Supplementary Methods and Results on the Synthesis of S-15176-Me

Supplementary methods and results on the Synthesis of S-15176-Me

All nonaqueous reactions were carried out under a positive atmosphere of argon in dried glassware unless otherwise indicated. Materials were obtained from commercial suppliers and used without further purification. Solvents were dried and distilled according to standard protocols.

Synthesis of S-15176-Me

2,6-Di-tert-butyl-4-mercaptophenol (2)1)

To a solution of 2,6-di-tert-buthylphenol 1 (5 g, 24.3 mmol)and I2 (615 mg, 2.43 mmol) in toluene (6.4 mL) was added S2Cl2 (0.15mL) at 20 °C. After having been stirred at 20 °C for 2 h, three 0.05-mL portions and a 0.7-mL portion of S2Cl2were added successively to the mixturewith a 40- min interval between them. After having been stirred at 20 °C for 2 h, H2O (1.32 mL, 73.5 mmol) was added; and the mixture was allowed to stand to cause liquid separation.To the resultant toluene layer were added EtOH (1.27 mL, 14.6 mmol), ZnCl2 (143 mg, 0.97 mmol), and Zn powder (2.85 g, 43.6 mmol);and to this resulting mixture was added 35% aqueous HCl (10.7 mL, 0.128 mol) dropwise over a 1-h period at 60 °C. After having been stirred at rt for 20 min, the resulting mixture was allowed to stand still to cause liquid separation. To the resultant organic layer were added H2O and 12 M HCl aq., and then the organic phase was washed with H2O. The resulting organic layer was extracted with 8% aqueous KOH (degassed); and the combined extracts were acidified(pH<1.5) with 12 M HCl aq. and then extracted with Et2O. The organic layer was washed with brine, dried over MgSO4, and concentrated to give 2(3.77 g) as colorless crystals, which were used for the next reaction without further purification.

Mp: 172.8-176.2 °C; IR (KBr tablet) 3620, 2956, 1425; 1H-NMR (400 MHz, CDCl3)  7.17 (2H, s), 5.15 (1H, s, OH, D2O exchangeable),3.35 (1H, s, SH, D2O exchangeable), 1.42 (18H, s); 13C-NMR (100 MHz, CDCl3)  152.82 (C), 136.93 (C), 128.27 (CH), 118.25 (C), 34.32 (C), 30.12(CH3); HRMS (ESI-TOF) m/z Calcd for C14H22ONaS (M++Na): 261.1289, found 261.1279.

2,6-Di-tert-butyl-4-[3-(tert-butyldimethylsilyloxy)-propylsulfanyl]phenol (3)

The solution of 2 (3.7 g, 15.5mmol) in THF (37 mL) was added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil, 694mg, 17.4mmol, which was washed 3 times with hexane and suspended in THF (37 mL)) at 0 °C. After having been stirred at rt for 1 h, the reaction mixture was cooled to 0 °C, and then a solution of 1-tert-butyldimethylsilyloxy-3-bromopropane2) (4.4g, 17.4mmol) in THF (37 mL) was added dropwise via an addition funnel at 0 °C. After having been stirred at rt for 1 h, the reaction mixture was quenched with saturated aqueous K2CO3 and concentrated in vacuo. The residue was extracted with Et2O; and the combined extracts were washed with brine, dried over MgSO4, and concentrated to give 3(6.76 g) as a yellow oil, which was used to the next reaction without further purification.

IR (neat) 3645, 2955, 1471, 1251, 1101; 1H-NMR (400 MHz, CDCl3)  7.23 (2H, s), 5.18 (1H, s, OH, D2O exchangeable), 3.71 (2H, t, J = 6.0 Hz), 2.90 (2H, t, J = 7.2 Hz), 1.81 (2H, quint, J = 7.0 Hz), 1.43 (18H, s), 0.88 (9H, s), 0.04 (6H, s); 13C-NMR (100 MHz, CDCl3)  153.10 (C), 136.58 (C), 128.51 (CH), 125.28 (C), 61.63 (CH2), 34.38 (C), 32.56 (CH2), 32.42 (CH2), 30.20 (CH3), 25.92 (CH3), 18.29 (C), -5.32 (CH3); HRMS (ESI-TOF) m/z Calcd for C23H42O2NaSiS (M++Na): 433.2573, found 433.2571.

