922
LIU ET AL.
Fig. 1. Reported results of the asymmetric addition of diethylzinc to benz-
aldehyde catalyzed by selected norbornane-based b- and g-amino alcohols
derivatives.
the other reagents were purchased from commercial suppliers and used
without further purification. Reactions were monitored by thin-layer
chromatography (TLC) carried out on 0.25-mm silica gel plates visual-
ized with UV light and/or by staining with ethanol phosphomolybdic
acid. Flash column chromatography was performed on silica gel H (10–
40 l). NMR spectra were recorded on 300 MHz instruments. Chemical
shifts (d) are given in ppm relative to trimethyl silane (TMS), coupling
constants (J) in Hz. IR spectra were recorded on a PerkinElmer-GX spec-
trometer. Melting points were determined on an X-6 digital melting-point
apparatus and were uncorrected. Optical rotations were measured on a
PerkinElmer 341 Polarimeter at k 5 589 nm. Analytical high-perform-
ance liquid chromatography (HPLC) was carried out on WATERS 510
instrument (2487 dual k absorbance Detector and 515 HPLC pump)
using chiral column. Time of flight high resolution mass spectrometer
(TOF HRMS) was recorded on a Bruker Apex-2.
Fig. 2. Pyrrolidine-based g-amino alcohols and derivatives.
8.1 Hz, 2H) ppm; 13C NMR (CDCl3, 75.5 MHz): d 5 20.89, 20.93, 25.9,
32.8, 43.9, 45.5, 55.8, 77.8, 125.3, 126.2, 128.62, 128.65, 135.4, 135.7,
144.8, 146.2 ppm; IR (KBr) m 3412, 3329, 3242, 3022, 2959, 2853, 1613,
1508, 1409, 1180, 1086, 822, 806, 778, 729, 585, 566 cm21. TOF HRMS:
calcd. for C20H26NO [M 1 H]1 296.2014; found 296.2083.
(S)-1,1-Diphenyl-2-(pyrrolidin-2-yl)ethanol 2a. White solid; mp
136–1378C, [a]D255 124.2 (c 5 1.0, CHCl3); 1H NMR (CDCl3, 300
MHz): d 5 1.41–1.58 (m, 2H), 1.78–1.88 (m, 2H), 1.99–2.08 (dd, J 5 13.9
Hz, 11.9 Hz, 1H), 2.17 (s, 1H), 2.38–2.44 (dd, J 5 14.1 Hz, 2.98 Hz, 1H),
2.80–2.96 (m, 2H), 3.23–3.30 (m, 1H), 7.13–7.34 (m, 6H), 7.42–7.45 (d, J
5 7.63 Hz, 2H), 7.52–7.55 (d, J 5 7.59 Hz, 2H) ppm; 13C NMR (CDCl3,
75.5 MHz): d 5 25.9, 32.8, 43.8, 45.5, 55.7, 78.0, 125.4, 126.0, 126.3,
127.9, 147.7, 148.8 ppm; IR(KBr) m 3414, 3328, 3256, 2958, 2853, 1617,
1492, 1445, 1125, 1061, 748, 697 cm21. TOF HRMS: calcd. for C18H21NO
[M 1 H]1 268.1701; found 268.1703.
The Procedure for the Synthesis of Compound 4
Methyl homoprolinate hydrochloride 3 (3.6 g, 20 mmol) and triethyl
amine (TEA) (7 ml, 50 mmol) were dissolved in dry CH2Cl2 (40 ml). The
solution was cooled down to 08C with ice bath. (Boc)2O (5.4 g, 24.7
mmol) was added dropwise. After the addition, the reaction mixture was
warmed to r.t. slowly and stirred overnight and then diluted with CH2Cl2
and separated the organic phase. The aqueous solution was extracted
with CH2Cl2 (3 3 50 ml). The combined organic layers were washed
with saturated NH4Cl solution, brine, and dried over Na2SO4. The sol-
vent was evaporated in vacuo and the residue was purified by silica gel
chromatography to give 470 (4.65 g, 96%) as light yellow oil.
(S)-1,1-Bis(4-propylphenyl)-2-(pyrrolidin-2-yl)ethanol 2c.
Color-
less oil, [a]D25 5 114.4 (c 5 1.0, CHCl3). 1H NMR (CDCl3, 300 MHz): d
5 0.89–0.98 (m, 6H), 1.42–1.68 (m, 6H), 1.81–1.87 (m, 2H), 1.99–2.08
(dd, J 5 13.7 Hz, 12.1 Hz, 1H), 2.37–2.42 (dd, J 5 14.1 Hz, 2.78 Hz, 1H),
2.49–2.59 (m, 4H), 2.83–2.93 (m, 2H), 3.26–3.29 (m, 1H), 7.06–7.14 (m,
4H), 7.35(d, J 5 8.07 Hz, 2H), 7.44 (d, J 5 8.0 Hz, 2H) ppm; 13C NMR
(CDCl3, 75.5 MHz): d 5 13.8, 13.9, 24.45, 24.47, 25.9, 32.7, 37.56, 37.59,
44.0, 45.4, 55.8, 77.8, 125.2, 126.1, 127.9, 128.0, 140.1, 140.5, 144.9, 146.4
ppm; IR (neat) m 2958, 1613, 1452, 1295, 1260, 1182, 1101, 1018, 841, 745,
602 cm21. TOF HRMS: calcd. for C24H34NO [M 1 H]1 352.264; found
352.264.
