Supporting Information. Copyright Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, 2007

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1 Supporting Information Copyright Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, 2007

2 Organocatalytic Asymmetric Sulfa-Michael Addition to α,β- Unsaturated Ketones Paolo Ricci, Armando Carlone, Giuseppe Bartoli, Marcella Bosco, Letizia Sambri and Paolo Melchiorre* Department of Organic Chemistry A. Mangini Alma Mater Studiorum - Bologna University v.le Risorgimento 4, I Bologna, Italy pm@ms.fci.unibo.it Contents General Methods..... S2 Materials S2 Determination of Enantiomeric Purity..... S2 Determination of Absolute Configuration....S2 Experimental Procedures S3 S1

3 General Methods. The 1 H and 13 C NMR spectra were recorded at 400 MHz and 100 MHz, respectively. The chemical shifts (δ) are referenced to residual signals of the solvents (CHCl ppm for 1 H NMR and 77.0 ppm for 13 C NMR). Coupling constants are given in Hz. The following abbreviations are used to indicate the multiplicity: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad signal. Purification of reaction products was carried out by flash chromatography (FC) on silica gel ( mesh). Organic solutions were concentrated under reduced pressure on a Büchi rotary evaporator. Mass spectra were obtained from the Department of Organic Chemistry A. Mangini Mass Spectroscopy facility. Optical rotations are reported as follows: [α] D rt (c in g per 100 ml, solvent). All reactions were carried out in air and using undistilled solvent without any precautions to exclude moisture, unless otherwise noted. Materials. Commercial grade reagents and solvents were used without further purification; otherwise, where necessary, they were purified as recommended. 1 Thiols 1 were purchased from Aldrich and Fluka. α,β-unsaturated ketones 2 were purchased and used as received, prepared by Wittig reaction with commercially available acetylmethylenetriphenylphosphorane (when R 2 = Me), or by addition of ethyl Grignard to the corresponding unsatured aldehyde followed by oxidation with MnO 2 (when R 2 = Et). N-protected amino acids were purchased from Aldrich or Fluka and used as received. 9-Amino(9-deoxy)epi-hydroquinine was prepared from commercially available hydroquinine following the literature procedure. 2 Determination of Enantiomeric Purity. Chiral HPLC analysis was performed on an Agilent series instrumentation. Daicel Chiralpak AD-H or AS-H columns and Daicel Chiralcel OD-H with i- PrOH/hexane as the eluent were used. HPLC traces were compared to racemic samples prepared by FeCl 3 -catalyzed reaction. 3 Determination of Absolute Configuration. The absolute configuration of the optically active compound 3g was assigned to be (S) by comparison of the measured optical rotation with the value reported in the literature. 4 All other absolute configurations were assigned by analogy based on an uniform reaction mechanism. 1 W. L. F. Armarengo, D. D. Perrin, In Purification of Laboratory Chemicals, 4 th ed.; Butterworth Heinemann: Oxford, B. Vakulya, Sz. Varga, A. Csámpai, T. Soos, Org. Lett. 2005, 7, C.-M. Chu,W.-J. Huang, C. Lu, P. Wu, J.-T. Liu, C.-F. Yao, Tetrahedron Lett. 2006, 47, a) J. Skarżewski, M. Zielińska-Blajet, I. Turowska-Tyrk, Tetrahedron: Asymmetry 2001, 12, S2

