HPLC RESOLUTION OF cis- AND trans-b-PHENYLPROLINE
was stirred at room temperature for a total of 3 days, with further portions of
3.54–3.65 (m, 1H); 3.69, 3.71 (two s, 3H); overlapped with 3.67–3.78
(m, 1H); 4.24, 4.38 (two d, 1H, J= 6.7, 6.0 Hz, respectively); 7.20–7.36
(m, 5H). 13C NMR (CDCl3, 100 MHz) d 28.40, 28.56; 32.42, 33.14; 46.12,
46.28; 48.88, 50.08; 52.13, 52.35; 65.26, 65.94; 80.25, 80.36; 127.05, 127.10;
127.28, 127.40; 128.88, 128.92; 140.66, 141.03; 153.74, 154.39; 173.21, 173.35.
HRMS (ESI) C17H23NNaO4 [M + Na]+: calcd 328.1519, found 328.1519.
di-tert-butyl dicarbonate (1.92g, 8.83mmol) being added after 24 and 48h.
The solvent was evaporated, and the residue was partitioned between water
(120 ml) and diethyl ether (50 ml). The organic layer was discarded, and the
aqueous phase was further washed with diethyl ether (2ꢀ 30ml). The
aqueous solution was acidified with solid citric acid and extracted with
dichloromethane (4ꢀ 50 ml). The combined organic extracts were dried
over anhydrous MgSO4, filtered, and evaporated to provide a white solid.
The subsequent esterification reaction was carried out in one of the
following ways. (A) The solid obtained was dissolved in a 2:1 toluene/
methanol mixture (100ml) at room temperature, and a 2M solution of
(trimethylsilyl)diazomethane in diethyl ether was added in small portions
until a permanently colored solution was obtained. After 10min, a small
quantity of silica gel was added, and stirring was continued until the yellow
color disappeared. The solvent was eliminated, and the residue was purified
by column chromatography (eluent: hexanes/ethyl acetate 7:3) to afford 6
as a 7:3 mixture of cis/trans isomers (4.99 g, 16.35 mmol, 93% yield from
5). (B) The white solid was dissolved in anhydrous methanol (40ml), and
cesium carbonate (5.88g, 18.03 mmol) was added. The resulting mixture
was stirred at room temperature for 30 min and then evaporated to dryness.
The residue was dissolved in N,N-dimethylformamide (40ml), and methyl
iodide (1.22ml, 19.67 mmol) was added. After stirring at room temperature
for 4 days, evaporation of the solvent and purification by column chromatog-
raphy (eluent: hexanes/ethyl acetate 7:3) afforded 6 as a 7:3 mixture of cis/
trans isomers (4.75g, 15.57mmol, 88% yield from 5). The analytical and
spectroscopic characterization of pure cis-6 and trans-6 are given below.
Resolution of cis-6: isolation of methyl (2R,3R)- and (2S,3S)-N-(tert-
butoxycarbonyl)-b-phenylprolinate [(2R,3R)-6 and (2S,3S)-6]. High-
performance liquid chromatography resolution of racemic cis-6 (5.40 g)
dissolved in chloroform (9.00 ml) was carried out by successive injections
(one every 12.5min) of 700 ml on a 250 ꢀ 20mm Chiralpak IA column. A
mixture of n-hexane/2-propanol 90:10 was used as the eluent working at a
flow rate of 16ml/min and with UV monitoring at 210 nm. Three separate
fractions were collected. Optically pure (2R,3R)-6 (2.690 g) and (2S,3S)-6
(2.676 g) were respectively obtained by evaporation of the first and third
fractions. The second fraction contained 17mg of (2R,3R)-6/(2S,3S)-6
mixture and was discarded.
20
(2R,3R)-6: mp 99 ꢂC. ½aꢃD ꢁ101.2 (c 0.77, MeOH).
20
(2S,3S)-6: mp 99 ꢂC. ½aꢃD +102.0 (c 0.67, MeOH).
Spectroscopic data were identical to those described for cis-6.
