808 Journal of Natural Products, 2008, Vol. 71, No. 5
Murphy et al.
∼1:1 mixture of syn- and anti-rotamers around the carbamate was
obtained): Rf 0.24 (silica, 1:1 petroleum ether-EtOAc, visualization
UV/PMA); [R]20D +20 (c 0.10, CHCl3); IR (thin film) νmax 1748, 1705,
1418, 1351, 1201 cm-1; 1H NMR (CDCl3, 500 MHz) δ 7.38–7.30 (5H,
m, CBz), 5.14 (2H, m, CBz), 4.43 (1H, d, 10.0 Hz, H-2), 4.38 (1H, m,
H-4), 4.26 (1H, q, 7.0 Hz, Et), 4.08 (1H, m, Et), 3.78 (1/2H, d, 11.7
Hz, H-5a), 3.73 (1/2H, d, 11.7 Hz, H-5a), 3.64 (1/2H, dd, 12.2 Hz, 4.6
Hz, H-5b), 3.60 (1/2H, dd, 11.8 Hz, 4.5 Hz, H-5b), 2.34 (1H, m, H-3a),
2.12 (1H, m, H-3b), 1.31 (3/2H, t, 7.3 Hz, Et), 1.15 (3/2H, t, 7.2 Hz,
Et); 13C NMR (CDCl3, 75 MHz) δ 174.7 (C, ester CdO), 174.5 (C,
ester CdO), 154.9 (C, CBz CdO), 154.2 (C, CBz CdO), 136.3 (C,
CBz), 136.2 (C, CBz), 128.5 (CH, CBz), 128.4 (CH, CBz), 128.1 (CH,
CBz), 127.9 (CH, CBz), 127.8 (CH, CBz), 71.3 (CH, C-4), 70.3 (CH,
C-4), 67.3 (CH2, CBz), 62.0 (CH2, Et), 61.9 (CH2, Et), 58.3 (CH, C-2),
57.9 (CH, C-2), 56.2 (CH2, C-5), 55.9 (CH2, C-5), 38.6 (CH2, C-3),
37.7 (CH2, C-3), 13.9 (CH3, Et); HRESIMS m/z 294.1329 [M + H]+
4.1 ppm (294.1341 calcd for C15H20NO5).
cis-4-Methyl-L-proline Ethyl Ester, 3. N-CBz-4-Exomethylene-L-
proline ethyl ester (2, 15 mg, 0.052 mmol) was dissolved in CH2Cl2 (1
mL) and 10% Pd/C (1.5 mg) added. The reaction was placed under an
atmosphere of H2(g) by means of a balloon and stirred at room
temperature for 16 h. The catalyst was removed by filtration through
a pad of Celite using CH2Cl2 (15 mL) and the solvent removed in Vacuo
to give the product (5.5 mg, 0.035 mmol, 67%) as a colorless oil: [R]20
D
–36 (c 0.31, CHCl3) (cis:trans, ∼7:1); IR (thin film) νmax 3418, 1743,
1
1263, 1230 cm-1; H NMR (CDCl3, 500 MHz) δ 4.47 (1H, t, 8.8 Hz,
H-2), 4.30 (2H, q, 7.1 Hz, Et), 3.68 (1H, m, H-5a), 2.98 (1H, br t, 10.5
Hz, H-5b), 2.63–2.56 (2H, m, H-3a and H-4), 1.66 (1H, m, H-3b),
1.32 (3H, t, 7.1 Hz, Et), 1.13 (3H, d, 6.4 Hz, H-6); 13C NMR (CDCl3,
75 MHz) δ 169.1 (C, ester CdO), 62.9 (CH2, Et), 59.0 (CH, C-2),
52.3 (CH2, C-5), 36.8 (CH2, C-3), 33.2 (CH, C-4), 16.4 (CH3, C-6),
14.0 (CH3, Et); HRESIMS m/z 158.1183 [M + H]+ 1.3 ppm (158.1181
calcd for C8H16NO2).
cis-4-Methyl-D-proline Ethyl Ester, ent-3. As described above,
N-CBz-4-Keto-L-proline Ethyl Ester, 1. Chromium trioxide (6.30
g, 63.0 mmol, 13 equiv) was dissolved in a mixture of pyridine (10.2
mL) and CH2Cl2 (50 mL) and stirred at room temperature for 15 min.
