Supporting Information. New Syntheses of E7389 C14-C35 and Halichondrin C14-C38

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1 Supporting Information New Syntheses of E7389 C14-C35 and alichondrin C14-C38 Building Blocks: Reductive Cyclization and xy-michael Cyclization Approaches Cheng-Guo Dong, James A. enderson, Yosuke Kaburagi, Takeo Sasaki, Dae-Shik Kim, Joseph T. Kim, Daisuke Urabe, aibing Guo and Yoshito Kishi* Department of Chemistry and Chemical Biology, arvard University 12 xford Street, Cambridge, Massachusetts Table of Contents 1. General Procedures and thods...s2 2. Synthesis outlined in Scheme S2 3. Synthesis outlined in Scheme S4 4. Synthesis outlined in Scheme S12 5. Synthesis outlined in Scheme S15 6. Synthesis outlined in Scheme S17 7. Synthesis outlined in Scheme S19 8. NMR Spectra...S22 S1

2 1. General Procedures and thods NMR spectra were recorded on a Varian Inova 500 or 600 spectrometer. Chemical shifts are reported in parts per million (ppm). For 1 NMR spectra (CDCl 3 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 NMR 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. Reagents and solvents were commercial grade and were used as supplied. 2. Synthesis outlined in Scheme 3 I S 3 -pyr, Et 3 N, DMS, C 2 Cl 2 I TBDPS S-1 TBDPS S-2 To a solution of alcohol S-1 (940 mg, 1.8 mmol) in C 2 Cl 2 (7 ml) and DMS (3.5 ml) at 0 C were added sequentially Et 3 N (1.24 ml, 9.0 mmol) and sulfur trioxide pyridine complex (857 mg, 5.4 mmol). After stirring at rt for 3h, the reaction was quenched with saturated aqueous N 4 Cl ( ml) and extracted with EtAc (3 x 25 ml). The combined organics were washed with brine, dried over Na 2 S 4, filtered, and concentrated. The crude residue was purified over a short plug of silica gel (hexanes/ EtAc = 9:1) to provide ketone S-2 (861 mg, 92%). [α] D -3.0 (c 1.0, CCl 3 ); 1 NMR (500 Mz, CDCl 3 ) δ 1.02 (3, d, J = 6.8 z), 1.05 (9, s), (2, m), 2.29 (1, dd, J = 16.6, 6.8 z), (2, m), 2.63 (1, dd, J = 16.6, 6.3 z), (3, m), 5.70 (1, d, J = 2.0 z), (1, m), (6, m), (4, m); 13 C NMR (125 Mz, CDCl 3 ) δ 8.5, 135.5, , 127.6, 1.5, 62.9, 49.3, 41.9, 40.0, 26.8, 26.4, 21.1, 19.2; R-MS (ESI) m/z [(M+) + calcd for C I 2 Si: ]. I 1,3-propanediol CSA, benzene reflux I TBDPS S-2 TBDPS 6 To a 100 ml round bottom flask fitted with a Dean-Stark apparatus and condenser was added ketone S-2 (1.0 g, 1.92 mmol), 1,3-propanediol (3 ml), anhydrous benzene (50 ml) and camphorsulfonic acid (45 mg, 0.19 mmol). The solution was heated to reflux under nitrogen. After ca. 3 h 5 ml of solvent was removed from the Dean-Stark receiver and replaced with 5 ml of anhydrous benzene. The solvent removal and S2

3 replacement was repeated twice more over the course of 12 h. After a total of 16 h, the reaction was cooled to room temperature, quenched with saturated aqueous NaC 3 ( ml) and extracted with EtAc (3 x ml). The combined organics were washed with brine, dried over Na 2 S 4, filtered, and concentrated. The crude residue was purified by passage over a short silica plug (hexanes/etac/et 3 N = 9:1:0.01) to provide ketal 6 (1.04 g, 93% yield). [α] D -5.5 (c 1.0, CCl 3 ); 1 NMR (500 Mz, CDCl 3 ) δ 1.05 (9, s), 1.08 (3, d, J = 6.3 z), (4, m), (1, m), (1, m), (1, m), (1, m), (2, m), (5, m), 5.63 (1, d, J = 1.5 z), 6.11 (1, s), (6, m), (4, m); 13 C NMR (125 Mz, CDCl 3 ) δ 135.5, 133.9, 129.5, 127.6, 124.7, 123.4, 100.0, 63.9, 59.4, 59.3, 41.4, 29.9, 26.8, 26.6, 25.2, 23.0, 19.2; R-MS (ESI) m/z [(M+) + calcd for C I 3 Si: ]. Bz S 2 Ph Bz C 1b I 26 CrCl 2 i-pr/ph/-unnat-menthol/ NiCl 2 dmp/licl, Mn, Cp 2 ZrCl 2 / CN (0.4 M)/rt Bz Bz S 2 Ph TBDPS 7b TBDPS 6 To a solution of (S)-sulfonamide A (189 mg, 379 µmol), and proton sponge (Aldrich, purified by sublimation; 81 mg, 379 µmol) in C 3 CN (Baker, ultra low water; 4.3 ml) in a glove box was added CrCl 2 (Aldrich, 99.99% or Strem, 99.9%; 42 mg, 340 µmol) and the resulting solution was stirred for 1 h at rt. Next, the above chromium complex solution was added to a separate flask containing LiCl (Aldrich, anhydrous, 146 mg, 3.44 mmol), Mn powder (Aldrich, 99.99%; 189 mg, 3.44 mmol), NiCl 2 dmp (21 mg, 60 µmol), aldehyde 1b (1.01 g, 1.72 mmol) and vinyl iodide 6 (1.32 g, 2.58 mmol). Finally, Zr(Cp) 2 Cl 2 (Aldrich, 98%; 503 mg, 1.72 mmol) was added and the reaction was stirred in the glove box at rt until TLC analysis confirmed consumption of aldehyde 1b (ca. 3h). The reaction was then removed from the glove box, diluted with EtAc (2 ml) and 1M potassium serinate (3.5 ml), and then stirred vigorously for 30 min. The mixture was subsequently poured into saturated aqueous NaC 3 (50 ml) and extracted with EtAc (3 x 50 ml). The combined organic layers were dried over anhydrous Na 2 S 4, filtered, and concentrated. The resulting residue (dr = ca. 50:1 by 1 NMR analysis) was purified by Si 2 flash column chromatography (hexanes/etac/et 3 N = 8:2:0.02) to provide the allylic alcohol 7b (1.51g, 92%, dr = ca. 50:1): 1 NMR (500 Mz, C 6 D 6 ) δ (1, m), 1.17 (9, s), 1.29 (3, d, J = 6.5 z), (1, m), (3, m), (1, m), (1, m), 2.02 (1, dd, J = 14.5 z, 5.0 z), (2, m), (1, m), (1, m), 2.60 (1, dd, J = 14.0 z, 9.0 z), (2, m), 2.82 (1, dd, J = 14.0 z, 5.0z), 2.96 (1, d, J = 2.5 z), 3.26 (3, s), (4, m), (3, m), (2, m), (1, m), 4.50 (2, d, J = S3

