Proline Derivatives
FULL PAPER
HRMS (ESI): m/z: calcd for C35H36N4O8Na: 663.24254, found 663.24312
[M ++Na].
(s, 1H, NH, Gly), 4.92 (s, 1H, 2-H), 5.15 (s, 2H, OCH2Ph), 6.69 (brs, 1H,
NH, Z), 7.30–7.44 (m, 5H, Ph-H); 13C NMR (75.5 MHz, C2D2Cl4, APT,
1008C): d=24.1 (+, C-4*), 28.1 [+, C(CH3)3, C-3*], 32.7 (+, C- 1’), 41.0
(ꢀ, C-2, Gly), 47.8 (ꢀ, C-5), 51.9 (+, OCH3), 61.6 (+, C-2), 66.6 (ꢀ,
OCH2Ph), 80.8 [ꢀ, C(CH3)3], 127.6, 127.8, 128.2 (+, Ph-C), 136.3 (ꢀ, Ph-
C), 156.2 (ꢀ, 2ꢂNCO2), 169.5, 170.5 (ꢀ, C-1, C-1, Gly); IR (KBr): n˜ =
3320 (br, N-H), 2977 (C-H), 1702 (br, C=O), 1528, 1394 (tBu), 1368
(tBu), 1254, 1178, 1123, 872, 775, 699 cmꢀ1; MS (ESI): positive mode: m/z
(%):917 (100) [2M ++Na], 470 (24) [M ++Na]; negative mode: m/z (%):
893 (67) [2MꢀꢀH], 492 (49) [Mꢀ+COOH], 446 (100) [MꢀꢀH].
Methyl
(2S,2’R,3R,4R)-N-Fmoc-glycyl-3,4-(Z-aminomethano)prolyl-l-
phenylalaninate (19): According to GP 4, the tert-butyl ester group in 15
(153 mg, 250 mmol) was cleaved and the acid then coupled with phenyla-
lanine methyl ester hydrochloride (53.9 mg, 250 mmol) according to GP 3.
After column chromatography (10 g silica gel, 1ꢂ5 cm, hexane/EtOAc
4:1, Rf =0.25), 19 (166 mg, 93%) was obtained as a colorless amorphous
solid. M.p. 76–838C; [a]D20 =ꢀ18.88 (c=0.5, CHCl3); 1H NMR (300 MHz,
C2D2Cl4, 1008C): d=1.80–1.92 (m, 1H, 4-H), 2.00–2.15 (m, 1H, 3-H),
2.30–2.36 (m, 1H, 1’-H), 3.04 (dd, 2J=14.0, 3J=7.5 Hz, 1H, 1’-H, Phe),
3.22 (dd, 2J=14.0, 3J=7.5 Hz, 1H, 1’-H, Phe), 3.41–3.51 (m, 1H, 5-H),
3.54–3.96 (m, 3H, 5-H, 2-H, Gly), 3.76 (s, 3H, OMe), 4.27 (t, 3J=7.5 Hz,
1H, 9-H, Fmoc), 4.46 (d, 3J=7.5 Hz, 2H, 1’-H, Fmoc), 4.69 (s, 1H, NH,
Phe), 4.81–4.92 (m, 2H, 2-H, 2-H, Phe), 5.14 (s, 2H, OCH2Ph), 5.39–5.48
(m, 1H, NH, Fmoc), 6.80 (brs, 1H, NH, Z), 7.09–7.18 (m, 2H, Ph-H,
Phe), 7.18–7.48 (m, 12H, Ph-H, Phe, Fmoc, Z), 7.62 (d, 3J=7.5 Hz, 2H,
Ph-H, Fmoc), 7.79 (d, 3J=7.5 Hz, 2H, Ph-H, Fmoc); 13C NMR
(75.5 MHz, C2D2Cl4, APT, 1008C): d=24.2 (+, C-4*), 25.7 (+, C-3*),
32.2 (+, C- ’1), 37.5 (ꢀ, C- ’1, Phe), 43.4 (ꢀ, C-2, Gly), 47.2 (+, C-9,
Fmoc), 47.4 (-, C-5), 52.0 (+, C-2, Phe), 52.8 (+, OCH3), 61.3 (+, C-2),
66.7 (ꢀ, OCH2Ph*), 67.0 (ꢀ, C- 1’, Fmoc), 119.7, 124.8, 126.9, 127.5, 127.6,
127.9, 128.2, 128.3, 128.9 (+, Ph-C, Phe, Fmoc, Z), 135.8 (ꢀ, Ph-C, Phe),
136.2 (ꢀ Ph-C, Z), 141.1, 143.7 (ꢀ, Ph-C, Fmoc), 155.7, 156.0 (ꢀ, NCO2),
167.7, 168.4, 171.2 (ꢀ, C-1, C-1, Phe, C-1, Gly); IR (KBr): n˜ =3316 (N-
H), 2951 (C-H), 1726 (C=O), 1664, 1524, 1451, 1247, 1217, 759, 741,
700 cmꢀ1; MS (ESI): positive mode: m/z (%): 1455 (100) [2M ++Na], 739
(22) [M ++Na]; negative mode: m/z (%): 1477 (16) [2Mꢀ+COOH], 761
(33) [Mꢀ+COOH]; HRMS (ESI): m/z: calcd for C41H40N4O8Na:
739.27384, found 739.27447 [M ++Na].