After this time N-CBz-trans-4-hydroxy-L-proline ethyl ester (1.4 g, 4.77
mmol) dissolved in CH2Cl2 (20 mL) was added to the mixture. The
reaction was stirred at room temperature for 16 h, and then filtered
through a silica pad using 50% EtOAc in petroleum ether (200 mL).
After removal of the solvents in Vacuo, the product (1.18 g, 4.05 mmol,
85%) was obtained as a colorless oil (an inseparable ∼1:1 mixture of
syn- and anti-rotamers around the carbamate was obtained): Rf 0.43
using N-CBz-4-exomethylene-D-proline ethyl ester, ent-2: colorless oil
obtained in quantitative yield; [R]20 +39 (c 0.30, CHCl3) (cis:trans,
D
∼7:1).
N-CBz-trans-4-Methyl-L-proline Ethyl Ester, 5. N-CBz-4-Exo-
methylene-L-proline ethyl ester (2, 30 mg, 0.104 mmol) was dissolved
in CHCl3 (1 mL), and Ir(cod)pyr(PCy3)]PF6 (Crabtree’s catalyst, 3 mg,
0.004 mmol, 4 mol %) was added. The reaction was placed under an
atmosphere of H2(g) by means of a balloon and stirred at room
temperature for 5 days. The crude product was purified on silica using
a stepwise gradient of 2% to 6% diethyl ether in petroleum ether to
give the product (25 mg, 0.087 mmol, 84%) as a colorless oil, plus
isomerization product 4 (3 mg, 0.010 mmol, 10%) as a colorless oil.
Inseparable ∼1:1 mixtures of syn- and anti-rotamers around the
carbamate were obtained for both products. 4: Rf 0.29 (silica, 4:1
(silica, 2:1 petroleum ether-EtOAc, visualization UV/PMA); [R]20
D
–4 (c 1.00, CHCl3); IR (thin film) νmax 1767, 1743, 1713, 1416, 1192,
1
1158 cm-1; H NMR (CDCl3, 500 MHz) δ 7.38–7.32 (5H, m, CBz),
5.20 (2H, m, CBz), 4.85 (1/2H, d, 10.8 Hz, H-2), 4.81 (1/2H, d, 10.8
Hz, H-2) 4.22 (1H, q, 7.2 Hz, Et), 4.09 (1H, m, Et), 3.96 (2H, m, H-5),
2.95 (1H, m, H-3a), 2.60 (1H, dd, 18.8 Hz, 2.6 Hz, H-3b), 1.27 (3/2H,
t, 7.2 Hz, Et), 1.16 (3/2H, t, 7.2 Hz, Et); 13C NMR (CDCl3, 75 MHz)
δ 207.8 (C, C-4), 207.1 (C, C-4), 171.3 (C, ester CdO), 154.9 (C,
CBz CdO), 154.1 (C, CBz CdO), 135.9 (C, CBz), 129.0 (CH, CBz),
128.5 (CH, CBz), 128.3 (CH, CBz), 128.0 (CH, CBz), 67.7 (CH2, CBz),
61.8 (CH2, Et), 56.0 (CH, C-2), 52.6 (CH2, C-5), 52.4 (CH2, C-5), 41.1
(CH2, C-3), 40.6 (CH2, C-3), 14.0 (CH3, Et); HRESIMS m/z 292.1191
[M + H]+ 2.1 ppm (292.1185 calcd for C15H18NO5).
