Dynamic Kinetic Resolution
FULL PAPER
1
1454, 1252, 1082, 1070, 1058, 1044, 1030, 701; MS (IE): m/z (%): 339 (1)
[M]+, 308 (2) [MꢀCH2OH]+, 232 (6), 205 (10) [MꢀCONHCH2Ph]+, 175
(60) [MꢀCH2OH-CONHCH2Ph]+, 106 (9) [NHCH2Ph]+, 91 (100)
[PhCH2]+; HRMS (EI+): m/z: calcd for C19H21N3O3: 339.158292; found:
339.159463.
CH2OMe), 3.29 (m, 1H, = ofC H2OMe), 3.26 (s, 3H, OCH3), 3.14 (m,
2
1H,
1
1
= ofC H2NCH2), 2.82 (m, 1H, = ofC H2NCH2), 1.81 (m, 4H,
4 4
CH2CH2NCH2CH2); 13C NMR (CDCl3): d = 164.8 (CO), 161.0 (CO),
135.9 (iPh), 128.8 (Ph), 128.6 (Ph), 127.7 (Ph), 72.0 (CH2OMe), 59.0
(OCH3), 57.3 (CH-CO-Py), 50.4 (CH-CH2OMe), 46.1 (NCH2), 45.7
(CH2Ph + NCH2), 26.0 (NCH2CH2), 23.9 (NCH2CH2); IR: n˜ = 3265,
2921, 2851, 1702, 1642, 1451, 1343, 1254, 1128, 1097, 704 cmꢀ1; MS
(FAB+): m/z (%): 318 (34) [M+H]+, 231 (49), 155 (19), 154 (89), 137
(100), 109 (47); HRMS (FAB+): m/z: calcd for C17H24N3O3: 318.181767;
found: 318.181607.
Preparation of 34: Pyrrolidine (2 mL, 24 mmol) was added to a stirred
solution of 29 (5.07 g, 15.7 mmol) in CH2Cl2 (30 mL). The solution was
stirred at room temperature for 24 h, and then washed consecutively with
an aqueous HCl (1m) solution and brine. After drying with MgSO4, the
organic phase was evaporated. The white solid compound was dissolved
in acetonitrile (15 mL), and then Ag2O (5.5 g, 24 mmol) and CH3I (6 mL)
were added. The reaction mixture was stirred under argon atmosphere
for 3 d at 408C and after filtration, the crude reaction mixture was dilut-
ed with CH2Cl2 and washed with 10% aq. ammonia. The organic phase
was dried with MgSO4, evaporated and the residue was purified by
column chromatography (80% ethyl acetate/hexane), after which the
product 34 (3.77 g, 59%) was obtained as an oil. [a]D = +128 (c = 1.1,
CHCl3); 1H NMR (CDCl3): d = 7.32–7.21 (m, 10H, Ph), 5.04 (d, J =
Partial spectral data obtained for 37 from the mixture of 36 and 37:
1
1H NMR (CDCl3): d = 4.75 (d, J = 15.5 Hz, 1H, = ofPh-C H2), 4.50 (d,
2
1
J = 9.0 Hz, 1H, CH-CO-Py), 4.13 (d, J = 15.5 Hz, 1H, = ofPh-C H2),
2
3.18 (s, 3H, OCH3); 13C NMR (CDCl3): d = 137.3 (iPh), 70 (CH2OMe).
Preparation of 38 and 39: A solution ofa mixture of 36 and 37 (1.51 g,
4.76 mmol) in dry THF (10 mL) was added at 08C to a stirred suspension
ofNaH (60% in oil, 190 mg, 4.76 mmol) in dry THF (30 mL). The reac-
tion mixture was stirred for 10 min at 08C, and afterwards CH3I (0.3 mL,
4.76 mmol) was added, and the stirring was continued at room tempera-
ture for 2 h. The mixture was diluted with CH2Cl2, washed with aq
NH4Cl, and dried with MgSO4. After evaporation, the residue was puri-
fied by column chromatography (3% MeOH/CH2Cl2) and a mixture of
regioisomers 38 and 39 (1.43 g, 91%) was obtained.
