Asymmetric synthesis of H1 receptor antagonist (R,R)-clemastine
(R)-1-(4-Chlorophenyl)-1-phenylethane-1,2-diol (13)
(400 MHz, CDCl3) d 7.80 (d, 2H, J = 8.0 Hz), 7.78 (d,
2H, J = 8.0 Hz), 7.34 (t, 2H, J = 7.6 Hz), 7.19–7.17 (m,
1H), 6.47 (t, 1H, J = 7.6 Hz), 4.63 (d, 1H, J = 16.4 Hz),
4.57 (d, 1H, J = 16.4 Hz), 4.43–4.36 (m, 2H), 3.73 (s, 3H),
3.60 (dd, 1H, J = 8.4, 6.4 Hz), 3.51 (dd, 1H, J = 8.4,
6.4 Hz), 1.35 (s, 3H), 1.30 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 196.11, 159.79, 134.92, 133.51, 128.94, 128.69,
128.38, 127.78, 113.93, 109.98, 83.29, 78.84, 770.99,
65.91, 55.07, 26.45, 25.45; IR (KBr, disc): cm-1 2980,
2927, 1698, 1610, 1584, 1513, 1450, 1240; [a]2D3 -86.6
(c 0.51, CHCl3); LRMS (FAB): m/z (relative intensity) 379
([M?Na]?, 100 %); HRMS (FAB) calcd. for C21H24O5Na
[M?Na]? 379.1521, found 379.1515.
To the solution of 12 (56 mg, 0.12 mmol) in CH2Cl2 (3 mL)
were added SnCl2 (5 mg) and EtSH (30 mg, 0.48 mmol).
The reaction mixture was stirred at room temperature for 1 h
before it was diluted with ethyl acetate (20 mL). The organic
layer was washed with aqueous NaHCO3, dried over anhy-
drous Na2SO4, filtered, and then concentrated in vacuo. The
resulting crude residue was purified by column chromatog-
raphy on silica gel (20 % ethyl acetate in hexane) to give the
title compound 13 as a white solid (15.8 mg, 53 %): mp
1
84–86 °C; H NMR (400 MHz, CDCl3) d 7.38–7.19 (m,
9H), 4.09 (d, 1H, J = 11.4 Hz), 4.02 (d, 1H, J = 11.4 Hz),
3.16 (bs, 1H), 1.84 (bs, 1H); 13C NMR (100 MHz, CDCl3) d
143.35, 142.38, 133.19, 128.44, 128.38, 127.88, 127.56,
126.25, 78.17, 68.89; IR (KBr, disc): cm-1 3371, 3295, 3057,
2925, 1489, 1210; HPLC analysis: CHIRALCEL OD col-
umn, eluent = 5 % isopropanol in hexane, flow
rate = 0.5 mL/min, minor (S form) tR = 49.7 min, major
(R form) tR = 57.1 min, minor/major = 1/80 (97 % ee);
[a]2D6 -8.3 (c 1.63, CHCl3); LRMS(FAB) m/z (relative
intensity) 271 (M??Na, 4 %), [213 (M?–OH, 31 %), 197
(M?–OHCl, 25 %], 154 (100 %).
(1R)-1-(4-Chlorophenyl)-2-{(1S)-[(4R)-(2,2-
dimethyl-[1,3]-dioxolan-4-yl)]-(4-
methoxyphenyl)methoxy}-1-phenylethanol (12)
A mixture of ketone 11 (126 mg, 0.35 mmol) and MgBr2-
OEt2 (357 mg, 1.42 mmol, pre-dried with heat gun under
vacuum) in CH2Cl2 (7 mL) was sonicated in ultrasonic
cleaning water bath for 10 min, and then cooled to -78 °C.
4-Chlorophenylmagnesium bromide in diethyl ether solu-
tion (0.71 mL, 0.71 mmol, 1 M in Et2O) was added drop-
wise to the mixture. After being stirred at -78 °C for 2 h, the
mixture was allowed to warm to room temperature. The
reaction mixture was quenched with aqueous NaHCO3
(1 mL) and diluted with dichloromethane (30 mL). The
organic layer was stirred with aqueous NH4Cl (10 mL) for
10 min. The layers were separated, and the aqueous layer
was extracted twice with dichloromethane (20 mL). The
combined organic layer were washed with brine, dried over
anhydrous Na2SO4, filtered, and then concentrated in vacuo.