petroleum ether-EtOAc, visualization UV/PMA); IR (thin film) νmax
1
1751, 1709, 1427, 1203, 1183 cm-1; [R]20 –87 (c 0.30, CHCl3); H
D
NMR (CDCl3, 500 MHz) δ 7.38–7.30 (5H, m, CBz), 6.40 (1/2H, br s,
H-5), 6.32 (1/2H, br s, H-5), 5.15 (2H, m, CBz), 4.70 (1/2H, dd, 12.0
Hz, 5.0 Hz, H-2), 4.64 (1/2H, dd, 12.0 Hz, 5.0 Hz, H-2), 4.23 (1H, q,
7.0 Hz, Et), 4.08 (1H, q, 7.1 Hz, Et), 2.99 (1H, m, H-3a), 2.53 (1H, m,
H-3b), 1.70 (3/2H, br s, H-6), 1.68 (3/2H, br s, H-6), 1.28 (3/2H, t, 7.1
Hz, Et), 1.15 (3/2H, t, 7.1 Hz, Et); 13C NMR (CDCl3, 75 MHz) δ 128.5
(CH, CBz), 128.0 (CH, CBz), 127.9 (CH, CBz), 124.3 (CH, C-5), 123.7
(CH, C-5), 67.3 (CH2, CBz), 67.1 (CH2, CBz), 61.4 (CH2, Et), 58.7
(CH, C-2), 58.6 (CH, C-2), 39.6 (CH2, C-3), 14.1 (CH3, Et), 13.2 (CH3,
C-6), quaternary carbons not observed; HRESIMS m/z 290.1404 [M
+ H]+ 4.1 ppm (290.1392 calcd for C16H20NO4). 5: Rf 0.24 (silica, 4:1
petroleum ether-EtOAc, visualization UV/PMA); [R]20D –43 (c 1.00,
CHCl3) (cis:trans, ∼1:15); IR (thin film) νmax 1747, 1710, 1417, 1357,
N-CBz-4-Keto-D-proline Ethyl Ester, ent-1. As described above
using N-CBz-cis-4-hydroxy-D-proline ethyl ester: colorless oil obtained
in 87% yield; [R]20 +4 (c 1.00, CHCl3).
D
N-CBz-4-Exomethylene-L-proline Ethyl Ester, 2. To N-CBz-4-
keto-L-proline ethyl ester (1, 100 mg, 0.34 mmol) dissolved in
anhydrous toluene (1 mL) was added a toluene solution of dimethylti-
tanocene24 (∼0.88 mmol in ∼ 1 mL, 2.6 equiv), and the reaction was
heated to 90 °C for 3 h. After cooling to room temperature the mixture
was added dropwise to stirred petroleum ether (50 mL), whereupon a
yellow precipitate formed and was stirred for a further 30 min. The
precipitate was removed by filtration through a bed of Celite, and the
solvents were removed in Vacuo. The crude residue was purified by
chromatography on silica using a stepwise gradient of 2–10% diethyl
ether in petroleum ether to give the product (54 mg, 0.19 mmol, 56%)
as a colorless oil (an inseparable ∼1:1 mixture of syn- and anti-rotamers
around the carbamate was obtained): Rf 0.57 (silica, 2:1 petroleum
1
1194 cm-1; H NMR (CDCl3, 500 MHz) δ 7.38–7.28 (5H, m, CBz),
5.18–5.04 (2H, m, CBz), 4.41 (1/2H, dd, 9.0 Hz, 2.6 Hz, H-2), 4.36
(1/2H, dd, 9.0 Hz, 2.6 Hz, H-2), 4.19 (1H, q, 7.4 Hz, Et), 4.05 (1H, m,
Et), 3.78 (1H, m, H-5a), 3.05 (1/2H, dd, 10.1 Hz, 8.5 Hz, H-5b), 2.99
(1/2H, dd, 10.1 Hz, 8.8 Hz, H-5b), 2.41 (1H, m, H-4), 2.09 (1H, m,
H-3a), 1.84 (1H, m, H-3b), 1.26 (3/2H, t, 7.2 Hz, Et), 1.14 (3/2H, t,
7.2 Hz, Et), 1.05 (3/2H, d, 6.7 Hz, H-6), 1.03 (3/2H, d, 6.7 Hz, H-6);
13C NMR (CDCl3, 75 MHz) δ 172.8 (C, ester CdO), 172.6 (C, ester
CdO), 154.2 (C, CBz CdO), 136.7 (C, CBz), 128.4 (CH, CBz), 128.3
(CH, CBz), 127.91 (CH, CBz), 127.85 (CH, CBz), 127.8 (CH, CBz),
127.7 (CH, CBz), 66.94 (CH2, CBz), 66.88 (CH2, CBz), 61.1 (CH2,
Et), 61.0 (CH2, Et), 59.5 (CH, C-2), 59.1 (CH, C-2), 53.6 (CH2, C-5),
53.3 (CH2, C-5), 38.5 (CH2, C-3), 37.6 (CH2, C-3), 32.0 (CH, C-4),
31.1 (CH, C-4), 17.33 (CH3, C-6), 17.29 (CH3, C-6), 14.14 (CH3, Et),
14.05 (CH3, Et); HRESIMS m/z 292.1545 [M + H]+ 1.4 ppm (292.1549
calcd for C16H22NO4).