4 5.0 z), 4.97 (1, s), 5.29 (1, s), (1, m), (6, m), (4, m), (5, m), (2, m), (4, m), (2, m), (2, m). Bz Bz S 2 Ph Bz TMSTf/Et 3 Si, C 2 Cl 2-78 C! 0 C Bz S 2 Ph TBDPS 7b 8b To a solution of 7b (1.51 g, 1.57 mmol) and Et 3 Si (1.59 ml, 15.7 mmol) in C 2 Cl 2 (15 ml) at -78 C under nitrogen was added TMSTf (0.57 ml, 3.15 mmol) dropwise. After 5 min, TLC showed complete conversion of the starting material to a less polar spot (R f = 0.8, hexanes/etac = 1:1). The reaction was then stirred at 0 C until TLC analysis confirmed complete silyl deprotection (ca. 2h). The reaction was quenched at 0 C with saturated aqueous NaC 3 ( ml) and extracted with C 2 Cl 2 (3 x 25 ml). The combined organic layers were dried over anhydrous Na 2 S 4, filtered, concentrated, and the resulting residue was passed through a silica gel plug (hexanes/etac = 3:1, then 1:1) to provide 8b (1.07 g, 95%): [α] D -9.9 (c 1.0, CCl 3 ); 1 NMR (600 Mz, CDCl 3 ) δ (1, m), 1.05 (3, d, J = 6.6 z), (3, m), (2, m), 1.63 (1, br), (1, m), (1, m), (1, m), (1, m), (2, m), (1, m), (2, m), 3.40 (3, s), (1, m), (2, m), 3.70 (1, dd, J = 9.0, 3.6 z), 3.74 (1, dt, J = 13.8, 10.2 z), (1, m) 3.87 (1, d, J = 3.6 z), 4.78 (1, d, J = 1.2 z), 4.83 (1, s), (1, m), (4, m), (4, m), 7.68 (1, t, J = 7.2 z), 7.93 (2, d, J = 7.8 z), 8.00 (2, d, J = 7.2 z), 8.04 (2, d, J = 7.8 z); 13 C NMR (125 Mz, CDCl 3 ) δ 166.2, 166.0, 150.5, 139.6, 133.9, 133.0, 130.0, 129.8, 129.7, 129.6, 129.4, 128.3, 127.9, 105.0, 86.1, 81.3, 77.8, 77.1, 75.5, 70.3, 65.6, 62.7, 58.0, 57.5, 43.1, 42.6, 37.1, 35.5, 32.4, 30.2, 28.9, 17.9; R-MS (ESI) m/z [(M+) + calcd for C S: ]. 3. Synthesis outlined in Scheme 5 Bz Bz S 2 Ph Dess-Martin oxidation Bz Bz S 2 Ph C 8b 11b S4

5 To a stirred solution of 8b (1.07g, 1.49 mmol) and NaC 3 (628 mg) in C 2 Cl 2 (14 ml) was added Dess-Martin periodinane (761 mg, 1.79 mmol) and the solution was stirred at rt for 30 min. The reaction was then quenched by addition of 25wt% Na 2 S 2 3 saturated aqueous NaC 3 (50 ml) and the resulting solution was stirred vigorously until both liquid phases were clear. The organic phase was separated and the aqueous phase was extracted with C 2 Cl 2 (3 x 50 ml). The combined organic phases were dried over anhydrous Na 2 S 4, filtered, concentrated, and the resulting oil was purified over a short pad of Si 2 (hexanes/etac = 1:1) to provide aldehyde 11b (1.03g, 96%), which was used for the next step: 1 NMR (600 Mz, CDCl 3 ) δ (1, m), 1.06 (3, d, J = 6.5 z), (3, m), (1, m), (1, m), (1, m), (4, m), (1, m), (2, m), (1, m), 3.41 (3, s), 3.64 (1, dd, J = 9.5, 4.0 z), 3.72 (1, dt, J = 9.5, 4.5 z), (1, m), 3.88 (1, d, J = 3.5 z), 4.56 (2, d, J = 4.5 z), 4.78 (1, d, J = 1.5 z), 4.84 (1, s), (1, m), (4, m), (4, m), (1, m), 7.93 (2, d, J = 8.5 z), 8.00 (2, d, J = 9.0), 8.04 (2, d, J = 7.0 z), 9.65 (1, t, J = 1.0 z) Synthesis of E7389 C14-C35 building block bearing of TBDPS- group Bz I Cl S 2 Ph Bz b C CrCl 2 i-pr/phcl 2 /-c-ex() 2, NiCl 2 dmp, LiCl, Mn, Cp 2 ZrCl 2 CN (0.4 M), rt Bz Bz 35 S 2 Ph 30 Cl 14 TBDPS TBDPS a N N 19 13b S (R)-B Cl Cl To a solution of (R)-sulfonamide B (165 mg, 306 µmol), and proton sponge (66 mg, 310 µmol) in C 3 CN (3.5 ml) in a glove box was added CrCl 2 (34 mg, 280 µmol) and the resulting solution was stirred for 1 h at rt. Next, the above chromium complex solution was added to a separate flask containing 11b (1.00 g, 1.39 mmol), vinyl iodide 12a (1.07 g, 2.09 mmol), LiCl (118 mg, 2.78 mmol), Mn (153 mg, 2.78 mmol) and NiCl 2 dmp (8.7 mg, 27 µmol). Finally, Zr(Cp) 2 Cl 2 (407 mg, 1.39 mmol) was added and the reaction was stirred in the glove box at rt until TLC analysis confirmed consumption of 11b (ca. 3h). The reaction was then removed from the glove box, diluted with EtAc (3 ml) and 1M potassium serinate (2.5 ml), and then stirred vigorously for 30 min. The mixture was subsequently poured into saturated aqueous NaC 3 (50 ml) and extracted with EtAc (3 x 50 ml). The combined organic layers were dried over anhydrous Na 2 S 4, filtered, and concentrated. The resulting residue (dr = ca. 32:1 by 1 NMR analysis) was purified by Si 2 flash column chromatography (hexanes/etac/et 3 N = 9:1:0.01) to provide the allylic alcohol 13b (1.32g, 86%, dr = ca. 32:1), which was used S5

6 for the next step without further purification: 1 NMR (600 Mz, CDCl 3 ) δ 1.03 (9, s), (2, m), 1.05 (3, d, J = 6.6 z), (1, m), (2, m), (1, m), (4, m), (1, m), (2, m), (1, m), (2, m), 2.35 (1, dd, J = 15.0, 6.0 z), 2.48 (1, dd, J = 15.0, 7.8 z), (1, m), (2, m), 3.41 (3, s), (1, m), (2, m), (2, m), (1, m), 3.88 (1, d, J = 3.0 z), 3.98 (1, dd, J = 7.8, 4.8 z), (1, m), (2, m), 4.78 (1, s), 4.84 (1, s), 4.88 (1, s), 5.07 (1, s), (1, m), (10, m), (2, m), 7.57 (2, t, J = 7.2 z), (5, m), 7.93 (2, d, J = 7.2 z), 8.00 (2, d, J = 7.2 z), 8.04 (2, d, J = 7.2 z). Bz Bz 35 S 2 Ph 30 Bz Bz 35 S 2 Ph 30 K, 18-crown-6, toluene Cl 14 TBDPS 14 TBDPS b 3b A flame-dried flask under argon atmosphere was charged with K (525 mg, 3.88 mmol, 30 wt%, dispersion in mineral oil), washed with anhydrous hexanes (2 x 25 ml), and then dried in vacuo for 1 h. After addition of toluene (60 ml) the suspension was cooled to -78 C. To the suspension was added 13b (1.30 g, 1.17 mmol, azeotropically dried from toluene 3 times) and 18-crown-6 (621 mg, 2.35 mmol) in toluene (10 ml). The reaction mixture was stirred at - C for 14 h and then poured into a solution of 1N Cl (100 ml) and EtAc (100 ml). The resulting solution was stirred at rt for 1 h and then extracted with EtAc (3 x 50 ml). The combined organic layers were washed with brine, dried over anhydrous Na 2 S 4, filtered, and concentrated. The resulting residue was purified by flash column chromatography (hexanes/etac = 4:1) to provide the product 3b (1.105 g, 88%, 76% overall yield from 11b). [α] D -6.7 (c 1.0, CCl 3 ); 1 NMR (600 Mz, CDCl 3 ) δ (1, m), 1.05 (9, s), 1.06 (3, d, J = 7.2 z), (2, m), (6, m), 1.72 (1, ddd, J = 12.6, 8.4, 1.8 z), 1.92 (1, ddd, J = 12.4, 9.0, 3.6 z), (3, m), (2, m), (1, m), 2.62 (1, ddd, J = 13.8, 7.8, 5.4 z), (2, m), (1, m), 3.43 (3, m), (3, m), 3.74 (1, dt, J = 9.6, 9.0 z), 3.84 (1, ddd, J = 12.6, 6.6, 3.0 z), (2, m), 4.23 (1, m), (2, m), 4.68 (1, d, J = 1.8 z), 4.77 (1, d, J = 1.8 z), 4.83 (1, s), 4.89 (1, d, J = 1.8 z), (1, m), (10, m), (4, m), (5, m), 7.93 (2, d, J = 7.2 z), 8.01 (2, d, J = 7.2 z), 8.05 (2, d, J = 7.2 z); 13 C NMR (125 Mz, CDCl 3 ) δ 166.2, 166.0, 151.4, 150.5, 139.7, 135.5, 134.0, 133.9, 133.1, 129.8, 129.7, 129.5, 129.4, 128.3, 127.9, 127.5, 104.8, 104.7, 86.0, 81.2, 79.3, 77.9, 77.1, 77.0, 75.2, 70.3, 65.6, 63.7, 57.9, 57.5, 43.0, 42.6, 38.7, 37.4, 35.4, 31.6, 31.5, 31.3, 30.2, 29.0, 26.8, 19.1, 17.9; R-MS (ESI) m/z [(M+) + calcd for C SSi: ]. Structure confirmation of 3b by spectroscopic comparison to an authentic sample was achieved after cleavage of the benzoate esters (K 2 C 3,, rt) and protection of the S6

