76
M.J. Corr, D. O’Hagan / Journal of Fluorine Chemistry 155 (2013) 72–77
water (200 mL) and brine (200 mL), dried over anhydrous Na2SO4
and the solvent was removed in vacuo. Purification by column
chromatography using silica gel (ethyl acetate/pet. ether 2:3) gave
(2R,3S)-3-((R)-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)fluoromethyl)-
oxiran-2-yl)methanol 10 (0.48 g, 77%) as a colourless oil (dr 10:1);
A
solution
of
(R)-4-((R)-((2S,3R)-3-((benzyloxy)methyl)
oxiran-2-yl)fluoromethyl)-2-2dimethyl-1,3-dioxolane 16 (0.529 g,
1.8 mmol, 1.0 eq) in triethylamine trihydrofluoride (5.3 mL,
32.1 mmol, 18.0 eq) and triethylamine (2.3 mL, 16.2 mmol, 9.0 eq)
was heated at 100 8C under argon for 3 days. The reaction mixture
was cooled to r.t. and quenched with sat. NaHCO3 solution (150 mL)
and extracted with DCM (2 Â 150 mL). The combined organic layers
were washed withbrine(200 mL), dried over anhydrousNa2SO4 and
the solvent was removed in vacuo. Purification by column
chromatography using silica gel (ethyl acetate/pet. ether 1:9) gave
(1S,2S,3S)-4-(benzyloxy)-1-((R)-2,2,-dimethyl-1,3-dioxolan-4-yl)-
1,3-difluorobutan-2-ol 12 (0.259, 46%) as a colourless oil, as a single
[a]
D +4.48 (c 1.09, CHCl3). Data for major diastereoisomer; 1H NMR
(300 MHz, CDCl3) = 1.37 (3H, s, CH3), 1.45 (3H, s, CH3), 3.31–3.38
d
(2H, m, CH), 3.68–3.73 (1H, m, CH2), 3.97–4.15 (3H, m, CH2, CH2),
4.20–4.28 (1H, m, CH), 4.51 (1H, ddd, J(H,F) = 47.8 Hz, J(H,H) = 6.4,
3.2 Hz, CHF); 13C NMR (75 MHz, CDCl3)
d = 25.3 (CH3), 26.7 (CH3),
53.4 (d, J(C,F) = 25.9 Hz, CH), 55.3 (d, J(C,F) = 6.5 Hz, CH), 60.9 (CH2),
65.9 (d, J(C,F) = 4.5 Hz, CH2), 74.3 (d, J(C,F) = 25.9 Hz, CH), 90.2 (d,
J(C,F) = 178.7 Hz, CHF), 110.4 (C); 19F{1H} NMR (282 MHz, CDCl3)
diastereoisomer; [a D
]
À6.68 (c 0.80, CHCl3), lit [9]. [a D
]
À6.238 (c
d
= À199.6 (1F, s); IR (thin film) nꢀ = 3461, 2989, 2937, 1457, 1383,
1.25, CHCl3); 1H NMR (400 MHz, CDCl3)
d
= 1.37 (3H, s, CH3), 1.45
1374, 1260, 1222, 1157, 1071, 976, 917, 845; MS (ESI) 229 (100)
[M+Na]+; HRMS: m/z calcd for C9H15F1Na1O4 [M+Na]+: 229.0852;
found: 229.0840.
