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T. Hirose et al. / Tetrahedron 67 (2011) 6633e6643
1H), 5.30 (dd, J¼17.3, 1.6 Hz, 1H), 5.22 (dd, J¼10.5, 1.4 Hz, 1H), 5.06
(s, 2H), 4.56 (d, J¼5.7 Hz, 2H), 3.94 (m, 6H), 3.86 (dd, J¼7.0, 4.9 Hz,
1H), 2.80 (dd, J¼17.8, 4.6 Hz, 1H), 2.75 (dd, J¼16.5, 7.0 Hz, 1H), 1.76
(m, 6H), 1.36 (m, 90H), 0.88 (t, J¼6.2 Hz, 9H); 13C NMR (67.5 MHz,
the procedure described above to afford pure Fmoc-Orn(Dde)-N-Me-
Phe-Asp(OAllyl)-O-TAGa (3.59 g,100%) as a colorless powder. Rf¼0.38
(siliga gel, hexane/EtOAc/AcOH¼1/1/0.1); IR (KBr)
n
(cmꢂ1) 3288 (w),
2917 (s), 1575 (m), 1118 (m); [
a
]
2D3ꢂ18.1 (c 1.0, CHCl3); mp 57e58 ꢁC;
CDCl3)
d
(ppm) 174.0, 171.0, 153.2, 138.3, 131.8, 130.3, 118.4, 107.0,
1H NMR (400 MHz, DMF, 80 ꢁC)
d
(ppm) 7.98 (d, J¼5.1 Hz, 2H), 7.93
77.5, 77.0, 76.5, 73.4, 69.1, 67.4, 65.4, 38.9, 31.9, 30.3, 29.7, 29.6, 29.4,
29.3, 26.1, 22.6, 22.6,14.1,14.0 (many signals, especially alkyl chains,
overlapped.); HRMS (FAB, NBA matrix) m/z: 1068.9565 [(MþH)þ;
calcd for C68H126O7N: 1068.9534].
(d, J¼5.1 Hz, 2H), 7.52 (d, J¼5.1 Hz, 2H), 7.44 (d, J¼5.1 Hz, 2H),
7.36e7.28 (complex m, 8H), 6.82 (s, 2H), 6.01 (m,1H), 5.41 (dt, J¼11.6,
1.1 Hz, 1H), 5.30 (dd, J¼7.2, 0.7 Hz, 1H), 5.21 (s, 2H), 5.26e4.97
(complex m, 3H), 4.66 (d, J¼3.3 Hz, 2H), [4.14 (t, J¼4.2 Hz), 4.06
(t, J¼4.5 Hz), total 6H, due to rotamer], 3.50e2.76 (complex m, 9H),
2.63 (m, 3H), 2.41 (s, 4H), 1.86 (m, 6H), 1.54e1.26 (complex m, 94H),
4.2.6. Fmoc-N-Me-Phe-Asp(OAllyl)-O-TAGa. At room temperature,
to a solution of 14 (3.51 g, 3.28 mmol) in CH2Cl2 (66 mL) was added
Fmoc-N-Me-Phe-OH (7) (1.45 g, 3.61 mmol), i-Pr2NEt (1.42 mL,
8.20 mmol), and PyBop (2.05 g, 3.93 mmol), and the mixture was
stirred for 3 h. Then, the reaction mixture was then recrystallized
by the procedure described in Section 4.2.3 to afford Fmoc-N-Me-
Phe-Asp(OAllyl)-O-TAGa (4.76 g, 100%) as a colorless powder.
