V.J.A. Jameson et al. / Tetrahedron 71 (2015) 8444e8453
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37.4(C50), 38.8 (C100), 39.0 (C10), 69.9 (C40), 75.0(C2),118.0 (C4a),127.3
(C5), 123.8, 128.8 (2C, 2ꢂ s, C7, C8), 139.8 (C6), 150.0 (C8a).
129.1 (1C, 2ꢂ s, C7, C8), 127.8 (C5), 130.5 (6C, d, JC3P¼12.8, C50), 133.6
(6C, d, JCCP¼10.1 Hz, C40), 135.1 (3C, d, JC4P¼3.0 Hz, C60), 139.8 (C6),
149.3 (C8a); 31P NMR (121 MHz, CDCl3):
d (ppm) 27.0.
4.2.10. (4-(6-Methanesulfonyloxy-2,5,7,8-tetramethyl-chromen-2-yl)
butyl)triphenyl -phosphonium methanesulfonate (24). A mixture of
23 (0.314 g, 0.72 mmol) and triphenylphosphine (0.981 g,
3.74 mmol) was placed in a Kimax tube, flushed with argon, sealed
and the reaction was stirred as a melt at 90 ꢀC for 48 h. The cooled
residue was dissolved in CH2Cl2 (w2 mL) and precipitated from
petroleum ether 40e60 (100 mL) three times. The residual solvents
were removed in vacuo to give 24 as a white solid (0.464 g,
0.67 mmol, 92%). HRMS (þve ESI) m/z calcd for [M]þ: 601.2536,
4.2.13. (2-(6-Hydroxy-2,5,7,8-tetramethyl-chromen-2-yl)ethyl)tri-
phenylphosphonium methanesulfonate, MitoE2 (1). A solution of
lithium diisopropylamide was prepared by adding diisopropyl-
amine (0.30 mL, 0.216 g, 2.13 mmol) to anhydrous THF (4 mL) at
ꢁ78 ꢀC followed by n-BuLi (1.8 M in hexane, 1.0 mL, 1.8 mmol). The
solution was stirred at ꢁ78 ꢀC for 30 min and then allowed to warm
to 0 ꢀC. The lithium diisopropylamide solution was then added to
a solution of 26 (0.195 g, 0.29 mmol) in anhydrous THF (4 mL) with
stirring at 0 ꢀC. After 30 min the solution was allowed to warm to
room temperature and then aqueous saturated NH4OMs (10 mL)
was added. The aqueous layer was extracted with CH2Cl2 (3ꢂ10 mL)
and the combined organic phases dried over anhydrous MgSO4,
filtered and concentrated in vacuo to give a pale yellow oil (1.003 g).
The crude product was dissolved in CH2Cl2 (0.5 mL) and pre-
cipitated from Et2O (20 mL) twice then chromatographed on silica
gel with elution with 1:9 EtOH:CH2Cl2 and finally passed through
an anion exchange column loaded with ꢁOMs in methanol. The
residual solvents were removed by freeze drying to give 1 as
found: 601.2555; 1H NMR (500 MHz, CDCl3)
d (ppm) 1.21 (3H, s,
H12), 1.52e1.59 (2H, m, H10), 1.59e1.82 (6H, m, H3, H20, H30), 1.94
(3H, s, H11), 2.17 (3H, s, H9), 2.19 (3H, s, H10), 2.54 (2H, t, J¼6.8 Hz,
H4), 2.71 (3H, s, H1000), 3.22 (3H, s, H100), 3.48e3.70 (2H, m, H40),
7.65e7.70 (6H, m, H70), 7.74e7.80 (9H, m, H60, H80); 13C NMR
(125 MHz) CDCl3: d (ppm) 12.0 (C11), 13.7 (C9), 14.5 (C10), 20.6 (C4),
22.0 (1C, d, JCP¼50.3 Hz, C40), 23.1 (1C, d, JCCP¼4.4 Hz, C30), 24.0
(C12), 24.6 (1C, d, JC3P¼16.1 Hz, C20), 30.9 (C3), 38.7 (C100), 38.8 (C10),
39.6 (C1000), 75.3 (C2), 118.2 (C4a), 118.5 (1C, d, JCP¼85.6 Hz, C50),
123.6, 128.6 (2C, 2ꢂ s, C7, C8), 127.3 (C5), 130.5 (1C, d, JC3P¼12.5 Hz,
C70), 133.6 (1C, d, JCCP¼9.9 Hz, C60), 135.0 (1C, d, JC4P¼2.9 Hz, C80),
a white solid (52.8 mg, 89.3
mmol, 31%). HRMS (þve ESI) m/z calcd
139.6 (C6), 149.9 (C8a); 31P NMR (121 MHz, CDCl3):
d (ppm) 25.5.
