Supporting Information

Transcription

1 Supporting nformation A Toolbox Approach to the Search for Effective Ligands for Catalytic Asymmetric Cr-diated Coupling Reactions aibing Guo, Cheng-Guo Dong, Dae-Shik Kim, Daisuke Urabe, Jiashi Wang, Joseph T. Kim, Xiang Liu, Takeo Sasaki, and Yoshito Kishi* Department of Chemistry and Chemical Biology, arvard University 12 xford Street, Cambridge, Massachusetts kishi@chemistry.harvard.edu Table of Contents 1. General Procedures and thods... S2 2. Preparation of icl 2 DMP Complex... S2 3. Synthesis of Chiral Sulfonamide Ligands S3 4. Cr-diated Coupling Reactions S10 5. MR Spectra of Sulfonamides and Coupling Reactions....S18 S1

2 1. General Procedures and thods MR spectra were recorded on a Varian nova 500 or 600 spectrometer. Chemical shifts are reported in parts per million (ppm). For 1 MR spectra (CDCl 3 and/or C 6 D 6 ), the residual solvent peak was used as the internal reference (7.26 ppm in CDCl 3 ; 7.15 ppm in C 6 D 6 ), while the central solvent peak as the reference (77.0 ppm in CDCl 3 ; ppm in C 6 D 6 ) for 13 C MR spectra. Analytical thin layer chromatography (TLC) was performed with E. rck pre-coated TLC plates, silica gel 60F-254, layer thickness 0.25 mm. TLC plates were visualized by staining with potassium permanganate, or p- anisaldehyde. Flash chromatography separations were performed on E. rck Kieselgel 60 ( ) mesh silica gel. All reactions were conducted under an inert atmosphere. Reaction vessels were oven-dried and allowed to cool under vacuum (1 mmg). Reagents and solvents were commercial grade and were used as supplied. 2. Preparation of icl 2 DMP Complex icl 2 DMP was prepared with modifications of the procedures reported. 1 To a stirred solution of 2,9-dimethylphenanthroline hemihydrate (5.0 g, 24.0 mmol) in Et (400 ml) and triethyl orthoformate (5 ml) was added a solution of icl (6.85 g, 28.8 mmol) in Et (100 ml) dropwise at rt. After stirring for 9 h at rt, the resultant crystalline precipitate was collected by filtration and washed with Et (100 ml x 2) and Et 2 (100 ml), to give yellow crystalline solid (7.72 g). While heated at 200 C for 20 min under reduced pressure, the yellow crystalline solid turned into the purple crystalline solid, corresponding to the β-form of icl 2 DMP known in literature. The purple crystalline solid was suspended in 1.5 L of C 3 C and heated to reflux for 5 h under 2. The resultant solution was filtered through glass wool while hot, and the filtrate was cooled down to rt, to give yellow brown crystals, corresponding to the α-form of icl 2 DMP. The resultant yellow brown crystals were collected by decantation and dried under reduced pressure, to furnish yellow brown crystals (5.30 g). The crystals were again heated at 220 C under reduced pressure for 20 min, to convert α- to β-form. The purple crystalline solid (β-form) was suspended in 1.2 L of C 3 C and heated to reflux for 3 h under 2 atmosphere. The resultant solution was filtered through glass wool while hot, and the filtrate was cooled down to rt, to give yellow brown crystals. The crystals were collected by filtration and washed with ice-cold C 3 C (100 ml), to give 4.21 g of yellow brown crystals (α-form of icl 2 DMP). The yellow brown crystals were grounded and dried under reduced pressure at 110 C for 3 h, to give α-form (yellow) of icl 2 DMP (3.90 g, mmol, 48%) as a fine crystalline powder, which was used for the i/cr-mediated couplings. An X-ray analysis confirmed that the yellow brown crystal used in this study is α-form of icl 2 DMP and exists as a dimer (Figure S-1), corresponding to the structure reported by Butcher and Sinn. 1b 1 (a) Preston,. S.; Kennard, C.. L. J. Chem. Soc. (A), 1969, (b) Butcher, R. J.; Sinn, E. norg. Chem. 1977, 16, (c) Dockum, B. W.; Reiff, W. M. norg. Chem. 1982, 21, S2

3 Figure S-1. X-ray structure of α-form of icl 2 DMP 3. Synthesis of Chiral Sulfonamides 3.1. General Synthetic Route of Chiral Sulfonamides Scheme S-1 summarizes the general synthetic route for preparation of the chiral sulfonamides used in this study. A typical experimental procedure is given for the synthesis of ligand (S)-sulfonamide 6. For some cases, the transformation of S-4 to S-7 was carried out via a slightly different route, i.e., (1) C 2 quench of the dianion formed from S-4, (2) amide formation with S-6, (3) Ms 2, and (4) TFA. Depending on the commercial availability of starting materials, the synthesis started with any intermediate indicated. For example, o-anisidine was used to prepare S-4 for the synthesis of sulfonamides (S)-2, (R)-2, (S)-3 and (R)-3. Scheme S-1 R 3 S-2 F R3 R S-1 S-3 Boc S-4 2 R 1 S-6 R 2 S-8 S 2 Cl C R 3 R3 R 3 2 Boc R 1 S-5 S-7 R 1 S R 2 S-9 S3