4 Experimental Procedures General Procedure for the Organocatalytic Sulfa-Michael Addition to α,β-unsaturated Ketones. All the reactions were carried out in undistilled toluene without any precautions to exclude water. In an ordinary test tube equipped with a magnetic stirring bar, 9-amino(9-deoxy)epi-hydroquinine (10-20 mol%) and D-N-Boc phenylglycine (20-40 mol%) as the chiral counter-anion were dissolved in 0.8 ml of toluene. The solution was stirred for 20 minutes at room temperature to allow the formation of the catalytic salt A. After addition of α,β-unsaturated ketones 2 (0.2 mmol), the mixture was stirred at the appropriate temperature for 10 minutes. Then thiol 1 (0.24 mmol, 1.2 equiv) was added in one portion, the tube was closed with a rubber stopper and stirring was continued for the indicated time. Then the crude reaction mixture was diluted with hexane (2 ml) and flushed through a short plug of silica, using hexane/et2o 1/1 as the eluent. Solvent was removed in vacuo, and the residue was purified by flash chromatography to yield the desired product. Ph 3a Ph 3a (Table 2, entry 1). The reaction was carried out at -20 C for 66 h using 15 was isolated by column chromatography (hexane/ Et 2 O = 85/15) in 81% yield and 85% ee. The ee was determined by HPLC analysis using a Chiralcel OD-H column (90/10 hexane/i-proh; flow rate 0.75 ml/min; λ = 214, 254 nm; τ major = 10.4 min; τ minor = 11.9 min). [α] D rt= (c = 1.0, CHCl 3, 85% ee). HRMS: m/z calcd for C 17 H 18 OS: ; found: H NMR (400 MHz, CDCl 3 ): δ = 2.02 (s, 3H), (m, 2H), 3.50 (AB system, J = 13.3 Hz, 2H), 4.22 (t, J = 7.2 Hz, 1H), (m, 10H); 13 C NMR (150 MHz, CDCl 3 ): δ = 30.4, 35.7, 43.9, 49.9, 127.0, 127.4, 127.9, 128.4, 128.5, 128.9, 137.8, 141.5, Ph 3b p-clc 6 H 4 3b (Table 2, entry 2). The reaction was carried out at -20 C for 46 h using 15 mol% of catalytic salt A following the general procedure. The title compound was isolated by column chromatography (hexane/ Et 2 O = 85/15) in 78% yield and 84% ee. The ee was determined by HPLC analysis using a Chiralcel OD-H column (95/5 hexane/i-proh; flow rate 0.75 ml/min; λ = 214, 254 nm; τ minor = 11.6 min; τ major = 12.3 min). [α] D rt = (c = 1.0, CHCl 3, 84% ee). HRMS: m/z calcd for C 17 H 17 ClOS: ; found: H NMR (400 MHz, CDCl 3 ): δ = 2.02 (s, 3H), 2.90 (brd, J = 7.2 Hz, 2H), 3.49 (AB system, J = 13.3 Hz, 2H), 4.17 (t, J = 7.2 Hz, 1H), (m, 9H); 13 C NMR (150 MHz, CDCl 3 ): δ = 30.5, 35.7, 43.1, 49.9, 127.1, 128.5, 128.7, 128.9, 129.3, 132.9, 137.5, 140.2, S3

5 Ph 3c S 3c (Table 2, entry 3). The reaction was carried out at -20 C for 66 h using 15 was isolated by column chromatography (hexane/ Et 2 O = 85/15) in 84% yield and 84% ee. The ee was determined by HPLC analysis using a Chiralpak AD-H column (80/20 hexane/i-proh; flow rate 0.75 ml/min; λ = 214, 254 nm; τ major = 8.4 min; τ minor = 9.5 min). [α] D rt= (c = 1.0, CHCl 3, 84% ee). HRMS: m/z calcd for C 15 H 16 OS 2 : ; found: H NMR (400 MHz, CDCl 3 ): δ = 2.05 (s, 3H), (m, 2H), 3.62 (AB system, J = 13.3 Hz, 2H), 4.52 (t, J = 7.4 Hz, 1H), (m, 3H), (m, 5H); 13 C NMR (150 MHz, CDCl 3 ): δ = 30.5, 36.0, 39.1, 50.8, 124.8, 125.8, 126.4, 127.1, 128.5, 128.9, 137.6, 146.3, Ph 3d Pent 3d (Table 2, entry 4). The reaction was carried out at -20 C for 96 h using 20 was isolated by column chromatography (hexane/ Et 2 O = 90/10) in 81% yield and 89% ee. The ee was determined by HPLC analysis using a Chiralpak AS-H column (98/2 hexane/i-proh; flow rate 0.75 ml/min; λ = 214, 254 nm; τ major = 10.3 min; τ minor = 10.8 min). [α] D rt= (c = 1.0, CHCl 3, 89% ee). HRMS: m/z calcd for C 16 H 24 OS: ; found: H NMR (400 MHz, CDCl 3 ): δ = 0.86 (t, J = 7.0 Hz, 3H), (m, 8H), 2.08 (s, 3H), (m, 2H), (m, 1H), 3.73 (AB system, J = 13.2 Hz, 2H), (m, 5H); 13 C NMR (150 MHz, CDCl 3 ): δ = 14.0, 22.5, 26.3, 30.5, 31.5, 35.1, 35.7, 40.4, 49.6, 126.9, 128.4, 128.9, 138.5, Ph 3e Pent 3e (Table 2, entry 5). The reaction was carried out at -20 C for 96 h using 20 was isolated by column chromatography (hexane/ Et 2 O = 85/15) in 75% yield and 96% ee. The ee was determined by HPLC analysis using a Chiralcel OD-H column (99/1 hexane/i-proh; flow rate 0.75 ml/min; λ = 214, 254 nm; τ major = 7.8 min; τ minor = 8.5 min). [α] D rt= (c = 1.0, CHCl 3, 96% ee). HRMS: m/z calcd for C 17 H 26 OS: ; found: H NMR (400 MHz, CDCl 3 ): δ = 0.86 (t, J = 7.2 Hz, 3H), 1.03 (t, J = 7.2 Hz, 3H), (m, 8H), 2.36 (q, J = 7.2 Hz, 2H), (m, 2H), (m, 1H), 3.72 (AB system, J = 13.2 Hz, 2H), (m, 5H); 13 C NMR (150 MHz, CDCl 3 ): δ = 7.6, 14.0, 22.5, 26.3, 31.5, 35.2, 35.9, 36.7, 40.6, 48.5, 126.9, 128.4, 128.9, 138.6, Ph 3f 3f (Table 2, entry 6). The reaction was carried out at -20 C for 96 h using 20 was isolated by column chromatography (hexane/ Et 2 O = 95/5) in 55% yield and 94% ee. The ee was S4

