6618
A. Armstrong et al. / Tetrahedron 62 (2006) 6614–6620
method: ee 80%, de 98.5%, major diastereoisomer: tR 15.9
and 16.7, minor diastereoisomer: tR 16.2 and 16.4.
dC (75.5 MHz, CDCl3) 171.6 (C]O), 92.8 (C, JC–F
180.0 Hz), 76.1 (CH, JC–F 17.7 Hz), 73.4 (CH), 66.0 (CH,
JC–F 34.5 Hz), 64.5 (CH2, JC–F 18.9 Hz), 35.5 (CH2), 27.7
(CH2), 24.8 (CH2, JC–F 5.3 Hz), 20.8 (CH3).
Diol 16: To a solution of 15 (3.0 g, 13.8 mmol) in THF
(130 mL) at 0 ꢁC was slowly added LiAlH4 (1 g,
26.3 mmol) and the mixture was allowed to warm to room
temperature. After 2 h, Na2SO4$10H2O was slowly added
at 0 ꢁC and further stirred at room temperature for 1 h.
The mixture was filtered over MgSO4 and further washed
with EtOAc (300 mL). Evaporation of the volatiles gave
a crude oil, which was purified by flash chromatography
on silica gel (Et2O to EtOAc) to give 16 (1.70 g, 70%) as
1.7:1 mixture of two diastereoisomers, nmax/cmꢀ1 3392,
2957, 1459, 1260, 1075, 1027, 862; m/z (CI); Found:
(M+NH4)+, 194.1189. C8H17NO3F requires 194.1192. The
two isomers could be separated for analytical purposes:
less polar isomer, mp 72–73 ꢁC; dH (250 MHz, CDCl3)
4.44 (1H, br t), 4.22 (1H, br t), 4.13–4.04 (1H, m, H-1),
3.91–3.73 (2H, m, H-3,5), 2.37–2.25 (1H, m, H-4), 2.23–
2.11 (3H, m, 2OH, H-4), 2.01–1.90 (3H, m, 7, H6), 1.64
(1H, d, J 15.0 Hz, H-6); dC (75.5 MHz, CDCl3) (less polar)
95.4 (C, JC–F 172.6 Hz), 75.9 (CH, JC–F 18.1 Hz), 73.4 (CH),
66.0 (CH, JC–F 35.0 Hz), 63.9 (CH2, JC–F 21.3 Hz), 35.5
(CH2), 27.7 (CH2), 24.9 (CH2, JC–F 6.0 Hz).
To a solution of the mixture of diastereoisomeric acetates
(430 mg, 1.97 mmol) in CH2Cl2 (50 mL) was added mole-
˚
cular sieves 4 A (1.15 g), 4-NMO (406 mg, 3.5 mmol) fol-
lowed by a catalytic amount of TPAP. The mixture was
stirred at room temperature and after 45 min filtered through
a silica path and rinsed with EtOAc (75 mL). The volatiles
were evaporated under reduced pressure and the crude prod-
uct was purified by flash chromatography (petroleum ether/
Et2O 3:2) to give 17a (370 mg, 87%) as a white solid, mp
58–59 ꢁC; [a]D20 +20.6 (c 0.34, CH2Cl2) at 80% ee; nmax
/
cmꢀ1 2986, 2969, 1747, 1729, 1233, 1053, 1055; dH
(250 MHz, CDCl3) 4.80–4.69 (2H, m, H-1,5), 4.53 (1H,
dd, J 15.0, 13.7 Hz, CHHOAc), 4.37 (1H, dd, J 31.8,
13.7 Hz, CHHOAc), 3.15 (1H, dt, J 14.6, 4.3 Hz, H-4ax),
2.33 (1H, d, J 14.6 Hz, H-4eq), 2.13 (3H, s, CH3),
2.09–2.03 (2H, m, H-6,7), 1.86–1.59 (2H, m, H-6,7); dC
(75.5 MHz, CDCl3) 201.1 (C]O, J 24.1 Hz), 170.3
(C]O), 94.4 (C, J 187.4 Hz), 78.0 (CH, J 20.1 Hz),
77.2 (CH), 61.3 (CH2, J 21.4 Hz), 47.6 (CH2, J 1.3 Hz),
28.0 (CH2), 23.7 (CH2, J 4.0 Hz), 20.7 (CH3); m/z (CI);
Found: (M+NH4)+, 234.1137. C10H17NO4F requires
234.1142.
More polar isomer, mp 102–103 ꢁC; dH (250 MHz, CDCl3)
4.54–4.48 (2H, m, CH2–OH), 4.08 (1H, dd, J 17.0,
12.8 Hz), 3.80–3.65 (2H, m, H-3,5), 2.35–2.29 (2H, br s,
2OH), 2.04–1.96 (2H, m, 2H-4), 1.91–1.66 (4H, m, 2H-6,
2H-7); dC (75.6 MHz, CDCl3) 95.9 (C, JC–F 180.7 Hz),
76.3 (CH, JC–F 18.3 Hz), 73.9 (CH), 64.9 (CH, JC–F
20.5 Hz), 63.9 (CH2, JC–F 24.4 Hz), 37.9 (CH2), 27.3
(CH2), 25.3 (CH2, JC–F 5.0 Hz).