4 3.2 Experimental Details for General Synthetic Route Summarized in Scheme S F S-1 S-2 2 S-3 To a slurry of a (5.1 g, 60% in mineral oil, 1.8 equiv) in anhydrous TF (350 ml) was added unnatural menthol (S-2, 15.6 g, 1.4 equiv) at 0 C with stirring for 1 h. To the cooled reaction mixture (-78 C) was slowly added 2-fluronitrobenzene S-1 (7.47 ml, 70.9 mmol, 1.0 equiv) via syringe. The reaction was allowed to warm to rt and stirred for 6 h at rt before quenched with water at 0 C. The organic solvent (TF) was removed in vacuo and the slurry was extracted with EtAc (2 times). The combined organic layers were washed with brine, water, dried over a 2 S 4 and filtered. The solvent was removed in vacuo to afford crude S-3, which was used for the next step without further purification: mp = 36 C; [α] D (c 1.0, CCl 3 ); 1 MR (600 Mz, CDCl 3 ) δ 7.75 (d, J = 2.1 z, 1 ), (m, 1 ), 7.08 (d, J = 8.5 z, 1 ), (m, 1 ), (m, 1 ), (m, 1 ), (m, 1 ), (m, 2 ), (m, 1 ), 1.48 (dddd, J = 12.3, 9.1, 6.0, 3.1z, 1 ), (m, 2 ), (m, 7 ), 0.75 (d, J = 6.7 z, 3 ); 13 C MR (125 Mz, CDCl 3 ) δ 151.5, 140.8, 133.6, 125.4, 119.6, 115.1, 79.2, 47.6, 39.6, 34.2, 31.4, 25.8, 23.4, 22.0, 20.7, 16.3; R-MS (ES) m/z [(M+a) + ; calcd for C a: ]. 2 2 Boc S-3 S-4 To a solution of S-3 (~70 mmol from the previous step) in anhydrous EtAc (100 ml) was added Pd/C (1.0 g, equiv). A hydrogen balloon was attached to a needle, with the needle immersed in the solution. After the reaction was stirred for 10 h, the slurry was filtered through Celite and concentrated to give crude aniline S-4, which was used for the next step without further purification. To a solution of the crude amine (~70 mmol from the previous step) in anhydrous TF (140 ml) was added (Boc) 2 (16.3 g, 1.05 equiv). After refluxing overnight, the reaction was quenched with water. The organic solvent (TF) was removed in vacuo and the water slurry was extracted with EtAc (2 times). The combined organic layers were washed with a (1 ), brine, water, dried over a 2 S 4 and filtered. The solvent was removed in vacuo and the residual was filtered through a short silica plug to afford S-4 (20.0 g, 81% yield over three steps): mp = 60 C; [α] D (c 1.0, CCl 3 ); 1 MR (600 Mz, CDCl 3 ) δ 8.06 (br s, 1 ), 7.07 (br s, 1 ), (m, 2 ), (m, S4

5 1 ), (m, 1 ), (m, 1 ), (m, 1 ), (m, 2 ), (m, 10 ), (m, 1 ), (m, 1 ), (m, 2 ), 0.95 (d, J = 7.0 z, 3 ), 0.91 (d, J = 6.4 z, 3 ), 0.80 (d, J = 6.7 z, 3 ); 13 C MR (125 Mz, CDCl 3 ) δ 152.8, 145.9, 145.8, 129.2, 122.2, 120.8, 118.3, 112.6, 80.4, 78.6, 47.9, 40.3, 34.4, 31.4, 28.3, 27.4, 26.2, 23.7, 22.0, 20.7, 16.7; R-MS (ES) m/z [(M+a) + ; calcd for C a: ]. C Boc S-4 Boc S-5 Phenoxycyanide was prepared according to the literature. 2 To a solution of S-4 (10.4 g, 28.8 mmol) in anhydrous Et 2 (100 ml) was added t-buli (40.6 ml, 1.7 M in pentane, 2.4 equiv) slowly via syringe at -78 C. The reaction mixture was warmed to -10 C and stirred for additional 90 min before cooled to -78 C. PhC (4.2 g in 20 ml ether) was added dropwise. The reaction was slowly warmed to 0 C and quenched with a (0.5 ). The slurry was extracted with EtAc (3 times) and the combined organic layers were washed with a (0.5 ), brine, water, dried over a 2 S 4 and filtered. The solvent was removed in vacuo and the residual was purified by chromatography to afford S-5 (8.5 g, 77% yield): mp = 69 C; [α] D (c 1.0, CCl 3 ); 1 MR (600 Mz, CDCl 3 ) δ (m, 1 ), 7.16 (t, J = 7.9 z, 1 ), (m, 1 ), 6.44 (br s, 1 ), 4.06 (m, 1 ), (m, 2 ), (m, 2 ), (m, 1 ), 1.53 (s, 9 ), (m, 1 ), (m, 2 ), (m, 7 ), 0.76 (d, J = 7.0 z, 3 ); 13 C MR (125 Mz, CDCl 3 ) δ 152.8, 151.3, 130.5, 126.1, 124.6, 117.3, 117.0, 110.9, 81.6, 79.6, 47.8, 40.1, 34.2, 31.4, 28.1, 26.3, 23.8, 22.0, 20.6, 16.8; R-MS (ES) m/z [(M+) + ; calcd for C : ]. C + 2 Boc S-5 S-6 2 S-7 To a solution of S-5 (4.0 g, 10.8 mmol) in anhydrous chlorobenzene (20 ml) was added ZnCl 2 (3.14 g, 23 mmol, 2.1 equiv) and (S)-valinol (S-6) (1.78 g, 1.5 equiv) at rt. The solution was heated to reflux for 20 h before quenched with water. The slurry was treated with ammonium hydroxide (10 ml) with stirring for 30 min and extracted with EtAc (3 times). The combined organic layers were washed with brine and water, dried 2 Murray, R. E.; Zweifel G. Synthesis, 1980, 150. S5