for [M]þ: 495.2459, found: 495.2462; 1H NMR (500 MHz, CD2Cl2):
d
(ppm) 1.37 (3H, s, H12), 1.87 (2H, t, J¼7.0 Hz, H3), 1.69e1.78,
4.2.11. 2-(6-(Methanesulfonyloxy)-2,5,7,8-tetramethylchromen-2-yl)
ethyl methanesulfonate (25). A solution of 15 (0.013 g, 0.51 mmol)
1.93e2.02 (2H, 2ꢂ m, H10), 2.03 (3H, s, H11), 2.06 (3H, s, H9), 2.15
(3H, s, H10), 2.39e2.48, 2.53e2.62 (2H, 2ꢂ m, H4), 2.60 (3H, s,
H1000), 3.04e3.22, 3.28e3.46 (2H, 2ꢂ m, H20), 3.70 (1H, s (br), H100),
7.53 (6H, dd, J¼12.7, 7.6 Hz, H40), 7.63 (6H, td, J¼7.7, 3.5 Hz, H50),
and Et3N (424
mL, 0.310 g, 3.06 mmol) was stirred in anhydrous
CH2Cl2 (6 mL) at room temperature for 5 min. MsCl (88.0
mL, 0.129 g,
1.13 mmol) was added and the reaction was stirred for a further 1 h.
The reaction mixture was diluted with CH2Cl2 (5 mL). This was
washed with H2O (5ꢂ20 mL), dried over anhydrous MgSO4, filtered
and concentrated in vacuo to give a white solid (0.224 g) which,
after recrystallisation from EtOH to give 25 as white crystals
(0.167 g, 0.41 mmol, 81%). Analysis calcd for C17H26O7S2: C 50.2, H
6.4, S; 15.8, found: C 50.3, H 6.6, S 15.7; TLC: Rf 0.76 (1þ:9
Et2O:CH2Cl2); mp 126.7 ꢀC; HRMS (þve ESI) m/z calcd for [MþNa] :
7.83 (3H, t, J¼7.4 Hz, H60); 13C NMR (125 MHz, CD2Cl2):
d (ppm) 11.7
(C9), 12.0 (C11), 12.7 (C10), 17.9 (1C, d, JCP¼54.8 Hz, C20), 20.7 (C4),
24.4 (C12), 29.9 (C10), 32.0 (C3), 39.7 (3C, s, C1000), 73.7 (1C, d,
JC3P¼13.5 Hz, C2), 117.4 (C4a), 118.1 (1C, d, JCP¼86.4 Hz, C30), 120.7
(C5), 122.0, 123.0 (1C, 2ꢂ s, C7, C8), 130.9 (6C, d, JC3P¼12.9, C50),
133.6 (6C, d, JCCP¼9.8 Hz, C40), 135.8 (3C, d, JC4P¼3.1 Hz, C60), 144.2
(C8a), 146.6 (C6); 31P NMR (121 MHz, CD2Cl2):
d (ppm) 26.1.
429.1012, found: 429.1002; 1H NMR (500 MHz, CDCl3):
d
(ppm) 1.31
4.2.14. (4-(6-Hydroxy-2,5,7,8-tetramethyl-chroman-2-yl)-butyl)tri-
phenylphosphonium methanesulfonate, MitoE4 (2). A solution of
lithium diisopropylamide (2.07 mmol) in anhydrous THF (4.0 mL)
was prepared as for 2 above and added to a solution of 24 (0.192 g,
0.28 mmol) in anhydrous THF (4.0 mL) stirring at 0 ꢀC. After 30 min
the solution was allowed to warm up to room temperature and then
aqueous saturated NH4OMs (10 mL) was added. The aqueous layer
was extracted with CH2Cl2 (3ꢂ10 mL). The combined organic phases
were dried over anhydrous MgSO4, filtered and concentrated in
vacuo to give a pale yellow oil. The crude product was dissolved in
CH2Cl2 (0.5 mL) and precipitated from Et2O (20 mL) twice and then
purified by column chromatography on silica gel and elution with
1:9 EtOH:CH2Cl2 to afford 2 as a white solid (0.091 g, 0.15 mmol,
53%). TLC: Rf 0.22 (1:9 EtOH:CH2Cl2); HRMS (þve ESI) m/z calcd for
[M]þ: 523.2760, found: 523.2771; 1H NMR (500 MHz, CD2Cl2)
(3H, s, H12), 1.86 (2H, td, J¼7.0, 1.5 Hz, H3), 2.03e2.16 (2H, m, H10),
2.09 (3H, s, H11), 2.21 (3H, s, H9), 2.24 (3H, s, H10), 2.63 (2H, t,
J¼7 Hz, H4), 3.00 (3H, s, H30), 3.24 (3H, s, H100), 4.38e4.52 (2H, m,
H20); 13C NMR (125 MHz, CDCl3):
d (ppm) 12.1 (C10), 13.7 (C9), 14.5
(C11), 20.5 (C4), 24.0 (C12), 31.5 (C3), 37.5 (C30), 38.8(0) (C100),
38.8(2) (C10), 66.1 (C20), 73.8 (C2), 117.7 (C4a), 123.9, 129.1 (2C, 2ꢂ s,
C7, C8), 127.5 (C5), 140.0 (C6), 149.4 (C8a).
