEM32\1\DATA\LIPF\81128\ 环己烯酮 - 丙二酸酯 2.D Racemic adduct (sample in CH 2 Cl 2 ) pa 1 8 FID1 A, 前部信号 (D:\CHEM32\1\DATA\LIPF\81128\ 环己烯酮 - 丙二酸酯 3.D) 峰面积 : 峰面积 : Asymmetric adduct (sample in CH 2 Cl 2 ) S11

12 diisopropyl 2-(3-oxocyclohexyl)malonate (1ac) pa FID1 A, 前部信号 (D:\CHEM32\1\DATA\LIPF\81128\ 环己烯酮 - 丙二酸酯 4.D) 峰面积 : 峰面积 : Racemic adduct (sample in CH 2 Cl 2 ) pa FID1 A, 前部信号 (D:\CHEM32\1\DATA\LIPF\81128\ 环己烯酮 - 丙二酸酯 5.D) 峰面积 : 峰面积 : Asymmetric adduct (sample in CH 2 Cl 2 ) S12

13 diethyl 2-(3-oxocycloheptyl)malonate (1ba) VWD1 A, 波长 =22 nm (LIPF\81127\ 烯酮 - 丙二酸酯 2.D) 峰面积 : Racemic adduct (sample in EtOH) VWD1 A, 波长 =22 nm (LIPF\81127\ 烯酮 - 丙二酸酯 4.D) Asymmetric adduct (sample in EtOH) S13

14 diethyl 2-(3-oxocyclopentyl)malonate (1ca) VWD1 A, 波长 =22 nm (LIPF\8624\ 烯酮 - 丙二酸酯 39.D) Racemic adduct (sample in EtOH) # Time Area Height Width Symmetry Area% VWD1 A, 波长 =22 nm (LIPF\8624\ 烯酮 - 丙二酸酯 4.D) Asymmetric adduct (sample in EtOH) # Time Area Height Width Symmetry Area% S14

15 diethyl 2-(2,2-dimethyl-5-oxocyclohexyl)malonate (1da) VWD1 A, 波长 =22 nm (LIPF\8624\ 烯酮 - 丙二酸酯 47.D) Racemic adduct (sample in EtOH) # Time Area Height Width Symmetry Area% VWD1 A, 波长 =22 nm (LIPF\8624\ 烯酮 - 丙二酸酯 48.D) Asymmetric adduct (sample in EtOH) # Time Area Height Width Symmetry Area% S15

16 diethyl 2-(3-oxo-1-phenylbutyl)malonate (12aa) 8 VWD1 A, 波长 =254 nm (LIPF\8624\ 烯酮 - 丙二酸酯 19.D) Racemic adduct (sample in EtOH) VWD1 A, 波长 =254 nm (LIPF\8624\ 烯酮 - 丙二酸酯 2.D) 峰面积 : Asymmetric adduct (sample in EtOH) S16

17 dimethyl 2-(3-oxo-1-phenylbutyl)malonate (12ab) 3 VWD1 A, 波长 =22 nm (LIPF\8624\ 烯酮 - 丙二酸酯 5.D) Racemic adduct (sample in EtOH) VWD1 A, 波长 =22 nm (LIPF\8624\ 烯酮 - 丙二酸酯 49.D) Asymmetric adduct (sample in EtOH) S17

18 diisopropyl 2-(3-oxo-1-phenylbutyl)malonate (12ac) 16 VWD1 A, 波长 =254 nm (LIPF\81127\ 烯酮 - 丙二酸酯 5.D) Racemic adduct (sample in EtOH) VWD1 A, 波长 =254 nm (LIPF\81127\ 烯酮 - 丙二酸酯 6.D) Asymmetric adduct (sample in EtOH) S18

19 diethyl 2-(1-(4-chlorophenyl)-3-oxobutyl)malonate (12ba) VWD1 A, 波长 =254 nm (LIPF\8624\ 烯酮 - 丙二酸酯 11.D) Racemic adduct (sample in EtOH) VWD1 A, 波长 =254 nm (LIPF\8624\ 烯酮 - 丙二酸酯 12.D) Asymmetric adduct (sample in EtOH) S19

20 diethyl 2-(1-(2-bromophenyl)-3-oxobutyl)malonate (12ca) VWD1 A, 波长 =22 nm (LIPF\8624\ 烯酮 - 丙二酸酯 31.D) Racemic adduct (sample in EtOH) VWD1 A, 波长 =22 nm (LIPF\8624\ 烯酮 - 丙二酸酯 32.D) Asymmetric adduct (sample in EtOH) S2

21 diethyl 2-(1-(4-bromophenyl)-3-oxobutyl)malonate (12da) VWD1 A, 波长 =22 nm (LIPF\8624\ 烯酮 - 丙二酸酯 43.D) Racemic adduct (sample in EtOH) VWD1 A, 波长 =22 nm (LIPF\8624\ 烯酮 - 丙二酸酯 44.D) Asymmetric adduct (sample in EtOH) S21

22 diethyl 2-(1-(2-nitrophenyl)-3-oxobutyl)malonate (12ea) 17.5 VWD1 A, 波长 =254 nm (LIPF\8624\ 烯酮 - 丙二酸酯 53.D) Racemic adduct (sample in EtOH) VWD1 A, 波长 =254 nm (LIPF\8624\ 烯酮 - 丙二酸酯 54.D) Asymmetric adduct (sample in EtOH) S22

