Helvetica Chimica Acta ± Vol. 84 (2001)
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1044s, 923w, 855w, 813w, 783w, 735m, 697s, 625m. H-NMR: 7.29 ± 7.19 (m, 10 arom. H); 7.05 (br. s, NH); 5.16
(d, J 8.5, NH); 5.00 (s, PhCH2(Z)); 4.55 (dd, J 7.0, 8.3, CH(a)(Hyp)); 4.43, 4.37 (AB, J 11.7,
PhCH2(Hyp)); 4.13 ± 4.03 (m, CH(g)(Hyp), CH(a)(Leu)); 3.68 ± 3.58 (m, CH2(d)(Hyp)); 3.66 (s, MeO);
2.28 ± 2.19, 1.96 ± 1.85 (2m, CH2(b)(Hyp)); 1.56 ± 1.49 (m, CH(g)(Leu)); 1.53, 1.48 (2s, 2 Me(Aib)); 1.44 ± 1.31
(m, CH2(b)(Leu)); 0.83 (d, J 6.2, 2 Me(Leu)). 13C-NMR: 171.8, 171.5, 169.6 (3s, 3 CO); 155.3 (s, CO(carba-
mate)); 136.5, 135.3 (2s, 2 arom. C); 127.6, 127.5, 127.2, 127.1, 127.0, 126.6 (6d, 10 arom. C); 77.4
(d, CH(g)(Hyp)); 70.3 (t, PhCH2(Hyp)); 66.0 (t, PhCH2(Z)); 58.6 (d, CH(a)(Hyp)); 55.8 (s, C(a)(Aib));
52.7 (d, CH(a)(Leu)); 52.1 (t, CH2(d)(Hyp)); 51.3 (q, MeO); 40.4 (t, CH2(b)(Leu)); 32.1 (t, CH2(b)(Hyp));
.
23.7 (d, CH(g)(Leu)); 22.5, 22.3, 21.9, 20.9 (4q, 2 Me(Aib), 2 Me(Leu)). ESI-MS: 590 ([M Na] ), 568 (M ).
3.2. Methyl N-{[(9H-Fluoren-9-yl)methoxy]carbonyl}-(S)-valyl-dimethylglycyl-(2S,4R)-4-(benzyloxy)pro-
linate (Fmoc-Val-Aib-Hyp(Bn)-OMe, 12b). According to the GP, Fmoc-Val-OH (139 mg, 0.41 mmol) in
CH2Cl2 (5 ml) and 10 (124 mg, 0.41 mmol), CC (AcOEt/hexane 1:1): 250 mg (95%) of 12b. Colorless, thick oil,
which solidified under h.v. IR (KBr): 3381m, 3314s, 2962m, 2884m, 1721s, 1684s, 1614s, 1524s, 1469s, 1451s, 1420s,
1382m, 1360m, 1288m, 1242s, 1208s, 1180s, 1030m, 999m, 859w, 810w, 790w, 760m, 734s, 697m, 621w. 1H-NMR:
7.76 ± 7.22 (m, 13 arom. H); 7.11 (br. s, NH); 5.40 (d, J 8.7, NH); 4.63 (t-like, J 7.2, CH(a)(Hyp)); 4.50 ± 4.38
(m, PhCH2(Hyp), CH2O(Fmoc)); 4.22 ± 4.17 (m, CH(Fmoc), CH(g)(Hyp)); 3.97 ± 3.94 (m, CH(a)(Val));
3.76 ± 3.71 (m, CH2(d)(Hyp)); 3.73 (s, MeO); 2.29 ± 2.25, 2.07 ± 1.94 (2m, CH2(b)(Hyp), CH(b)(Val)); 1.66, 1.61
(2s, 2 Me(Aib)); 0.93, 0.88 (2d, J 6.6, 2 Me(Val)). 13C-NMR: 172.6, 172.5 (2s, CO(Hyp), CO(Aib)); 169.3
(s, CO(Val)); 156.3 (s, CO(carbamate)); 143.9, 141.2, 137.3 (3s, 5 arom. C); 128.4, 127.9, 127.6, 127.1, 126.9, 125.0,
119.8 (7d, 13 arom. C); 77.4 (d, CH(g)(Hyp)); 71.2 (t, PhCH2(Hyp)); 66.7 (t, CH2O(Fmoc)); 60.3 (d, CH(a)-
(Val)); 59.6 (d, CH(a)(Hyp)); 56.9 (s, C(a)(Aib)); 53.0 (t, CH2(d)(Hyp)); 52.2 (q, MeO); 47.1 (d, CH(Fmoc));
33.1 (t, CH2(b)(Hyp)); 31.2 (d, CH(b)(Val)); 22.9, 22.8 (2q, 2Me(Aib)); 19.0, 17.7 (2q, 2 Me(Val)). ESI-MS:
664 ([M Na] ). Anal. calc. for C17H22N2O3 (641.77): C 69.25, H 6.75, N 6.55; found: C 69.16, H 7.04, N 6.49.
