1156
Vol. 53, No. 9
Orn; Boc-Dap(Z)-OH or Boc-Dab(Z)-OH was prepared from Boc-Asn-OH
or Boc-Gln-OH (1.0 eq), BTIB8—11) (1.5 eq), pyridine (2.0 eq) and Z-DSP
(1.3 eq)], triethylamine (Et3N: 16.4 mmol) and isobutyl chloroformate
(IBCF: 16.4 mmol) in tetrahydrofuran (THF: 50 ml) at ꢂ15 °C. The reaction
mixture was stirred at 5 °C overnight. Then 6.9 N HCl/dioxane (34.1 mmol)
was added to the reaction mixture at ꢂ15 °C, and the resulting solution was
stirred for 30 min. The solution was diluted with ice-cold water and ex-
tracted with AcOEt. The AcOEt phase was washed with water, 5% aqueous
NaHCO3 and saturated aqueous NaCl solution, then dried over Na2SO4.
After removal of Na2SO4, the solvent was removed in vacuo and petroleum
ether was added to the residue to afford crystals, which were collected by fil-
tration. If necessary, recrystallization from ethanol was performed.
CH2Cl, AcOEt/n-hexaneꢀ6 : 5 (v/v) in the case of Boc-Ala-Dap(Z)-CH2Cl
and Boc-Ala-Ala-CH2Cl].
Boc-Dap(Z)-Dap(Z)-CH2Cl Yield: 1.33 g (66.8%), mp 175—178 °C,
Rf 1 0.56, [a]D25 ꢂ51.8° (cꢀ0.2, DMF). H-NMR (DMSO-d6 containing 1%
1
pyridine-d5) d: 8.54 (d, 1H, Jꢀ7.1 Hz, a-NH), 7.37—7.29 (m, 10H, Ar–H),
7.23 (br, 1H, b-NH), 7.14 (br, 1H, b-NH), 6.90 (d, 1H, Jꢀ6.7 Hz, a-NH),
5.03 (s, 2H, –CH2–Ph), 5.02 (s, 2H, –CH2–Ph), 4.60 and 4.53 (AB-q, 2H,
Jꢀ16.8 Hz, –CH2Cl), 4.40 (br, 1H, a-CH), 4.03 (br, 1H, a-CH), 3.51 (m,
1H, b-CHA), 3.40—3.24 (m, 3H, b-CHB and b-CH2), 1.38 (9H, s, tert-
butyl), 13C-NMR (DMSO-d6 containing 1% pyridine-d5) d: 199.2 (q,
COCH2Cl), 170.9, 156.33, 156.26 and 155.3 (q, carbonyl), 136.9 and 136.8
(q, phenyl), 128.3—127.6 (t, phenyl), 78.6 (q, tert-butyl), 65.5 (s, –CH2-Ph),
56.7 and 54.9 (t, a-CH), 47.9 (s, –CH2Cl), 41.61 and 40.1 (s, b-CH2), 28.0
(p, tert-butyl). Anal. Calcd for C28H35ClN4O8: C, 56.9; H, 5.97; N, 9.48.
Found: C, 56.8; H, 6.08; N, 9.56.
Boc-Dap(Z)-CH2Cl Yield: 2.90 g (75.9%), mp 94—97 °C, Rf 1 0.84,
[a]D25 ꢃ50.9° (cꢀ0.5, CHCl3). 1H-NMR (CDCl3) d: 7.37—7.31 (m, 5H,
Ar–H), 5.69 (d, 1H, Jꢀ6.0 Hz, a-NH), 5.22 (br, 1H, b-NH), 5.07 (s, 2H,
–CH2–Ph), 4.59 (br, 1H, a-CH), 4.42 and 4.30 (AB-q, 2H, Jꢀ15.6 Hz,
–CH2Cl), 3.70 (br, 1H, b-CHA), 3.59 (m, 1H, b-CHB), 1.44 (9H, s, tert-
butyl), 13C-NMR (CDCl3) d: 200.3 (q, COCH2Cl), 157.1 and 155.5 (q, car-
bonyl), 136.9 (q, phenyl), 128.6, 128.3 and 128.1 (t, phenyl), 80.7 (q, tert-
butyl), 67.3 (s, –CH2–Ph), 58.2 (t, a-CH), 46.5 (s, –CH2Cl), 41.9 (s, b-CH2),
28.3 (p, tert-butyl). Anal. Calcd for C17H23ClN2O5: C, 55.1; H, 6.25; N, 7.55.
Found: C, 55.3; H, 6.31; N, 7.55.
