Helvetica Chimica Acta – Vol. 95 (2012)
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dione (12; 79%). 3: colorless oil. [a]2D5 ¼ þ52.24 (c ¼ 0.495, CHCl3). IR (KBr): 3339, 3327, 2965, 2940,
2872, 1744, 1709, 1632, 1524, 1456, 1250, 1171, 754, 698. 1H-NMR (CDCl3, 400 MHz): 7.24 (s, 5 H); 5.52 (s,
2 H); 4.46 (d, J ¼ 8.0, 1 H); 4.99 (s, 2 H); 4.89 (d, J ¼ 5.6, 1 H); 4.48 (s, 1 H); 4.02 (q, J ¼ 7.2, 1 H); 3.60 (s,
3 H); 3.02 – 3.14 (m, 2 H); 2.91 (s, 3 H); 2.82 (s, 3 H); 2.11 – 2.28 (m, 1 H); 1.51 – 1.67 (m, 2 H); 1.37 – 1.52
(m, 2 H); 1.33 (s, 9 H); 1.29 (d, J ¼ 9.6, 3 H); 1.06 – 1.19 (m, 2 H); 0.83 (d, J ¼ 6.4, 3 H); 0.71 (d, J ¼ 6.4,
3 H). 13C-NMR (CDCl3): 172.6; 171.4; 169.7; 168.8; 156.1; 136.3; 127.9; 127.6; 127.5; 79.1; 65.9; 57.9; 52.8;
51.6; 40.2; 31.6; 29.7; 28.9; 28.8; 27.8; 26.9; 21.9; 19.1; 17.8; 17.4; 13.8. EI-MS: 592 ([M þ H]þ).
Methyl N-Methyl-d-valinate (Me-d-Val-OMe; 13) [12]. As described for Me-d-Ala-OMe (7), from
Boc-d-Val-OH. 1H-NMR (D2O, 300 MHz): 4.02 – 4.18 (m, 1 H); 3.81 (s, 3 H); 2.71 (d, J ¼ 5.76, 3 H); 0.52
(d, J ¼ 2.48, 3 H).
Methyl N2-[(tert-Butoxy)carbonyl]-N6-[(phenylmethoxy)carbonyl]-l-lysyl-N-methyl-d-valinate
(Boc-Lys(Cbz)-Me-d-Val-OMe; 6). As described for 11, with 13 · HCl (0.736 g, 2.49 mmol), Boc-
i
Lys(Cbz)-OH (4; 1.044 g, 2.74 mmol), DMF (7 ml), BOP (1.21 g, 2.74 mmol), and Pr2NEt (1.12 ml,
6.23 mmol) (24 h stirring at r.t.). Partitioning, extraction, and workup as described (eluent AcOEt/
hexane 1:5): 1.124 g (89%) of pure 6. [a]2D5 ¼ þ50.32 (c ¼ 0.186, CHCl3). IR (KBr): 3323, 2968, 2936,
2872, 1717, 1701, 1647, 1526, 1250, 1169, 1015, 739, 698. 1H-NMR (CDCl3, 400 MHz): 7.24 (s, 5 H); 4.98 (s,
2 H); 4.69 (d, J ¼ 10.8, 1 H); 4.01 (q, J ¼ 7.2, 1 H); 3.59 (s, 3 H); 3.03 – 3.17 (m, 2 H); 2.94 (s, 3 H); 2.06 –
2.19 (m, 1 H); 1.49 – 1.62 (m, 2 H); 1.35 – 1.49 (m, 2 H); 1.32 (s, 9 H); 1.23 – 1.38 (m, 2 H); 0.89 (d, J ¼ 6.4,
3 H); 0.73 (d, J ¼ 6.4, 3 H). 13C-NMR (CDCl3): 172.9; 170.8; 156.3; 155.4; 136.4; 128.2; 127.8; 127.7; 79.3;
66.2; 61.7; 51.8; 50.0; 40.5; 32.7; 31.1; 28.9; 28.1; 27.1; 21.9; 19.5; 18.5. EI-MS: 507 (Mþ).
N2-[(tert-Butoxy)carbonyl]-N6-[(phenylmethoxy)carbonyl]-l-lysyl-N-methyl-d-valine
(Boc-
Lys(Cbz)-Me-d-Val-OH; 14). To a stirred and cooled (08) soln. of 6 (0.72 g, 1.42 mmol) in THF/H2O
2 :1 (30 ml), LiOH (0.70 g, 17.07 mmol) was added. After 12 h stirring, the mixture was quenched with
aq. NH4Cl soln. (50 ml) and extracted with AcOEt (3 ꢁ 80 ml). The extracts were washed with H2O
(50 ml) and brine (50 ml), dried (MgSO4), and concentrated: 0.66 g (94%) of 14. Colorless oil. [a]D25
¼
þ80.59 (c ¼ 0.1685, CHCl3). IR (KBr): 3331, 3325, 2967, 2936, 2872, 1701, 1636, 1524, 1368, 1254, 1169,
1024, 698. 1H-NMR (CDCl3, 400 MHz): 7.32 (s, 5 H); 5.07 (s, 2 H); 4.71 (d, J ¼ 10.4, 1 H); 4.11 (q, J ¼ 7.2,
1 H); 3.08 – 3.22 (m, 2 H); 3.06 (s, 3 H); 2.06 – 2.25 (m, 1 H); 1.59 – 1.73 (m, 2 H); 1.47 – 1.61 (m, 2 H);
1.41 (s, 9 H); 1.07 – 1.25 (m, 2 H); 0.87 (d, J ¼ 6.4, 3 H); 0.83 (d, J ¼ 6.4, 3 H). 13C-NMR (CDCl3): 173.6;
172.4; 156.4; 155.5; 136.3; 128.1; 127.7; 127.6; 79.4; 66.3; 60.1; 50.1; 40.3; 32.2; 31.7; 29.1; 27.9; 26.9; 21.9;
19.6; 18.6. EI-MS: 493 ([M þ H]þ).