7 resulting diol as the acetonide (2,2-DMP, 2 C, p-ts, rt), furnishing 22 1 from the preceding paper Synthesis of E7389 C14-C35 building block bearing of Pv- group Bz S 2 Ph Bz S 2 Ph Bz Bz C 11b + Cl I Cl Pv Pv 12b S-3 To a solution of (R)-sulfonamide ligand B (7.5 mg, 15 µmol) and proton sponge (3.3 mg, 15 µmol) in C 3 CN (175 µl) in a glove box was added CrCl 2 (1.7 mg, 14 µmol) and the resulting solution was stirred for 1 h at rt. Next, the above chromium complex solution was added to a separate flask containing 11b (50 mg, 69 µmol), vinyl iodide 12b (49 mg, 139 µmol), LiCl (6 mg, 139 µmol), Mn (8 mg, 139 µmol), and NiCl 2 dmp (0.4 mg, 1 µmol). Finally, Zr(Cp) 2 Cl 2 ( mg, 69 µmol) was added and the reaction was stirred in the glove box at rt until TLC analysis confirmed consumption of 11b (ca. 1.5 h). The reaction was then removed from the glove box, diluted with EtAc (300 µl) and 1M potassium serinate (0 µl), and then stirred vigorously for 30 min. The mixture was subsequently poured into saturated aqueous NaC 3 (5 ml) and extracted with EtAc (3 x 5 ml). The combined organic layers were dried over anhydrous Na 2 S 4, filtered and concentrated. The resulting residue (dr = ca. 28:1 by 1 NMR analysis) was purified by passage through a silica plug (hexanes/etac/et 3 N = 9:1:0.01 then hexanes/etac = 1:1) to provide the allylic alcohol S-3 (56 mg, 85%, dr = ca. 28:1), which was used for the next step without further purification: 1 NMR (600 Mz, CDCl 3 ) δ 1.06 (3, d, J = 6.2 z), (1, m), (9, m), (1, m), (2, m), (4, m), (2, m), (2, m), 1.97 (1, ddd, J = 13.3, 8.8, 4.0 z), 2.14 (1, ddd, J = 13.8, 8.9, 4.8 z), (2, m), (1, m), 2.43 (1, d, J = 3.8 z), 2.52 (1, dd, J = 14.9, 7.6 z), 2.67 (1, q, J = 6.2 z), (2, m), 3.43 (3, s), (1, m), (2, m), 3.84 (1, td, J = 6.5, 3.4 z), 3.88 (1, d, J = 3.2 z), (3, m), (2, m), 4.78 (1, s), 4.84 (1, s), 4.88 (1, s), 5.07 (1, s), (1, m), (4, m), (4, m), (1, m), 7.93 (2, d, J = 8.2 z), (4, m). 1 Kim, D.-S.; Dong, C.-G.; Kim, J. T.; Guo,.; uang, J.; Tiseni, P. S.; Kishi, Y. J. Am. Chem. Soc. 09, 131, S7

8 Bz Bz S 2 Ph Bz Bz S 2 Ph K, Ph Cl 18-C-6, - C Pv Pv S-3 S-4 A flame-dried flask under argon atmosphere was charged with K (50 mg, 30 wt%, dispersion in mineral oil), washed with anhydrous hexanes (2 x 2 ml), and then dried in vacuo for 1 h. After addition of toluene (4 ml) the suspension was cooled to -78 C. To the suspension was added S-3 (46 mg, 48 µmol, azeotropically dried from toluene 3 times) and 18-crown-6 (42 mg, 159 µmol) in toluene (700 µl). The reaction mixture was stirred at - C for 14 h and then poured into a solution of 1N Cl (10 ml) and EtAc (10 ml). The resulting solution was stirred at rt for 1 h and then extracted with EtAc (3 x 5 ml). The combined organic layers were washed with brine, dried over anhydrous Na 2 S 4, filtered, and concentrated. The resulting residue was purified by silica gel flash column chromatography (hexanes/etac = 4:1) to provide the product S-4 (36 mg, 83%). [α] D -9.0 (c 1.0, CCl 3 ); 1 NMR (600 Mz, CDCl 3 ) δ 1.06 (3, d, J = 6.8 z), (1, m), (9, m), (3, m), (4, m), (2, m), 1.89 (1, ddd, J = 13.1, 9.4, 3.4 z), (3, m), (2, m), (2, m), (2, m), (1, m), 3.42 (3, s), 3.62 (1, dd, J = 9.8, 3.4 z), 3.73 (1, dt, J = 9.4, 4.8 z), 3.83 (1, td, J = 6.5, 3.2 z), (2, m), (2, m), 4.24 (1, br s), 4.57 (2, d, J = 4.9 z), (1, m), 4.76 (1, s), 4.82 (1, s), 4.89 (1, d, J = 2.0 z), (1, m), (4, m), (4, m), (1, m), (2, m), (4, m); 13 C NMR (125 Mz, CDCl 3 ) δ 178.5, 166.2, 166.0, 151.1, 150.5, 139.7, 133.9, 133.0, 130.1, 129.8, 129.7, 129.6, 129.4, 128.3, 127.9, 104.9, 104.8, 86.1, 81.2, 79.4, 77.9, 77.1, 75.2, 70.3, 65.6, 64.2, 57.9, 57.5, 43.1, 42.6, 38.8, 38.7, 37.4, 35.5, 31.6, 31.5, 31.4, 30.2, 27.1, 25.2, 17.9; R-MS (ESI) m/z [(M+) + calcd for C S: ]. Bz S 2 Ph TBS S 2 Ph Bz TBS 1. K 2 C 3, 2.TBSCl, imid., C 2 Cl 2 Pv Pv S-4 S-5 To a solution of bis-benzoate ester S-4 (10 mg, 11 µmol) in (0 µl) at rt was added K 2 C 3 (1 mg, 7 µmol). The reaction was stirred for 1 h at which time TLC analysis showed conversion of the starting material to a more polar spot (R f = 0.6, S8