Boc-Dab(Z)-Dab(Z)-CH2Cl Yield: 580 mg (36.3%), mp 58—68 °C,
Rf 1 0.28, [a]D25 ꢂ34.6° (cꢀ1.0, DMF). 1H-NMR (CDCl3) d: 7.37—7.29 (m,
10H, Ar-H), 7.23 (br, 1H, g-NH), 6.89 (br, 1H, a-NH), 5.40 (br, 2H, g-NH
and a-NH), 5.16—5.08 (m, 4H, –CH2–Ph), 4.73 (br, 1H, a-CH), 4.30—
4.09 (m, 2H, –CHACl and a-CH), 3.73 (m, 1H, g-CHA), 3.63 (d, 1H,
Jꢀ10.8 Hz, –CHBCl), 3.52 (br, 1H, g-CHAꢄ), 3.28 (m, 1H, g-CHB), 3.11 (br,
1H, g-CHBꢄ), 2.15 (m, 1H, b-CHA), 1.93 (m, 1H, b-CHAꢄ), 1.82—1.77 (m,
2H, b-CHB and b-CHBꢄ), 1.42 (9H, s, tert-butyl), 13C-NMR (CDCl3) d:
199.0 (q, COCH2Cl), 172.0, 156.9 and 154.5 (q, carbonyl), 136.3 and 136.0
(q, phenyl), 128.7—127.8 (t, phenyl), 80.3 (q, tert-butyl), 67.3 and 67.1 (s,
–CH2–Ph), 52.6 and 52.2 (t, a-CH), 45.5 (s, g-CH2), 44.8 (s, –CH2Cl), 37.9
(s, g-CH2), 33.9 (s, b-CH2), 28.0 (p, tert-butyl), 27.9 (s, b-CH2). Anal. Calcd
for C30H39ClN4O8·0.2n-Hexane: C, 58.9; H, 6.58; N, 8.81. Found: C, 58.9;
H, 6.70; N, 8.80.
Boc-Dab(Z)-CH2Cl Yield: 1.20 g (58.0%), mp 88—95 °C, Rf 1 0.76,
[a]D25 ꢂ8.77° (cꢀ0.2, CHCl3). 1H-NMR (CDCl3) d: 7.36—7.31 (5H, m,
Ar–H), 5.45 (br, 2H, a-NH and g-NH), 5.10 (s, 2H, –CH2–Ph), 4.57 (br, 1H,
a-CH), 4.23 (s, 2H, –CH2Cl), 3.47 (br, 1H, g-CHA), 3.11 (br, 1H, g-CHB),
2.09 (m, 1H, b-CHA), 1.67 (m, 1H, b-CHB), 1.44 (9H, s, tert-butyl), 13C-
NMR (CDCl3) d: 202.1 (q, COCH2Cl), 159.1 and 157.7 (q, carbonyl), 136.5
(q, phenyl), 128.6—128.3 (t, phenyl), 80.7 (q, tert-butyl), 66.9 (s,
–CH2–Ph), 55.0 (t, a-CH), 46.5 (s, –CH2Cl), 37.1 (s, g-CH2), 31.7 (s, g-
CH2), 28.4 (p, tert-butyl). Anal. Calcd for C18H25ClN2O5·0.3H2O: C, 55.3;
H, 6.59; N, 7.16. Found: C, 55.1; H, 6.47; N, 7.08.