ether-EtOAc, visualization UV/PMA); [R]20 –16 (c 1.00, CHCl3);
D
IR (thin film) νmax 1747, 1714, 1417, 1360, 1196, 896 cm-1; 1H NMR
(CDCl3, 500 MHz) δ 7.38–7.29 (5H, m, CBz), 5.14 (2H, m, H-6), 5.02
(2H, m, CBz), 4.55 (1/2H, dd, 9.6 Hz, 2.9 Hz, H-2), 4.50 (1/2H, dd,
9.6 Hz, 2.9 Hz, H-2), 4.17 (3H, m, H-4, Et), 4.07 (1H, m, Et), 2.98
(1H, m, H-3a), 2.64 (1H, br d, 16.1 Hz, H-3b), 1.26 (3/2H, t, 7.2 Hz,
Et), 1.14 (3/2 H, t, 7.2 Hz, Et); 13C NMR (CDCl3, 75 MHz) δ 172.1
(C, ester CdO), 172.0 (C, ester CdO), 154.9 (C, CBz CdO), 154.3
(C, CBz CdO), 142.9 (C, C-4), 142.0 (C, C-4), 136.5 (C, CBz), 136.4
(C, CBz), 128.8 (CH, CBz), 128.6 (CH, CBz), 128.5 (CH, CBz), 128.4
(CH, CBz), 128.01 (CH, CBz), 127.97 (CH, CBz), 127.9 (CH, CBz),
127.8 (CH, CBz), 108.3 (CH2, C-6), 108.2 (CH2, C-6), 67.13 (CH2,
CBz), 67.07 (CH2, CBz), 61.3 (CH2, Et), 61.2 (CH2, Et), 59.0 (CH,
C-2), 58.9 (CH, C-2), 51.0 (CH2, C-5), 50.5 (CH2, C-5), 36.8 (CH2,
C-3), 36.0 (CH2, C-3), 14.1 (CH3, Et), 14.0 (CH3, Et); HRESIMS m/z
290.1404 [M + H]+ 4.1 ppm (290.1392 calcd for C16H20NO4).
N-CBz-4-Exomethylene-D-proline Ethyl Ester, ent-2. As described
above, using N-CBz-4-keto-D-proline ethyl ester, ent-1: colorless oil
Note. If this reaction was allowed to proceed for 16 h and then
purified, no hydrogenated product 5 was isolated, and an approximately
quantitative yield of 4 was recovered. If purified 4 was reacted under
the same conditions as above, its conversion to 5 could be observed
by proton NMR spectroscopy over the course of several days.
N-CBz-trans-4-Methyl-D-proline Ethyl Ester, ent-5. As described
above, using N-CBz-4-exomethylene-D-proline ethyl ester, ent-2: color-
less oil obtained in 80% yield; [R]20 +41 (c 0.31, CHCl3) (cis:trans,
D
∼1:15).
cis-4-Methyl-L-proline Hydrochloride, 6. cis-4-Methyl-L-proline
ethyl ester (3, 3.3 mg, 0.021 mmol) was dissolved in 6 M HCl(aq) (300
µL), sealed in a thick-walled glass tube, and heated to 70 °C for 6 h.
After cooling to room temperature, the reaction was extracted with
obtained in 42% yield; [R]20 +15 (c 1.00, CHCl3).
D