6 over a 2 S 4 and filtered. The solvent was removed in vacuo and the residual was purified by chromatography to afford pure product S-7 (2.64 g, 69%) and the deprotected starting material S-5 (0.79 g, 27%), which was subjected to the same procedure, to give additional S-7 (0.650 g, 17%). The combined yield of S-6 was 3.29 g (85% yield): [α] D (c 1.0, CCl 3 ); 1 MR (600 Mz, CDCl 3 ) δ 7.28 (m, 1 ), 6.82 (dd, J = 7.9, 1.5 z, 1 ), 6.56 (t, J = 8.1 z, 1 ), 6.38 (br s, 2 ), (m, 1 ), (m, 2 ), (m, 1 ), (m, 1 ), 2.17 (td, J = 12.6, 1.9 z, 1 ), 1.74 (td, J = 6.5, 3.3 z, 2 ), (m, 1 ), (m, 1 ), 1.45 (m, 1 ), (m, 1 ), 1.03 (d, J = 6.7 z, 3 ), (m, 2 ), (m, 9 ), 0.79 (d, J = 7.0 z, 3 ); 13 C MR (125 Mz, CDCl 3 ) δ 163.7, 144.9, 140.5, 120.8, 114.4, 113.7, 108.8, 78.0, 72.9, 68.8, 48.2, 40.4, 34.5, 33.2, 31.4, 26.2, 23.8, 22.1, 20.8, 19.0, 18.7, 16.8; R- MS (ES) m/z [(M+) + ; calcd for C : ]. Cl + S 2 S-7 S-8 S (S)-6 To a solution of condensation product S-7 (2.50 g, 6.97 mmol) in anhydrous pyridine (8 ml) was added benzenesulfonic chloride (1.8 ml, 2.0 equiv) and DMAP (170 mg, 0.2 equiv). The solution was stirred overnight before quenched with water. The mixture was extracted with EtAc (2 times) and the combined organic layers were washed with Cl (1, 3 times), brine and water. The organic layer was dried over a 2 S 4 and filtered. The solvent was removed in vacuo to afford a crude product. The crude product was dissolved in anhydrous methanol. To the solution was added K 2 C 3 (1.92 g, 2.0 equiv) and the solution was stirred for 30 min. The reaction was quenched with water and extracted with EtAc. The solvent was removed in vacuo and the residual was purified by chromatography to afford (S)-6 (3.06 g). Recrystallization from EtAc/exane gave white needles (2.62 g, 75%): mp = 117 C; [α] D (c 1.0, CCl 3 ); 1 MR (600 Mz, CDCl 3 ) δ 11.8 (br s, 1 ), (m, 2 ), (m, 1 ), (m, 2 ), 7.37 (dd, J = 7.9, 1.5 z, 1 ), 7.08 (t, J = 8.1 z, 1 ), 7.00 (d, J = 8.5 z, 1 ), 4.38 (dd, J = 8.8, 7.3 z, 1 ), (m, 2 ), 3.89 (td, J = 10.6, 4.2 z, 1 ), (m, 1 ), 1.84 (dq, J = 13.4, 6.6 z, 1 ), 1.78 (dtd, J = 14.0, 6.9, 3.2 z, 1 ), (m, 1 ), 1.44 (dq, J = 13.5, 3.5 z, 1 ), (m, 1 ), 1.08 (d, J = 6.7 z, 3 ), 0.98 (d, J = 6.7 z, 3 ), 0.86 (d, J = 6.7 z, 3 ), (m, 2 ), 0.65 (d, J = 7.0 z, 3 ), 0.61 (qd, J = 12.6, 3.5 z, 1 ), 0.52 (d, J = 7.0 z, 3 ), (m,1 ); 13 C MR (125 Mz, CDCl 3 ) δ 163.4, 151.6, 143.3, 131.6, 129.4, 128.4, 126.6, 124.6, 120.5, 119.5, 116.1, 78.6, 72.8, 69.8, 46.1, 39.3, 34.3, 33.2, 31.5, 25.0, 22.7, 22.1, 20.7, 18.7, 18.7, 15.6; R-MS (ES) m/z [(M+) + ; calcd for C S: ]. S6

7 3.3. Spectroscopic Data of Representative Chiral Sulfonamides S (S)-i-Pr// Ligand (2): mp = 114 C; [α] D (c 1.0, CCl 3 ); 1 MR (600 Mz, CDCl 3 ) δ 11.9 (br s, 1 ), 7.45 (dd, J = 7.8, 1.6 z, 1 ), 7.12 (t, J = 7.9 z, 1 ), (m, 1 ), 4.39 (dd, J = 9.7, 8.2 z, 1 ), 4.16 (ddd, J = 9.7, 8.0, 6.6 z, 1 ), (m, 1 ), 3.93 (s, 3 ), 3.38 (s, 3 ), 1.83 (dq, J = 13.5, 6.7 z, 1 ), 1.06 (d, J = 6.7 z, 3 ), 0.97 (d, J = 7.0 z, 3 ); 13 C MR (125 Mz, CDCl 3 ) δ 163.1, 151.8, 129.7, 124.1, 121.5, 118.0, 115.6, 72.6, 69.7, 55.9, 43.1, 33.1, 18.6; R-MS (ES) m/z [(M+) + ; calcd for C S: ]. X S X X= S (S)-t-Bu/3,5-(C-phenothiazine) 2 Ph/ Ligand (3): mp = 173 C; [α] D (c 1.0, CCl 3 ); 1 MR (600 Mz, CDCl 3 ) δ 12.5 (br s, 1 ), (m, 2 ), (m, 6 ), (m, 3 ), (m, 10 ), (m, 1 ), 4.41 (d, J = 10.3 z, 1 ), (m, 2 ), 3.44 (s, 3 ), 1.10 (s, 9 ); 13 C MR (100 Mz, CDCl 3 ) δ 166.2, 163.3, 151.2, 143.7, 138.6, 135.0, 132.4, 131.5, 129.1, 127.9, 127.0, 126.9, 126.8, 123.9, 120.8, 117.0, 115.0, 76.0, 68.0, 54.7, 33.9, 25.9; R-MS (ES) m/z [(M+) + ; calcd for C S 3 : ]. S Cl Cl (R)-i-Pr/PhCl 2 /-c-ex() 2 Ligand (4): mp = 97 C; [α] D (c 1.0, CCl 3 ); 1 MR (500 Mz, CDCl 3 ) δ 12.2 (br s, 1 ), (m, 2 ), (m, 1 ), 7.41 (dd, J = 7.8, 1.0 z, 1 ), 7.12 (t, J = 8.1 z, 1 ), 7.01 (d, J = 7.3 z, 1 ), S7