(3H, s, CH3), 2.80 (1H, d, J(H,H) = 5.3 Hz, OH), 3.84 (1H, dd,
J(H,H) = 3.6, 0.7 Hz, CHAHB), 3.89–3.91 (1H, m, CHAHB), 4.07 (1H,
ddd, J(H,H) = 9.0, 5.2, 1.8 Hz, CHAHB), 4.13 (1H, ddd, J(H,H) = 9.0, 6.3,
1.4 Hz, CHAHB), 4.20–4.31 (1H, m, CH), 4.39–4.46 (1H, m, CH), 4.53–
4.67 (3H, m, CH2, CHF), 4.84 (1H, dm, J(H,F) = 46.1 Hz, CHF), 7.30–
4.10. (R)-4-((R)-((2S,3R)-3-((benzyloxy)methyl)oxiran-2-
yl)fluoromethyl)-2-2dimethyl-1,3-dioxolane 11
7.40 (5H, m, ArH); 13C NMR (100 MHz, CDCl3)
d = 25.4 (CH3), 26.7
(CH3), 66.2 (d, J(C,F) = 4.0 Hz, CH2), 69.4 (d, J(C,F) = 21.8 Hz, CH2),
71.0(dd, J(C,F) = 24.8, 21.8 Hz, CH), 73.9(d, J(C,F) = 29.2 Hz, CH), 74.0
(CH2), 90.7 (dd, J(C,F) = 175.1, 6.3 Hz, CHF), 91.8 (dd, J(C,F) = 176.4,
3.6 Hz, CHF), 110.2 (C), 128.0 (CH), 128.2 (CH), 128.8 (CH), 137.6 (C);
19F{1H} NMR (282 MHz, CDCl3)
d
= À196.6 (1F, s), À200.7 (1F, s); MS
(ESI) 655 (65) [2M+Na]+, 339 (100) [M+Na]+, 317 (35) [M+H]+, 277
(25); HRMS: m/z calcd for C16H22F2Na1O4 [M+Na]+: 339.1384;
found: 339.1372.
Sodium hydride (60% in oil, 0.233 g, 5.8 mmol, 1.5 eq) was added
to a solution of (2R,3S)-3-((R)-((R)-2,2-dimethyl-1,3-dioxolan-4-
yl)fluoromethyl)oxiran-2-yl)methan-ol 10 (0.8 g, 3.9 mmol, 1.0 eq)
in dry DMF (25 mL) at 0 8C under argon and stirred at 0 8C for 30 min.
Benzyl bromide (0.7 mL, 5.8 mmol, 1.5 eq) was added and the
reaction mixture was stirred at 0 8C for 1 h, then warmed to r.t. and
stirred for 18 h. The reaction mixture was quenched with water
(100 mL) and extracted with ethyl acetate (250 mL). The organic
layer was separated and washed with water (2 Â 200 mL), brine
(250 mL),driedover anhydrousNa2SO4 andthesolventwasremoved
in vacuo. Purification by column chromatography using silica gel
(ethyl acetate/pet. ether 1:9) gave (R)-4-((R)-((2S,3R)-3-((benzylox-
y)methyl)oxiran-2-yl)fluoro-methyl)-2-2dimethyl-1,3-dioxolane
4.12. (R)-4-((1R,2R,3S)-4-(benzyloxy)-1,2,3-trifluorobutyl)-2,2-
dimethyl-1,3-dioxolane 13 [9]
Deoxofluor1 solution (50% in THF, 0.65 mL, 1.5 mmol, 3.0 eq)
was added to a solution of (1S,2S,3S)-4-(benzyloxy)-1-((R)-2,2,-
dimethyl-1,3-dioxolan-4-yl)-1,3-difluorobutan-2-ol 12 (0.16 g,
0.5 mmol, 1.0 eq) in dry DCM (30 mL) under argon at 0 8C. The
reaction mixture was stirred at 0 8C for 1 h, then warmed to r.t. and
stirred for 18 h. The solvent was removed in vacuo. Purification by
column chromatography using silica gel (ethyl acetate/pet. ether
1:9) gave (R)-4-((1R,2R,3S)-4-(benzyloxy)-1,2,3-trifluorobutyl)-2,2-
11(0.93 g, 81%)asacolourlessoil(dr10:1);[
a
]D À0.48(c1.04, CHCl3).