13
1.10 (s, 6H), 1.09 (t, J¼4.9 Hz, 9H); C NMR (125 MHz, DMF, 80 ꢁC);
171.8, 154.7, 145.0, 141.5, 139.8, 134.1, 133.0, 132.6, 131.7, 130.3, 129.9,
128.6, 128.5, 127.7, 125.0, 122.6, 121.3, 118.6, 109.6, 108.8, 108.8, 80.5,
74.4, 70.8, 70.7, 68.3, 67.7, 66.5, 66.1, 64.7, 56.0, 54.2, 53.2, 52.4, 51.0,
44.4, 44.1, 43.9, 43.0, 40.9, 38.3, 37.6, 34.1, 33.5, 33.0, 31.7, 31.6,
31.4, 31.2, 31.0, 30.9, 30.8, 30.6, 30.6, 30.4, 30.4, 29.1, 27.5, 27.4,
27.1, 26.6, 23.7, 18.2, 14.8 (many signals were overlapped, and some
appropriate signals were disappeared due to the equilibrium of
rotamer.); HRMS (FAB, NBA matrix) m/z: 1752.2551 [(MþNa)þ, calcd
for C108H168O13N4Na: 1752.2506].
Rf¼0.48 (silica gel, hexane/EtOAc¼3/1); IR (KBr)
n
(cmꢂ1) 3399 (w),
2917 (s), 1683 (m); [
a]
D21ꢂ17.8 (c 1.0, CHCl3); mp 49e51 ꢁC; 1H NMR
(400 MHz, pyridine-d5, 90 ꢁC)
d
(ppm) 7.84 (d, J¼6.1 Hz, 2H),
7.65e7.29 (complex m, 11H), 6.92 (s, 2H), 5.95 (m, 1H), 5.36 (s, 2H),
5.27 (m, 2H), 4.65 (d, J¼5.1 Hz, 2H), 4.49e4.12 (complex m, 5H),
[4.29 (t, J¼4.3 Hz), 4.17 (t, J¼4.1 Hz), total 6H, due to rotamer], 3.63
(d, J¼3.8 Hz, 1H), 3.60 (d, J¼3.8 Hz, 1H), 3.31 (dd, J¼11.1, 4.6 Hz, 1H),
3.19 (dd, J¼15.7, 4.6 Hz, 1H), 3.12 (s, 3H), [2.08 (m), 1.93 (m), total
6H, due to rotamer], 1.42 (m, 90H), 0.97 (t, J¼5.1 Hz, 9H); 13C NMR
4.2.9. Orn(Dde)-N-Me-Phe-Asp(OAllyl)-O-TAGa (16). Following the
procedure described for general procedure of Fmoc deprotection,
Fmoc-Orn(Dde)-N-Me-Phe-Asp(OAllyl)-O-TAGa (3.59 g, 2.07 mmol)
was converted to 16 (3.13 g, 100%) as a colorless powder. Rf¼0.33
(100 MHz, pyridine-d5, 90 ꢁC)
d (ppm) 171.4, 171.2, 171.0, 170.6,
(silica gel, CHCl3/MeOH¼10/1); IR (KBr)
n
(cmꢂ1) 3452 (w), 2918 (s),
170.5, 154.1, 144.8, 141.9, 139.8, 138.6, 132.8, 131.5, 129.9, 129.6,
129.3, 128.9, 128.2, 127.6, 127.6, 127.0, 126.9, 125.6, 125.5, 121.7,
120.5, 120.3, 118.2, 108.4, 73.8, 70.0, 68.1, 67.9, 67.8, 65.6, 61.0, 50.5,
49.7, 47.9, 39.7, 37.1, 36.8, 35.3, 32.2, 31.2, 31.1, 30.1, 30.1, 30.0, 30.0,
29.8, 29.6, 26.7, 26.7, 22.9, 14.2 (many signals, especially alkyl
chains, overlapped.); HRMS (FAB, NBA) m/z: 1474.0873 [(MþNa)þ,
calcd for C93H146O10N2Na: 1474.0875].