9 EtAc). The reaction was quenched with saturated aqueous NaC 3 (5 ml), extracted with EtAc (3 x 5 ml) and the combined organics were dried over Na 2 S 4, filtered, and concentrated. The crude residue was purified over a short plug of silica gel (hexanes/etac = 4:1, then EtAc) to provide diol (7 mg, 91%). 1 NMR (600 Mz, CDCl 3 ) δ 1.07 (3, d, J = 6.2 z), (1, m), (9, s), (1, m), (2, m), (4, m), (2, m), (1, m), 1.92 (1, ddd, J = 13.2, 9.4, 3.2 z), 2.00 (1, dt, J = 14.8, 8.9 z), (3, m), 2.32 (1, t, J = 6.3 z), (2, m), (2, m), 3.27 (1, d, J = 2.3 z), (1, m), 3.40 (3, s), 3.55 (1, dt, J = 11.3, 5.5 z), 3.59 (1, dd, J = 10.3, 2.9 z), 3.65 (1, ddd, J = 11.0, 7.2, 3.8 z), 3.82 (1, dt, J = 9.4, 5.0 z), (4, m), (2, m), 4.26 (1, br s), 4.68 (1, d, J = 1.8 z), (1, m), 4.84 (1, s), 4.91 (1, d, J = 1.8 z), (2, m), (1, m), 7.96 (2, dd, J = 8.2, 0.9 z). To a solution of the diol described above (7 mg, 10 µmol) in C 2 Cl 2 (100 µl) at 0 C were added imidazole (3.4 mg, 50 µmol) and TBSCl (4.5 mg, 30 µmol). The reaction was stirred at rt for 3 h and then quenched with saturated aqueous NaC 3 (1 ml). The solution was extracted with C 2 Cl 2 (3 x 2 ml) and the combined organics were dried over Na 2 S 4, filtered, and concentrated. The crude residue was passed over a short plug of silica gel (hexanes/etac = 2:1) to furnish bis-tbs ether S-5 (8.8 mg, 94%). [α] D (c 0.84, CCl 3 ); 1 NMR (500 Mz, CDCl 3 ) δ (12, m), 0.89 (18, s), 1.05 (3, d, J = 6.8 z), (1, m), 1.19 (9, s), (3, m), (3, m), (2, m), (3, m), 2.01 (1, ddd, J = 13.7, 6.3, 4.9 z), (3, m), (1, m), (1, m), (2, m), (1, m), (3, m), (1, m), (2, m), 3.67 (1, dt, J = 9.8, 4.9 z), (3, m), 3.96 (1, t, J = 6.3 z), (2, m), (1, m), 4.66 (1, d, J = 2.0 z), (1, m), 4.85 (1, s), 4.90 (1, d, J = 2.0 z), 7.61 (2, t, J = 7.8 z), 7.69 (1, t, J = 7.6 z), (2, m); 13 C NMR (125 Mz, CDCl 3 ) δ 178.5, 151.2, 150.5, 139.7, 133.8, 129.4, 128.0, 127.9, 104.8, 85.7, 80.6, 79.3, 78.2, 76.7, 75.3, 71.3, 67.8, 64.1, 58.0, 57.5, 43.3, 42.6, 42.2, 38.7, 38.6, 37.4, 35.4, 33.1, 31.6, 31.5, 31.4, 27.1, 26.0, 25.9, 25.2, 22.4, 18.4, 18.3, 18.1, 17.9, -4.0, -4.7, -5.3; R- MS (ESI) m/z [(M+) + calcd for C SSi 2 : ] Synthesis of E7389 C14-C35 building block bearing of 2,2-dimethyl-propylene ketal S9

10 Bz S 2 Ph Bz Bz S 2 Ph Bz C 11b Cl I Cl + 12c S-6 To a solution of (R)-sulfonamide B (6.6 mg, 12 µmol), and proton sponge (2.6 mg, 12 µmol) in C 3 CN (140 µl) in a glove box was added CrCl 2 (1.4 mg, 11 µmol) and the resulting solution was stirred for 1 h at rt. Next, the above chromium complex solution was added to a separate flask containing 11b (40 mg, 55 µmol), vinyl iodide 12c (49 mg, 111 µmol), LiCl (5 mg, 111 µmol), Mn (6 mg, 111 µmol), and NiCl 2 dmp (0.3 mg, 1 µmol). Finally, Zr(Cp) 2 Cl 2 (16 mg, 55 µmol) was added and the reaction was stirred in the glove box at rt until TLC analysis confirmed consumption of 11b (ca. 3 h). The reaction was then removed from the glove box, diluted with EtAc (0 µl) and 1M potassium serinate (0 µl), and then stirred vigorously for 30 min. The mixture was subsequently poured into saturated aqueous NaC 3 (5 ml) and extracted with EtAc (3 x 10 ml). The combined organic layers were dried over anhydrous Na 2 S 4, filtered, and concentrated. The resulting residue (dr = ca. 31:1 by 1 NMR analysis) was passed through a silica plug (hexanes/etac/et 3 N = 9:1:0.01 then hexanes/etac = 1:1) to provide the allylic alcohol S-6 (45 mg, 87%, dr = ca. 31:1), which was used for the next step without further purification: 1 NMR (600 Mz, CDCl 3 ) δ 0.70 (3, s), 1.06 (3, d, J = 5.9 z), (1, m), 1.16 (3, s), (1, m), (1, m), (3, m), (2, m), (3, m), (4, m), 2.36 (1, dd, J = 15.2, 5.9 z), 2.47 (1, dd, J = 15.1, 8.1 z), 2.67 (1, q, J = 6.2 z), 3.09 (3, d, J = 6.7 z), (2, m), 3.42 (3, s), 3.58 (2, d, J = 10.3 z), (2, m), (1, m), 3.90 (1, d, J = 3.5 z), (1, m), (2, m), 4.45 (1, t, J = 4.1 z), (2, m), 4.78 (1, s), 4.84 (1, s), 4.90 (1, s), 5.07 (1, s), (1, m), (4, m), (4, m), (1, m), (2, m), (4, m). Bz Bz S 2 Ph Cl 1. K, Ph 18-C-6, -! C 2., rt S 2 Ph S-6 S-7 S10

11 A flame-dried flask under argon atmosphere was charged with K (50 mg, 30 wt%, dispersion in mineral oil), washed with anhydrous hexanes (2 x 3 ml), and then dried in vacuo for 1 h. After addition of toluene (4 ml) the suspension was cooled to -78 C. To the suspension was added S-6 (45 mg, 47 µmol, azeotropically dried from toluene 3 times) and 18-crown-6 (41 mg, 155 µmol) in toluene (700 µl). The reaction mixture was stirred at - C for 14 h and then 500 ml was added and the reaction was stirred at rt for 4 h. The reaction was quenched by 1N Cl (10 ml) and EtAc (10 ml). The resulting solution was stirred at rt for 1 h and then extracted with EtAc (3 x 10 ml). The combined organic layers were washed with brine, dried over anhydrous Na 2 S 4, filtered, and concentrated. The resulting residue was purified by passage through a silica plug (hexanes/etac = 4:1 then EtAc) to provide S-7 (28 mg, 85%): 1 NMR (500 Mz, CDCl 3 ) δ 0.71 (3, s), 1.06 (3, d, J = 6.3 z), (1, m), 1.17 (3, s), (2, m), (3, m), (4, m), (1, m), (1, m), 1.91 (1, ddd, J = 13.1, 9.6, 3.2 z), (1, m), (3, m), 2.38 (1, br. s.), (2, m), (2, m), 3.29 (1, s), (3, m), (3, m), (3, m), (1, m), 3.81 (1, dt, J = 9.4, 4.8 z), (4, m), 4.23 (1, br. s.), 4.43 (1, t, J = 4.4 z), (1, m), 4.78 (1, s), 4.83 (1, s), (1, m), (2, m), (1, m), 7.95 (2, d, J = 7.3 z). S 2 Ph TBS S 2 Ph TBS TBSCl, imid., C 2 Cl 2 S-7 S-8 To a solution of S-7 (28 mg, 39 µmol) and imidazole (14 mg, 198 µmol) in C 2 Cl 2 (300 µl) at 0 C was added TBSCl (18 mg, 118 µmol) and the reaction was warmed to room temperature. After 1 h the reaction was quenched with sat. aq. NaC 3 (1 ml) and extracted with C 2 Cl 2 (3 x 2 ml). The combined organics were dried over anhydrous Na 2 S 4, filtered, and concentrated. The resulting residue was purified by passage through a silica plug (hexanes/etac = 4:1) to provide bis-tbs ether S-8 (37 mg, 99%). [α] D (c 1.0, CCl 3 ); 1 NMR (600 Mz, CDCl 3 ) δ 0.04 (6, d, J = 3.8 z), 0.10 (6, d, J = 5.6 z), 0.71 (3, s), 0.89 (18, s), (1, m), 1.06 (3, d, J = 6.4 z), 1.18 (3, s), (2, m), (3, m), 1.59 (1, br s), (2, m), (2, m), (2, m), (1, m), (3, m), (2, m), (2, m), 3.44 (3, s), (3, m), 3.48 (1, dd, J = 10.3, 5.3 z), (3, m), 3.67 (1, dt, J = 9.7, 4.8 z), (2, m), 3.87 (1, d, J=3.2 z), (1, m), 4.22 (1, br s), 4.44 (1, t, J = 4.7 z), 4.63 (1, d, J = 2.1 z), (1, m), 4.85 (1, s), 4.88 (1, d, J = 2.1 z), 7.61 (2, t, J = 7.8 z), 7.69 (1,t, J = 7.5 z), 7.94 (2, d, J = 7.3 z); 13 C NMR (125 Mz, CDCl 3 ) δ 151.5, S11