Methyl (2S,2’R,3R,4R)-N-Boc-glycyl-3,4-(Z-aminomethano)prolylglyci-
nate (21): According to GP 4, the Boc group in 20 (112 mg, 250 mmol)
was cleaved and the free amine then coupled with N-Boc-glycine
(43.8 mg, 250 mmol) according to GP 3. After column chromatography
(10 g silica gel, 1ꢂ5 cm, hexane/EtOAc 5:1, Rf =0.18) 21 (71 mg, 56%)
was obtained as a colorless amorphous solid. M.p. 67–708C; [a]D20
=
1
ꢀ63.28 (c=0.5, CHCl3); H NMR (300 MHz, C2D2Cl4, 1008C): d=1.46 [s,
9H, C(CH3)3], 1.88–1.98 (m, 1H, 4-H*), 2.08–2.17 (m, 1H, 3-H*), 2.35–
2.40 (m, 1H, 1’-H), 3.66–3.75 (m, 2H, 5-H*), 3.76 (s, 3H, OCH3), 3.80–
3.90 (m, 2H, 2-H*, Gly), 3.97–4.06 (m, 2H, 2-H, Gly), 4.94 (s, 1H, 2-H),
5.02 (s, 1H, NH, Gly), 5.12 (s, 2H, OCH2Ph), 5.24 (s, 1H, NH, Boc), 6.92
(brs, 1H, NH, Z), 7.28–7.42 (m, 5H, Ph-H); 13C NMR (75.5 MHz,
C2D2Cl4, APT, 1008C): d=24.4 (+, C-4*), 26.0 (+, C-3*), 28.1 [+, C-
(CH3)3], 32.4 (+, C- 1’), 41.0 (ꢀ, C-2, Gly), 43.3 (ꢀ, C-2, Gly), 47.6 (ꢀ, C-
5), 51.9 (+, OCH3), 61.3 (+, C-2), 66.7 (ꢀ, OCH2Ph), 79.7 [ꢀ, C(CH3)3],
127.6, 127.9, 128.3 (+, Ph-C), 136.2 (ꢀ, Ph-C), 155.3, 156.1 (ꢀ, NCO2),
168.4, 169.4, 169.5 (ꢀ, C-1, C-1, Gly, C-1, Gly); IR (KBr): n˜ =3324 (N-
H), 2977 (C-H), 2937 (C-H), 1716 (C=O), 1659 (C=O), 1528, 1454, 1439,
1394 (tBu), 1367 (tBu), 1251, 1213, 1175, 1050, 741, 699 cmꢀ1; MS (ESI):
positive mode: m/z (%): 1535 (7) [3M ++Na], 1031 (100) [2M ++Na],
527 (64) [M ++Na]; negative mode: m/z (%): 1007 (20) [2MꢀꢀH], 549
(69) [Mꢀ+COOH], 503 (64) [MꢀꢀH]; HRMS (ESI): m/z: calcd for
C24H32N4O8Na: 527.21124, found 527.21137 [M ++Na].