1577 (w), 1119 (w); [
a]
23ꢂ25.9 (c 1.0, CHCl3); mp 52e53 ꢁC; 1H NMR
(270 MHz, CDCl3)
d
(ppDm) 7.18 (m, 5H), 6.50 (s, 2H), 5.82 (m,1H), 5.25
(m, 2H), 5.11 (d, J¼11.9 Hz, 1H), 5.00 (d, J¼11.6 Hz, 1H), 4.86 (m, 1H),
4.76 (m. 1H), 4.48 (d, J¼5.9 Hz, 2H), 3.96 (m, 6H), 3.12e2.79 (com-
plex, 7H), 2.82 (s, 3H), 2.48 (s, 3H), 2.36 (s, 3H), 2.34 (s, 1H), 1.76 (m,
6H), 1.57 (m, 2H), 1.24 (complex m, 92H), [1.04 (s), 1.01(s), total 6H,
due to rotamer], 0.88 (t, J¼6.6 Hz, 9H); 13C NMR (67.5 MHz, CDCl3)
d
(ppm) 173.2, 172.0, 170.2, 170.1, 169.4, 153.1, 138.3, 137.6, 131.5,
4.2.7. N-Me-Phe-Asp(OAllyl)-O-TAGa (15). Following the procedure
described for general procedure for Fmoc deprotection, Fmoc-N-
Me-Phe-Asp(OAllyl)-O-TAGa (3.00 g, 2.07 mmol) was converted to
15 (2.55 g, 100%) as a colorless powder. Rf¼0.21 (silica gel, hexane/
130.0, 128.9, 128.7, 128.7, 128.4, 126.8, 118.8, 107.7, 106.9, 77.5, 77.2,
77.0, 76.5, 73.3, 69.1, 67.7, 65.6, 61.2, 51.2, 48.8, 42.9, 36.3, 33.3, 33.1,
31.8, 30.2, 30.0, 29.6, 29.6, 29.3, 29.3, 28.3, 28.2, 26.0, 25.5, 22.6, 17.8,
14.1, 14.0 (many signals, especially alkyl chains, overlapped); HRMS
(FAB) m/z: 1530.1804 [(MþNa)þ, calcd for C93H158O11N4Na:
1531.1825].
EtOAc¼3/1); IR (KBr)
n
(cmꢂ1) 3336 (w), 2916 (s), 1730 (w), 1469
22
(w), 987.4(w); [
a
]
ꢂ10.5 (c 1.0, CHCl3); mp 64e66 ꢁC; 1H NMR
(270 MHz, CDCl3)
d
D(ppm) 8.08 (d, J¼8.9 Hz, 1H), 7.25 (m, 4H), 6.50
(s, 2H), 5.85 (m, 1H), 5.29 (dd, J¼17.6, 1.4 Hz, 1H), 5.22 (dd, J¼10.5,
1.6 Hz,1H), 5.06 (s, 2H), 4.93 (m,1H), 4.52 (d, J¼5.4 Hz, 2H), 3.94 (m,
6H), 3.18 (complex m, 2H), 3.07 (dd, J¼16.7, 4.6 Hz, 1H), 2.79 (dd,
J¼16.7, 4.6 Hz, 1H), 2.64 (dd, J¼13.5, 9.7 Hz, 1H), 2.23 (s, 3H), 1.75
(m, 6H), 1.36 (m, 90H), 0.88 (t, J¼6.2 Hz, 9H); 13C NMR (67.5 MHz,
4.2.10. Fmoc-
temperature, to a solution of 16 (2.50 g, 1.66 mmol) in CH2Cl2 (33 mL)
was added Fmoc- -Ala-OH (9) (713 mg, 2.16 mmol), i-Pr2NEt
D-Ala-Orn(Dde)-N-Me-Phe-Asp(OAllyl)-O-TAGa. At room
D
(0.87 mL, 4.98 mmol), and PyBop (1.30 g, 2.49 mmol), and the solu-
tion was stirred for 3 h. The reaction mixture was then recrystallized
CDCl3)
d (ppm) 173.5, 170.5, 170.2, 153.1, 138.2, 137.3, 131.6, 130.0,
by the procedure described in Section 4.2.3 to afford Fmoc-
Orn(Dde)-N-Me-Phe-Asp(OAllyl)-O-TAGa (2.99 g, 100%) as a colorless
D
-Ala-
129.0, 128.6, 126.8, 118.5, 106.9, 77.5, 77.0, 76.5, 73.3, 69.0, 67.8, 65.9,
65.5, 47.9, 39.2, 36.4, 35.2, 31.9, 31.9, 30.3, 29.7, 29.6, 29.6, 29.4, 29.3,
26.1, 22.6, 14.1, 14.1 (many signals, especially alkyl chains, over-
lapped.); HRMS (FAB, NBA matrix) m/z: 1230.0372 [(MþH)þ, calcd
for C78H137O8N2: 1230.0375].