12 150.6, 139.8, 133.9, 129.5, 127.9, 104.8, 104.6, 101.8, 85.8, 80.7, 79.1, 78.3, 77.2, 76.9, 75.3, 71.4, 67.8, 58.1, 57.5, 43.2, 42.6, 38.6, 37.5, 35.5, 33.1, 31.6, 31.3, 31.2, 30.1, 29.3, 26.0, 25.9, 22.9, 21.8, 18.3, 18.1, 17.9, -4.0, -4.7, -5.3; RMS (ESI) m/z [(M+) + calcd for C SSi 2 : ]. 4. Synthesis outlined in Scheme 6 Bz PMB Bz 27 C 14b 1. CrCl 2 i-pr/ph/-unnat-menthol/ NiCl 2 dmp/licl, Mn, Cp 2 ZrCl 2 / Bz Bz PMB I TBSTf/Et 3 Si, C 2 Cl 2 / -78 C 3. TBAF/TF TBDPS S-9 6 To a solution of (S)-sulfonamide A (18.1 mg, 37 µmol) and proton sponge (7.8 mg, 37 µmol) in C 3 CN (400 µl) in a glove box was added CrCl 2 (4.0 mg, 33 µmol) and the resulting solution was stirred for 1 h at rt. Next, the above chromium complex solution was added to a separate flask containing aldehyde 14b (100 mg, 0.16 mmol), vinyl iodide 6 (128 mg, 0.24 mmol), LiCl (14.0 mg, 0.33 mmol), Mn (18.2 mg, 0.33 mmol), and NiCl 2 dmp (2 mg, 6 µmol). Finally, Zr(Cp) 2 Cl 2 (48.5 mg, 0.16 mmol) was added and the reaction was stirred in the glove box at rt for 3h. The reaction was removed from the glove box, diluted with EtAc (400 µl) and 1M potassium serinate (350 µl), and then stirred vigorously for 30 min. The mixture was subsequently poured into saturated aqueous NaC 3 (10 ml) and extracted with EtAc (3 x 10 ml). The combined organic layers were dried over anhydrous Na 2 S 4, filtered, and concentrated. The resulting residue (dr = ca. 50:1 by 1 NMR analysis) was purified by Si 2 flash column chromatography (hexanes/etac/et 3 N = 8:2:0.02) to provide the allylic alcohol (153 mg, 88%, dr = ca. 50:1): 1 NMR (500 Mz, C 6 D 6 ) δ 0.91 (3, d, J = 7.0 z), (1, m), 1.18 (9, s), 1.30 (3, d, J = 7.0 z), (2, m), (6, m), (2, m), (4, m), 2.26 (1, dt, J = 15.5 z, 2.5 z), (1, m), (2, m), (1, m), 3.30 (3, s), (4, m), (3, m), (3, m), 4.35 (1, d, J = 11.0 z), (2, m), (1, m), 4.96 (1, s), 5.29 (1, s), (2, m), (3, m), (6, m), (6, m), (3, m), (2, m), (2, m). To a solution of the allylic alcohol (153 mg, 140 µmol) and Et 3 Si (146 µl, 1.44 mmol) in C 2 Cl 2 (1.5 ml) at -78 C under nitrogen was added TBSTf (33 µl, 140 µmol) dropwise. After 1 min, the reaction was quenched at -78 C with saturated aqueous NaC 3 (1 ml) and extracted with C 2 Cl 2 (3 x 10 ml). The combined organics were dried over anhydrous Na 2 S 4, filtered, concentrated and the resulting residue was passed through a silica gel plug (hexanes/etac = 9:1) to provide the TBDPS-protected S-9 S12

13 (132 mg, 93%): 1 NMR (600 Mz, CDCl 3 ) δ (12, m), 1.17 (3, d, J = 7.2 z), (2, m), (2, m), (2, m), (1, m), (3, m), (3, m), 2.36 (1, dt, J = 15.6 z, 3.0 z), 3.31 (1, t, J = 8.4 z), (1, m), 3.41 (1, t, J = 3.0 z), (2, m), (1, m), (2, m), 3.78 (3, s), (1, m), (1, m), (1, m), 4.55 (2, ABq, J = 18.0 z, 10.8 z), 4.70 (1, d, J = 1.2 z), 4.78 (1, s), 5.06 (1, br s), (2, m), (2, m), (10, m), 7.53 (2, dt, J = 7.2 z, 27.0 z), (4, m), (4, m). To a stirred solution of the TBDPS-protected S-9 (132 mg, 130 µmol) in TF (1.3 ml) at 0 C was added TBAF (400 ml, 400 µmol, 1M in TF). The reaction was allowed to warm and stirred at rt for 3 h. The reaction was cooled to 0 C and quenched with saturated aqueous NaC 3 (2 ml). The aqueous layer was extracted with EtAc (3 x ml) and the combined organics were washed with brine, dried over Na 2 S 4, filtered and concentrated. The resulting residue was passed through a silica gel plug (hexanes/etac = 5:1, then 1:1) to provide alcohol S-9 (93 mg, 96%). [α] D -6.5 (c 0.2, CCl 3 ); 1 NMR (600 Mz, CDCl 3 ) δ 0.98 (3, d, J = 6.0 z), (1, m), 1.18 (3, d, J = 7.2 z), (2, m), (3, m), (2, m), (2, m), (2, m), 2.19 (1, br s), 2.38 (1, ddd, J = 18.6, 6.6, 3.0 z), 3.18 (1, t, J = 7.8 z), (1, m), 3.44 (1, dd, J = 3.6, 3.0 z), (2, m), (1, m), (2, m), 3.79 (3, s), (1, m), (3, m), 4.52 (1, d, J = 10.8 z), 4.58 (1. d, J = 10.8 z), 4.71 (1, d, J = 1.8 z), 4.80 (1, d, J = 1.0 z), 5.07 (1, br s), 6.86 (2, d, J = 8.4 z), 7.27 (2, d, J = 11.4 z), 7.37 (2, t, J = 7.8 z), 7.43 (2, t, J = 7.8 z), (2, m), 8.02 (2, d, J = 8.4 z), 8.08 (2, d, J = 8.4 z); 13 C NMR (125 Mz, CDCl 3 ) δ 166.5, 159.1, 150.9, , 130.3, 130.2, 129.9, 129.5, 129.4, 128.3, 113.7, 104.3, 82.3, 80.2, 77.1, 75.6, 74.1, 72.9, 72.3, 68.3, 63.2, 62.6, 61.7, 55.2, 43.1, 39.6, 35.6, 35.1, 32.5, 31.1, 29.1, 17.9, 17.7; R-MS (ESI) m/z [(M+) + calcd for C : ]. Bz PMB Bz PMB Bz Dess-Martin oxidation Bz S-9 C S-10 To a stirred solution of S-9 (93 mg, 130 µmol) and NaC 3 (54 mg) in C 2 Cl 2 (1.2 ml) was added Dess-Martin periodinane (66 mg, 150 µmol) and the solution was stirred at rt for 30 min. The reaction was then quenched by addition of 25wt% Na 2 S 2 3 saturated aqueous NaC 3 (10 ml) and the resulting solution was stirred vigorously until both liquid phases were clear. The organic phase was separated and the aqueous phase was extracted with C 2 Cl 2 (3 x 10 ml). The combined organic phases were dried over anhydrous Na 2 S 4, filtered, concentrated, and the resulting oil was purified over a short S13