Boc-Orn(Z)-Orn(Z)-CH2Cl Yield: 1.39 g (43.0%), mp 110—111 °C,
Rf 1 0.69, [a]D25 ꢂ36.5° (cꢀ0.25, DMF). H-NMR (CDCl3) d: 7.32—7.29
1
(m, 11H, Ar–H and a-NH), 5.30 (br, 1H, a-NH), 5.22 (br, 2H, 2ꢁd-NH),
5.06 (s, 4H, –CH2–Ph), 4.69 (br, 1H, a-CH), 4.27 (br, 1H, a-CH), 4.21 (s,
2H, –CH2Cl), 3.33 (br, 1H, d-CHA), 3.17 (br, 3H, d-CHB and d-CH2),
1.85—1.78 (m, 2H, b-CH2), 1.55 (br, 6H, b-CH2 and 2ꢁgCH2), 1.42 (9H, s,
tert-butyl), 13C-NMR (CDCl3) d: 200.8 (q, COCH2Cl), 172.9, 157.1, 156.8
and 155.9 (q, carbonyl), 136.5 (q, phenyl), 128.5—127.8 (t, phenyl), 80.1 (q,
tert-butyl), 66.8 (s, –CH2–Ph), 56.0 and 53.1 (t, a-CH), 46.6 (s, –CH2Cl),
40.2 and 39.7 (s, d-CH2), 29.8 (s, b-CH2), 28.4 (p, tert-butyl), 28.3 (s, b-
CH2), 26.2 (s, g-CH2). Anal. Calcd for C32H43ClN4O8: C, 59.4; H, 6.70; N,
8.66. Found: C, 59.7; H, 6.65; N, 8.83.
Boc-Orn(Z)-CH2Cl Yield: 4.80 g (88.9%), mp 69—73 °C, Rf 1 0.69,
[a]D25 ꢂ25.5° (cꢀ0.2, CHCl3). 1H-NMR (CDCl3) d: 7.36—7.30 (m, 5H,
Ar–H), 5.18 (br, 1H, a-NH), 5.09 (s, 2H, –CH2–Ph), 4.94 (br, 1H, d-NH),
4.51 (br, 1H, a-CH), 4.24 (s, 2H, –CH2Cl), 3.23 (m, 2H, d-CH2), 1.87 (br,
1H, b-CHA), 1.62—1.48 (m, 3H, b-CHB and g-CH2), 1.44 (9H, s, tert-
butyl), 13C-NMR (CDCl3) d: 201.6 (q, COCH2Cl), 156.6 and 155.6 (q, car-
bonyl), 136.5 (q, phenyl), 128.6—128.1 (t, phenyl), 80.5 (q, tert-butyl), 66.8
(s, –CH2–Ph), 57.0 (t, a-CH), 46.5 (s, –CH2Cl), 40.3 (s, d-CH2), 28.5 (s, b-
CH2), 28.3 (p, tert-butyl), 26.1 (s, g-CH2). Anal. Calcd for C19H27ClN2O5: C,
57.3; H, 6.80; N, 7.20. Found: C, 57.2; H, 6.82; N, 7.02.
Boc-Ala-Ala-CH2Cl (12) Yield: 603 mg (45.6%), mp 125—130 °C, Rf 2
Boc-Ala-Me Boc-Ala-chloromethyl ketone (CMK)20) (1.00 g, 4.51
mmol) dissolved in 20 ml of MeOH was hydrogenated over Pd-black catalyst
and the pH of the reaction mixture was kept at 7 to 8 by Et3N. The catalyst
was removed by filtration after 4 h, and the solution was evaporated in
vacuo. The resulting residue was extracted with AcOEt, which was washed
by 10% citric acid, 5% NaHCO3 and saturated aqueous NaCl solution, then
dried over Na2SO4. After removal of Na2SO4, the solvent was removed to
obtain the desired product as an oil. Yield: 806 mg (95.5%). 1H-NMR
(CDCl3) d: 5.24 (br, 1H, a-NH), 4.3 (br quint, 1H, Jꢀ6.9 Hz, a-CH), 2.03
(s, 3H, COCH3), 1.44 (9H, s, tert-butyl), 1.34 (d, 3H, Jꢀ7.2 Hz, methyl of
Ala), 13C-NMR (CDCl3) d: 207.3 (q, COCH3), 155.2 (q, carbonyl of
tert-butyloxycarbonyl), 79.8 (q, tert-butyl), 55.7 (t, a-CH), 28.4 (p, tert-
butyl), 26.4 (p, COCH3), 17.7 (p, methyl of Ala). Anal. Calcd for
C9H17NO3·0.1H2O: C, 57.2; H, 9.17; N, 7.41. Found: C, 57.1; H, 8.97; N,
7.29.
General Procedure for Synthesis of Boc-Xaa(Z)-Xaa(Z)-CH2Cl
[XaaꢀDap, Dab, Orn], Boc-Dap(Z)-Ala-CH2Cl, Boc-Ala-Dap(Z)-CH2Cl
and Boc-Ala-Ala-CH2Cl To a solution of a mixed anhydride [prepared
from Boc-Xaa(Z)-OH or Boc-Ala-OH (3.37 mmol), Et3N (3.37 mmol) and
IBCF (3.37 mmol) in THF (50 ml)], dimethylformamide (DMF: 50 ml) solu-
tion containing H-Xaa(Z)-CH2Cl or H-Ala-CH2Cl [prepared from Boc-
Xaa(Z)-CH2Cl (4.04 mmol) or Boc-Ala-CH2Cl and 7.2 N HCl/dioxane
(36.4 mmol)] and Et3N (4.04 mmol) was added at 0 °C. The reaction mixture
was stirred at same temperature for 1 h and at room temperature overnight.