The resulting crude residue was purified by column chro-
matography on silica gel (12 % ethyl acetate in hexane) to
give 91.1 mg (55 %) of the titled compound as pale yellow
(R)-2-(4-Chlorophenyl)-2-hydroxy-2-phenylethyl
methanesulfonate (14)
To the solution of diol 13 (43.7 mg, 0.18 mmol) in pyridine
(3 mL) was added dropwise methanesulfonyl chloride
(72 lL, 0.88 mmol) at 0 °C. After being stirred for 2 h, the
reaction mixture was quenched with water (5 mL) and
diluted with dichloromethane (30 mL). The organic layer
was washed with aqueous CuSO4 and brine, dried over
anhydrous Na2SO4, filtered, and then concentrated in vacuo.
The resulting crude residue was purified by column chro-
matography on silica gel (15 % ethyl acetate in hexane) to
give the title compound 14 as a white solid (54.1 mg, 94 %):
mp 108–110 °C; 1H NMR (400 MHz, CDCl3) d 7.38–7.26
(m, 9H), 4.67 (d, J = 10.8 Hz, 1H), 4.64 (d, J = 10.8 Hz,
1H), 3.33 (brs, 1H), 2.89 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 141.9, 140.9, 133.9, 128.6, 128.2, 127.9, 126.3,
76.9, 73.9, 37.5; IR (KBr, disc): cm-1 3479, 3032,
2937,1490, 1357; LRMS(FAB) m/z (relative intensity) 349
(M??Na, 7 %), 309 (M?–OH, 58 %), 275 (M?–OHCl,
23 %), 231 (M?–CH3SO3, 47 %) 154 (100 %).
1
syrup. H NMR (400 MHz, CDCl3) d 7.27–7.25 (m, 4H),
7.20–7.17 (m, 6H), 7.14–7.12 (m, 1H), 7.08 (d, 2H,
J = 8.8 Hz), 6.81 (d, 2H, J = 8.8 Hz), 4.31 (bs, 1H),
4.20–4.13 (m, 2H), 4.05 (d, 1H, J = 10.2 Hz), 3.73 (s, 3H),
3.60 (d, 1H, J = 10.2 Hz), 3.56 (dd, 1H, J = 8.8, 6.4 Hz),
3.44 (dd, 1H, J = 8.8, 6.4 Hz), 1.36 (s, 3H), 1.27 (s, 3H); 13
C
NMR (100 MHz, CDCl3) d 160.15, 144.31, 143.48, 132.92,
129.91, 128.44, 128.66, 128.35, 128.29, 127.48, 126.40,
114.33, 110.38, 85.82, 79.39, 77.86, 76.11, 66.23, 55.47,
26.97, 25.75; IR (NaCl, neat): cm-1 3446, 3032, 2986, 1512,
1490, 1448, 1243; [a]D23 ?14.3 (c 2.23, CHCl3,); HPLC
(chiralcel OD column) eluent, 0.25 % i-PrOH/hexane; flow
rate, 0.8 mL/min; detection 254 nm light; tR of (R)-major
65.5 min; tR of (S)-minor 62.2 min (major:minor = 80:1,
97 % de); LRMS (FAB) calcd. for [M?Na]?: LRMS (FAB):
m/z (relative intensity) 491 ([M?Na]?, 1 %); HRMS (FAB)
calcd. for C27H29ClO5Na 491.1601, found 491.1602.
(R)-1-(4-Chlorophenyl)-1-phenylethanol (2)
To the solution of mesylate 14 (45 mg, 0.14 mmol) in THF
(3 mL) at 0 °C was added dropwise lithium triethylboro-
hydride (0.55 mL, 1.0 M solution in THF, 0.55 mmol) via
syringe. The mixture was stirred at 0 °C for 1 h. The
reaction mixture was quenched with aqueous NH4Cl
123