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4.40 ± 4.00 (m, CHCH2O of Fmoc, CH(2) of Pro); 3.44 ± 3.32 (m, CH2(5) of Pro); 2.24 ± 1.82 (m, CH2(3) and
CH2(4) of Pro); 1.36, 1.33 (2s, 2 Me of Aib). 13C-NMR: 175.3, 171.2 (2s, 2 CO); 153.8( s, CO (urethane)); 144.0,
143.7, 143.4, 140.6 (4s, 4 arom. C); 127.5, 127.0, 125.5, 125.2, 125.0, 120.0 (6d, 8arom. CH); 66.7 ( t, CHCH2O of
Fmoc); 59.2 (d, C(2) of Pro); 54.8( s, C(2) of Aib); 47.0 (t, C(5) of Pro); 46.5 (d, CHCH2O of Fmoc); 31.0
(t, C(3) of Pro); 25.1, 24.4 (2q, 2 Me of Aib); 22.7 (t, C(4) of Pro). ESI-MS (MeOH): 445 (48, [M Na] ), 423
(100, [M H] ). Anal. calc. for C24H26N2O5 (422.48): C 68.23, H 6.20, N 6.63; found: C 68.10, H 6.28, N 6.42.
2.3. N-[(9H-Fluoren-9-ylmethoxy)carbonyl]-l-prolyl-2-amino-2-methylpropanoylglycyl-2-amino-2-methyl-
propanoyl-2-amino-N,2-dimethyl-N-phenylpropanamide (Fmoc-Pro-Aib-Gly-Aib-Aib-N(Me)Ph; 7). Accord-
ing to GP 3, with Z-Gly-Aib-Aib-N(Me)Ph [5] (6; 0.54 g, 1.15 mmol), Pd/C (60 mg), and MeOH (6 ml),
overnight). CC (CH2Cl2/MeOH 15 :1) yielded 0.385 g (100%) of H-Gly-Aib-Aib-N(Me)Ph as a white foam,
which was used directly in the next step.
According to GP 4, with Fmoc-Pro-Aib-OH (5; 0.442 g, 1.05 mmol), H-Gly-Aib-Aib-N(Me)Ph (0.385 g,
1.15 mmol), PyBOP (0.544 g, 1.05 mmol), and DIEA (0.27 g, 2.1 mmol) in abs. CH2Cl2/MeCN 4 :1 (10 ml). CC
(AcOEt/MeOH 13 :1, CH2Cl2/MeOH 15 :1) yielded 0.536 g (69%) of 7. White powder. M.p. 136 ± 1388. IR:
3323m, 3064w, 2984m, 2940m, 1673s, 1594m, 1534s, 1494m, 1452s, 1425m, 1391m, 1361m, 1336m, 1281m, 1244m,
1195m, 1168m, 1125m, 1091m, 1017w, 991w, 760m, 741m, 708m. 1H-NMR: 8.77, 8.04, 7.90, 7.88 (4s, 4 NH); 7.64 ±
7.15 (m, 13 arom. H); 4.37 ± 4.12 (m, CHCH2O of Fmoc, CH(2) of Pro); 3.52 ± 3.41 (m, CH2 of Gly, CH2(5) of
Pro); 3.22 (s, MeN); 2.15 ± 1.85 (m, CH2(3) and CH2(4) of Pro); 1.39, 1.36, 1.28, 1.21 (4s, 6 Me of 3 Aib).
13C-NMR (CD3OD): 178.1, 176.2, 175.5, 175.2, 171.6 (5s, 5 CO); 156.8( s, CO (urethane)); 147.0, 145.0, 144.9,
142.5 (4s, 5 arom. C); 130.2, 128.9, 128.1, 126.2, 125.9, 121.0 (6d, 13 arom. CH); 69.0 (t, CHCH2O of Fmoc); 61.5
(d, C(2) of Pro); 58.4, 58.2, 57.6 (3s, 3 C(2) of 3 Aib); 48.24 (t, C(5) of Pro); 48.20 (d, CHCH2O of Fmoc); 45.4
(t, C(2) of Gly); 41.0 (q, MeN); 31.0 (t, C(3) of Pro); 25.6 (t, C(4) of Pro); 27.1, 26.5, 26.4, 26.1, 24.4, 24.0
(6q, 6 Me of 3 Aib). ESI-MS (MeOH/CH2Cl2): 784 (32, [M K] ), 632 (100, [M À N(Me)Ph] ). Anal. calc. for
C41H50N6O7 ´ 1/2 H2O (747.89): C 65.84, H 6.87, N 11.24; found: C 65.87, H 6.80, N 11.25.
