Organic & Biomolecular Chemistry
Page 4 of 5
DOI: 10.1039/C5OB00479A
5.73 (m, 5H), 5.70-5.66 (m, 2H), 5.64-5.61 (m, 1H), 2.97
was purified by column chromatography on silica gel
(s, 1H). 13C-NMR (100 MHz; CD3OD): δ 142.5, 128.93, 60 (petroleum ether:EtOAc= 5:1) and was obtained as light
o
1
128.77, 128.65, 128.46, 128.0, 127.0, 67.9. Enantiomeric
excess was determined by HPLC on Chiralpak OD-H
column (n-hexane-isopropanol 85:15 V/V, flow rate 0.5
mL/min, 254 nm), major enantiomer tR = 18.9 min, minor
white solid 18.6 g, with 68% yield. m.p. 83-85 C. H
NMR (400 MHz, CDCl3), δ 7.39-7.54 (m, 5H), 6.28 (s,
1H), 3.90 (t, J=8.5, 1H), 3.90 (t, J =8.5, 1H), 1.68-2.7 (m,
8H), 1.21 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 208.57,
5
enantiomer ts = 14.3 min, 99
% ee. LC-MS(ESI) 65 177.013, 148.11, 144.71, 130.39, 128.72, 128.67, 128.06,
Calculated for [C15H13N3OH]+: 252.1131, Found: 252.1131.
74.46, 48.68, 41.86, 38.91, 32.76, 27.34, 24.67. LC-
MS(ESI): calculated for C20H27N3O3 [C20H25N3O3H]+:
356.1896, Found: 356.1812.
10 General Procedure for synthesis of compound 5a and
5b:
(4-(cyclohex-1-en-1-yl)-5-phenyl-2H-1,2,3-triazol-2-
yl)methyl pivalate (1c). To the solution of compound 1b
(30.0g, 0.13mol) in acetone (60 mL), chloromethylene
15 pivalate (23.4g,0.26mol) and K2CO3 (35.9g, 0.26mol)
were added. The mixture was stirring at RT for 12h. The
white solid was removed by filtrating. After removing the
solvent under vacuum, the resulting crude product was
purified by column chromatography on silica gel
20 (petroleum ether: EtOAc= 10:1). The product was obtained
as white solid 35.3g (85% yield). m.p. 76-78 oC. 1HNMR
(400 MHz, CDCl3): δ 7.68-7.70 (d, J = 7.2Hz, 2H), 7.36-
7.48(m,3H), 6.26(s, 2H), 6.08(m, 1H), 2.32-2.38(m, 2H),
2.12-2.18(m, 2H), 1.66-1.80(m, 4H), 1.24(s, 9H); 13C
25 NMR(100 MHz, CDCl3): δ177.0, 148.3, 145.7, 131.2,
130.2, 128.5, 128.5, 128.3, 128.2, 74.6, 38.9, 27.5, 27.0,
70 (4-(2-hydroxycyclohexyl)-5-phenyl-2H-1,2,3-triazol-2-
yl)methyl pivalate (5a/5b) To the solution of compound
1e (2.0g, 5.6mmol) into 20 mL MeOH at 0 C, NaBH4
o
(0.43g, 11.2mmol) was added. After stirring at 0 oC for 3h,
the mixture was quenched by 50 mL H2O, extracted by 50
75 mL EtOAc three times. The combined organic layer was
washed by 100 mL brine twice, dried by MgSO4. Solvent
was removed under vacuum. The crude product was
purified by column chromatography on silica gel
(petroleum ether: EtOAc= 5:1).
80 cis-5a was obtained as light yellow oil 1.0 g (52% yield)
1H NMR (400 MHz, CDCl3) δ 7.4-7.65 (m, 5H), 6.28 (s,
1H), 4.17 (m, 1H), 3.10 (m, 1H), 1.25-2.1 (m, 8H), 1.23 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 176.92, 150.14,
146.89, 130.33, 128.86, 128.71, 128.08, 74.23, 67.91,
85 39.16, 38.92, 32.16, 26.91, 26.89, 25.88, 19.50. LC-
MS(ESI): calculated for [C20H27N3O3H]+: 358.2052,
Found: 358.2119.
trans-5b was obtained as light yellow oil 0.83g (43 %
yield). 1H NMR (400 MHz, CDCl3) δ 7.4-7.65 (m, 5H),
90 6.28 (s, 1H), 4.15(m, 1H), 2.98 (m, 1H), 1.25-2.1 (m, 8H),
1.23 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 177.02,
149.19, 147.85, 130.56, 128.73, 128.58, 128.02, 74.39,
73.44, 43.57, 38.91, 34.41, 31.86, 26.92, 25.66, 24.84. LC-
MS(ESI): calculated for [C20H27N3O3H]+ :358.2052,
95 Found:358.2119.
25.5, 22.6, 21.8.