23 diethyl 2-(1-(4-nitrophenyl)-3-oxobutyl)malonate (12fa) 1 VWD1 A, 波长 =254 nm (LIPF\8624\ 烯酮 - 丙二酸酯 14.D) Racemic adduct (sample in EtOH) VWD1 A, 波长 =254 nm (LIPF\8624\ 烯酮 - 丙二酸酯 13.D) Asymmetric adduct (sample in EtOH) S23

24 diethyl 2-(3-oxo-1-o-tolylbutyl)malonate (12ga) 6 VWD1 A, 波长 =22 nm (LIPF\8624\ 烯酮 - 丙二酸酯 35.D) Racemic adduct (sample in EtOH) VWD1 A, 波长 =22 nm (LIPF\8624\ 烯酮 - 丙二酸酯 36.D) Asymmetric adduct (sample in EtOH) S24

25 diethyl 2-(3-oxo-1-m-tolylbutyl)malonate (12ha) 4 VWD1 A, 波长 =22 nm (LIPF\8624\ 烯酮 - 丙二酸酯 33.D) Racemic adduct (sample in EtOH) VWD1 A, 波长 =22 nm (LIPF\8624\ 烯酮 - 丙二酸酯 34.D) Asymmetric adduct (sample in EtOH) S25

26 diethyl 2-(3-oxo-1-p-tolylbutyl)malonate (12ia) 3 VWD1 A, 波长 =22 nm (LIPF\8624\ 烯酮 - 丙二酸酯 37.D) Racemic adduct (sample in EtOH) VWD1 A, 波长 =22 nm (LIPF\8624\ 烯酮 - 丙二酸酯 38.D) Asymmetric adduct (sample in EtOH) S26

27 diethyl 2-(1-(2-methoxyphenyl)-3-oxobutyl)malonate (12ja) 5 4 VWD1 A, 波长 =254 nm (LIPF\8624\ 烯酮 - 丙二酸酯 29.D) Racemic adduct (sample in EtOH) VWD1 A, 波长 =254 nm (LIPF\8624\ 烯酮 - 丙二酸酯 3.D) 峰面积 : Asymmetric adduct (sample in EtOH) E S27

28 dimethyl 2-(1-(2-nitrophenyl)-3-oxobutyl)malonate (12eb) VWD1 A, 波长 =254 nm (LIPF\8624\ 烯酮 - 丙二酸酯 55.D) Racemic adduct (sample in EtOH) VWD1 A, 波长 =254 nm (LIPF\8624\ 烯酮 - 丙二酸酯 56.D) Asymmetric adduct (sample in EtOH) S28

29 diethyl 2-(3-oxo-1-(thiophen-2-yl)butyl)malonate (12ka) 12 1 VWD1 A, 波长 =22 nm (LIPF\81127\ 烯酮 - 丙二酸酯.D) Racemic adduct (sample in EtOH) VWD1 A, 波长 =22 nm (LIPF\81127\ 烯酮 - 丙二酸酯 1.D) Asymmetric adduct (sample in EtOH) S29

30 diethyl 2-(2-oxoheptan-4-yl)malonate (12la) 5 VWD1 A, 波长 =22 nm (LIPF\8624\ 烯酮 - 丙二酸酯 2.D) Racemic adduct (sample in EtOH) VWD1 A, 波长 =22 nm (LIPF\8624\ 烯酮 - 丙二酸酯 3.D) Asymmetric adduct (sample in EtOH) S3

31 diethyl 2-(2-oxooctan-4-yl)malonate (12ma) 14 VWD1 A, 波长 =22 nm (LIPF\8624\ 烯酮 - 丙二酸酯.D) Racemic adduct (sample in EtOH) VWD1 A, 波长 =22 nm (LIPF\8624\ 烯酮 - 丙二酸酯 1.D) Asymmetric adduct (sample in EtOH) S31

32 diethyl 2-(3-oxo-1-phenylpentyl)malonate (12na) VWD1 A, 波长 =254 nm (LIPF\81127\ 烯酮 - 丙二酸酯 19.D) Racemic adduct (sample in EtOH) VWD1 A, 波长 =254 nm (LIPF\81127\ 烯酮 - 丙二酸酯 2.D) Asymmetric adduct (sample in EtOH) S32

33 E: Copies of 1 H, and 13 C NMR spectra of Adducts S33

34 S34

35 S35

36 S36

37 S37

38 S38

39 S39

40 S4

41 S41

42 S42

43 S43

44 S44

45 S45

46 S46

47 S47

48 S48

49 S49

50 S5

51 S51

52 S52

53 S53

54 S54

55 S55

56 E: References 1. Sinisterra, J. V.; Garcia-Raso, A. Synthesis 1984, 6, (a) Wascholowski, V.; Knudsen, K. R.; Mitchell, C. E. T.; Ley, S. V. Chem. Eur. J. 28, 14, (b) Guo, R.; Chen, X.; Elpelt, C.; Song, D.; Morris, R. H. Org. Lett. 25, 7, (c) Watanabe, M.; Murata, K.; Ikariya, T. J. Am. Chem. Soc. 23, 125, (d) Halland, N.; Aburel, P. S.; Jørgensen, K. A. Angew. Chem., Int. Ed. 23, 42, S56