2.4. N-[(9H-Fluoren-9-ylmethoxy)carbonyl]-l-propyl-2-amino-2-methylpropanoylglycyl-2-amino-2-meth-
ylpropanoyl-2-amino-2-methylpropanoic Acid (Fmoc-Pro-Aib-Gly-Aib-Aib-OH; 8). According to GP 2, with
7 (0.478g, 0.65 mmol) in 3 n HCl (MeCN/H2O 1:1, 6 ml). The solvent was evaporated, H2O (5 ml) added, and
the precipitated product filtered, washed with H2O and Et2O, and dried under h.v.: 0.38g (91%) of pure 8. White
powder. M.p. 185.5 ± 187.58. IR: 3325m, 2983m, 2938m, 1662s, 1603m, 1525s, 1452s, 1362m, 1338m, 1289m,
1210m, 1133m, 1019w, 98 9w, 942w, 8 68w, 759m, 741m. 1H-NMR (CD3OD): 7.80 ± 7.28 (m, 8arom. H); 4.43 ± 4.21
(m, CHCH2O of Fmoc, CH(2) of Pro); 3.76 ± 3.50 (m, CH2 of Gly, CH2(5) of Pro); 2.22 ± 1.88 (m, CH2(3) and
CH2(4) of Pro); 1.48, 1.43, 1.31, 1.19 (4s, 6 Me of 3 Aib). 13C-NMR (CD3OD): 181.3, 179.9, 176.1, 174.6, 169.7
(5s, 6 CO); 156.4 (s, CO (urethane)); 144.8, 143.1, 142.4 (3s, 4 arom. C); 128.9, 128.0, 127.7, 126.0, 125.7, 121.0,
120.9 (7d, 8arom. CH); 70.2 ( t, CHCH2O of Fmoc); 60.7 (d, C(2) of Pro); 58.6, 58.3, 57.1 (3s, 3 C(2) of 3 Aib);
48.6 (t, C(5) of Pro); 47.4 (d, CHCH2O of Fmoc); 44.7 (t, C(2) of Gly); 31.3 (t, C(3) of Pro); 25.7 (t, C(4) of
Pro); 25.0, 24.3, 24.1, 22.9 (4q, 6 Me of 3 Aib). ESI-MS (MeOH NaI): 672 (100, [M Na] ).
2.5. Fmoc-Pro-Aib-Gly-Aib-Aib-Phe-OtBu (9). According to GP 4, with 8 (0.338g, 0.52 mmol), HCl ´ H-
Phe-OtBu (0.147 g, 0.57 mmol), PyBOP (0.27 g, 0.52 mmol), and DIEA (0.2 g, 1.56 mmol) in abs. CH2Cl2/
MeCN 3 :2 (10 ml) for 20 h. CC (CH2Cl2/MeOH 20 :1) yielded 0.358g (81%) of 9. White powder. M.p. 166.5 ±
167.58. IR: 3323m, 2981m, 2936m, 1671s, 1535s, 1453s, 1425m, 1363m, 1336m, 1283m, 1247m, 1160s, 1128m, 990w,
847w, 759m, 741m, 701m. 1H-NMR (CD3OD): 7.79 ± 7.15 (m, 13 arom. H); 4.44 ± 4.17 (m, CHCH2O of Fmoc,
CH(2) of Phe, CH(2) of Pro); 3.87 ± 3.50 (m, CH2 of Gly, CH2(5) of Pro); 3.07 ± 3.02 (m, CH2 of Phe); 2.25 ± 1.85
(m, CH2(3) and CH2(4) of Pro); 1.44, 1.42, 1.41, 1.35, 1.30, 1.15 (6s, 6 Me of 3 Aib, Me3C). 13C-NMR (CD3OD):
177.9, 176.9, 175.8, 175.2, 172.2, 172.1 (6s, 6 CO); 156.8( s, CO (urethane)); 145.0, 144.9, 142.6, 138.5
(4s, 5 arom. C); 130.4, 129.2, 128.9, 128.1, 127.5, 126.1, 125.9, 121.0 (8d, 13 arom. CH); 82.4 (s, Me3C); 69.0
(t, CHCH2O of Fmoc); 61.5, 56.5 (2d, C(2) of Pro, C(2) of Phe); 48.3 (t, C(5) of Pro); 48.2 (d, CHCH2O of
Fmoc); 45.3, 38.4 (2t, C(2) of Gly, C(3) of Phe); 31.0 (t, C(3) of Pro); 28.1 (q, Me3C); 26.9, 26.8, 26.7 (3q, 6 Me
of 3 Aib); 25.6 (t, C(4) of Pro). ESI-MS (MeOH NaI): 876 (100, [M Na] ). Anal. calc. for C47H60N6O9 ´
1/3 H2O (859.03): C 65.71, H 7.12, N 9.78; found: C 65.70, H 7.26, N 9.72.
3. N-[(Benzyloxy)carbonyl]-l-phenylalanyl-l-prolyl-2-amino-2-methylpropanoylglycyl-2-amino-2-methyl-
propanoyl-2-amino-2-methylpropanoic Acid tert-Butyl Ester (Z-Phe-Pro-Aib-Gly-Aib-Aib-OtBu; 13). 3.1. N-
[(Benzyloxy)carbonyl]-l-phenylalanyl-2-amino-N,2-dimethyl-N-phenylpropanamide
(Z-Phe-Pro-Aib-
N(Me)Ph; 10). A soln. of Fmoc-Pro-Aib-N(Me)Ph (4; 2.479 g, 4.84 mmol) in CH2Cl2/Et2NH 1:1 (20 ml) was
stirred for 3 h at r.t. After evaporation, CC (CH2Cl2/MeOH 12 :1) gave 1.21 g (86%) of H-Pro-Aib-N(Me)Ph,
which was used directly in the next step.