4.2.12. (2-(6-(Methanesulfonyloxy)-2,5,7,8-tetramethyl-2H-chro-
men-2-yl)ethyl)triphenyl-phosphonium methanesulfonate (26). A
mixture of 25 (0.300 g, 0.74 mmol), NaI (0.558 g, 3.74 mmol) and
triphenylphosphine (1.55 g, 3.69 mmol) was flushed with argon in
a Kimax tube then sealed and the reaction was stirred as a melt at
90 ꢀC for 48 h. The crude product was dissolved in CH2Cl2 (w2 mL)
and precipitated from petroleum ether 40e60 (100 mL) three times.
The product was dissolved in methanol and passed down an anion
exchange column loaded with ꢁOMs. The residual solvents were
removed to give 26 as a white solid (0.450 g, 0.67 mmol, 91%). The UV
spectrum of this compound has been reported previously.23 HRMS
(þve ESI) m/z calcd for [M]þ: 573.2223, found: 573.2225; 1H NMR
d
(ppm) 1.18 (3H, s, H12), 1.42e1.66 (2H, m, H10), 1.66e1.79 (6H, m,
H3, H20, H30),1.94 (3H, s, H11), 2.07 (3H, s, H9), 2.08 (3H, s, H10), 2.55
(2H, t, J¼6.8 Hz, H4), 2.61 (3H, s, H1000), 3.14e3.24 (2H, m, H40), 3.47
(1H, s, H100), 7.62e7.72 (12H, m, H60, H70), 7.84 (3H, t J¼7.3 Hz, H80);
13C NMR (125 MHz) CD2Cl2:
d (ppm) 11.6 (C9), 11.9 (C11), 12.5 (C10),
21.0 (C4), 23.0 (1C, d, JCP¼50.6 Hz, C40), 23.2 (C30), 24.1 (C12) 25.1 (1C,
d, JC3P¼15.9 Hz, C20), 32.1 (C3), 38.2 (C10), 39.6 (C1000), 74.3 (C2), 117.6
(C4a),118.3 (1C, d, JCP¼85.6 Hz, C50),119.7 (C5),122.0,122.2 (2C, 2ꢂ s,
C7, C8),130.9 (6C, d, JC3P¼12.5 Hz, C70),133.8 (6C, d, JCCP¼9.8 Hz, C60),
135.7 (3C, d, JC4P¼2.6 Hz, C80), 145.2 (C6), 145.5 (C8a); 31P NMR
(500 MHz, CDCl3):
d (ppm) 1.45 (3H, s, H12), 1.88e1.08 (4H, m, H3,
H10), 2.01 (3H, s, H11), 2.12 (3H, s, H9), 2.22 (3H, s, H10), 2.40e2.60
(2H, m, H4), 2.66 (3H, s, H1000), 3.25 (2H, s, H100), 3.26e3.48, 3.92e4.04
(2H, 2ꢂ m, H20), 7.61e7.67 (6H, m, H50), 7.71e7.78 (9H, m, H40, H60),
7.71e7.78; 13C NMR (125 MHz, CDCl3):
d
(ppm) 12.2 (C11), 13.6 (C9),
(121 MHz, CD2Cl2): d (ppm) 24.8.
14.6 (C10), 17.4 (1C, d, JCP¼53.4 Hz, C20), 20.3 (C4), 23.9 (C12), 30.5
(C3), 31.0 (1C, d, JCCP¼3.8 Hz, C10), 38.8 (C100), 39.5 (C1000), 75.2 (1C, d,
JC3P¼13.9 Hz, C2), 118.1 (C4a), 118.3 (1C, d, JCP¼86.1 Hz, C15), 123.3,
4.2.15. (6-(6-Hydroxy-2,5,7,8-tetramethyl-chroman-2-yl)-hexyl)tri-
phenyl phosphonium methanesulfonate, MitoE6 (3). A solution of