3.3. Methyl N-[(tert-Butoxy)carbonyl]-(S)-alanyl-dimethylglycyl-(2S,4R)-4-(benzyloxy)prolinate (Boc-
Ala-Aib-Hyp(Bn)-OMe, 12c). According to the GP, Boc-Ala-OH (78 mg, 0.41 mmol) in CH2Cl2 (5 ml) and
10 (123 mg, 0.41 mmol), CC (CH2Cl2, 1.25% MeOH): 177 mg (88%) of 12c. Colorless solid. M.p. 207 ± 2098. IR
(KBr): 3368s, 3285s, 3062w, 2979m, 2935m, 2795w, 1730s, 1713s, 1683s, 1611s, 1546s, 1525s, 1500m, 1471m, 1456m,
1425s, 1376s, 1356s, 1299m, 1263m, 1242s, 1212s, 1173s, 1138m, 1114m, 1068m, 1036m, 1018m, 946w, 862w, 807w,
791w, 735m, 695w, 646m, 628m. 1H-NMR ((D6)DMSO): 8.03 (br. s, NH); 7.34 ± 7.27 (m, 13 arom. H); 6.74 (br. s,
NH); 4.48 (s, PhCH2(Hyp)); 4.32 ± 4.26, 4.21 ± 4.13 (2m, CH(a)(Hyp), CH(g)(Hyp)); 4.08 ± 3.97, 3.82 ± 3.74
(2m, CH2(d)(Hyp); 3.62 (d, J 7.7, CH(a)(Ala)); 3.59 (s, MeO); 2.12 ± 1.88 (m, CH2(b)(Hyp)); 1.33 (s, Me3C);
1.33, 1.31 (2s, 2 Me(Aib)); 1.17 (d, J 7.1, Me(Ala)). 13C-NMR ((D6)DMSO): 172.3, 171.5 (2s, 3 CO); 154.8
(s, CO(carbamate)); 138.0 (s, 1 arom. C); 128.0, 127.3 (2d, 5 arom. C); 77.9 (s, Me3C); 76.4 (d, CH(g)(Hyp));
70.0 (t, PhCH2(Hyp)); 58.7 (d, CH(a)(Hyp)); 55.2 (s, C(a)(Aib)); 51.5 (t, CH2(d)(Hyp)); 51.4 (q, MeO); 49.4
(d, CH(a)(Ala)); 32.6 (t, CH2(b)(Hyp)); 27.9 (q, Me3C); 24.7, 24.2 (2q, 2 Me(Aib)); 18.1 (q, Me(Ala)). CI-MS:
727 (50, [2M 255] ), 492 (95, [M 1] ), 236 (100, [M 255] ). Anal. calc. for C25H37N3O7 ´ 0.33 H2O (497.60):
C 60.34, H 7.63, N 8.44; found: C 60.45, H 7.58, N 8.30.
3.4. Methyl N-{[(9H-Fluoren-9-yl)methoxy]carbonyl}-(S)-phenylalanyl-glycyl-dimethylglycyl-(2S,4R)-4-
(benzyloxy)prolinate (Fmoc-Phe-Gly-Aib-Hyp(Bn)-OMe, 13). According to the GP, Fmoc-Phe-Gly-OH
(120 mg, 0.27 mmol) in CH2Cl2 (5 ml) and 10 (82 mg, 0.27 mmol), CC (AcOEt): 195 mg (97%) of 13. Colorless
enamel. IR (KBr): 3297m, 3363m, 3030m, 2945m, 1744s, 1649s, 1622s, 1522s, 1452s, 1410s, 1363m, 1333m, 1259s,
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1206s, 1177m, 1032m, 945w, 914w, 856w, 741s, 700m, 647w, 621w. H-NMR: 7.74 ± 7.21 (m, 18 arom. H, 2 NH);
5.81 (d, NH); 4.63 (t-like, J 7.3, CH(a)(Hyp)); 4.51 ± 4.08 (m, PhCH2(Hyp), CH2O(Fmoc), CH(a)(Phe),
CH(Fmoc), CH(g)(Hyp)); 3.98 ± 3.68 (m, CH2(d)(Hyp), CH2(a)(Gly)); 3.64 (s, MeO); 3.22 ± 3.01
(m, CH2(b)(Phe)); 2.24 ± 2.02, 1.95 ± 1.88 (2m, CH2(b)(Hyp)); 1.52, 1.51 (2s, 2 Me(Aib)). 13C-NMR: 172.9,
172.3, 171.8, 167.7 (4s, 4 CO); 156.3 (s, CO(carbamate)); 143.6, 141.2, 137.6, 136.7 (4s, 6 arom. C); 129.1, 128.6,
128.3, 127.7, 127.5, 127.0, 126.9, 124.9, 119.9 (9d, 18 arom. C); 77.3 (d, CH(g)(Hyp)); 71.2 (t, PhCH2(Hyp)); 66.1
(t, CH2O(Fmoc)); 59.5 (d, CH(a)(Hyp)); 56.8 (s, C(a)(Aib)); 56.6 (d, CH(a)(Phe)); 52.8 (t, CH2(d)(Hyp));
52.0 (q, MeO); 47.0 (d, CH(Fmoc)); 43.3 (t, CH2(a)(Gly)); 37.4 (t, CH2(b)(Phe)); 33.3 (t, CH2(b)(Hyp)); 24.5,
23.9 (2q, 2 Me(Aib)). ESI-MS: 769 ([M Na] ). Anal. calc. for C43H46N4O8 ´ 0.75 H2O (760.38): C 67.92, H 6.30,
N 7.37; found: C 67.79, H 6.24, N 7.14.
3.5. Methyl N-[(tert-Butoxy)carbonyl]-(S)-alanyl-dimethylglycyl-(2S,4R)-4-(benzyloxy)prolyl-(S)-valinate
(Boc-Ala-Aib-Hyp(Bn)-Val-OMe, 14). To a soln. of 12c (78 mg, 0.16 mmol) in THF/MeOH/H2O 3 :1:1 (5 ml)
was added LiOH ´ H2O (20 mg, 0.48 mmol), and the mixture was stirred at r.t. After 20 h, the mixture was
transferred into a separatory funnel, diluted with 5% KHSO4 soln., and extracted with CH2Cl2 (3Â). The
combined org. phase was dried (MgSO4) and concentrated in vacuo, yielding 76 mg (quant.) of Boc-Ala-Aib-