8 (m, 1 ), (m, 3 ), (m, 1 ), 1.79 (br d, J = 12.2 z, 1 ), 1.70 (br d, J = 12.2 z, 1 ), 1.54 (dt, J = 9.5, 1.6 z, 1 ), (m, 2 ), 1.08 (d, J = 6.8 z, 3 ), 0.98 (d, J = 6.8 z, 3 ), 0.86 (d, J = 6.3 z, 3 ), 0.84 (d, J = 6.3 z, 3 ), 0.39 (q, J = 12.2 z, 1 ), 0.25 (q, J = 12.7 z, 1 ), 0.19 (q, J = 12.2 z, 1 ); 13 C MR (125 Mz, CDCl 3 ) δ 163.4, 150.6, 146.3, 135.3, 131.4, 128.9, 125.2, 124.9, 120.8, 119.2, 117.2, 77.1, 72.6, 69.9, 43.0, 39.1, 39.0, 33.1, 30.4, 30.4, 22.0, 18.7, 18.6; R-MS (ES) m/z [(M+) + ; calcd for C Cl S: ]. S Cl Cl (R)-i-Pr/PhCl 2 / Ligand: mp = 134 C; [α] D (c 1.0, CCl 3 ); 1 MR (500 Mz, CDCl 3 ) δ 12.4 (br s, 1 ), 7.87 (d, J = 2.4 z, 2 ), 7.52 (t, J = 1.7 z, 1 ), (m, 1 ), 7.12 (t, J = 8.1 z, 1 ), 6.98 (d, J = 8.3 z, 1 ), 4.43 (t, J = 8.5 z, 1 ), 4.18 (td, J = 8.8, 6.8 z, 1 ), 4.12 (t, J = 7.8 z, 1 ), 3.47 (s, 3 ), 1.86 (dq, J = 13.4, 6.6 z, 1 ), 1.10 (d, J = 6.8 z, 3 ), 0.99 (d, J = 6.3 z, 3 ); 13 C MR (125 Mz, CDCl 3 ) δ 163.3, 151.6, 145.9, 135.0, 131.5, 128.8, 125.1, 124.5, 121.2, 117.9, 115.3, 72.5, 69.9, 55.0, 33.1, 18.7, 18.6 R-MS (ES) m/z [(M+) + ; calcd for C Cl S: ]. S F 3 C CF 3 (S)-t-Bu/Ph(CF 3 ) 2 /-c-ex() 2 Ligand (5): mp = 132 C; [α] D (c 1.0, CCl 3 ); 1 MR (500 Mz, CDCl 3 ) δ 12.5 (br s, 1 ), 8.48 (s, 2 ), 8.04 (s, 1 ), 7.44 (dd, J = 7.8, 1.5 z, 1 ), 7.14 (t, J = 8.1 z, 1 ), 6.99 (dd, J = 7.3, 1.5 z, 1 ), 4.37 (t, J = 9.3 z, 1 ), 4.24 (t, J = 8.5 z, 1 ), 4.17 (dd, J = 9.8, 8.3 z, 1 ), 4.02 (tt, J = 11.1, 4.0 z, 1 ), (m, 1 ), (m, 1 ), (m, 1 ), (m, 2 ), 1.01 (s, 9 ), 0.77 (d, J = 6.3 z, 3 ), 0.74 (d, J = 6.8 z, 3 ), 0.24 (q, J = 11.7 z, 1 ), (q, J = 12.2 z, 1 ), (q, J = 11.9 z, 1 ) ); 13 C MR (125 Mz, CDCl 3 ) δ 163.6, 150.3, 146.5, 132.5, 132.2, 128.7, 126.8, 126.7, 125.0, 125.0, 123.7, 121.6, 120.9, 119.0, 116.9, 76.9, 76.0, 68.1, 42.6, 38.9, 38.8, 34.0, 30.3, 30.3, 25.8, 21.8, 21.7; R-MS (ES) m/z [(M+) + ; calcd for C F S: ]. S8

9 S (S)-i-Pr/2-ap/-c-ex() 2 Ligand (7): mp = 152 C; [α] D (c 1.0, CCl 3 ); 1 MR (500 Mz, CDCl 3 ) δ 11.9 (br s, 1 ), 8.49 (s, 1 ), (m, 1 ), (m, 3 ), (m, 2 ), (m, 1 ), 7.08 (t, J = 8.0 z, 1 ), (m, 1 ), 4.32 (t, J = 8.2 z, 1 ), (m, 2 ), (m, 1 ), 1.81 (dd, J = 6.8, 13.6 z, 1 ), (m, 1 ), (m, 1 ), (m, 1 ), (m, 2 ), 1.06 (d, J = 6.9 z, 3 ), 0.95 (d, J = 6.6 z, 3 ), 0.53 (d, J = 6.6 z, 3 ), 0.51 (d, J = 6.6 z, 3 ), (m, 3 ); 13 C MR (125 Mz, CDCl 3 ) δ 163.3, 151.0, 140.3, 134.6, 132.2, 129.7, 129.1, 128.5, 128.2, 127.8, 127.4, 127.2, 124.6, 122.7, 120.8, 119.5, 117.3, 77.1, 72.6, 69.7, 42.6, 38.7, 38.5, 33.0, 30.2, 30.1, 21.7, 21.7, 18.7, 18.6; R-MS (ES) m/z [(M+) + ; calcd for C S: ]. S (R)-i-Pr/Ph/aphthyl Ligand (8): mp = 116 C; [α] D (c 0.50, CCl 3 ); 1 MR (500 Mz, CDCl 3 ) δ 11.1 (br s, 1 ), 8.78 (d, J = 7.8 z, 1 ), (m, 1 ), 7.71 (d, J = 8.8 z, 1 ), (m, 3 ), (m, 1 ), (m, 2 ), (m, 2 ), 4.02 (dd, J = 9.8, 8.3 z, 1 ), 3.80 (t, J = 8.5 z, 1 ), 3.71 (dd, J = 9.3, 7.3 z, 1 ), 1.64 (dq, J = 13.7, 6.8 z, 1 ), 1.04 (d, J = 6.8 z, 3 ), 0.87 (d, J = 6.8 z, 3 ); 13 C MR (125 Mz, CDCl 3 ) δ 162.8, 138.2, 135.9, 135.6, 132.4, 130.5, 128.3, 128.0, 127.9, 127.5, 127.2, 126.4, 126.3, 123.9, 117.6, 72.7, 69.7, 32.9, 19.2, 18.6; R- MS (ES) m/z [(M+) + ; calcd for C S: ]. S F 3 C CF 3 S9

