Helvetica Chimica Acta ± Vol. 84 (2001)
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1H-NMR (Z Aib1 Aib2 Bin Aib3 OH): 7.89 ± 7.69 (m, 6 arom. H); 7.41 ± 7.05 (m, 11 arom. H); 7.01, 6.73,
6.70 (3s, 3 NH (Aib2, Aib3, Bin)); 6.11 (s, NH (Aib1)); 4.08 (br. m, CH2 (Z)); 3.26 ± 3.04 (dd, J ꢀ 13.8, 2 H C(b)
(Bin)); 2.87 ± 2.82 (dd, J ꢀ 13.4, 2 H C(b) (Bin)); 1.67, 1.52, 1.41, 1.30, 1.28, 1.27 (6s, 18 H, Me(b), Me(b')
(Aib)). 13C-NMR: 176.3, 175.5, 174.8, 172.8 (CO (Aib1, Aib2, Aib3, Bin)); 155.9 (CO (Z)); 135.6 ± 125.0
(arom. C); 70.0 (C(a), (Bin)); 66.3 (CH2 (Z)); 57.2, 56.9, 56.7 (C(a) (Aib1, Aib2, Aib3)); 42.2, 35.9 (C(b), C(b')
(Bin)); 27.2, 26.1, 25.9, 24.2, 23.2, 22.6 (C(b), C(b') (Aib1, Aib2, Aib3)). Anal. calc. for C44H46N4O7 ´ H2O
(760.856): C 69.45, H 6.36, N 7.36; found: C 69.41, H 6.38, N 7.21.
Oxazol-5(4H)-one from Z Aib Aib (S)-Bin Aib OH. Z Aib Aib (S)-Bin Aib OH (0.372 g,
0.50 mmol) was treated with Ac2O as described above for the oxazol-5(4H)-one from Z Aib Aib (S)-
Bin OH to give 0.359 g (99%) of crude oxazolone as a solid, which was used in the next step without further
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purification. M.p. 1888. [a] 82, [a] 83, [a] 93, [a] 108, [a]
239 (c 0.3, MeOH).
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Rf 0.50 (C). 1H-NMR (Z Aib1 Aib2 Bin Aib3 ox): 7.91 ± 7.86 (m, 3 arom. H); 7.81 ± 7.66 (dd, J 8.3,
2 arom. H); 7.46 ± 7.10 (m, 12 arom. H); 7.09, 6.20 (2s, 2 NH (Aib2, Bin)); 4.92 (s, NH (Aib1)); 4.72 ± 4.45
(dd, J ꢀ 12.2, CH2 (Z)); 3.41 ± 3.27 (dd, J ꢀ 14.0, 2 H C(b) (Bin)); 3.02 ± 2.95 (dd, J ꢀ 13.1, 2 H C(b) (Bin));
1.44, 1.39, 1.37, 1.36, 1.28, 1.26 (6s, 18 H, Me(b), Me(b') (Aib)). Anal. calc. for C44H44N4O6 ´ 0.5 H2O (733.832):
C 72.01, H 6.18, N 7.63; found: C 72.34, H 6.29, N 7.49.
Z
Aib Aib (S)-Bin Aib Aib OtBu (14). A soln. of H Aib OtBu (0.166 g, 1.04 mmol), obtained as
described above for 13, and the oxazol-5(4H)-one from Z Aib Aib (S)-Bin Aib OH (0.351 g, 0.48 mmol)
in MeCN (20 ml), was refluxed for 40 h and then treated as described above for Z Aib Aib (S)-
Bin Aib OtBu. CC (column 2 Â 51 cm, silica gel, B) of the crude product gave 0.346 g (81%) of pure 14. Solid.
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M.p. 2528. [a] 6, [a] 5, [a] 3, [a]
38, [a]
400 (c 0.2, MeOH). Rf 0.65 (C).
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1H-NMR (Z Aib1 Aib2 Bin Aib3 Aib4 OtBu): 7.87 ± 7.73 (m, 4 arom. H); 7.40 ± 7.07 (m, 13 arom. H);
7.52, 6.72, 6.69, 6.47 (4s, 4 NH (Aib2, Aib3, Aib4, Bin)); 6.21 (s, NH (Aib1)); 4.06 ± 4.02 (dd, J ꢀ 12.3, CH2 (Z));
3.28 ± 3.13 (dd, J ꢀ 13.8, 2 H C(b) (Bin)); 2.86 ± 2.80 (dd, J ꢀ 13.8, 2 H C(b) (Bin)); 1.42 (s, tBuO); 1.66, 1.53,
1.51, 1.48, 1.47, 1.42 (masked), 1.27, 1.21 (8s, 24 H, Me(b), Me(b') (Aib)). 13C-NMR: 174.3, 174.2, 174.0, 173.7,
171.0 (CO (Aib1, Aib2, Aib3, Aib4, Bin)); 155.8 (CO (Z)); 136.2 ± 124.9 (arom. C); 79.7 (tBuO); 70.2 (C(a)
(Bin)); 66.5 CH2 (Z)); 57.0, 56.6, 56.5, 55.9 (C(a) (Aib1, Aib2, Aib3, Aib4)); 42.5, 35.3 (C(b), C(b') (Bin)); 27.8
(tBuO); 27.7, 26.5, 25.9, 24.2, 23.2, 23.0, 22.74, 22.71 (C(b), C(b') (Aib1, Aib2, Aib3, Aib4)). Anal. calc. for
C52H61N5O8 ´ 0.5 H2O (893.056): C 69.93, H 7.00, N 7.84; found: C 69.92, H 7.05, N 7.82.