14 pad of Si 2 (hexanes/etac = 1:1) to provide aldehyde S-10 (90 mg, 97%), which was used for the next step: 1 NMR (600 Mz, C 6 D 6 ) δ (1, m), 0.86 (3, d, J = 6.6 z), 0.99 (3, d, J = 7.2 z), 1.21 (1, ddd, J = 12.6, 4.2, 1.8 z), (4, m), (2, m), (6, m), 2.39 (1, ddd, J = 12.6, 6.0, 3.0 z), 3.00 (1, t, J = 3.0 z), (2, m), (1, m), 3.30 (3, s), 3.92 (1, t, J = 6.6 z), 4.34 (1, d, J = 10.8 z), (3, m), (1, m), 4.69 (1, d, J = 1.8 z), 4.90 (1, s), 5.00 (1, br s), 6.83 (2, d, J = 6.0 z), (6, m), 7.27 (2, d, J = 6.6 z), 8.16 (2, d, J = 6.6 z), 8.34 (2, d, J = 7.8 z), 9.44 (1, t, J = 1.8 z). Bz PMB Bz S-10 C I Cl 14 TBDPS 19 Bz 1. CrCl 2 i-pr/phcl 2 /-c-ex() 2, NiCl 2 dmp, LiCl, Mn, Cp 2 ZrCl 2 CN (0.4 M), rt 2. K, 18-crown-6, toluene Bz PMB 14 TBDPS 19 12a 15b To a solution of (R)-sulfonamide B (14.8 mg, 27 µmol) and proton sponge (5.9 mg, 27 µmol) in C 3 CN (310 µl) in a glove box was added CrCl 2 (3.0 mg, 25 µmol) and the resulting solution was stirred for 1 h at rt. Next, the above chromium complex solution was added to a separate flask containing 11b (90.0 mg, 125 µmol), vinyl iodide 13 (96.4 mg, 187 µmol), LiCl (10.6 mg, 250 µmol), Mn (13.7 mg, 250 µmol), and NiCl 2 dmp (0.8 mg, 2.5 µmol). Finally, Zr(Cp) 2 Cl 2 (36.6 mg, 125 µmol) was added and the reaction was stirred in the glove box at rt until TLC analysis confirmed consumption of S-10 (ca. 3h). The reaction was then removed from the glove box, diluted with EtAc (300 µl) and 1M potassium serinate (250 µl), and then stirred vigorously for 30 min. The mixture was subsequently poured into saturated aqueous NaC 3 ( ml) and extracted with EtAc (3 x 10 ml). The combined organic layers were dried over anhydrous Na 2 S 4, filtered, and concentrated. The resulting residue (dr = ca. 29:1 by 1 NMR analysis) was purified by Si 2 flash column chromatography (hexanes/etac/et 3 N = 9:1:0.01) to provide the allylic alcohol (122 mg, 87%, dr = 29:1), which was used for the next step without further purification. 1 NMR (600 Mz, CDCl 3 ) δ 0.97 (3, d, J = 6.6 z), 1.04 (9, s), 1.18 (3, d, J = 7.2 z), (2, m), (6, m), (3, m), (3, m), (3, m), (2, m), 2.54 (1, dd, J = 15.6 z, 8.4 z), 2.67 (1, d, J = 3.6 z), 3.19 (1, t, J = 8.4 z), 3.28 (1, m), 3.43 (1, t, J = 3.6 z), (3, m), (1, t, J = 6.6 z), (1, m), 3.79 (3, s), (1, m), 4.03 (1, dt, J = 8.4 z, 4.0 z), (1, m), (2, m), 4.55 (2, q, J = 21.6 z, 10.8 z), 4.72 (1, s), 4.82 (1, s), 4.89 (1, s), 5.05 (1, br s), 5.12 (1, s), 6.86 (2, d, J = 9.0 z), 7.28 (2, d, J = 9.0 z), (10, m), (2, m), (4, d, J = 7.2 z), 8.05 (4, dd, J = 34.2 z, 7.2 z). S14

15 A flame-dried flask under argon atmosphere was charged with K (50 mg, 357 µmol, 30 wt%, dispersion in mineral oil), washed with anhydrous hexanes (2 x 5 ml), and then dried in vacuo for 1 h. After addition of toluene (6 ml) the suspension was cooled to -78 C. To the suspension was added the allylic alcohol (122 mg, 100 µmol, azeotroped from toluene 3 times) and 18-crown-6 (86.0 mg, 3 µmol) in toluene (1 ml). The reaction mixture was stirred at - C for 14 h then poured into a solution of 1N Cl (10 ml) and EtAc (10 ml). The resulting solution was stirred at room temperature for 1 h and then extracted with EtAc (3 x 10 ml). The combined organic layers were washed with brine, dried over anhydrous Na 2 S 4, filtered, and concentrated. The resulting residue was purified by Si 2 flash column chromatography (hexanes/etac = 4:1) to provide the product 15b (97 mg, 89%, 77% overall yield from S-10): [α] D (c 1.25, CCl 3 ); 1 NMR (600 Mz, CDCl 3 ) δ 0.94 (1, m), 0.98 (3, d, J = 6.0 z), 1.01 (9, s), (1, m), 1.15 (3, d, J = 7.2 z), (9, m), (1, m), (3, m), (4, m), (1, m), (1, m), 3.26 (1, t, J = 8.4 z), (1, m), (1, m), (2, m), (1, m), 3.75 (3, m), (2, m), (1, m), (1, m), 4.27 (1, br), (2, m), 4.53 (2, s), 4.67 (1, s), 4.75 (1, s), 4.76 (1, s), 4.87 (1, d, J = 1.8 z), 5.05 (1, br), 6.82 (2, d, J = 6.6 z), 7.24 (2, d, J = 8.4 z), (9, m), (2, m), 7.62 (4, d, J = 8.4 z), 7.99 (2, d, J = 8.4 z), 8.00 (2, d, J = 9.6 z); 13 C NMR (125 Mz, CDCl 3 ) δ 166.6, 159.1, 151.6, 151.4, 135.5, 133.9, 132.8, 132.7, 130.6, 130.3, 130.2, 129.9, 129.5, 129.4, 129.3, 128.3, 127.5, 113.7, 104.6, 104.1, 82.0, 80.2, 79.4, 77.2, 75.1, 74.0, 73.0, 72.1, 68.3, 63.7, 63.3, 61.8, 55.2, 43.2, 39.7, 38.8, 35.7, 34.9, 32.5, 31.6, 31.5, 31.4, 31.1, 29.0, 26.8, 19.1, 18.0, 17.7; R-MS (ESI) m/z [(M+) + calcd for C Si: ]. Structure confirmation of 15b by spectroscopic comparison to an authentic sample was achieved after cleavage of the benzoate esters (K 2 C 3 (cat.),, rt) and protection of the resulting diol as bis-tbs silyl ether (TBSTf, Et 3 N, C 2 Cl 2, 0 C); furnishing 18b 1 from the preceding paper. 5. Synthesis outlined in Scheme 7 35 S 2 Ph 30 C 1a CrCl 2 i-pr/ph/-unnat-menthol NiCl 2 dmp LiCl, Mn, Cp 2 ZrCl 2 CN (0.4 M) 35 S 2 Ph 30 2 C I Pv 2 C S Pv 16 To a stirred solution of (S)-sulfonamide A (53.5 mg, 107 µmol) and proton sponge (23.0 mg, 107 µmol) in CN (1.22 ml) was added CrCl 2 (11.9 mg, 97.6 µmol) at rt in a S15