1
1
14.5 Hz, 1H,
= ofPh-C H2), 4.66 (d, J = 15.7 Hz, 1H, = ofPh-C H2),
2 2
1
4.25 (d, J = 15.7 Hz, 1H, = ofPh-C H2), 4.00 (d, J = 9.3 Hz, 1H, CH-
CO-Py), 3.84 (d, J = 14.5 Hz, 1H,
CH2OMe), 3.38–3.51 (m, 3H, = ofC H2NCH2
(t, J = 8.9 Hz, 1H, = ofC H2OMe), 3.11 (m, 1H, = ofC H2NCH2), 3.12
2
1
=
2
ofPh-C H2), 3.69 (m, 1H, CH-
1
+
1= ofC H2OMe), 3.30
2
2
1
1
2
4
1
(s, 3H, OCH3), 2.60 (m, 1H,
=
ofC H2NCH2), 1.73 (m, 4H,
4
1H NMR (the number ofthe protons is calculated with respect to the in-
tegral of the peak at 4.30 for the minor and at 4.07 for the major product
CH2CH2NCH2CH2); 13C NMR (CDCl3): d = 165.6 (CO), 160.4 (CO),
137.6 (iPh), 136.3 (iPh), 128.7 (Ph), 128.4 (Ph), 127.7 (Ph), 127.6 (Ph),
127.2 (Ph), 70.3 (CH2OMe), 58.7 (OCH3), 56.0 (CH), 54.0 (CH), 46.6
(CH2), 46.0 (CH2), 45.7 (CH2), 25.9 (NCH2CH2), 23.4 (NCH2CH2); IR: n˜
=3062, 3029, 2973, 2927, 2875, 1699, 1649, 1447, 1358, 1237, 1130, 1099,
703 cmꢀ1; MS (EI): m/z (%): 408 (2) [M+H]+, 375 (4) [MꢀMeOH]+, 362
(2) [MꢀMeOCH2]+, 309 (25) [MꢀCOPy]+, 98 (25), 91 (100) [PhCH2]+,
55 (25); HRMS (EI+): m/z: calcd for C24H29N3O3: 407.220892; found:
407.219322.
1
38): d = 7.33–7.21 (m, Ph ofboth isomers), 4.98 (d, J = 14.5 Hz, 1H, =
2
ofPh-C H2 major), 4.69 (d, J = 15.3 Hz, 1H, = ofPh-C H2
39), 4.30 (d,
= ofPh-
2
1
minor
2
J = 8.9 Hz, 1H, CH-CO-Pyminor), 4.19 (d, J = 15.3 Hz, 1H,
1
CH2 minor), 4.07 (d, J = 8.9 Hz, 1H, CH-CO-Pymajor), 3.82 (d, J = 14.5 Hz,
1
1H,
=
ofPh-C H2 major), 3.71 (m, 1H, CH-CH2OMe), 3.60–3.22 (m,
2
CH2OMe + 3= ofC H2NCH2 ofboth isomers), 3.25 (s, 3H, OC H3 major),
4
3.17 (s, 3H, OCH3 minor), 2.83 (s, 3H, NCH3 major), 2.79 (s, 3H, NCH3 minor),
1
2.72 (m, = ofC H2NCH2 ofboth isomers), 1.81 (m, C H2CH2NCH2CH2 of
4
Preparation of 35: A solution of 34 (3.479 g, 8.5 mmol), 60% perchloric
acid (0.4 mL, 4.0 mmol), and 10 wt.% palladium on charcoal (1.03 g,
1 mmol Pd) in MeOH (200 mL) was hydrogenated at 65 psi for a period
of4 d at room temperature. The catalyst was removed by ifltration and
the solution was neutralized with solid NaHCO3. After filtration of the
latter, the crude reaction mixture was subjected to a column chromatog-
raphy (10% MeOH/CH2Cl2) and the product 35 was obtained in a quan-
titative yield as a white solid. [a]D = ꢀ458 (c = 1.4, CHCl3); 1H NMR
both isomers); 13C NMR (CDCl3): d = 165.8 (COminor), 165.6 (COmajor),
160.4 (CO), 137.4 (iPhminor), 136.3 (iPhmajor), 128.8 (Ph), 128.4 (Ph), 127.8
(Ph), 127.5 (Ph), 127.2 (Ph), 70.1 (CH2OMemajor), 69.8 (CH2OMeminor),
58.8 (OCH3), 56.5 (CH), 56.1 (CH), 46.4 (CH2), 46.2 (CH2), 46.0 (CH2),
45.7 (CH2), 30.0 (NCH3 major), 29.8 (NCH3 major), 26.1 (NCH2CH2 minor), 26.0
(NCH2CH2 major), 23.9 (NCH2CH2); IR: n˜ = 2971, 2927, 2877, 1696, 1647,
1449, 1403, 1342, 1245, 1098, 704 cmꢀ1; MS (EI): m/z (%): 332 (2)
[M+H]+, 299 (6) [MꢀMeOH]+, 233 (31) [MꢀCOPy]+, 98 (35), 91 (100)
[PhCH2]+, 56 (23), 55 (30); HRMS (EI+): m/z: calcd for C18H25N3O3:
331.189592; found: 331.188348.