6 determined by HPLC analysis using a Chiralcel OD-H column (98/2 hexane/i-proh; flow rate 0.75 ml/min; λ = 214, 254 nm; τ minor = 9.9 min; τ major = 10.2 min). [α] D rt= (c = 1.0, CHCl 3, 94% ee). HRMS: m/z calcd for C 13 H 18 OS: ; found: H NMR (400 MHz, CDCl 3 ): δ = 1.02 (t, J = 7.6 Hz, 3H), 1.26 (d, J = 6.8 Hz, 3H), (m, 2H), 2.58 (AB system, J = 6.0, 16.4 Hz, 2H), (m, 1H) 3.75 (AB system, J = 13.2, 2H), (m, 5H); 13 C NMR (150 MHz, CDCl 3 ): δ = 7.6, 21.5, 35.1, 35.6, 36.6, 49.6, 127.0, 128.5, 128.8, 138.3, Ph 3g Ph Ph (S)-3g (Table 2, entry 7). The reaction was carried out at RT for 40 h using 20 was isolated by column chromatography (hexane/et 2 O = 95/5) in 75% yield and 54% ee. The ee was determined by HPLC analysis using a Chiralpak AS-H column (90/10 hexane/i-proh; flow rate 0.75 ml/min; λ = 214, 254 nm; τ minor = 9.2 min; τ major = 11.1 min). [α] D rt= (c = 1.0, CH 2 Cl 2, 54% ee); lit. [4] [α] D rt= + 136, (R)-3g (c = 1.02, CH 2 Cl 2, >95% ee). ESI: m/z calcd for C 22 H 20 OS+H + : 332; found: H NMR (400 MHz, CDCl 3 ): δ = (m, 4H), (m, 1H), (m, 15H); 13 C NMR (150 MHz, CDCl 3 ): δ = 35.8, 44.1, 45.2, 126.9, 127.2, 128.0, 128.1, 128.4, 128.5, 128.6, 128.9, 133.1, 136.7, 137.8, 141.7, a Ph 4a (Table 3, entry 1). The reaction was carried out at RT for 116 h using 20 mol% of column chromatography (hexane/acoet = 92/8) in 59% yield and 95% ee. The ee was determined by HPLC analysis using a Chiralcel OD-H column (80/20 hexane/i-proh; flow rate 0.75 ml/min; λ = 214, 254 nm; τ major = 5.8 min; τ minor = 6.3 min). [α] D rt= (c = 1.0, CHCl 3, 95% ee). HRMS: m/z calcd for C 14 H 20 OS: ; found: H NMR (400 MHz, CDCl 3 ): δ = 1.20 (s, 9H), 2.05 (s, 3H), (m, 2H), 4.41 (t, J = 7.6 Hz, 1H), (m, 5H); 13 C NMR (150 MHz, CDCl 3 ): δ = 30.9, 31.2, 42.5, 44.2, 52.1, 126.8, 127.6, 128.4, 144.5, b p-clc 6 H 4 4b (Table 3, entry 2). The reaction was carried out at RT for 116 h using 20 was isolated by column chromatography (hexane/ Et 2 O = 85/15) in 70% yield and 94% ee. The ee was determined by HPLC analysis using a Chiralpak AD-H column (90/10 hexane/i-proh; flow rate 0.75 ml/min; λ = 214, 254 nm; τ major = 5.2 min; τ minor = 5.5 min). [α] D rt= (c = 1.0, CHCl 3, 94% ee). HRMS: m/z calcd for C 14 H 19 ClOS: ; found: H NMR (400 MHz, CDCl 3 ): δ = 1.18 (s, 9H), 2.05 (s, 3H), (m, 2H), 4.38 (t, J = 6.9 Hz, 1H), S5