Synthesis of (2R,3R)-N-(tert-butoxycarbonyl)-b-phenylproline
[(2R,3R)-7]. A 2N solution of lithium hydroxide in methanol/water 1:1
(200 ml) was added to (2R,3R)-6 (2.20 g, 7.21 mmol), and the reaction
mixture was stirred at room temperature for 48 h. After evaporation of
the solvent, the residue was taken up in water and extracted with
dichloromethane (2 ꢀ40 ml) (138 mg, 0.45 mmol, of unreacted starting
compound were recovered by evaporation of the dichloromethane extracts).
Neutralization of the aqueous phase with solid citric acid followed by 1 N
HCl resulted in the precipitation of (2R,3R)-7, which was collected by
Synthesis of trans N-(tert-butoxycarbonyl)-b-phenylproline (trans-7)
and isolation of cis methyl N-(tert-butoxycarbonyl)-b-phenylprolinate
(cis-6). A 0.5N aqueous solution of NaOH (64.2 ml, 32.09mmol) was
added to a solution of 6 (7:3 mixture of cis/trans isomers) (9.79g,
32.09mmol) in methanol (50 ml). After stirring at 25ꢂC for 22h, methanol
was evaporated, and the remaining aqueous solution was diluted with water
and extracted with dichloromethane (3ꢀ 50ml). The combined organic
extracts were dried over anhydrous MgSO4, filtered, and evaporated to af-
ford pure cis-6 as a white solid (7.21g, 23.63 mmol, 74% yield). If necessary,
additional purification can be accomplished by recrystallization from hex-
anes. The aqueous layer was acidified by the addition of solid citric acid
and extracted with dichloromethane (4ꢀ 40ml). The combined organic
extracts were dried over anhydrous MgSO4 and filtered. Evaporation of
the solvent provided trans-7 as a white solid (2.28g, 7.82mmol, 24% yield).
Combined yield (cis-6 + trans-7): 98%.
20
vacuum filtration (1.87 g, 6.42 mmol, 89% yield). mp 166 ꢂC. ½aꢃD ꢁ115.6
(c 0.33, MeOH). IR (nujol) n 3300–2500, 1715, 1699, 1478 cmꢁ1 1H NMR
.
(CDCl3, 400 MHz) d 1.38, 1.47 (two s, 9H); 2.07–2.16 (m, 1H); 2.43–2.64
(m, 1H); 3.40–3.50 (m, 1H); 3.60–3.89 (m, 2H); 4.45, 4.56 (two d, 1H, J=8.5,
8.2 Hz, respectively); 7.20–7.33 (m, 5H). 13C NMR (CDCl3, 100 MHz) d
27.53; 28.41, 28.56; 45.84, 46.24; 47.14, 48.04; 63.51, 64.11; 80.49, 80.59;
127.64, 127.73; 127.92, 128.03; 128.60; 136.32, 136.48; 153.85, 154.64; 176.72,
176.76. HRMS (ESI) C16H22NO4 [M + H]+: calcd. 292.1543, found 292.1555.
Synthesis of (2S,3S)-N-(tert-butoxycarbonyl)-b-phenylproline
[(2S,3S)-7]. An identical procedure to that described above was
applied to transform (2S,3S)-6 (2.20 g, 7.21 mmol) into (2S,3S)-7
(1.85 g, 6.37mmol, 88% yield) (unreacted material recovered: 164 mg,
cis-6: mp 74 ꢂC. IR (nujol)
n .
1746, 1702, 1453 cmꢁ1 1H NMR
(CDCl3, 400 MHz) d 1.39, 1.47 (two s, 9H); 2.11 (m, 1H); 2.49–2.66 (m, 1H);
3.24, 3.27 (two s, 3H); 3.40–3.50 (m, 1H); 3.60–3.73 (m, 1H); 3.83, 3.92
(two m, 1H); 4.46, 4.55 (two d, 1H, J= 8.7 Hz); 7.19–7.33 (m, 5H). 13C NMR
(CDCl3, 100 MHz) d 27.47; 28.31, 28.47; 45.85, 46.21; 47.16, 48.02; 51.26,
51.36; 63.87, 64.35; 80.01, 80.04; 127.46, 127.53; 127.85, 127.92; 128.35,
128.38; 136.69, 136.78; 153.69, 154.32; 171.72, 171.79. HRMS (ESI)
C17H24NO4 [M + H]+: calcd 306.1700, found 306.1713.
