F. Kelleher et al. / Tetrahedron 66 (2010) 3525–3536
3533
4.5.1. (R,R) Diastereoisomer (15b). Yellow oil (0.78 g, 92%). Rf: 0.3
4.8.1. (S,R) Diastereoisomer (22a). Colourless oil, (0.12 g,18%). Rf: 0.7
(40% ethyl acetate/petroleum ether). [
]D þ8.18 (c 0.55 in MeOH). IR,
(Thin film)/cmꢁ1: 2976, 1686, 1678. 1H NMR (two rotamers present)
(10% MeOH/DCM), [
a
]
D
þ11.0 (c 1 in MeOH). IR, (Thin film)/cmꢁ1
:
a
3335, 3030, 2994, 1685. 1H NMR
d: 8.10–8.01 (m, 0.5H), 7.87–7.81
(m, 0.5H), 7.55–7.48 (m, 2H), 7.46–7.21 (m, 4H), 6.14 (q, 1H,
J¼7.0 Hz), 3.28–3.22 (m, 1H), 3.18–3.05 (m, 1H), 2.98–2.91 (m, 1H),
2.56–2.45 (m, 1H), 2.14–1.68 (m, 7H), 1.60 (d, 3H, J¼7.1 Hz). 13C NMR
d
: 7.36–7.24 (m, 5H), 6.18–6.11 (m,1H), 3.75–3.63 & 3.60–3.52 (2ꢃm,
1H), 3.38–3.30 (m,1H), 2.61 & 2.56 (2ꢃs, 3H), 2.16–1.96 (m, 4H),1.59
(s, 3H), 1.56 & 1.52 (2ꢃs, 3H), 1.48 (s, 9H). 13C NMR (two rotamers
d
: 176.1, 135.1, 133.8, 131.5, 128.8, 128.6, 128.4, 126.8, 125.0, 124.2,
present) d: 173.0, 153.5, 141.3, 128.5, 127.1 & 126.8, 80.3, 66.2, 51.7,
123.6, 68.4, 47.3, 46.2, 39.1, 35.2, 34.3, 25.8, 16.3. HRMS (ESI) cal-
46.7, 38.1, 29.7, 28.3, 24.7, 23.8, 22.1. HRMS (ESI) calculated for
culated for C19H23N2O [MþH]þ: 295.1810. Found: 295.1802.
C19H29N2O3 [MþH]þ: 347.2335. Found: 347.2318.
4.6. ( )-2-Methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-
4.8.2. (R,R) Diastereoisomer (22b). Colourless oil, (0.21 g, 31%). Rf:
butyl ester 2-methyl ester (20)
0.6 (40% ethyl acetate/petroleum ether). [
MeOH). IR, (Thin film)/cmꢁ1: 2972, 1680, 1678. 1H NMR (two
rotamers present) : 7.40–7.26 (m, 5H), 6.21–6.09 (m, 1H), 3.78–
a
]
þ23.9 (c 0.67 in
D
To a solution of 19 (0.5 g, 2.18 mmol) in dry THF (2 ml) at ꢁ20 ꢀC,
was added a 1.0 M solution of LiHMDS in THF (3.1 ml, 3.1 mmol)
slowly while keeping the temperature below ꢁ15 ꢀC. The solution
was stirred for 1.5 h, under nitrogen, at this temperature. Methyl
iodide (0.25 ml, 3.1 mmol) was added slowly at ꢁ20 ꢀC. The solution
was stirred while allowing it to warm to ambient temperature. After
18 h the solutionwas quenched with a saturated aqueous solution of
NH4Cl (5 ml), extracted with ethyl acetate (3ꢃ20 ml), washed with
a brine solution (3ꢃ10 ml) and then dried over MgSO4. The resulting
solution was concentrated in vacuo and was purified by column
chromatography on silica gel, using 10% ethyl acetate/petroleum
ether, giving a colourless oil (0.38 g, 72%). Rf: 0.50 (20% ethyl acetate/
petroleum ether). IR, (Thin film)/cmꢁ1: 2975, 1750, 1692, 1418. 1H
d
3.62 & 3.59–3.51 (2ꢃm, 1H), 3.36–3.23 (m, 1H), 2.65 & 2.50 (2ꢃs,
3H), 2.25–1.92 (m, 4H), 1.59 & 1.57 (2ꢃs, 3H), 1.51 & 1.42 (2ꢃd,
J¼1.1 Hz, 3H, H), 1.25 & 1.19 (2ꢃs, 9H). 13C NMR (two rotamers
present) d: 172.8, 153.1, 141.6, 141.4, 128.6, 127.2 & 126.9, 80.1, 66.0,
51.9, 47.2 & 47.0, 38.6 & 38.2, 29.6 & 29.4, 28.7, 24.7 & 24.5, 23.8 &
23.6, 22.1 & 21.8. HRMS (ESI) calculated for C19H29N2O3 [MþH]þ:
347.2335. Found: 347.2325.
The reaction was then conducted using (S)-N-methylbenzyl-
amine, following the method previously described, forming the
(R,S) and (S,S) diastereoisomers 22c and 22d.
4.8.3. (R,S) Diastereoisomer (22c). Colourless oil, (0.13 g, 19%). [a]
D
NMR (two rotamers present)
d
: 3.75 (s, 3H), 3.70–3.64 (m,1H), 3.62–
ꢁ8.2 (c 0.55 in MeOH). Analytical data is identical to that of the (S,R)
diastereoisomer. HRMS (ESI) calculated for C19H29N2O3 [MþH]þ:
347.2335. Found: 347.2320.
3.43 (m,1H), 2.23–2.05 (m,1H), 2.04–1.92 (m, 3H),1.58 (s, 3H),1.45 &
1.41 (2ꢃs, 9H). 13C NMR (two rotamers present)
d: 175.4,153.6, 79.9,
64.8, 52.1, 47.9, 40.1, 28.2, 23.1, 22.3.
4.8.4. (S,S) Diastereoisomer (22d). Colourless oil, (0.24 g, 35%). [a]
D
4.7. ( )-2-Methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-
butyl ester (21)
ꢁ24 (c 0.7 in MeOH). Analytical data is identical to that of the (R,R)
diastereoisomer. HRMS (ESI) calculated for C19H29N2O3 [MþH]þ:
347.2335. Found: 347.2335.
A suspension of 20 (1.25 g, 5.14 mmol) and NaOH (0.204 g,
5.1 mmol) in MeOH/H2O (1:1, 20 ml) was heated at reflux tem-
perature for 5 h. The solvent was removed in vacuo, and the residue
was partitioned between diethyl ether and H2O (1:1, 20 ml). The
aqueous phase was then washed with diethyl ether (3ꢃ10 ml),
acidified to pH 3 using 1 N HCl, followed by extraction with diethyl
ether. The ether layer was then dried over MgSO4 and concentrated
in vacuo yielding the product (1.10 g, 93%), which was used without
further purification. Rf: 0.10 (20% ethyl acetate/petroleum ether).
Mp: 91–94 ꢀC. IR, (Thin film)/cmꢁ1: 2978, 1740, 1648, 1432. 1H NMR
4.9. 2-Methyl-pyrrolidine-2-carboxylic acid methyl-
(1-phenyl-ethyl)-amide (17a–d)
To a solution of 22(a–d) (0.145 g, 0.42 mmol) in DCM (0.3 ml)
was added TFA (0.3 ml, 1.28 mmol), and it was stirred at ambient
temperature for 16 h. It was then concentrated in vacuo, dissolved
in H2O (40 ml), and the pH was adjusted to w8 by adding Et3N
dropwise, at 0 ꢀC. It was then extracted with DCM (3ꢃ20 ml), dried
over MgSO4 and concentrated in vacuo yielding an oil, which was
purified on silica gel using 5% MeOH/DCM.