powder. Rf¼0.51 (silica gel, CHCl3/MeOH¼10/1); IR (KBr)
n
(cmꢂ1
)
3286 (w), 2918 (s), 1576 (m), 1118 (m); [
a]
23ꢂ21.9 (c 1.0, CHCl3); mp
D
58e59 ꢁC; 1H NMR (400 MHz, CDCl3)
d
(ppm) 7.99 (d. J¼7.2 Hz, 1H),
7.76 (d, J¼7.2 Hz, 1H), 7.73 (d, J¼7.6 Hz, 1H), 7.58 (m, 2H), 7.41e7.11
(complex m, 10H), 6.48 (d, J¼7.0 Hz, 2H), 5.78 (m, 1H), 5.37e4.73
(complex m, 6H), 4.49 (d, J¼5.6 Hz, 1H), 4.46 (d, J¼5.9 Hz, 1H),
4.40e4.18 (complex m, 3H), 3.91 (t, J¼6.5 Hz, 6H), 3.36e2.86 (com-
plex m. 6H), 2.83 (s, 3H), 2.48 (s, 3H), 2.33 (s, 4H), 1.74 (m, 6H), 1.64
(m, 2H), 1.25 (complex m, 95H), 1.01 (m, 6H), 0.88 (t, J¼6.7 Hz, 9H);
4.2.8. Fmoc-Orn(Dde)-N-Me-Phe-Asp(OAllyl)-O-TAGa. At room tem-
perature, to a solution of 15 (2.55 g, 2.07 mmol) in CH2Cl2/DMF (10/1)
(42 mL) was added Fmoc-Orn(Dde)-OH (8) (1.61 g, 3.11 mmol),
i-Pr2NEt (1.08 mL, 6.21 mmol), and PyBrop (1.45 g, 3.11 mmol), and
the solutionwas stirred for 3 h. The reaction mixture was then cooled
to 0 ꢁC and ice-cool MeOH (210 mL) was added. The resulting het-
erogeneous solution was stirred for a further 10 min at 0 ꢁC, and
the colorless precipitate was filtered and washed with additional
MeOH to afford the mixture of 15 and Fmoc-Orn(Dde)-N-Me-Phe-
Asp(OAllyl)-O-TAGa, which was again subjected to condensation
reaction under the same conditions. After replicating the condensa-
tion reaction twice, the reaction mixture was recrystallized again by
13C NMR (100 MHz, CDCl3)
d (ppm) 173.7, 173.4, 172.0, 171.9, 171.6,
170.7,170.3,170.21,170.16,169.3,168.8,153.2,143.7,141.3,141.2,138.4,
138.3, 137.7, 131.5, 131.4, 129.9, 129.0, 128.9, 128.0, 127.8, 127.7, 127.7,
127.1, 127.1, 127.0, 126.8, 125.1, 125.0, 120.0, 120.0, 118.9, 118.7, 107.9,
107.0, 73.5, 69.2, 68.1, 67.2, 65.8, 65.8, 62.1, 50.2, 49.4, 49.0, 49.4, 49.0,
48.5, 48.3, 42.8, 42.6, 31.9, 30.3, 30.0, 29.7, 29.7, 29.6, 29.6, 29.4, 29.4,
29.3, 29.1, 26.0, 22.3, 17.8, 14.1 (many signals, especially alkyl chains,