tert-Butyl-[3-(3,5-di-tert-butyl-4-methoxyphenylsulfanyl)propoxy]dimethylsilane(4)

To a solution of 3 (6.76 g, 16.5 mmol) in DMF (54 mL) weresuccessively added Ba(OH)2 (5.63 g, 32.9 mmol) and MeI (8.5 mL, 0.137 mol) at rt. After having been stirred at rtfor overnight, the reaction mixture was quenched with water and extracted with Et2O. The combined extracts were washed with 1 M NaOH aq.,brine, dried over MgSO4 and concentrated to give 4(6.23 g) as a yellow oil, which was used for the next reaction without further purification.

IR (neat) 2956, 1471, 1362, 1101; 1H-NMR (400 MHz, CDCl3)  7.24 (2H, s), 3.72 (2H, t, J = 6.0 Hz), 3.67 (3H, s), 2.95 (2H, t, J = 7.4 Hz), 1.83 (2H, quint, J = 6.8 Hz), 1.41 (18H, s), 0.88 (9H, s), 0.04 (6H, s); 13C-NMR (100 MHz, CDCl3)  158.36 (C), 144.26 (C), 129.36 (C), 128.50 (CH), 64.23 (CH3), 61.63 (CH2) 35.83 (C), 32.43 (CH2), 31.99 (CH3), 31.29 (CH2), 25.93 (CH3), 18.31 (C), -5.32 (CH3); HRMS (ESI-TOF) m/z Calcd for C24H45O2SiS (M++H): 425.2910, found 425.2912.

3-(3,5-Di-tert-butyl-4-methoxyphenylsulfanyl)propan-1-ol (5)

To a solution of4 (6.22 g, 20 mmol) in THF (90 mL) was added TBAF (100 mL, 1.0 M solution in THF, 0.1 mol); and the resulting mixture was stirred at rt for overnight. The reaction mixture was quenched with saturated aqueous NH4Cl and then extracted with AcOEt. The combined extracts were washed with brine, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography (hexane : AcOEt = 80 : 20) to afford 5 (2.44 g, 32% for 4 steps) as a yellow oil.

IR (neat) 3359, 2959, 1445, 1362, 1255, 1115, 1012; 1H-NMR (400 MHz, CDCl3)  7.26 (2H, s), 3.79 (2H, q, OH, D2O exchangeable), 3.67 (3H, s), 2.99 (2H, t, J = 7.0 Hz), 1.90 (2H, quint, J = 6.5 Hz), 1.41 (18H, s); 13C-NMR (100 MHz, CDCl3)  158.48 (C), 144.35 (C), 128.89 (C), 128.65 (CH), 64.20 (CH3), 61.41 (CH2), 35.80 (C), 31.94 (CH3), 31.88 (CH2), 31.42 (CH2); HRMS (ESI-TOF) m/z Calcd for C18H30O2NaS (M++Na): 333.1864, found 333.1857.

3-(3,5-Di-tert-butyl-4-methoxyphenylsulfanyl)-propylmethanesulfonate (6)

To a solution of5 (1.3 g, 4.19 mmol) and Et3N (1.15 mL, 8.4 mmol) in CH2Cl2 (26 mL) was added MsCl (0.49 mL, 6.3 mmol) at 0 °C. The reaction mixture was stirred at rt for 5 h, and then quenched with water and extracted with CH2Cl2. The combined extracts were washed with aqueous 1 M HCl aq., saturated aqueous NaHCO3, brine, and dried over MgSO4 and concentrated to give 6 (1.53 g) as a yellow oil, which was used for the next reaction without further purification.

Mp: 56.8-57.6 °C; IR (KBr tablet) 2966, 1409, 1353, 1223, 1169; 1H -NMR (400 MHz, CDCl3)  7.26 (2H, s), 4.36 (2H, t, J = 6.0 Hz), 3.68 (3H, s), 2.05 (2H, quint, J = 6.5 Hz), 1.41 (18H, s); 13C-NMR (100 MHz, CDCl3)  158.93 (C), 144.62 (C), 129.34 (CH), 127.95 (C), 68.15 (CH2), 64.25 (CH3), 37.27 (CH3), 35.84 (C), 31.94 (CH3), 30.86 (CH2), 28.75 (CH2); HRMS (ESI-TOF) m/z Calcd for C19H32O4NaS2 (M++Na): 411.1640, found 411.1639.