Data for major diastereoisomer; 1H NMR (500 MHz, CDCl3)
d
= 1.37
(3H, s, CH3), 1.45 (1H, s, CH3), 3.23 (1H, ddd, J(H,F) =
13.9 Hz, J(H,H) = 3.4, 2.4 Hz, CH), 3.35 (1H, dt, J(H,H) = 5.3, 2.5 Hz,
CH), 3.52 (1H, dd, J(H,H) = 11.6, 5.4 Hz, CHAHB), 3.82 (1H, dd,
J(H,H) = 11.6, 2.7 Hz, CHAHB), 4.03 (1H, ddd, J(H,H) = 8.7, 5.4, 1.2 Hz,
CHAHB), 4.09–4.15 (1H, m, CHAHB), 4.18–4.27 (1H, m, CH), 4.49 (1H,
ddd, J(H,F) = 48.1 Hz, J(H,H) = 6.1, 3.2 Hz, CHF), 4.57 (1H, d,
J(H,H) = 12.1 Hz, CHAHB), 4.61 (1H, d, J(H,H) = 12.1 Hz, CHAHB),
dimethyl-1,3-dioxolane 13 (0.085 g, 53%) as a colourless oil; [a D
]
À16.98 (c 0.95, CHCl3); 1H NMR (400 MHz, CDCl3)
d = 1.37 (3H, s,
CH3), 1.37 (3H, s, CH3), 3.73–3.92 (2H, m, CH2), 4.06 (1H, ddd,
J(H,H) = 9.1, 4.0, 2.0 Hz, CHAHB), 4.11–4.15 (1H, m, CHAHB), 4.11–
4.15(1H, m, CH), 4.33–4.40(1H, m, CH), 4.43–4.64 (3H, m, CH2, CHF),
4.81–5.14 (2H, m, CHF), 7.31–7.39 (5H, m, ArH); 19F{1H} NMR
7.29–7.39 (5H, m, ArH); 13C NMR (125 MHz, CDCl3)
d = 25.3 (CH3),
26.7 (CH3), 53.6 (d, J(C,F) = 25.7 Hz, CH), 54.1 (d, J(C,F) = 6.8 Hz, CH),
65.8 (d, J(C,F) = 4.7 Hz, CH2), 69.4 (CH2), 73.5 (CH2), 74.4 (d,
J(C,F) = 26.0 Hz, CH), 90.2 (d, J(C,F) = 179.1 Hz, CHF), 110.4 (C),
128.0 (CH), 128.0 (CH), 128.7 (CH), 137.9 (C); 19F{1H} NMR
(376 MHz, CDCl3)
d
= À198.3 (1F, d, J(F,F) = 14.3 Hz), À209.4 (1F, d,
J(F,F) = 9.8 Hz), À214.2 (1F, dd, J(F,F) = 14.3, 9.8 Hz); MS (ESI) 341
(100) [M+Na]+, 319 (20) [M+H]+, 91 (45); HRMS: m/z calcd for
(282 MHz, CDCl3)
d
= À199.6 (1F, s); IR (thin film) nꢀ = 2988, 2936,
C
16H21F3Na1O3 [M+Na]+: 341.1340; found: 341.1329. Data were in
2892, 1497, 1455, 1382, 1373, 1258, 1216, 1156, 1104, 1072, 1001,
845, 740, 699; MS (ESI) 655 (65) [2M+Na]+, 339 (100) [M+Na]+, 317
(35) [M+H]+, 277 (25); HRMS: m/z calcd for C16H21F1Na1O4 [M+Na]+:
319.1322; found: 319.1311.
agreement with the previously reported compound [9].
4.13. (2S,3R,4R)-4-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,3,4-
trifluorobutan-1-ol 14 [9]
4.11. (1S,2S,3S)-4-(benzyloxy)-1-((R)-2,2,-dimethyl-1,3-dioxolan-4-
yl)-1,3-difluorobutan-2-ol 12 [9]
A solution of sodium bromate (142 mg, 0.9 mmol, 3.0 eq) in
water (3 mL) was added to a solution of (R)-4-((1R,2R,3S)-4-
(benzyloxy)-1,2,3-trifluorobutyl)-2,2-dimethyl-1,3-dioxolane