Then the solvent was removed in vacuo and the residue was extracted with
AcOEt, which was washed with 10% citric acid, 5% aqueous NaHCO3 and
saturated aqueous NaCl, then dried over Na2SO4. After removal of Na2SO4,
the solvent was evaporated down and the residue was precipitated from
ether, then the crystals were colleted by filtration. If necessary, the resulting
crude products were purified by silica gel chromatography [mobile phase:
AcOEt/n-hexaneꢀ1 : 1 (v/v) for the purification of Boc-Dab(Z)-Dab(Z)-
0.45, [a]D21 ꢂ56.2° (cꢀ1.0, CHCl3). H-NMR (CDCl3) d: 8.39 (br, 1H, a-
1
NH), 5.04 (d, 1H, Jꢀ7.1 Hz, a-NH), 4.76 (quint, 1H, Jꢀ7.1 Hz, a-CH),
4.29 and 4.25 (AB-q, 2H, Jꢀ15.8 Hz, –CH2Cl), 4.17 (br, 1H, a-CH), 1.45
(9H, s, tert-butyl), 1.40 (d, 3H, Jꢀ7.2 Hz, methyl of Ala), 1.36 (d, 3H,
Jꢀ7.1 Hz, methyl of Ala), 13C-NMR (CDCl3) d: 201.2 (q, COCH2Cl),
172.8, and 155.5 (q, carbonyl), 80.5 (q, tert-butyl), 52.0 (t, a-CH), 50.0 (t,
a-CH), 46.1 (s, –CH2Cl), 28.3 (p, tert-butyl), 18.0 (p, methyl of Ala), 17.1
(p, methyl of Ala). Anal. Calcd for C12H21ClN2O4: C, 49.2; H, 7.23; N, 9.57.
Found: C, 49.3; H, 6.99; N, 9.31.
Boc-Dap(Z)-Ala-CH2Cl (10) Yield: 1.15 g (57.6%), mp 182—183 °C,
Rf 1 0.60, Rf 3 0.28, [a]D21 ꢂ54.4° (cꢀ1.0, DMF). H-NMR (DMSO-d6) d:
1
8.43 (d, 1H, Jꢀ7.0 Hz, a-NH of Ala), 7.38—7.27 (m, 5H, Ar–H), 7.21 (br,
1H, b-NH of Dap), 6.86 (d, 1H, Jꢀ7.2 Hz, a-NH of Dap), 5.02 (s, 2H,
–CH2–Ph), 4.58 and 4.51 (AB-q, 2H, Jꢀ16.9 Hz, –CH2Cl), 4.34 (p, 1H,
Jꢀ7.0 Hz, a-CH of Ala), 4.02 (br-q, 1H, Jꢀ6.7 Hz, a-CH of Dap), 3.29 (t,
2H, Jꢀ5.8 Hz, b-CH2 of Dap), 1.38 (9H, s, tert-butyl), 1.20 (d, 3H,
Jꢀ7.1 Hz, methyl of Ala), 13C-NMR (DMSO-d6) d: 200.9 (q, COCH2Cl),
170.4, 156.2 and 155.2 (q, carbonyl), 136.9 (q, phenyl), 128.2, 127.7 and
127.6 (t, phenyl), 78.4 (q, tert-butyl), 65.4 (s, –CH2–Ph), 54.6 (t, a-CH of
Dap), 52.3 (t, a-CH of Ala), 47.5 (s, –CH2Cl), 41.8 (s, b-CH2 of Dap), 28.0
(p, tert-butyl), 15.6 (p, methyl of Ala). Anal. Calcd for C20H28ClN3O6: C,
54.4; H, 6.39; N, 9.51. Found: C, 54.2; H, 6.38; N, 9.44.
Boc-Ala-Dab(Z)-CH2Cl (11) Yield: 374 mg (56.0%), mp 114—118 °C,
Rf 2 0.40, [a]D21 ꢃ53.4° (cꢀ1.0, CHCl3). H-NMR (CDCl3) d: 7.36—7.28
1
(m, 5H, Ar–H), 7.25 (br, 1H, a-NH of Dap), 5.64 (br, 1H, b-NH of Dap),
5.06 (s, 2H, –CH2–Ph), 5.03 (br, 1H, a-NH of Ala), 4.85 (m, 1H, a-CH of
Dap), 4.45 and 4.29 (AB-q, 2H, Jꢀ15.7 Hz, –CH2Cl), 4.07 (br quint, 1H,
Jꢀ6.9 Hz, a-CH of Ala), 3.71 (m, 2H, b-CH2 of Dap), 1.42 (9H, s, tert-
butyl), 1.32 (d, 3H, Jꢀ7.1 Hz, methyl of Ala), 13C-NMR (CDCl3) d: 199.6
(q, COCH2Cl), 173.3, 157.4 and 155.7 (q, carbonyl), 136.2 (q, phenyl),
128.5, 128.2 and 128.0 (t, phenyl), 80.6 (q, tert-butyl), 67.1 (s, –CH2–Ph),