16 glove box. After stirring for 1 h, the resulting green solution was added to a reaction vial containing aldehyde 1a (1 mg, 488 µmol), iodide 16 (303 mg, 585 µmol), LiCl (41.3 mg, 976 µmol), Mn powder (53.6 mg, 976 µmol), and NiCl 2 dmp (8.2 mg, 24 µmol). To the mixture was added Zr(Cp) 2 Cl 2 (214 mg, 732 µmol), and the mixture was stirred at rt in a glove box. After the reaction completed (ca. 3 h), to the reaction mixture added Florisil and diluted with EtAc. After stirring for 30 min, the suspension was passed through a short silica gel plug, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtAc/hexanes = 1:1) to give coupling product (343 mg, 87%) as pale yellow oil. Based on 1 NMR analysis, diastereomer ratios at C27 was estimated to be >50:1 for both E- and Z-isomer. It was used for the next step without further purification C S 2 Ph t-buk/c 2 Cl 2 2. LiI/py/110 C 3. 2,4,6-Cl 3 PhCCl, followed by 1-hydroxylpyridine- 2-thione sodium salt 4. t-bus/h! Pv 35 S 2 Ph Pv S-11 3a To a stirred solution of unsaturated ester S-11 (143 mg, 178 µmol) in C 2 Cl 2 (3.6 ml) was added 1M TF solution of t-buk (89 µl, 89 µmol) at 0 C. After stirring for 10 min at 0 C, saturated N 4 Cl aqueous solution was added followed by EtAc. The separated organic phase was washed with brine and the aqueous layer was extracted with EtAc. The combined organic layer was dried over MgS 4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (EtAc/hexanes = 1:3) to give the oxy-michael product (colorless oil, 128 mg, 90% isolated yield, 94% yield based on the recovered SM) as a ca. 2:1 mixture of the C22 diastereomers and the recovered starting unsaturated ester (7.1 mg). The oxy-michael product was subjected to the next step without further purification. To a stirred solution of mixture of the methyl ester (100 mg, 124 µmol) in pyridine (6.2 ml) was added LiI (832 mg, 6.22 mmol) at 110 C. After stirring for 48 h at 110 C, the mixture was cooled down to rt, then diluted with EtAc. The organic phase was washed with 1N NaS 4 aqueous solution (x 2), 10% of Na 2 S 2 3 aqueous solution, and brine. The separated aqueous layer was extracted with EtAc (twice). The combined organic layer was dried over Na 2 S 4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (C 2 Cl 2 / = :1) to give carboxylic acid (89.3 mg, 91%) as pale yellow foam, which was used for the next step without further purification. To a stirred solution of carboxylic acid (89.3 mg, 113 µmol), polymer supported ünig base (3.42 meq, 660 mg, 2.26 mmol) and DMAP (1.4 mg, 11.3 µmol) in C 2 Cl 2 (3.8 ml) was added 2,4,6-trichlorobenzoyl chloride (176 µl, 1.13 mmol) at rt. After stirring for 60 min, the mixture was filtered though a pad of Celite and washed with C 2 Cl 2. The filtrate was concentrated under reduced pressure to give crude acid anhydride. Then, the S16

17 resulting mixed anhydride and 1-hydroxypyridine-2-thione sodium salt (168 mg, 1.13 mmol) were dissolved in benzene (3.3 ml). After the solution was degassed with freeze (3 times), the flask was wrapped with aluminum foil. The reaction mixture was stirred for 4 h at rt. t-bus (2.2 ml) was added to the reaction mixture and aluminum foil was removed. The reaction mixture was stirred under room light for further 12 h and concentrated under reduced pressure. The residue was passed through a short silica gel plug, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (EtAc/hexanes = 1:3) to give 3a (72.5 mg, 86%) as pale yellow oil. The spectroscopic data of the C14-C35 building block 3a were identical to those of the authentic sample previously reported; spectroscopic data of 3a: [α] D (c 1.00, CCl 3 ); 1 NMR (CDCl 3, 500 Mz) δ 1.07 (3, d, J = 6.5z), 1.19 (9, s), (2, m), 1.37 (3, s), 1.41 (3, s), (8, m), (2, m), 1.88 (1, dt, J = 12.5, 3.0 z), (2, m), (3, m), (2, m), (1, m), 3.44 (3, s), 3.60 (1, dd, J = 10.0, 2.5 z), 3.62 (1, dd, J = 15.0, 8.0 z), 3.73 (1, quintet, J = 5.0 z), 3.77 (1, dt, J = 10.0, 3.0 z), 3.91 (1, d, J = 3.0 z), 3.95 (1, quintet, J = 6.0 z), (3, m), 4.18 (1, quintet, J = 6.0 z), (1, br), 4.64 (1, d, J = 1.5 z), 4.78 (1, s), 4.85 (1. s), 4.90 (1, d, J = 1.5 z), 7.61 (2, dd, J = 8.0, 7.0 z), 7.70 (1, dd, J = 8.0, 1.5 z), 7.96 (2, dd, J = 7.0, 1.5 z); 13 C NMR (CDCl 3, 125 Mz) δ 17.97, 25.32, 25.83, 26.99, 27.26, 31.54, 31.61, 31.78, 32.24, 35.55, 37.53, 38.77, 38.81, 42.75, 43.16, 57.46, 58.02, 64.27, 69.46, 73.44, 75.32, 76.78, 77.14, 78.30, 79.43, 81.01, 85.72, , , , , , , , , ; R-MS (ESI) m/z [(M+) + calcd for C S, ]. 6. Synthesis outlined in Scheme 8 TBS TBS 14c I 26 2 C PMB C 14 Pv CrCl 2 i-pr/ph/-unnat-menthol NiCl 2 dmp LiCl, Mn, Cp 2 ZrCl 2 CN (0.4 M) TBS 38 TBS PMB 30 2 C S Pv 16 To a stirred solution of (S)-sulfonamide A (16.9 mg, 33.9 µmol) and proton sponge (7.3 mg, 33.9 µmol) in CN (0.39 ml) was added CrCl 2 (3.8 mg, 30.9 µmol) at rt in a glove box. After stirring for 1 h, the resulting green solution was added to a reaction vial containing aldehyde 14c (96.1 mg, 154 µmol), iodide 16 (96.0 mg, 185 µmol), LiCl (13.1 mg, 309 µmol), Mn powder (16.9 mg, 309 µmol), and NiCl 2 dmp (2.6 mg, 7.71 µmol). To the mixture was added Zr(Cp) 2 Cl 2 (67.6 mg, 231 µmol), and the mixture was stirred at rt in a glove box. After stirring for 3 h, Florisil was added, followed by dilution with EtAc. After stirring for 30 min, the suspension was passed through a short plug of silica S17