Z
(S)-Bin Aib OtBu. To a soln. of Z (S)-Bin OH (0.243 g, 0.5 mmol) and Et3N (0.084 ml, 0.6 mmol)
in toluene (2 ml) cooled to 58, a soln. of Piv-Cl (0.074 ml, 0.6 mmol) was added. The resulting suspension was
stirred at 58 for 1.5 h, then at r.t. for 2 h, and evaporated at 308. To the solid mixture (containing crude Z (S)-
Bin OPiv), a soln. of H Aib OtBu (0.225 g, 1.4 mmol; obtained as described above for 13) in toluene (10 ml)
was added. The mixture was stirred at 608 overnight, then evaporated and treated as described above for 13. The
crude product was submitted to CC (column 1.5 Â 41 cm, silica gel, A, then C): 0.097 g (40%) of recovered pure
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Z
[a]
(S)-Bin OH and 0.171 g (54%) of pure dipeptide. Solid. M.p. 1198. [a]
4, [a]
5, [a]
10,
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92, [a]
687 (c 0.2, MeOH). Rf 0.85 (B). 1H-NMR: 7.94 ± 7.83 (m, 4 arom. H); 7.55 (d, J 8.4,
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1 arom. H); 7.47 ± 7.19 (m, 13 H, arom. H, NH (Aib)); 5.24 ± 5.09 (d ´ br. d, J ꢀ 12.1, CH2 (Z)); 4.93 (s, NH
(Bin)); 3.44 ± 2.32 (dd, J ꢀ 12.9, 2H C(b) (Bin)); 3.31 ± 3.06 (br. dd, J ꢀ 13.2, 2 H C(b) (Bin)); 1.55, 1.50 (2s,
Me(b), Me(b') (Aib)); 1.43 (s, tBuO). 13C-NMR: 173.9, 170.6 (CO (Aib, Bin)); 155.1 (CO (Z)); 136.2 ±
125.1 (arom. C); 81.3 (tBuO); 70.6 (C(a) (Bin)); 66.7 CH2 (Z)); 56.8 (C(a) (Aib)); 42.2, 37.1 (C(b), C(b')
(Bin)); 27.7 (tBuO); 24.2, 24.0 (C(b), C(b') (Aib)). Anal. calc. for C40H40N2O5 (628.736): C 76.41, H 6.41, N 4.46;
found: C 76.14, H 6.53, N 4.27.
Z
(S)-Bin Aib OH. Z (S)-Bin Aib OtBu (0.162 g, 0.26 mmol) was C-deprotected in CF3COOH
(5 ml) and CH2Cl2 (5 ml) as described above for the synthesis of Z Aib Aib (S)-Bin OH to give 0.138 g
(93%) of crude dipeptide as a solid, which was used in the next step without further purification. M.p. 1938.
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[a]
11, [a]
14, [a]
21, [a]
116, [a]
762 (c 0.2, MeOH). Rf 0.10 (B). Anal. calc.
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for C36H32N2O5 ´ H2O (590.648): C 73.20, H 5.80, N 4.74; found: C 73.59, H 5.94, N 4.55.
Oxazol-5(4H)-one from Z (S)-Bin Aib OH. Z (S)-Bin Aib OH (0.130 g, 0.23 mmol) was treated
with Ac2O as described above for oxazol-5(4H)-one from Z Aib Aib (S)-Bin OH to give 0.125 g (99%) of
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the crude oxazolone as a glassy solid, which was used in the next step without further purification. [a] 10,
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[a] 5, [a] 4, [a]
53, [a]
531 (c 0.2, CHCl3). Rf 0.80 (B). 1H-NMR: 7.96 ± 7.83
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(m, 4 arom. H); 7.62 ± 7.23 (m, 13 arom. H); 5.20 ± 5.10 (d ´ br. d, J ꢀ 12.1, CH2 (Z)); 4.89 (s, NH (Bin)); 3.31 ±
3.18 (br. dd, J ꢀ 14.0, 2 H C(b) (Bin)); 3.25 ± 2.48 (dd, J ꢀ 12.9, 2 H C(b) (Bin)); 1.38, 1.26 (2s, Me(b),
Me(b'), Aib). Anal. calc. for C36H30N2O4 ´ 2 H2O (590.648): C 73.20, H 5.80, N 4.74; found: C 73.28, H 5.89, N 4.62.