10 (S)-t-Bu/Ph(CF 3 ) 2 / Ligand (9): mp = 77 C; [α] D (c 1.0, CCl 3 ); 1 MR (600 Mz, CDCl 3 ) δ 12.7 (br s, 1 ), (m, 2 ), 8.05 (s, 1 ), 7.47 (dd, J = 8.1, 1.3 z, 1 ), 7.14 (t, J = 8.2 z, 1 ), 6.97 (dd, J = 8.2, 1.5 z, 1 ), 4.37 (dd, J = 10.1, 8.3 z, 1 ), 4.24 (t, J = 8.3 z, 1 ), 4.19 (dd, J = 10.0, 8.2 z, 1 ), 3.36 (s, 3 ), 1.02 (s, 9 ) ); 13 C MR (125 Mz, CDCl 3 ) δ 163.6, 150.3, 146.5, 132.5, 132.2, 128.7, 126.8, 126.7, 125.0, 125.0, 123.7, 121.6, 120.9, 119.0, 116.9, 76.9, 76.0, 68.1, 42.6, 38.9, 38.8, 34.0, 30.3, 30.3, 25.8, 21.8, 21.7; R-MS (ES) m/z [(M+) + ; calcd for C F S: ]. For spectroscopic data of (S)-t-Bu/C 2 Ph() 2-2,6/ (10), see Reference. 3 S X X X= S (R)-i-Pr/Ph(C-phenothiazine) 2 /-c-ex() 2 Ligand (11): mp = 217 C; [α] D (c 1.0, CCl 3 ); 1 MR (600 Mz, CDCl 3 ) δ 11.6 (br s, 1 ), (m, 2 ), (m, 4 ), (m, 1 ), 7.31 (d, J = 7.6 z, 1 ), (m, 12 ), 7.07 (t, J = 7.9 z, 1 ), 7.00 (d, J = 8.5 z, 1 ), 4.27 (t, J = 9.2 z, 1 ), (m, 2 ), 3.98 (t, J = 8.2 z, 1 ), 1.84 (br d, J = 11.4 z, 1 ), (m, 2 ), 1.46 (br d, J = 12.6 z, 1 ), (m, 2 ), 1.04 (d, J = 6.7 z, 3 ), 0.93 (d, J = 6.7 z, 3 ), 0.80 (d, J = 6.6 z, 6 ), 0.69 (q, J = 11.7 z, 1 ), 0.63 (q, J = 11.8 z, 1 ), 0.48 (q, J = 12.2 z, 1 ) ); 13 C MR (125 Mz, CDCl 3 ) δ 165.9, 163.1, 151.5, 142.0, 138.7, 135.3, 132.5, 132.2, 129.5, 128.5, 128.0, 127.0, 126.9, 125.1, 120.5, 119.6, 117.7, 72.5, 69.9, 42.8, 39.4, 39.2, 33.1, 30.7, 22.0, 21.9, 18.8, 18.8; R-MS (ES) m/z [(M+) + ; calcd for C S 3 : ]. 4. Cr-diated Coupling Reactions General Procedure of Asymmetric Catalytic i/cr-diated Coupling. To a solution of a sulfonamide ligand (0.066 mmol) and proton sponge (Aldrich, purified by sublimation; 14.1 mg, mmol) in C (Baker, ultra low water; 1.5 ml) was added CrCl 2 (Aldrich, 99.99% or Strem, 99.9%; 7.5 mg, mmol) under nitrogen. The mixture was stirred for 1 h at rt under nitrogen. To this mixture were added LiCl (Aldrich, anhydrous, 10 mesh; 51 mg, 1.2 mmol), Mn powder (Aldrich, 99.99%, powder; 66 mg, 1.2 mmol), icl 2 DMP (4.2 mg, mmol), an aldehyde (0.60 mmol), a vinyl iodide (0.90 mmol), and Zr(Cp) 2 Cl 2 (Aldrich, 98%; 174 mg, 0.60 mmol). The mixture 3 Zhang, Z.; uang, J.; Ma, B.; Kishi, Y. rg. Lett. 2008, 10, S10

11 was stirred under nitrogen until the reaction was completed (by TLC), and diluted with ethyl acetate (20 ml). Florisil (ca. 150 mg) was added, and the reaction mixture was stirred for 30 min, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography, to furnish the coupling product. Diastereomer ratios (dr) were estimated from 1 MR (600 Mz). General Procedure of Catalytic on-asymmetric i/cr-diated Coupling. For preparation of 3,3 -dimethyl-2,2 -dipyridyl CrCl 3 complex (i) and 3,3 -dimethyl-2,2 - dipyridyl icl 2 complex (ii) see reference. 4 To a suspension of i (0.8 mg, 2 µmol), ii (0.3 mg, 1 µmol), LiCl (Aldrich, anhydrous, 17 mg, 0.40 mmol), Mn powder (22 mg, 0.40 mmol), and Zr(Cp) 2 Cl 2 (58 mg, 0.20 mmol) in C (Baker, ultra low water; 0.30 ml) were added an aldehyde (0.20 mmol) and a vinyl iodide (0.30 mmol). The mixture was stirred at rt under nitrogen until the reaction was completed (by TLC), diluted with ethyl acetate (10 ml), filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give the coupling product. Diastereomer ratios (dr) were estimated by 1 MR (600 Mz). General Procedure of Catalytic Asymmetric Co/Cr-diated Coupling. A sulfonamide ligand (45 µmol, 0.33 equiv) and CoPc (Aldrich, 97%; 0.39 mg, 0.68 µmol, equiv) were weighed outside a glove box and put in a flask. n a glove box, proton sponge (9.7 mg, 45 µmol, 0.33 equiv), CrCl 2 (5.1 mg, 42 µmol, 0.30 equiv) and DME (Baker, ultra low water; 0.8 ml) were added and the resulting mixture was then stirred at rt for 1 h. To the resulting green solution were added LiCl (12 mg, 0.27 mmol, 2.0 equiv), Mn powder (15 mg, 0.27 mmol, 2.0 equiv), Zr(Cp) 2 Cl 2 (80 mg, 0.27 mmol, 2.0 equiv) and a solution of aldehyde (0.14 mmol) and iodide (0.28 mmol, 2.0 equiv) in DME (0.11 ml) successively. The reaction mixture was stirred at rt in a glove box for 36 h. The resulting mixture was then poured into a slurry of florisil (0.5 g) in Et 2 (5 ml). The resulting mixture was stirred vigorously for 0.5 h and then filtered through a short pad of silica gel. The filtrate was concentrated under reduced pressure. Flash chromatography on silica gel provided the coupling product. Diastereomer ratios (dr) were estimated from 1 MR (600 Mz). General Procedure of Catalytic on-asymmetric Co/Cr-diated Coupling. To the mixture of 3,3 -dimethyl-2,2 -dipyridyl CrCl 3 complex (i) (2.4 mg, 7 µmol), CoPc (0.1 mg, 0.17µmol) were added LiCl (2.9 mg, 68 µmol), Mn powder (3.8 mg, 69 µmol), aldehyde (34 µmol), iodide (68 µmol), Zr(Cp) 2 Cl 2 (16 mg, 55 µmol), and DME (0.2 ml) successively. The reaction mixture was stirred at rt in a glove box for 20 h. The resulting mixture was then poured into a slurry of Florisil (0.5 g) in Et 2 (5 ml). The resulting mixture was stirred vigorously for 0.5 h and then filtered through a short pad of silica gel. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography, to furnish the coupling product. Diastereomer ratios (dr) were estimated from 1 MR (600 Mz) C19-C20 Bond Formation 4 amba, K.; Wang, J.; Cui, S.; Kishi, Y. rg. Lett. 2005, 7, S11