7 (m, 4H); 13 C NMR (150 MHz, CDCl 3 ): δ = 30.9, 31.2, 41.7, 44.4, 51.9, 128.5, 129.0, 132.4, 143.2, c p-no 2 C 6 H 4 4c (Table 3, entry 3). The reaction was carried out at RT for 116 h using 20 was isolated by column chromatography (hexane/acoet = 85/15) in 98% yield and 91% ee. The ee was determined by HPLC analysis using a Chiralpak AS-H column (80/20 hexane/i-proh; flow rate 0.75 ml/min; λ = 214, 254 nm; τ minor = 9.2 min; τ major = 9.9 min). [α] D rt= (c = 1.0, CHCl 3, 91% ee). HRMS: m/z calcd for C 14 H 19 NO 3 S: ; found: H NMR (400 MHz, CDCl 3 ): δ = 1.18 (s, 9H), 2.07 (s, 3H), 2.92 (AB system, J = 6.4, 17.2 Hz, 2H), 4.48 (t, J = 7.2 Hz, 1H), 7.57 (d, J = 8.4 Hz, 2H), 8.13 (d, J = 8.4 Hz, 2H); 13 C NMR (150 MHz, CDCl 3 ): δ = 30.7, 31.2, 41.5, 44.7, 51.6, 123.7, 128.7, 146.7, 152.6, d p-cnc 6 H 4 4d (Table 3, entry 4). The reaction was carried out at RT for 116 h using 20 was isolated by column chromatography (hexane/ Et 2 O = 70/30) in 96% yield and 94% ee. The ee was determined by HPLC analysis using a Chiralpak AD-H column (80/20 hexane/i-proh; flow rate 0.75 ml/min; λ = 214, 254 nm; τ major = 5.2 min; τ minor = 5.5 min). [α] D rt= (c = 1.0, CHCl 3, 94% ee). HRMS: m/z calcd for C 15 H 19 NOS: ; found: H NMR (400 MHz, CDCl 3 ): δ = 1.18 (s, 9H), 2.07 (s, 3H), 2.89 (AB system, J = 7.6, 17.2 Hz, 2H), 4.43 (t, J = 7.2 Hz, 1H), (m, 4H); 13 C NMR (150 MHz, CDCl 3 ): δ = 30.7, 31.1, 41.8, 44.7, 51.6, 110.6, 118.7, 128.6, 132.2, 150.5, e S 4e (Table 3, entry 5). The reaction was carried out at RT for 116 h using 20 mol% of catalytic salt A following the general procedure. The title compound was isolated by column chromatography (hexane/ Et 2 O = 80/20) in 65% yield and 92% ee. The ee was determined by HPLC analysis using a Chiralpak AS-H column (80/20 hexane/i-proh; flow rate 0.75 ml/min; λ = 214, 254 nm; τ major = 6.8 min; τ minor = 7.2 min). [α] D rt= (c = 1.0, CHCl 3, 92% ee). HRMS: m/z calcd for C 12 H 18 OS 2 : ; found: H NMR (400 MHz, CDCl 3 ): δ = 1.26 (s, 9H), 2.10 (s, 3H), (m, 2H), 4.70 (t, J = 7.2 Hz, 1H), (m, 1H), (m, 1H), (m, 1H); 13 C NMR (150 MHz, CDCl 3 ): δ = 30.9, 31.0, 37.4, 44.7, 53.0, 124.1, 124.4, 126.5, 149.7, S6