(two rotamers present) d: 3.62–3.42 (m, 2H), 2.60 (m, 1H), 2.45 &
2.28 (2ꢃm,1H),1.95–1.77 (m, 2H),1.62 (s, 3H),1.48 & 1.42 (2ꢃs, 9H).
13C NMR (two rotamers present)
38.4, 28.4, 22.8, 22.2.
d
: 176.5, 152.3, 80.6, 66.8, 48.7,
4.9.1. (S,R) Diastereoisomer (17a). Colourless oil, (0.09 g, 88%).
Rf: 0.6 (10% MeOH/DCM). [
a
]
þ18 (c 1 in MeOH). IR, (Thin film)/
D
cmꢁ1: 3276, 2974, 1676. 1H NMR (two rotamers present)
d: 7.40–
4.8. 2-Methyl-2-[methyl-(1-phenylethyl)-carbamoyl]-
pyrrolidine-1-carboxylic acid tert-butyl ester (22a and 22b)
7.22 (m, 5H), 6.04 & 5.35 (2ꢃq, J¼7.0 Hz, 1H), 3.47–3.41 & 3.11–3.02
(2ꢃm, 2H), 2.74 (s, 3H), 2.30–1.95 (m, 4H), 1.75 & 1.70 (2ꢃs, 3H), 1.53
(d, J¼7.1 Hz, 3H). 13C NMR (two rotamers present)
d: 172.8, 139.4,
To a stirred solution of 21 (0.45 g, 1.96 mmol) in dry DMF (9 ml)
was added DIPEA (0.675 ml, 3.92 mmol), followed by (R)-N-methyl-
129.0, 127.7 & 127.1, 68.3, 52.7, 45.6, 36.2, 30.4, 25.6, 23.9, 15.2. HRMS
(ESI) calculated for C15H23N2O [MþH]þ: 247.1810. Found: 247.1821.
a
-methylbenzylamine (0.25 ml, 1.96 mmol) dropwise. After stirring
for 5 min. the solution was cooled to 0 ꢀC, and a solution of HATU
(0.752 g, 1.98 mmol) in dry DMF (9 ml) was added slowly. After
10 min at this temperature, the solution was allowed to warm to
ambient temperature and stirring was continued for 4 h. The so-
lution was diluted with EtOAc (200 ml), and then washed succes-
sively with 10% HCl solution (3ꢃ10 ml), saturated aqueous sodium
carbonate solution (3ꢃ10 ml), H2O (3ꢃ10 ml) and brine solution
(3ꢃ10 ml), and then dried over MgSO4. The solution was concen-
trated in vacuo giving the crude product (0.65 g), which was puri-
fied by column chromatography on silica gel in 10% ethyl acetate/
petroleum ether.
4.9.2. (R,R) Diastereoisomer (17b). Colourless oil, (0.092 g, 89%). Rf:
0.5 (10% MeOH/DCM). [
a
]
D þ25 (c 1 in MeOH). IR, (Thin film)/cmꢁ1
:
3270, 2976, 1674. 1H NMR (two rotamers present)
d: 7.36–7.23 (m,
5H), 6.06 & 5.56 (2ꢃq, J¼7.1 Hz, 1H), 3.26–3.20 & 3.01–2.92 (2ꢃm,
2H), 2.76 & 2.70 (2ꢃs, 3H), 2.17–1.83 (m, 4H), 1.59 (s, 3H), 1.51 (d,
J¼7.0 Hz, 3H). 13C NMR (two rotamers present)
d: 174.7, 130.1, 128.6,
127.4 & 126.3, 66.9, 52.3, 46.2 , 36.6, 30.4, 26.0, 25.6, 15.2. HRMS
(ESI) calculated for C15H23N2O [MþH]þ: 247.1810. Found: 247.1810.
4.9.3. (R,S) Diastereoisomer (17c). Colourless oil, (0.095 g, 92%).
[a
]
ꢁ18 (c 1 in MeOH). Analytical data is identical to that of the
D