12 Synthesis of aldehyde S-10 Bz BX xidation Bz C S-10 To a solution of alcohol (1.0 g, 5.1 mmol) in EtAc (25 ml) was added BX 5 (4.29 g, 15.3 mmol). The mixture was stirred at 80 C for 3 h and cooled down to 0 C; then diluted with pentane (30 ml). After addition of SrC 3 (8.7 g), the mixture was stirred at rt for 10 min and filtered through a celite pad with Et 2. The filtrate was concentrated under reduced pressure to give aldehyde S-10 (900 mg, 90%), which was used for the coupling reaction without further purification. 1 MR (600 Mz, C 6 D 6 ) δ 9.16 (d, J = 1.2 z, 1), 8.11 (dd, J = 1.3, 8.3 z, 2), (m, 1), (m, 2), 3.96 (t, J = 7.2 z, 2), 1.72 (t, J = 7.2 z, 2), 1.55 (m, 2) Synthesis of vinyl iodide S-11 Br + C TBDPS 1. cat. asymm. Cr-mediated propargylation; 2. CCl 3 C 2 /PPh 3 ; 3. B-iodo-9-BB. S Cl 14 TBDPS S-11 was synthesized from aldehyde in 3 steps. The details for this synthesis were submitted for publication Cr-diated Coupling Reactions 19 Cl Bz C S TBDPS 20 mol % Cr-catalyst 2 mol % icl 2 -DMP Bz 23 Bz Cl S-12 S-11 S Cl 14 TBDPS TBDPS 14 The reactions were carried out under the catalytic non-asymmetric 4 and asymmetric 6 conditions reported. Diastereomer ratios were estimated by the integrations of the olefinic proton (4.81 ppm vs ppm) in the 1 MR, see spectra attached on page S C29-C30 Bond Formation 5 Frigerio, M.; Santagostino, M.; Sputore, S. J. rg. Chem. 1999, 64, amba, K.; Cui, S.; Wang, J.; Kishi, Y. rg. Lett. 2005, 7, S12

13 C TBS 20 mol % Cr-catalyst 2 mol % icl 2 -DMP S TBS 30 C 2 27 C 2 27 S TBS C 2 27 C30-C38 aldehyde and C27-C29 vinyl iodide were prepared according to the reference. 7 The reactions were carried out under the catalytic non-asymmetric 4 and asymmetric 6 conditions reported. Diastereomer ratios were estimated by the integrations of the olefinic proton (6.10 ppm vs ppm) in the 1 MR, see spectra attached on page S C26-C27 Bond Formation Synthesis of C20-C26 vinyl iodides and The synthesis of vinyl iodide S-16 was previously reported. 8 Alternatively, was synthesized as shown below. Using the antipode of epoxide S-16, vinyl iodide, the antipode of, was prepared. The details of new synthesis will be published in a separate account. TBS S-16 TBS LiMDS// TF/-78 C 78% TBS 1. Li/TF/-78 C /Et/40 C 3. 2 /TMG/Ph/0 C TBS S-17 ca. 45% overall yield DnBzCl/DMAP Et 3 K 2 C 3 / TBS DnBz TBSCl/imidazole 97% yield TBS TBS 7 (a) Aicher, T. D.; Buszek, K. R.; Fang, F. G.; Forsyth, C. J.; Jung, S..; Kishi, Y.; Scola, P. M. Tetrahedron Lett. 1992, 33, (b) Stamos, D. P.; Chen, S. S.; Kishi, Y. J. rg. Chem. 1997, 62, Xie, C.; owark, P.; Kishi, Y. rg. Lett. 2002, 4, S13

14 : colorless oil; [α] D (c 1.0, CCl 3 ); 1 MR (CDCl 3, 500 z) δ 6.15 (d, J = 1.0 z, 1), 5.74 (d, J = 1.0 z, 1), (m, 3), 1.99 (m, 1), (m, 5), 1.23 (m, 1), 0.99 (d, J = 7.0 z, 3), 0.90 (s, 9), 0.89 (s, 9), 0.05 (s, 6), 0.04 (s, 6); 13 C MR (CDCl 3, 125 z) δ 124.7, 123.9, 70.0, 63.4, 43.8, 42.8, 34.2, 28.2, 26.1, 22.5, 18.4, 18.2, -3.7, -4.2, -5.2; R-MS (ES) m/z [(M+a) + calcd for C Si 2 a: ] Synthesis of C20-C26 vinyl iodides and V The vinyl iodide was synthesized via the synthetic route shown below. Using the antipode of epoxide, vinyl iodide V, the antipode of, was prepared. The details of new synthesis will be published in a separate account. TBS TBS LDA/TF/-78 C TBS 78% 1. Li/TF/-78 C 2. TBSCl/Ag 3 /Py /Et/80 C 3. 2 /TMG/Ph/0 C TBS TBS ca. 30% overall yield 1. TBAF 2. DnBzCl/DMAP/Et 3 1.K 2 C 3 / 2. TBSCl/imidazole PB PB : Colorless oil; [α] D (c 1.0, CCl 3 ); 1 MR (CDCl 3, 600 z) δ 6.10 (d, J = 1.2 z, 1), 5.69 (d, J = 1.2 z, 1), 3.64 (m, 1), (m, 2), 1.93 (q, J = 6.6 z, 1), (m, 3), 1.43 (m, 1), 1.30 (m, 1), 0.98 (d, J = 6.0 z, 3), 0.89 (s, 9), 0.88 (s, 9), 0.09 (s, 3), 0.06 (s, 3), 0.04 (s, 6); 13 C MR (CDCl 3, 125 z) δ 124.1, 123.4, 69.5, 63.4, 43.6, 42.8, 32.8, 28.3, 26.1, 26.0, 21.7, 18.4, 18.2, -4.1, -4.2, - 5.2; R-MS (ES) m/z [(M+) + ; calcd for C Si 2 : ] Cr-diated Coupling Reaction S 2 Ph Ph 2 S TBS mol % Cr-catalyst TBS mol % icl 2 -DMP C TBS C27-C35 Aldehyde of E7389 (23S, 25R); (23R, 25R); (23S, 25S); V (23R, 25S) 20 TBS 27 S-18 S-19 S14