Methyl N2-[(tert-Butoxy)carbonyl]-N6-[(phenylmethoxy)carbonyl)-l-lysyl-N-methyl-d-valyl-N-
methyl-d-alaninate (Boc-Lys(Cbz)-Me-d-Val-Me-d-Ala-OMe; 3). As described for 11, with 14 (0.96 g,
i
1.95 mmol), 7 · HCl (0.40 g, 2.54 mmol), DMF (15 ml), BOP (1.12 g, 2.54 mmol), and Pr2NEt (2.24 ml,
12.46 mmol). (24 h stirring at r.t.). Partitioning with 10% citric acid (100 ml) and AcOEt (100 ml),
extraction with AcOEt (2 ꢁ 100 ml), and workup as described with sat. NaHCO3 soln. (100 ml) and brine
(100 ml) (eluent AcOEt/hexane 2 :3): to give 1.15 g (94%) of pure 3. Colorless oil. [a]2D5 ¼ þ52.24 (c ¼
0.495, CHCl3). IR (KBr): 3339, 3327, 2965, 2940, 2872, 1744, 1709, 1632, 1524, 1456, 1250, 1171, 754, 698.
1H-NMR (CDCl3, 400 MHz): 7.24 (s, 5 H); 5.52 (s, 2 H); 4.46 (d, J ¼ 8.0, 1 H); 4.99 (s, 2 H); 4.89 (d, J ¼
5.6, 1 H); 4.48 (s, 1 H); 4.02 (q, J ¼ 7.2, 1 H); 3.60 (s, 3 H); 3.01 – 3.14 (m, 2 H); 2.91 (s, 3 H); 2.82 (s, 3 H);
2.16 – 2.31 (m, 1 H); 1.53 – 1.67 (m, 2 H); 1.39 – 1.54 (m, 2 H); 1.33 (s, 9 H); 1.29 (d, J ¼ 9.6, 3 H); 1.10 –
1.24 (m, 2 H); 0.83 (d, J ¼ 6.4, 3 H); 0.71 (d, J ¼ 6.4, 3 H). 13C-NMR (CDCl3): 172.6; 171.4; 169.7; 168.8;
156.1; 136.3; 127.9; 127.6; 127.5; 79.1; 65.9; 57.9; 52.8; 51.6; 40.2; 31.6; 29.7; 28.9; 28.8; 27.8; 26.9; 21.9; 19.1;
17.8; 17.4; 13.8. HR-EI-MS: 592.3444 (Mþ, C30H48N4O8þ ; calc. 592.3467).
N2-[(tert-Butoxy)carbonyl]-l-lysyl-N-methyl-d-valyl-N-methyl-d-alanine (Boc-Lys-Me-d-Val-Me-
d-Ala-OH; 15). As described for 14, with 3 (1.15 g, 1.94 mmol), THF/H2O 2 :1 (30 ml), and LiOH
(0.80 g, 19.40 mmol). Workup with AcOEt (3 ꢁ 100 ml), H2O (80 ml), and brine (80 ml): 1.12 g (100%)
of Boc-Lys(Cbz)-Me-d-Val-Me-d-Ala-OH. Colorless oil. [a]2D5 ¼ þ27.30 (c ¼ 0.2667, CHCl3). IR (KBr):
3568, 3321, 2967, 2938, 1705, 1697, 1632, 1524, 1456, 1250, 1169, 1022, 754. 1H-NMR (CDCl3, 400 MHz):
8.07 (s, 1 H); 7.22 (s, 5 H); 5.54 (d, J ¼ 7.6, 1 H); 5.00 (d, J ¼ 5.2, 1 H); 4.96 (s, 2 H); 4.48 (s, 1 H); 3.99 (q,
J ¼ 7.2, 1 H); 2.91 – 3.09 (m, 2 H); 2.90 (s, 3 H); 2.87 (s, 3 H); 2.16 – 2.27 (m, 1 H); 1.43 – 1.56 (m, 2 H);
1.32 – 1.47 (m, 2 H); 1.26 – 1.39 (m, 2 H); 1.29 (s, 9 H); 1.25 (d, J ¼ 11.2, 3 H); 0.82 (d, J ¼ 6.4, 3 H); 0.80