Beilstein J. Org. Chem. 2012, 8, 1233–1240.
shifts were reported in parts per million (ppm), and the residual Synthesis of quinine benzoate catalyst C-2
solvent peak was used as an internal reference, i.e., proton Benzoyl chloride (28 mg, 0.2 mmol) was added to a mixture of
(chloroform δ 7.26), carbon (chloroform δ 77.0). Multiplicity quinine (65 mg, 0.2 mmol) in CH2Cl2 (0.5 mL). After stirring at
was indicated as follows: s (singlet), d (doublet), t (triplet), q rt for 4 h, aqueous K2CO3 (2 M, 1 mL) was added. The reac-
(quartet), m (multiplet), dd (doublet of doublet), br s (broad tion mixture was extracted with CH2Cl2 (2 × 3 mL). The
singlet). Coupling constants were reported in hertz (Hz). CH2Cl2 layer was washed with aqueous HCl (2 M, 2 mL) and
LC–MS were performed on an Agilent 2100 system. A C18 H2O (3 mL). The combined organic extracts were dried
column (5.0 μm, 6.0 × 50 mm) was used for the separation. The (K2CO3) and evaporated. The white residue was purified by
mobile phases were methanol and water, both containing 0.05% flash column chromatography (18:1 CH2Cl2/MeOH) to give
trifluoroacetic acid. A linear gradient was used to increase from quinine benzoate C-2 (77 mg, 90%) as a colorless solid.
25:75 v/v methanol/water to 100% methanol over 7.0 min at a 1H NMR (CDCl3, 300 MHz) δ 1.69–2.00 (m, 5H), 2.42 (m,
flow rate of 0.7 mL/min. UV detections were conducted at 210, 1H), 2.82 (m, 2H), 3.19–3.40 (m, 2H), 3.49–3.56 (q, J = 7.2 Hz,
254 and 365 nm. Low-resolution mass spectra were recorded in 1H), 4.00 (s, 3H), 5.04 (m, 2H), 5.82 (m, 1H), 6.97 (d, J = 7.2,
APCI (atmospheric pressure chemical ionization). The high- 1H), 7.40–7.65 (m, 6H), 8.01–8.13 (m, 3H), 8.73 (d, 1H);
resolution mass spectra were obtained on a Finnigan/MAT 13C NMR (CDCl3, 75 MHz) δ 23.1, 27.2, 27.5, 39.0, 42.5, 56.0,
95XL-T spectrometer. Sorbent silica gel XHL TLC plates 56.1, 59.0, 73.5, 101.2, 115.2, 117.2, 122.3, 126.6, 127.9, 128.7,
(130815) were used for the thin-layer chromatography (TLC). 129.6, 129.6, 131.6, 131.8, 133.6, 140.6, 144.7, 147.2, 158.3,
Flash chromatography separations were performed on 165.1, 200.2; APCIMS m/z: 429.2 (M+ + 1).
YAMAZEN AI-580 flash column system with Agela silica gel
columns (230–400 μm mesh). The enantiomeric excesses of Synthesis of quinine acetate C-3
products were determined by chiral phase HPLC analysis on an Acetic anhydride (30 mg, 0.3 mmol) was added to a mixture of
SHIMADZU LC-20AD system.
quinine (65 mg, 0.2 mmol) in CH2Cl2 (0.5 mL). After stirring at
rt for 8 h, aqueous K2CO3 (2 M, 1 mL) was added, and the mix-
ture was extracted with CH2Cl2 (2 × 3 mL). The CH2Cl2 layer
Synthesis of fluorous quinine ester C-1
Thionyl chloride (1.19 g, 10 mmol) was added to a mixture of was washed with aqueous HCl (2 M, 2 mL) and H2O (3 mL).