8 4f Pent 4f (Table 3, entry 6). The reaction was carried out at RT for 116 h using 20 mol% of column chromatography (hexane/et 2 O = 95/5) in 76% yield and 91% ee. The ee was determined by HPLC analysis using a Chiralpak AS-H column (95/5 hexane/i-proh; flow rate 0.75 ml/min; λ = 214, 254 nm; τ minor = 4.6 min; τ major = 4.9 min). [α] D rt= (c = 1.0, CHCl 3, 91% ee). HRMS: m/z calcd for C 13 H 26 OS: ; found: H NMR (400 MHz, CDCl 3 ): δ = 0.86 (t, J = 6.8 Hz, 3H), 1.29 (s, 9H), (m, 8H), 2.14 (s, 3H), (m, 2H), (m, 1H); 13 C NMR (150 MHz, CDCl 3 ): δ = 14.0, 22.5, 26.5, 31.1, 31.4, 31.7, 37.3, 37.8, 43.4, 51.4, g 4g (Table 3, entry 7). The reaction was carried out at RT for 116 h using 20 mol% of column chromatography (hexane/ Et 2 O = 95/5) in 71% yield and 82% ee. The ee was determined by HPLC analysis using a Chiralpak AS-H column (90/10 hexane/i-proh; flow rate 0.75 ml/min; λ = 214, 254 nm; τ minor = 5.0 min; τ major = 5.4 min). [α] D rt= (c = 1.0, CHCl 3, 82% ee). HRMS: m/z calcd for C 9 H 18 OS: ; found: H NMR (400 MHz, CDCl 3 ): δ = (m, 12H), 2.11 (s, 3H), 2.62 (AB system, J = 6.4, 17.2 Hz, 2H), (m, 1H); 13 C NMR (150 MHz, CDCl 3 ): δ = 24.5, 30.9, 31.3, 32.8, 43.5, 52.6, h 4h (Table 3, entry 8). The reaction was carried out at RT for 116 h using 20 mol% of column chromatography (hexane/ Et 2 O = 95/5) in 46% yield and 88% ee. The ee was determined by HPLC analysis using a Chiralpak AS-H column (95/5 hexane/i-proh; flow rate 0.75 ml/min; λ = 214, 254 nm; τ minor = 4.6 min; τ major = 5.0 min). [α] D rt= (c = 1.0, CHCl 3, 88% ee). HRMS: m/z calcd for C 11 H 22 OS: ; found: H NMR (400 MHz, CDCl 3 ): δ = 0.87 (d, J = 6.8 Hz, 1H), 0.95 (d, J = 6.8 Hz, 1H), 1.28 (s, 9H), (m, 1H), 2.15 (s, 3H), (m, 2H), (m, 1H); 13 C NMR (150 MHz, CDCl 3 ): δ = 18.8, 19.2, 31.2, 31.4, 33.1, 43.0, 43.8, 48.2, i Ph 4i (Table 3, entry 9). The reaction was carried out at RT for 116 h using 20 mol% of catalytic salt A following the general procedure. The title compound was isolated by column chromatography (hexane/acoet = 90/10) in 49% yield and 87% ee. The ee was determined by HPLC analysis using a Chiralpak AS-H column (80/20 hexane/i- PrOH; flow rate 0.75 ml/min; λ = 214, 254 nm; τ minor = 5.0 min; τ major = 5.2 min). [α] D rt= (c = 1.0, CHCl 3, 87% ee). HRMS: m/z calcd for C 16 H 24 OS: ; found: H NMR (400 MHz, CDCl 3 ): δ = 1.31 (s, 9H), (m, 1H), (m, 1H), 2.14 (s, 3H), (m, 4H), (m, 1H), (m, 5H); 13 C NMR (150 MHz, CDCl 3 ): δ = 31.0, 31.4, 33.2, 37.6, 38.8, 43.6, 51.5, 125.8, 128.3, 128.4, 141.8, S7

9 O 4j S 4j (Table 3, entry 10). The reaction was carried out at RT for 5 h using 20 mol% of column chromatography (hexane/et 2 O = 85/15) in 96% yield and 87% ee. The ee was determined by HPLC analysis using a Chiralpak AD-H column (95/5 hexane/i-proh; flow rate 0.75 ml/min; λ = 214, 254 nm; τ major = 6.2 min; τ minor = 6.5 min). [α] D rt= (c = 2.0, CHCl 3, 87% ee). HRMS: m/z calcd for C 10 H 18 OS: ; found: H NMR (400 MHz, CDCl 3 ): δ = 1.32 (s, 9H), (m, 2H), (m, 5H), (m, 1H), (m, 1H); 13 C NMR (150 MHz, CDCl 3 ): δ = 24.7, 31.4, 34.4, 40.6, 40.7, 43.7, 50.9, k Ph Ph 4k (Table 3, entry 11). The reaction was carried out at RT for 116 h using 20 was isolated by column chromatography (hexane/et 2 O = 90/10) in 44% yield and 95% ee. The ee was determined by HPLC analysis using a Chiralpak AS-H column (90/10 hexane/i-proh; flow rate 0.75 ml/min; λ = 214, 254 nm; τ minor = 5.5 min; τ major = 5.7 min). [α] D rt= (c = 1.0, CHCl 3, 82% ee). HRMS: m/z calcd for C 19 H 22 OS: ; found: H NMR (400 MHz, CDCl 3 ): δ = 1.23 (s, 9H), (m, 2H), 4.67 (t, J = 7.2 Hz, 1H), (m, 1H), (m, 3H), (m, 5H), (m, 2H); 13 C NMR (150 MHz, CDCl 3 ): δ = 31.2, 42.5, 44.3, 47.5, 126.8, 127.7, 128.0, 128.4, 128.5, 133.0, 136.9, 144.7, S8