(2S,2’R,3R,4R)-Na-Boc-3,4-(Z-aminomethano)proline [(2S,2’R,3R,4R)-
16]: A 2m solution of HCl in EtOAc (5 mL) was added to a solution of
(2S,2’R,3R,4R)-14 (1.68 g, 3.88 mmol) in EtOAc (10 mL) and the result-
ing mixture was stirred for 11 h. All volatile compounds were removed in
vacuo. The residue was taken up in H2O (4 mL), the mixture cooled to
08C and treated with a 1m aq. solution of NaOH (7.76 mL, 7.76 mmol)
Methyl
(2S,2’R,3R,4R)-N-Boc-l-alaninyl-3,4-(Z-aminomethano)prolyl-
glycinate (22): According to GP 4, the Boc group in 20 (112 mg,
250 mmol) was cleaved and the free amine then coupled with N-Boc-ala-
nine (47.3 mg, 250 mmol) according to GP 3. After column chromatogra-
phy (10 g silica gel, 1ꢂ5 cm, hexane/EtOAc 3:1, Rf =0.19) 22 (79 mg,
and NaHCO3 (48.9 mg, 582 mmol).
A solution of Boc2O (932 mg,
4.27 mmol) in THF (5 mL) was added, the solution was warmed to ambi-
ent temperature and stirred for an additional 18 h. The reaction mixture
was saturated with NaCl and then acidified with KHSO4 up to pH 1–2.
The reaction mixture was extracted with EtOAc (5ꢂ10 mL). The com-
bined organic extracts were dried and concentrated in vacuo. Column
chromatography of the residue (30 g silica gel, 1ꢂ20 cm, hexane/EtOAc
2:1 + 1.5 vol.% HOAc, Rf =0.14, furnished (2S,2’R,3R,4R)-16 (936 mg,
64%) as a colorless foam. M.p. 69–738C; [a]2D0 =ꢀ54.68 (c=0.5, CHCl3);
1H NMR (300 MHz, CDCl3, rotamers): d=1.40, 1.43 [s, 9H, C(CH3)3],
1.68–1.82 (m, 1H, 4-H*), 1.85–2.00 (m, 1H, 3-H*), 2.42–2.51 (m, 1H,
1’-H), 3.48–3.63 (m, 1H, 5-H), 3.63–3.78 (m, 1H, 5-H), 4.37–4.54 (m, 1H,
2-H), 5.02–5.23 (m, 2H, OCH2Ph), 6.14 (brs, 1H, NH, Z), 7.26–7.42 (m,
5H, Ph-H), 8.40 (brs, 1H, COOH); 13C NMR (50.3 MHz, CDCl3, APT,
rotamers): d=24.6 (+, C-4*), 28.2, 28.3 [+, C(CH3)3, C-3*], 32.6 (+,
C-1’), 47.7, 47.9 (ꢀ, C-5), 60.4, 60.5 (+, C-2), 67.1 (ꢀ, OCH2Ph), 80.7,
81.3 [ꢀ, C(CH3)3], 128.3, 128.6 (+, 3ꢂPh-C), 136.0 (ꢀ, Ph-C), 154.0,
155.1 (ꢀ, NCO2), 175.7 (ꢀ, C-1); IR (KBr): n˜ =3324 (br, N-H), 2978 (C-
H), 2937 (C-H), 2887 (C-H), 1705 (br, C=O), 1526, 1396 (tBu), 1369
(tBu), 1256, 1173, 1127, 1070, 871, 776, 698 cmꢀ1; MS (ESI): positive
mode: m/z (%): 775 (100) [2M ++Na], 399 (34) [M ++Na]; negative
mode: m/z (%): 751 (69) [2MꢀꢀH], 375 (61) [MꢀꢀH]; HRMS (ESI): m/
z: calcd for C19H24N2O6Na: 399.15266, found 399.15295 [M ++Na].