15 C27-C35 aldehyde of E7389 was prepared according to the previously reported method. 9 The reactions were carried out under the catalytic non-asymmetric 4 and asymmetric 6 conditions reported. Diastereomer ratios were estimated by the integrations of the olefinic proton (: 5.05 ppm vs ppm; : 5.05 ppm vs ppm; : 5.00 ppm vs ppm; V: 4.89 ppm vs ppm) in the 1 MR, see spectra attached on pages S-31 to S C23-C24 Bond Formation 23 C TBDPS 30 mol % Cr-catalyst 0.5 mol % CoPc TBDPS S-20 S-21 C14-C23 aldehyde was prepared according to the method reported. 9 C24-C26 vinyl iodide was prepared via the previously reported route. 10 The reactions were carried out under the catalytic non-asymmetric 4 and asymmetric 6,11 conditions reported. Diastereomer ratio was estimated by the integrations of the olefinic proton (6.16 ppm vs ppm) in the 1 MR, see spectra attached on page S C11-C12 Bond Formation Synthesis of bisbenzoate protected C1-C11 alcohol S-22 9 Choi,.-w.; Demeke, D.; Kang, F.-A.; Kishi, Y.; akajima, K.; owak, P.; Wan, Z.-K.; Xie, C. Pure Appl. Chem. 2003, 75, Choi,.-w.; akajima, K.; Demeke, D.; Kang, F.-A.; Jun,.-S.; Wan, Z.-K.; Kishi, Y. rg. Lett. 2002, 4, For the Co/Cr-mediated coupling, it is important to keep the ratio of Co- and Cr-catalysts low. To measure an amount of CoPc with an acceptable accuracy, we used 30 mol % of Cr-catalyst for this screening. For preparative purposes, 20 mol% catalyst loading was sufficient to effect this coupling. S15

16 C 2 C 2 C 2 Ac 2 TFA/ 2 /C 2 Cl 2 pyridine 88% (2 steps) Ac Ac S-22 C 2 C 2 BzCl pyridine/c 2 Cl 2 92% Bz Bz Ac AcCl 95% Bz Bz S-23 To a solution of S-22 (200 mg, 0.56 mmol, prepared via the previously reported route 12 ) in pyridine (1 ml) was added acetic anhydride (0.53 ml, 5.6 mmol) and DMAP (3.4 mg, mmol) at 0 C. The reaction mixture was stirred overnight from 0 C to rt. The reaction was quenched with 1 Cl (10 ml), extracted with EtAc (3 x 20 ml) and the organic layer was neutralized with saturated aqueous ac 3 (10 ml), washed with brine (10 ml), dried over a 2 S 4, concentrated to give crude light yellow oil acetic ester. The crude alcohol was subjected to the next step without further purification. To a 10-mL round-bottom flask with acetic ester was added co-solvent mixture TFA/ 2 /C 2 Cl 2 (4/1/5) (3 ml). The reaction mixture was stirred vigorously at rt until TLC showed a complete disappearance of the starting material (~1 h). The reaction was diluted with EtAc, quenched carefully with sat. ac 3, and the organic phase were separated and the aqueous phase was extracted with EtAc (3 x 30 ml), washed with brine. The combined organic phases were dried over anhydrous a 2 S 4, concentrated, and the resulting oil was simply purified over a short pad of Si 2 eluting with 80% EtAc/hexanes to afford diol as a colorless oil (158 mg, 0.49 mmol, 88% in 2 steps). To a solution of diol (158 mg, 0.49 mmol) in C 2 Cl 2 (1 ml) and pyridine (0.6 ml) was added BzCl (0.3 ml) and DMAP (6 mg) at 0 C. The reaction mixture was stirred for 30 h from 0 C to rt. The reaction was quenched with 1 Cl (10 ml), extracted with EtAc (3 x 30 ml) and the organic layer was neutralized with saturated aqueous ac 3 (20 ml), washed with brine (20 ml), dried over a 2 S 4, concentrated to give a dibenzoate as crude light yellow oil. The resulting oil was purified over a short pad of Si 2 eluting with 30% EtAc/hexanes to afford dibenoate as a colorless oil (238 mg, 0.45 mmol, 92%). To a solution of dibenoate (238 mg, 0.45 mmol) in methanol (3 ml) and C 2 Cl 2 (3 ml) was added AcCl (145 ul). The reaction was stirred overnight and then quenched with Et 3 (0.2 ml), concentrated to give a crude oil. The resulting oil was purified over short pad of silic gel eluting with 50% EtAc/hexanes to afford primary alcohol S-23 (207 mg, 0.43 mmol, 95%) as a colorless oil: [α] D (c 1.0, CCl 3 ); 1 MR (CDCl 3, 600 z) 12 Stamos, D. P.; Kishi, Y. Tetrahedron Lett. 1996, 37, S16