(CDCl3): d = 4.73 (d, J = 9.3 Hz, 1H, CH-CO-Py), 4.21 (m, 1H, CH-
1
CH2OMe), 3.61 (m, 1H,
CH2NCH2
=
4
ofC H2NCH2), 3.50–3.27 (m, 5H, 3 H of
+
CH2OMe), 3.50 (s, 3H, OCH3), 2.03–1.83 (m, 4H,
CH2CH2NCH2CH2); 13C NMR (CDCl3): d = 167.9 (CO), 164.5 (CO),
71.5 (CH2OMe), 59.0 (OCH3), 55.9 (CH-CO-Py), 53.4 (CH-CH2OMe),
46.4 (NCH2), 46.2 (NCH2), 26.0 (NCH2CH2), 23.9 (NCH2CH2); IR: n˜ =
3385, 2976, 2930, 2882, 1695, 1632, 1455, 1343, 1268, 1196, 1097 cmꢀ1; MS
(EI): m/z (%): 227 (2) [M]+, 195 (6) [MꢀMeOH]+, 182 (7)
[MꢀMeOCH2]+, 129 (53) [MꢀCOPy]+, 99 (88), 98 (100), 84 (26), 70
(58), 56 (38), 55 (43); HRMS (EI+): m/z: calcd for C10H17N3O3:
227.126992; found: 227.126997.
Preparation of 40 and 41: A solution of 38 and 39 (1.43 g, 4.32 mmol),
60% perchloric acid (0.1 mL, 1 mmol), and 10 wt.% palladium on char-
coal (500 mg, 0.5 mmol) in MeOH (100 mL) was hydrogenated at 65 psi
for a period of 18 h. The catalyst was removed by filtration and the so-
lution was neutralized with solid NaHCO3. After filtration of the latter,
the crude reaction mixture was subjected to a column chromatography
(3% MeOH/CH2Cl2) and a mixture ofisomers 40 and 41 was obtained in
quantitative yield as a white solid.
1H NMR (the number ofthe protons is calculated with respect to the in-
tegral of the peak at 4.37 for the minor and at 4.51 for the major prod-
uct): d = 4.51 (d, J = 9.3 Hz, 1H, CH-CO-Pymajor), 4.37 (d, J = 9.3 Hz,
1H, CH-CO-Pyminor), 3.84–3.99 (m, CH-CH2OMe ofboth isomers), 3.21–
3.48 (m, CH2OMe + CH2NCH2 ofboth isomers), 3.18 (s, OC H3 ofboth
isomers), 2.69 (s, 3H, NCH3 major), 2.62 (s, 3H, NCH3 minor), 1.72–1.90 (m,
Preparation of 36 and 37: A solution ofcompound 35 (2.40 g, 11 mmol)
in dry THF (10 mL) was added to a stirred suspension ofNaH (60% in
oil, 260 mg, 6.5 mmol) in dry THF (40 mL) at 08C. The mixture was stir-
red for 10 min at 08C, and afterwards benzylbromide (770 mL, 6.5 mmol)
was added, and the stirring was continued at room temperature for 3 h.
The solvent was evaporated and the crude reaction mixture was purified
by column chromatography (ethyl acetate to 20% MeOH/CH2Cl2) to
obtain a mixture ofisomers 36 and 37 (1.22 g, 35%, 70% based on limit-
ing NaH) in 87:13 ratio (determined by NMR). A small sample ofthis
mixture was subjected to preparative TLC (3% MeOH/CH2Cl2) and
after several developments the major product 36 was isolated and charac-
terised.
CH2CH2N CH2CH2 ofboth products); 13C NMR (CDCl3): d
= 167.5
(CO), 165.4 (COminor), 161.9 (CO), 71.7 (CH2OMeminor), 69.7 (CH2OMemajor),
61.4 (CHCOPyminor), 58.9, 58.7, 54.2 (CHCOPymajor), 50.2 (CHCH2OMeminor),
46.4 (NCH2 major), 46.2 (NCH2 minor), 46.0 (NCH2 major), 45.9 (NCH2 minor),
29.3 (NCH3 minor), 29.1 (NCH3 major), 26.1 (NCH2CH2 minor), 26.0
(NCH2CH2 major), 24.0 (NCH2CH2 minor), 23.9 (NCH2CH2 major); IR: n˜
=
1
3419, 2975, 2934, 2884, 1690, 1634, 1455, 1407, 1344, 1262, 1193, 1095,
624 cmꢀ1; MS (EI): m/z (%): 241 (2) [M]+, 209 (4) [MꢀMeOH]+, 143
(39) [MꢀCOPy]+, 113 (53), 98 (100), 70 (27), 56 (37), 55 (52); HRMS
(EI+): m/z: calcd for C11H19N3O3: 241.142642; found: 241.143564.
Compound 36: H NMR (CDCl3): d = 7.30–7.18 (m, 5H, Ph), 5.00 (d, J
1
= 14.5 Hz, = ofPh-C H2), 4.13 (d, J = 8.9 Hz, 1H, CH-CO-Py), 3.87 (d,
2
1
J = 14.5 Hz, 1H, = ofPh-C H2), 3.87 (m, 1H, CH-CH2OMe), 3.52 (m,
2
1
1
1
1H,
= ofC H2NCH2), 3.46–3.37 (m, 2H, = ofC H2NCH2 + = of
4 4 2
Chem. Eur. J. 2005, 11, 330 – 343
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
341