(1H,1H,2H,2H-perfluorooctyl)benzoic acid (0.468 g, 1 mmol) The combined organic extracts were dried (K2CO3) and evapo-
and pyridine (75 mg, 1 mmol). After stirring of the mixture for rated. The white residue was purified by flash column chroma-
4 h at 50 °C, the reaction container was flushed with nitrogen tography (18:1 CH2Cl2/MeOH) to give quinine acetate C-3
gas to remove unreacted thionyl chloride. Quinine (0.275 g, (67 mg, 92%) as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ
0.85 mmol) and N,N-diisopropylethylamine (129 mg, 1 mmol) 1.26–1.89 (m, 5H), 2.42 (m, 1H), 2.12 (s, 3H), 2.23–2.36 (m,
in CH2Cl2 (3 mL) was added, and the solution was stirred for 2H), 2.37–2.70 (m, 2H), 3.00–3.16 (m, 2H), 3.34–3.42 (q, J =
24 h under reflux. After the reaction had been quenched with 7.2 Hz, 1H), 3.96 (s, 3H), 5.03 (m, 2H), 5.86 (m, 1H), 6.50 (d, J
H2O (2 mL) for 1 h, aqueous K2CO3 (2 M, 10 mL) was added, = 7.2 Hz, 1H), 7.35–7.44 (m, 3H), 8.02 (d, J = 9.0 Hz, 3H), 8.74
and the mixture was extracted with CH2Cl2 (3 × 10 mL). The (d, 1H); 13C NMR (CDCl3, 75 MHz) δ 21.1, 24.3, 27.5, 27.7,
CH2Cl2 layer was washed with aqueous HCl (ca. 2 M, 10 mL) 39.6, 42.4, 55.6, 56.5, 59.0, 73.7, 101.4, 114.5, 118.9, 121.8,
and H2O (20 mL). The combined extracts were dried over 127.0, 131.8, 141.7, 143.5, 144.8, 147.4, 149.6, 157.9, 170.0,
K2CO3 and evaporated. The slightly yellow residue was puri- 199.5, 200.2; ACPIMS m/z: 367.2 (M+ + 1).
fied by a fluorous silica gel cartridge (5 g). It was first eluted
with 80:20 MeOH/H2O (20 mL) and then with 100% MeOH. Synthesis of fluorous pyrrolidine ester C-6
The MeOH fraction was concentrated to give C-1 as a N,N'-Dicyclohexylcarbodiimide (DCC) (0.206 g, 1 mmol) was
yellowish solid (0.625 g, 95%). Mp 175–177 °C; 1H NMR added to a mixture of (1H,1H,2H,2H-perfluorooctyl)benzoic
(CDCl3, 300 MHz) δ 1.51–2.05 (m, 6H), 2.30–2.42 (m, 3H), acid (0.468 g, 1 mmol), N-Boc-L-prolinol (0.221 g, 1.1 mmol),
2.65–2.70 (m, 2H), 2.97–3.18 (m, 4H), 3.50 (q, J = 6.9 Hz, 1H), 4-dimethylaminopyridine (DMAP) (0.122 g, 1 mmol) in THF.
3.98 (s, 3H), 5.02 (m, 2H), 5.83 (m, 1H), 6.72 (d, J = 6.9 Hz, After being stirred for 24 h at rt, the mixture was directly loaded
1H), 7.32–7.51 (m, 5H), 8.01–8.07 (m, 3H), 8.72–8.73 (d, 1H); onto a fluorous silica-gel cartridge (5 g; eluted by 100%
13C NMR (CDCl3, 75 MHz) δ 24.2, 26.5, 27.6, 27.9, 32.4, 39.7, methanol) to give the N-Boc-L-prolinyl (1H,1H,2H,2H-perfluo-
42.6, 55.6, 56.7, 59.4, 74.5, 101.3, 114.6, 117.3, 118.6, 121.9, rooctyl)benzoate (0.618 g, 95%). The N-Boc ester was then
126.9, 128.3, 128.63, 130.2, 131.9, 141.7, 143.6, 144.8, 145.0, added to a mixture of TFA in CH2Cl2. After being stirred for
147.5, 156.0, 165.3; APCIMS m/z: 775.1 (M+ + 1); HRMS–ESI 12 h at 0 °C, the reaction mixture was loaded onto a fluorous
(m/z): [M + H]+ calcd. for C35H32F13N2O3, 775.2205; found, silica-gel cartridge (5 g) again to give the title compound
775.2214.
L-prolinyl (1H,1H,2H,2H-perfluorooctyl)benzoate (0.496 g,
1237