GC conditions: G-TA column (g-cyclodextrin, trifluoro-
acetyl), 20 mꢂ0.25 mm; carrier gas: helium; Isotherm3
method 130 ꢁC (40 min); ee 80%, de 98.5%, major dia-
stereoisomer: tR 19.5 and 21.2, minor diastereoisomer: tR
23.0 and 24.0.
4.1.5. (1R,2R,5S)-2-Fluoro-2-methyleneacetoxy-8-oxabi-
cyclo[3.2.1]octan-3-one 17a. A mixture of diastereoisomers
16 (885 mg, 5.2 mmol) was dissolved in pyridine (5 mL) and
treated with Ac2O (0.65 mL, 5.7 mmol) at ꢀ10 ꢁC. After
2 h, the solution was quenched by the addition of H2O
(11 mL) and extracted into EtOAc (35ꢂ3 mL). The com-
bined organic layers were dried, filtered and the volatiles
evaporated under reduced pressure to give a crude product,
which was purified by flash chromatography (4:1 CH2Cl2/
Et2O) to give a mixture of diastereoisomers (565 mg,
51%), nmax/cmꢀ1 3454, 2959, 1746, 1374, 1239, 1065,
1033, 969; m/z (CI); Found: (M+NH4)+, 236.1299.
C10H19NO4F requires 236.1298. The diastereomers could
be separated for analytical purposes; less polar isomer, white
solid, mp 82–83 ꢁC; dH (300 MHz, CDCl3) 4.64–4.46 (3H,
m, CHHOAc, H-1,3), 4.23 (1H, dd, J 13.0, 28.8 Hz,
CHHOAc), 3.77–3.65 (1H, m, H-5), 2.13 (3H, s, CH3),
2.07–1.77 (5H, m, OH, 2H-4, 2H-7), 1.71–1.67 (2H, m,
2H-6); dC (75.5 MHz, CDCl3) 170.0 (C]O), 92.8 (C, JC–F
180.0 Hz), 76.1 (CH, JC–F 18.4 Hz), 73.9 (CH, JC–F
12.1 Hz), 65.8 (CH), 63.6 (CH2, JC–F 24.7 Hz), 38.1
(CH2), 27.2 (CH2), 25.2 (CH2, J 5.4), 20.7 (CH3).
4.1.6. (1R,2R,5S)-2-Fluoro-2-methylenebenzoate-8-oxa-
bicyclo[3.2.1]octan-3-one 17b. To a solution of 16 (major
diastereomer) (50 mg, 0.28 mmol) in CH2Cl2 (1 mL) was
added Et3N (43 mL, 0.28 mmol). The mixture was cooled
to ꢀ40 ꢁC and benzoyl chloride (36 mL, 0.31 mmol) was
added slowly. After 2 h, the mixture was allowed to warm
to room temperature and quenched by the addition of a satu-
rated solution of NaHCO3 (aq) and extracted into Et2O
(5ꢂ3 mL). The combined organic extracts were dried
(MgSO4), filtered and the volatiles evaporated to give a crude
residue purified by flash chromatography on silica gel (1:1
CH2Cl2/Et2O) to give the benzoate (47 mg, 60%) as a white
solid, mp 110–111 ꢁC; nmax/cmꢀ1 3410, 2960, 2928, 1722,
1250, 1050; dH (300 MHz, CDCl3) 8.10–8.07 (2H, m,
2Har), 7.64–7.57 (1H, m, 1Har), 7.51–7.44 (2H, m, 2Har),
4.85–4.75 (1H, m), 4.63–4.57 (1H, m), 4.53–4.49 (2H, m),
3.91–3.69 (1H, m, H-5), 2.11–1.88 (6H, m), 1.84–1.70
(2H, m); dC (75.6 MHz, CDCl3) 166.15 (C]O), 133.5
(CH, JC–F 21.9 Hz), 130.0 (CH, JC–F 31.9 Hz), 129.5 (C),
128.6 (CH, JC–F 4.3 Hz), 93.2 (C, JC–F 181.0 Hz), 76.3
(CH, JC–F 18.7 Hz), 74.0 (CH), 64.5 (CH, J 20.4 Hz), 64.1
(CH2, JC–F 25.1 Hz), 38.2 (CH2), 27.2 (CH2), 25.2 (CH2,
JC–F 5.0 Hz); m/z (CI); Found: (M+NH4)+, 298.1453.
C15H21NO4F requires 298.1455.
More polar isomer, colourless oil, dH (300 MHz, CDCl3)
4.56 (1H, dd, J 27.6, 12.6 Hz, CHHOAc), 4.49–4.39 (1H,
m, H-1), 4.26–4.14 (2H, m, H-3, CHHOAc), 3.98–3.83
(1H, m, H-5), 2.57 (1H, br s, OH), 2.33–2.18 (1H, m,
H-4), 2.16–2.04 (2H, m, H-4, H-7), 2.15 (3H, s, CH3),
1.98–1.80 (2H, m, H-7, H-6), 1.63 (1H, d, J 14.5 Hz, H-6);
To a solution of the benzoate (45 mg, 0.16 mmol) in CH2Cl2
˚
(6 mL) was added activated MS 4 A (120 mg), followed by
4-NMO (41 mg, 0.35 mmol) and tetra-n-propylammonium
perruthenate (TPAP) (3 mg, 5 mol %). After 1 h, the solution