LC-MS(ESI) Calculated for
[C20H25N3O2H]+: 340.1947, Found: 340.1912.
(4-(7-oxabicyclo[4.1.0]heptan-1-yl)-5-phenyl-2H-1,2,3-
30 triazol-2-yl)methyl pivalate (1d). Compound 1c (35.0g,
o
0.11mol) was dissolved in 50ml dry DCM at 0 C in ice-
both under N2 atmosphere. And then the solution of m-
CPBA(26.9g, 0.17mol) in 20 ml dry DCM was added
dropwise over 10 mins. The reaction mixture was stirred
35 for 3 hours at RT and monitored by TLC. After the
completing of starting material, the reaction mixture was
filtrated to remove the white solid. The filtrate was then
washed with 10% Na2CO3 solution and brine. The organic
phase was dried with MgSO4 and concentrated under
40 vacuum. The crude product was purified by column
chromatography on silica gel (petroleum ether: EtOAc=
8:1). The product was obtained as white solid 31.2g (80%
yield). m.p. 40-42℃. 1H NMR (400 MHz, CDCl3): δ 7.80-
7.84 (d, J =7.2Hz, 2H), 7.39-7.49 (m, 3H), 6.23 (s, 2H),
45 3.48-3.51(m, 1H), 2.20-2.30(m, 1H), 1.91-2.20(m, 3H),
1.50-1.51(m, 2H), 1.30-1.42(m, 2H), 1.21(s, 9H); 13C
NMR(100 MHz, CDCl3): δ 177.0, 147.1, 130.1, 128.9,
127.6, 128.1 74.4, 65.9, 58.4, 55.2, 38.9, 28.4, 24.2, 19.6,
19.1, 15.2. LC-MS(ESI) Calculated for [C20H25N3O3H]+:
50 356.1896, Found: 356.1816.
General Procedure for kinetic resolution of 5a and 5b
with CalB.
To the solution of racemic alcohols 5a or 5b (1.07g, 3.0
mmol) in 30 mL of isooctane (HPLC grade), vinyl acetate
100 (688 mg, 8.0 mmol) and lipase B (480 mg) were added.
The mixture was then stirred in an orbital shaker (75 ℃,
160 rpm) at 24-72h. The mixture was then filtered and the
solvent evaporated. The residue was purified by silica gel
column chromatography gel (Hexane: EtOAc=4:1) to give
105 desired enantiopure alcohols (-)-5a and (+)-5b.
Asymmetric additions of diethylznic to aldehyes with
Chiral β-hydroxyl TA ligand (5a’):
(4-(2-oxocyclohexyl)-5-phenyl-2H-1,2,3-triazol-2-
To a solution of Chiral β-hydroxyl TA ligand 5a’ (0.2
yl)methyl pivalate (1e). The compound 1d (30.0g,
0.085mol) was added to an ice-cold 5 M LPDE solution
(17 mL) under N2 atmosphere and monitored by TLC. The
55 mixture was quenched by 50 mL H2O, and then extracted
by 50 mL CH2Cl2 three times. The combined organic
phase was washed by 50 mL brine twice, dried by MgSO4.
Solvent was removed under vacuum. The crude product
o
110 mmol) in toluene (1.0 ml) at 0 C under N2, 2.0 ml (1.0M,
2 mmol) diethylzinc in hexane was added. After stirring
for 30 min, aldehyde (1 mmol in 1 mL toluene) was added
slowly. The mixture was then stirred for 48 h at room
temperature. The reaction was quenched with saturated
115 ammoniumchloride solution (10 ml), and extracted with
diethyl ether (20ml) twice. The combined organic phase
4 | Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]