0.54mmol). mp 166ꢂC.½aꢃD20 +115.0 (c 0.38, MeOH). Spectroscopic data were
the same as those given for (2R,3R)-7.
Resolution of trans-6: isolation of methyl (2S,3R)- and (2R,3S)-
N-(tert-butoxycarbonyl)-3-b-phenylprolinate [(2S,3R)-6 and
(2R,3S)-6]. High-performance liquid chromatography resolution of race-
mic trans-6 (3.00g) dissolved in chloroform (6.00 ml) was carried out by
successive injections (one every 13.0min) of 600ml on a 250 ꢀ 20mm
Chiralpak IC column. A mixture of n-hexane/2-propanol/chloroform
75:15:10 was used as the eluent working at a flow rate of 17ml/min and with
UV monitoring at 220 nm. Three separate fractions were collected. Optically
pure (2S,3R)-6 (1.442 g) and (2R,3S)-6 (1.421 g) were respectively obtained
by evaporation of the first and third fractions. The second fraction contained
61mg of (2S,3R)-6/(2R,3S)-6 mixture and was discarded.
trans-7: mp 128 ꢂC. IR (nujol) n 3320–2560, 1734, 1631 cmꢁ1 1H NMR
.
(CDCl3, 400 MHz) d 1.42, 1.51 (two s, 9H); 1.97–2.10 (m, 1H); 2.28–2.39
(m, 1H); 3.44–3.55 (m, 1H); 3.56–3.70 (m, 1H); 3.72–3.85 (m, 1H); 4.28, 4.44
(two d, 1H, J= 6.2, 5.0 Hz, respectively); 7.21–7.37 (m, 5H). 13C NMR
(CDCl3, 100 MHz) d 28.41, 28.54; 32.55, 32.84; 46.11, 46.44; 47.13, 50.02;
65.40, 65.71; 80.85, 81.84; 127.13; 127.32, 127.53; 128.97; 140.55, 141.07;
153.77, 156.28; 174.69, 178.27. HRMS (ESI) C16H22NO4 [M + H]+: calcd.
292.1543, found 292.1555.
25
(2S,3R)-6: Oil. ½aꢃD +61.6 (c 0.75, CHCl3).
25
Synthesis of trans methyl N-(tert-butoxycarbonyl)-b-phenylprolinate
(trans-6). A 2M solution of (trimethylsilyl)diazomethane in diethyl ether
was added in small portions to a solution of trans-7 (3.06 g, 10.52 mmol)
in toluene/methanol 2:1 (60 ml) at room temperature until the yellow color
persisted. A small quantity of silica gel was added, and stirring was
continued until the color disappeared. Evaporation of the solvent and
purification by column chromatography (eluent: hexanes/ethyl acetate 7:3)
afforded trans-6 as a white solid (3.19 g, 10.45 mmol, 99% yield). mp 61 ꢂC.
IR (nujol) n 1747, 1704, 1491 cmꢁ1. 1H NMR (CDCl3, 400 MHz) d 1.41, 1.48
(two s, 9H); 1.98–2.08 (m, 1H); 2.25–2.36 (m, 1H); 3.39–3.47 (m, 1H);
(2R,3S)-6: Oil. ½aꢃD ꢁ60.8 (c 0.74, CHCl3).
Spectroscopic data were identical to those given for trans-6.
Synthesis of (2S,3R)-N-(tert-butoxycarbonyl)-b-phenylproline
[(2S,3R)-7]. A 2 N solution of lithium hydroxide in methanol/water 1:1
(90 ml) was added to (2S,3R)-6 (1.25g, 4.10mmol), and the reaction mixture
was stirred at room temperature for 24 h. After evaporation of the solvent,
the residue was taken up in water and washed with dichloromethane
(2ꢀ 30 ml). Neutralization of the aqueous solution with solid citric acid
followed by 1 N HCl resulted in the precipitation of (2S,3R)-7, which was
Chirality DOI 10.1002/chir