General Procedure for the Synthesis of Ligands 2a–2e
Synthesis of (S)-1,1-bis(4-methylphenyl)-2-(pyrrolidin-2-yl)etha-
nol 2b. To a solution of 4 (18.72 g, 80 mmol) in dry tetrahydrofuran
(THF) (500 ml) at 2788C under a nitrogen atmosphere, RMgBr (240 ml
of 1 M solution in THF) was added dropwise. The mixture was warmed
to r.t. gradually and stirred overnight. The reaction was quenched by sat-
urated aqueous NH4Cl, and THF was removed under reduced pressure
to give a milky residue. The residue was partitioned between ethyl ace-
tate and saturated NH4Cl solution. The organic layers were collected,
washed with brine, and dried over Na2SO4. The solvent was evaporated
in vacuo, and the residue was purified by silica gel chromatography to
give pure 5b in good yields (7.3 g, 96%).
(S)-1,1-Bis(4-pentylphenyl)-2-(pyrrolidin-2-yl)ethanol 2d.
White
solid; mp 76–778C, [a]D 5 122.3 (c 5 1.0, CHCl3); 1H NMR (CDCl3,
300 MHz): d 5 0.83–0.90 (q, J 5 14.3 Hz, 6H), 1.27–1.45 (m, 9H), 1.47–
1.61 (m, 5H), 1.78–1.82 (m, 2H), 1.94–2.03 (dd, J 5 13.7 Hz, 12.1 Hz,
1H), 2.33–2.39 (dd, J 5 14.0 Hz, 2.7 Hz, 1H), 2.49–2.58 (m, 4H), 2.81–
2.90 (m, 2H), 3.26 (m, 1H), 7.06 (d, J 5 8.1 Hz, 2H,), 7.11 (d, J 5 8.0 Hz,
2H), 7.32 (d, J 5 8.1 Hz, 2H), 7.42 (d, J 5 8.0 Hz, 2H) ppm; 13C NMR
(CDCl3, 75.5 MHz): d 5 13.9, 14.0, 22.50, 22.52, 26.0, 31.0, 31.1, 31.4,
31.6, 32.8, 35.40, 35.47, 44.0, 45.4, 55.7, 77.8, 125.2, 126.1, 127.8, 127.9,
140.4, 140.7, 145.0, 146.4 ppm; IR (KBr) m 3329, 3271, 3026, 2998, 2926,
2854, 1615, 1573, 1508, 1461, 1412, 1377, 1290, 1128, 1105, 904, 826, 728
cm21. TOF HRMS: calcd. for C28H42NO [M 1 H]1 408.3266; found
408.3232.
25
5b (4.9 g, 12.4 mmol) was added into the mixture of NaOH (14.87 g,
372 mmol) in 90 ml anhydrous ethanol and stirred for 2 days under
refluxed at 988C. Ethanol was removed in vacuo. Water was added to dis-
solve excess NaOH. The aqueous solution was extracted with CH2Cl2 (3
3 50 ml). The combined organic layers were washed with saturated
NH4Cl solution, saturated NaHCO3, brine, and dried over Na2SO4. The
solvent was removed in vacuo, and the residue was purified by silica gel
column chromatography to give 2b71 (3.48 g) as white solid; yield (95%).
(S)-1,1-Bis(3,5-bis(trifluoromethyl)phenyl)-2-(pyrrolidin-2-yl)ethanol
mp 88–898C, [a]D 5 122.3 (c 5 1, CHCl3); 1H NMR (CDCl3, 300
2e. White solid; mp 125–1268C, [a]D 5 –4.8 (c 5 0.5, CHCl3); 1H
25
25
MHz): d 5 1.39–1.55 (m, 2H), 1.76–1.86 (m, 2H), 1.96–2.05 (dd, J 5 14.0
Hz, 11.9 Hz, 1H), 2.26 (s, 3H), 2.31 (s, 3H), 2.34–2.39 (dd, J 5 14.1 Hz,
2.99 Hz, 1H), 2.81–2.93 (m, 2H), 3.22–3.29 (m, 1H), 7.05 (d, J 5 8.01 Hz,
2H), 7.11 (d, J 5 7.96 Hz, 2H), 7.30 (d, J 5 8.15 Hz, 2H), 7.40 (d, J 5
NMR (CDCl3, 300 MHz): d 5 1.50–1.64 (m, 2H), 1.85–1.96 (m, 2H), 1.98–
2.07 (dd, J 5 14.1 Hz, 12.2 Hz, 1H), 2.45–2.50 (dd, J 5 14.3 Hz, 2.97 Hz,
1H), 2.81–2.90 (m, 1H), 2.98–3.05 (m, 1H), 3.24–3.32 (m, 1H), 7.73 (s,
1H), 7.78 (s, 1H), 7.90 (s, 2H), 8.03 (s, 2H) ppm; 13C NMR (CDCl3, 75.5
Chirality DOI 10.1002/chir