5-(3-Bromo-propylsulfanyl)-1,3-di-tert-butyl-2-methoxy-benzene (7)

To a solution of 6 (1.4 g, 3.72 mmol) in acetone (29 mL) was added LiBr (1.29g, 1.49 mmol) at 0 °C, and the mixture was then stirred at rt for 2.5 h. Next, the reaction mixture was concentrated in vacuo to give a residue that was taken up into a mixture of AcOEt and H2O, after which the aqueous phase was extracted with AcOEt. The combined extracts were washed with saturated aqueous NaHCO3, brine, dried over MgSO4, and concentrated to give 7 (1.22 g) as a yellow oil, which was used for the next reaction without further purification.

IR (neat) 2961, 1407, 1362, 1115, 695; 1H-NMR (400 MHz, CDCl3)  7.26 (2H, s), 3.68 (3H, s), 3.54 (2H, t, J = 6.4 Hz), 3.01 (2H, t, J = 7.0 Hz), 2.14 (2H, quint, J = 6.7 Hz), 1.42 (18H, s); 13C-NMR (100 MHz, CDCl3)  158.75 (C), 144.48 (C), 129.12 (CH), 128.28 (C), 64.24 (CH3), 35.83 (C), 33.12 (CH2), 32.09 (CH2 x 2), 31.97 (CH3); HRMS (ESI-TOF) m/z Calcd for C18H29ONaSBr (M++Na): 395.1020, found 395.1024.

S-15176-Me (9)

N-[(3,5-Di-tert-butyl-4-methoxy-1-thiophenyl)]-3-propyl-N′-(2,3,4-trimethoxybenzyl)piperazine

To a solution ofa mixture of 7 (300mg, 0.803 mmol) and 1-(2,3,4-trimethoxybenzyl)-piperazine dihydrochloride 8 (409 mg, 1.21 mmol) in CH3CN (9 mL) were successively addedi-Pr2NEt (0.28 mL, 1.66 mmol) and NaI (181 mg, 1.21 mmol) at 0 °C. After having been stirred at 70 °C for overnight, the reaction mixturewas quenched with saturated aqueous NH4Cl, and then extracted with AcOEt. The combined extracts were washed with brine, dried over MgSO4,and concentrated. The residue was purified by silica gel column chromatography (hexane : AcOEt = 40 : 60to AcOEt) to afford S-15176-Me (9) (365mg, 82% for 3 steps) as a yellow oil.

IR (neat) 2955, 1456, 1221; 1H-NMR (400 MHz, CDCl3)  7.23 (2H, s), 6.97 (1H, d, J = 8.4 Hz), 6.62 (1H, d, J = 8.4 Hz), 3.87 (3H, s), 3.87 (3H, s), 3.85 (3H, s), 3.67 (3H, s), 3.47 (2H, s), 2.88 (2H, t, J = 7.2 Hz), 2.30-2.60 (10H, multi), 1.80 (2H, quint, J = 7.4 Hz), 1.40 (18H, s); 13C-NMR (100 MHz, CDCl3)  158.41 (C), 152.78 (C), 152.58 (C), 144.20 (C), 142.23 (C), 129.15 (C), 128.75 (CH), 125.08 (CH), 123.90 (C), 106.85 (CH), 64.18 (CH3), 61.09 (CH3), 60.69 (CH3), 57.30 (CH2), 56.41 (CH2), 55.89 (CH3) 53.23 (CH2), 52.77 (CH2), 35.76 (C), 32.92 (CH2), 31.94 (CH3), 26.68 (CH2); HRMS (ESI-TOF) m/z Calcd for C32H50N2O4NaS (M++Na): 581.3389, found 581.3387.

References

1) Yamamoto, T. Shimokawa, K. (2004) JP 2004107294

2) Ciesielski, J. Canterbury, D.P.Frontier, A.J. (2009) Beta-iodoallenolates as springboards for annulation reactions, Org. Lett.11, 4374–4377.

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