18 gel, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtAc/hexanes = 1:5) to give coupling product (135 mg, 86%) as pale yellow oil. Based on 1 NMR analysis, the diastereomeric ratio at C27 was estimated to be ca. 30:1 for both E- and Z-isomer. S-12 thus obtained was used for the next step without further purification. TBS TBS PMB 1. t-buk/c 2 Cl 2 2. LiI/py/110 C 3. 2,4,6-Cl 3 PhCCl, followed by 1-hydroxylpyridine- 2-thione sodium salt TBS PMB TBS 4. t-bus/h! 2 C 14 Pv 14 Pv S-12 15c To a stirred solution of unsaturated ester S-12 (141 mg, 139 µmol) in C 2 Cl 2 (2.8 ml) was added 1M TF solution of t-buk (70 µl, 70 µmol) at 0 C. After stirring for 10 min at 0 C, saturated N 4 Cl aqueous solution was added, followed by dilution with EtAc. The separated organic phase was washed with brine and the separated aqueous layer was extracted with EtAc. The combined organic layer was dried over MgS 4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (EtAc/hexanes = 1:10) to give the oxy-michael product (pale yellow oil, 125 mg, 88% isolated yield, 91% yield based on the consumed SM) as a ca. 3:2 mixture of the C22 diastereomers and the recovered starting unsaturated ester (4.2 mg). The oxy-michael product was subjected to the next step without further purification. To a stirred solution of the crude oxy-michael product (174 mg, 171 µmol) in pyridine (8.6 ml) was added LiI (1.15 g, 8.6 mmol) at 110 C. After stirring for 30 h at 110 C, the mixture was cooled down to rt, and solvent was evaporated. The resulting residue was diluted with EtAc, followed by saturated N 4 Cl aqueous solution. The separated organic phase was washed with saturated N 4 Cl aqueous solution (x 2), and brine, dried over Na 2 S 4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (EtAc/hexanes = 1:1) to give carboxylic acid (yellow oil, 116 mg, 68% yield, 90% based on the consumed SM) and the recovered starting methyl ester (43 mg). To a stirred solution of carboxylic acid (49.3 mg, 49.2 µmol), polymer supported unig base (3.42 meq, 144 mg, 492 µmol), and DMAP (0.6 mg, 5 µmol) in C 2 Cl 2 (1.5 ml) was added 2,4,6-trichlorobenzoyl chloride (38.5 µl, 246 µmol) at rt. After stirring for 90 min, the mixture was filtered though a pad of Celite and washed with C 2 Cl 2. The filtrate was concentrated under reduced pressure to give crude acid anhydride. Then, the resulting mixed anhydride and 1-hydroxypyridine-2-thione sodium salt (73.4 mg, 492 µmol) were dissolved in benzene (2.4 ml). After the solution was degassed with freeze S18

19 (3 times), the flask was wrapped with aluminum foil. The reaction mixture was stirred for 4 h at rt. t-bus (1.6 ml) was added to the reaction mixture and aluminum foil was removed. The reaction mixture was stirred under room light for further 12 h and concentrated under reduced pressure. The residue was passed through a short silica gel plug, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (EtAc/hexanes = 1:10) to give 15c (yellow oil, 38.5 mg, 82%). The spectroscopic data of the C14-C38 building block 15c thus synthesized were identical to those of the authentic sample previously reported; spectroscopic data of 15c: [α] D (c 1.00, CCl 3 ); 1 NMR (CDCl 3, 500 Mz) δ 0.02 (3, s), 0.04 (3, s), 0.04 (3, s), 0.05 (3, s), 0.87 (9, s), 0.89 (9, s), 1.07 (3, d, J = 6.5 z), 1.19 (9, s), 1.28 (3, d, J = 6.5 z), (3, m), (8, m), (4, m), 1.86 (1, ddd, J = 14.0, 7.5, 5.5 z), 1.99 (2, ddd, J = 14.0, 7.5, 5.5 z), (3, m), 3.09 (1, t, J = 9.0 z), 3.36 (1, dd, J = 7.5, 5.0 z), (2. m), 3.68 (1, ddd, J = 10.0, 6.0, 5.0 z), (3, m), 3.79 (3. s), 3.95 (1, t, J = 6.5 z), 3.99 (1, t, J = 6.5 z), 4.05 (2, dddd, J = 14.0, 10.0, 6.5, 3.5 z), 4.37 (1, br), 4.50 (1, d, J = 11.0 z), 4.59 (1, d, J = 11.0 z), 4.79 (1, d, J = 1.0 z), 4.83 (1, d, J = 1.5 z), 4.93 (1, d, J = 1.0 z), 4.96 (1, d, J = 1.5 z), 6.85 (2, d, J = 9.0z), 7.26 (2, d, J = 9.0z); 13 C NMR (CDCl 3, 125 Mz) δ -5.26, -5.18, -4.75, -4.30, 16.58, 18.13, 18.29, 18.46, 22.58, 25.36, 25.98, 26.08, 27.28, 31.57, 31.71, 33.66, 34.21, 34.72, 36.15, 38.81, 38.92, 39.57, 42.37, 43.45, 55.36, 59.82, 64.34, 66.50, 68., 72.11, 73.48, 73.58, 75.44, 77.57, 78.51, 79.62, 82.49, , , , , , , , , ; R-MS (ESI) m/z [(M+) + calcd for C Si: ]. 7. Synthesis outlined in Scheme 9 I 19 Cl 12 TBS C TBDPS 14 CrCl 2 (R)-Sufonamide C NiCl 2 dmp LiCl, Mn, Cp 2 ZrCl 2 CN (0.4 M) 90% TBS 21 Cl TBDPS N N S Cl Cl (R)-C To a ml vial with a stir bar were added (R)-sulfonamide C (190 mg, 0.43 mmol), CrCl 2 (48 mg, 0.39 mmol), proton sponge (92 mg, 0.43 mmol), and C 3 CN (5 ml) in a glove box. The mixture was stirred for 1 h at rt. The deep green solution of complex was transferred to another ml-vial charged with iodide 12 (2.0 g, 3.90 mmol), LiCl (331 mg, 7.81 mmol), Mn (429 mg, 7.81 mmol), NiCl 2 dmp (27 mg, 80 µmol), Zr(Cp) 2 Cl 2 (1.7 g, 5.82 mmol), and aldehyde (1.0 g, 5.74 mmol). The reaction mixture was stirred at rt for 2 h and taken out of the glove box. The mixture was diluted with 50% EtAc/hexanes S19

20 (10 ml). After addition of Florisil (4 g), the mixture was stirred at rt for 30 min and filtered through a silica gel pad (10 g) with 50% EtAc/hexanes. The filtrate was concentrated under reduced pressure and was roughly purified by flash column chromatography (EtAc/hexanes = 1:50) to give alcohol as a 24:1 diastereomeric mixture 21. TBS 21 Cl TBDPS K/18-crown-6/toluene/ -78 C!- C TBS 14 TBDPS S-13 K (2.6 g, 30 % wt, dispersion in mineral oil) was charged with a flask, washed by pentane, and dried in vacuo for 1h. After addition of toluene (300 ml), the suspension was cooled to -78 C. To the suspension were added 21 (dried by azeotropic removal of water with toluene) and 18-crown-6 (1.6 g, 6.05 mmol) in toluene (50 ml). The reaction mixture was stirred at - C for 14 h and then poured into a solution of 1N Cl solution (0 ml) and EtAc (0 ml). The resulting solution was stirred at rt for 1 h and the aqueous layer was extracted with EtAc. The organic layer was washed with brine, dried over anhydrous MgS 4, and filtered. The filtrate was concentrated under reduced pressure and was purified by flash column chromatography (EtAc/hexanes = 1:50) to give the cyclization product S-13 (1.68g, 82% for 2 steps) as a 24:1 diastereomeric mixture. TBS 14 TBDPS AcCl/, followed by medium-pressure column chromatography separation or Amano lipase PS-800 based workup 14 TBDPS S To a solution of S-13 (717 mg, 1.36 mmol) in (250 ml) was added AcCl (15 µl, mmol) at 0 C. The mixture was stirred at 0 C for 5 h. After addition of Et 3 N (1.0 ml) and C 2 Cl 2 (50 ml), the mixture was filtered through a silica gel pad (10 g) and washed with 10% /C 2 Cl 2. The filtrate was concentrated under reduced pressure and purified by flash column chromatography (10-% EtAc/hexanes), to give 22 (496 mg, 1. mmol, 88%) and the recovered starting material (32 mg). Separation of from its C diastereomer was achieved by either medium pressure column chromatography (silica gel, EtAc/hexanes=1:5 1:3, 93% recovery in a 3.5 g scale) or Amano lipase based method. To a solution of the crude 22 (658 mg, 1.6 mmol), DMAP ( mg, 0.16 mmol), and Et 3 N (0.7 ml, 5 mmol) in C 2 Cl 2 (10 ml) was added m-toluoyl chloride (0.3 ml, 2.3 mmol). The mixture was stirred at rt for 0.5 h. After dilution with hexanes ( ml), the mixture was filtered through a silica gel pad (10 g) with % EtAc/hexanes. The filtrate was concentrated under reduced pressure and was roughly purified by flash column chromatography (EtAc/hexanes=1:50 1:) to the m-toluate (860 mg, ~100%). S