61%) was obtained as a colorless amorphous solid. M.p. 63–658C; [a]D20
=
ꢀ65.38 (c=0.3, CHCl3); 1H NMR (300 MHz, C2D2Cl4, 1008C): d=1.25–
1.38 (m, 3H, CH3, Ala), 1.45 [s, 9H, C(CH3)3], 1.87–1.98 (m, 1H, 4-H*),
2.11–2.23 (m, 1H, 3-H*), 2.34–2.45 (m, 1H, 1’-H), 3.60–3.75 (m, 1H, 5-
H*), 3.74 (s, 3H, OCH3), 3.90–4.11 (m, 1H, 5-H*), 3.96 (dd, 2J=18.0,
3J=6.0 Hz, 1H, 2-H*, Gly), 4.05 (dd, 2J=18.0, 3J=6.0 Hz, 1H, 2-H*,
Gly), 4.25–4.46 (m, 1H, 2-H, Ala), 4.80 (s, 1H, NH, Gly), 4.98 (s, 1H, 2-
H), 5.13 (s, 2H, OCH2Ph), 5.17 (s, 1H, NH, Boc), 6.91 (brs, 1H, NH, Z),
7.28–7.43 (m, 5H, Ph-H); 13C NMR (75.5 MHz, C2D2Cl4, APT, 1008C):
d=17.8 (+, CH3, Ala), 24.4 (+, C-4*), 25.6 (+, C-3*), 28.1 [+,
C(CH3)3], 32.1 (+, C- 1’), 41.0 (ꢀ, C-2*, Gly), 48.0 (ꢀ, C-5), 48.4 (+, C-2,
Ala), 51.8 (+, OCH3), 61.0 (+, C-2), 66.7 (ꢀ, OCH2Ph), 79.6 [ꢀ,
C(CH3)3], 127.5, 127.8, 128.2 (+, Ph-C), 136.3 (ꢀ, Ph-C), 154.7, 156.0 (ꢀ,
NCO2), 169.4, 172.5 (ꢀ, C-1, C-1, Ala, C-1, Gly); IR (KBr): n˜ =3322 (N-
H), 2979 (C-H), 2936 (C-H), 2884 (C-H), 1711 (C=O), 1646 (C=O), 1526,
1455, 1393 (tBu), 1368 (tBu), 1252, 1212, 1170, 742, 699 cmꢀ1; MS (ESI):
positive mode: m/z (%): 1059 (100) [2M ++Na], 541 (37) [M +ꢀNa]; neg-
ative mode: m/z (%): 563 (69) [Mꢀ+COOH], 517 (100) [MꢀꢀH];
HRMS (ESI): m/z: calcd for C25H34N4O8Na: 541.22689, found 541.22682
[M ++Na].
Methyl (2S,2’R,3R,4R)-N-Boc-l-phenylalaninyl-3,4-(Z-aminomethano)-
prolylglycinate (23): According to GP 4, the Boc group in 20 (112 mg,
250 mmol) was cleaved and the free amine then coupled with N-Boc-phe-
nylalanine (66.3 mg, 250 mmol) according to GP 3. After column chroma-
tography (10 g silica gel, 1ꢂ5 cm, hexane/EtOAc 2:1, Rf =0.20) 23
(108 mg, 73%) was obtained as a colorless amorphous solid. M.p. 72–
758C; [a]2D0 =ꢀ41.28 (c=0.5, CHCl3); 1H NMR (300 MHz, C2D2Cl4,
1008C): d=1.44 [s, 9H, C(CH3)3], 1.78–1.89 (m, 1H, 4-H*), 2.06–2.16 (m,
1H, 3-H*), 2.29–2.41 (m, 1H, 1’-H), 2.94 (dd, 2J=14.0, 3J=7.5 Hz, 1H,
CH2Ph, Phe), 2.98–3.11 (m, 1H, CH2Ph, Phe), 3.18–3.31 (m, 1H, 5-H*),
Methyl
(2S,2’R,3R,4R)-Na-Boc-3,4-(Z-aminomethano)prolylglycinate
(20): According to GP 3 (2S,2’R,3R,4R)-16 (188 mg, 500 mmol) was treat-
ed with GlyOMe·HCl (62.8 mg, 500 mmol) to yield after column chroma-
tography (10 g silica gel, 1ꢂ5 cm, hexane/EtOAc 3:2, Rf =0.20), 20
(198 mg, 88%) as a colorless amorphous solid. M.p. 60–638C; [a]D20
=
1
ꢀ65.68 (c=0.5, CHCl3); H NMR (300 MHz, C2D2Cl4, 1008C): d=1.50 [s,
9H, C(CH3)3], 1.74–1.83 (m, 1H, 4-H*), 2.04–2.12 (m, 1H, 3-H*), 2.37–
2.42 (m, 1H, 1’-H), 3.52 (dd, 2J=11.0, 3J=4.5 Hz, 1H, 5-H), 3.68 (s, 3H,
OCH3), 3.68–3.78 (m, 1H, 5-H), 4.05 (d, 2J=6.0 Hz, 2H, 2-H, Gly), 4.46
Chem. Eur. J. 2005, 11, 6593 – 6600
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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