17 δ 8.01 (dd, J = 8.4, 1.2 z, 2), 7.84 (dd, J = 8.4, 1.2 z, 2), 7.61 (m, 1), (m, 3), 7.34 (dd, J = 8.4, 7.8 z, 2), 5.99 (dd, J = 3.0, 3.0 z, 1), 5.51 (dd, J = 6.6, 3.0 z, 1), 4.51 (dd, J = 5.4, 5.4 z, 1), 4.36 (ddd, J = 9.6, 7.2, 2.4 z, 1), 3.91 (m, 2), 3.74 (m, 1), 3.59 (s, 3), 3.44 (dd, J = 9.6, 2.4 z, 1), 2.52 (dd, J = 16.2, 6.6 z, 1), 2.36 (dd, J = 16.2, 6.6 z, 1), 2.17 (m, 1), 2.01 (m, 1), 1.90 (m, 1), 1.64 (m, 1), 1.49 (m, 1); 13 C MR (CDCl 3, 125 z) δ 171.3, 165.6, 165.0, 133.5, 133.3, 130.1, 129.8, 129.7, 129.2, 128.7, 128.5, 76.6, 75.1, 74.4, 68.7, 68.4, 64.1, 58.9, 51.7, 40.4, 30.3, 29.1; R-MS (ES) m/z [(M+a) + ; calcd for C a: ] Cr-diated coupling reactions 1 C 2 1 C 2 1 C 2 Bz C 11 Bz TMS 20 mol % Cr-catalyst 2 mol % icl 2 -DMP Bz Bz Bz Bz TMS TMS S-24 S-25 The reactions were carried out under the catalytic non-asymmetric 4 and asymmetric conditions reported. 6 Diastereomer ratios were estimated by the integrations of the C-11 proton (5.05 ppm vs ppm) in the 1 MR, see spectra attached on page S C 2 C TMS 20 mol % Cr-catalyst 2 mol % icl 2 -DMP 1 C C 2 TMS S-26 S TMS The reactions were carried out under the catalytic non-asymmetric 4 and asymmetric conditions reported. 5 Diastereomer ratios were estimated by the integrations of the C11 proton (4.13 ppm vs ppm) in the 1 MR, see spectra attached on page S-38. S17

18 5. MR Spectra S 1 MR of (S)-2 (600 Mz, CDCl 3 ) S 13 C MR of (S)-2 (125 Mz, CDCl 3 ) S18

19 X S X= S X 1 MR of (S)-3 (600 Mz, CDCl 3 ) X S X= S X 13 C MR of (S)-3 (100 Mz, CDCl 3 ) S19

20 S Cl Cl 1 MR of (R)-4 (500 Mz, CDCl 3 ) S Cl Cl 13 C MR of (R)-4 (125 Mz, CDCl 3 ) S20

21 S F 3 C CF 3 1 MR of (S)-5 (500 Mz, CDCl 3 ) S F 3 C CF 3 13 C MR of (S)-5 (125 Mz, CDCl 3 ) S21

22 S 1 MR of (S)-6 (600 Mz, CDCl 3 ) S 13 C MR of (S)-6 (125 Mz, CDCl 3 ) S22

23 S 1 MR of (S)-7 (500 Mz, CDCl 3 ) S 13 C MR of (S)-7 (125 Mz, CDCl 3 ) S23

24 S 1 MR of (R)-8 (500 Mz, CDCl 3 ) Chemical Shift (ppm) S 13 C MR of (R)-8 (125 Mz, CDCl 3 ) S24

25 S F 3 C CF 3 1 MR of (S)-9 (600 Mz, CDCl 3 ) S F 3 C CF 3 13 C MR of (S)-9 (100 Mz, CDCl 3 ) S25

26 S X X X= S 1 MR of (R)-11 (600 Mz, CDCl 3 ) S X X X= S 13 C MR of (R)-11 (100 Mz, CDCl 3 ) S26

27 Bz Cl TBDPS 1 MR of S-12 (600 Mz, C 6 D 6 ) C20! C20 " Bz Cl TBDPS 1 MR of S-13 (600 Mz, C 6 D 6 ) C20 " C20! S27

28 TBS C 2 1 MR of S-14 (600 Mz, CDCl 3 ) C30 " C30! TBS C 2 C30! 1 MR of S-15 (600 Mz, CDCl 3 ) C30 " S28

29 TBS TBS 1 MR of (500 Mz, CDCl 3 ) TBS TBS 13 C MR of (125 Mz CDCl 3 ) S29

30 TBS TBS 1 MR of (500 Mz CDCl 3 ) TBS TBS 13 C MR of (125 Mz CDCl 3 ) S30

31 TBS S 2 Ph 1 MR of S-18- (600 Mz, CDCl 3 ) TBS C27 " C27! TBS S 2 Ph 1 MR of S-19- (600 Mz, CDCl 3 ) C27 " TBS C27! S31

32 TBS S 2 Ph 1 MR of S-18- (500 Mz, CDCl 3 ) C27! TBS C27 " TBS S 2 Ph 1 MR of S-19- (600 Mz, CDCl 3 ) C27! TBS C27 " S32

33 TBS S 2 Ph 1 MR of S-18- (600 Mz, CDCl 3 ) TBS C27 " C27! TBS S 2 Ph 1 MR of S-19- (600 Mz, CDCl 3 ) TBS C27 " C27! S33

34 TBS S 2 Ph 1 MR of S-18-V (600 Mz, CDCl 3 ) TBS C27 " C27! TBS S 2 Ph 1 MR of S-19-V (600 Mz, CDCl 3 ) TBS C27! C27 " S34

35 TBDPS C24 " 1 MR of S-20 (600 Mz, CDCl 3 ) C24! TBDPS 1 MR of S-21 (600 Mz, CDCl 3 ) C24! C24 " S35

36 C 2 Bz Bz 1 MR of S-23 (600 Mz, CDCl 3 ) C 2 Bz Bz 13 C MR of S-23 (125 Mz, CDCl 3 ) S36

37 C 2 Bz Bz TMS C11! 1 MR of S-25 (600 Mz, CDCl 3 ) C11 " C 2 Bz Bz TMS 1 MR of S-24 (600 Mz, CDCl 3 ) C11 " C11! S37

38 C 2 TMS C11 " 1 MR of S-26 (600 Mz, CDCl 3 ) C11! S38