Synthesis of Hybrid Peptides with 12/10-Helix
for 15 min, treated with the above crude amine 2 and DIPEA (0.50
mL, 2.90 mmol), and stirred at room temperature for 5 h. The
reaction mixture was quenched with satd aq NH4Cl (10 mL) at 0
°C and diluted with CHCl3 (10 mL). It was sequentially washed
with 1 N HCl (10 mL), water (10 mL), and aq NaCl solution (10
mL). The organic layer was dried (Na2SO4) and evaporated to give
the residue, which was purified by column chromatography (silica
gel, 50% ethyl acetate in petroleum ether) to afford 9 (0.62 g, 67%)
as a white solid: mp 116-119 °C; [R]D ) +116.9 (c 0.25, CHCl3);
IR (KBr) 3269, 2987, 2937, 1754, 1739, 1688, 1661, 1554, 1373,
1168, 1058, 1021, 889, 858 cm-1; 1H NMR (500 MHz, CDCl3) δ
9.20 (s, 1H, NH-2), 5.87 (d, J ) 3.9 Hz, 1H, C1H-1), 5.49 (d, J )
9.7 Hz, 1H, NH-1), 4.55 (d, J ) 3.9 Hz, 1H, C2H-1), 4.51 (q, J )
7.2 Hz, 1H, CRH-2), 4.24 (m, 1H, CꢀH-1), 4.23 (dd, J ) 3.9, 7.2
Hz, 1H, C4H-1), 4.22 (m, 2H, -CH2), 3.72 (d, J ) 3.2 Hz, 1H,
C3H-1), 3.41 (s, 3H, OCH3-1), 2.51 (dd, J ) 5.7, 14.5 Hz, 1H,
CRH(pro-S)-1), 2.43 (dd, J ) 4.8, 14.5 Hz, 1H, CRH(pro-R)-1),
1.48 (d, J ) 7.2 Hz, 3H, CꢀH-2), 1.46, 1.31 (2s, 6H, acetonide-
CH3), 1.43 (s, 9H, BOC), 1.30 (t, J ) 7.2 Hz, 3H, -CH3); 13C
NMR (150 MHz, CDCl3, 278 K) δ 172.0, 169.2, 155.1, 111.8,
104.8, 83.4, 81.4, 80.1, 79.3, 79.1, 61.2, 57.8, 45.8, 34.9, 28.2, 26.6,
26.2, 16.1, 14.0; HRMS (ESI+) m/z calcd for C21H36N2O10 (M+ +
Na) 499.2267, found 499.2257.
(0.57 mL,3.32 mmol), and stirred at room temperature for 5 h.
Workup as described for 9 and purification by column chromatog-
raphy (silica gel, 50% ethyl acetate and petroleum ether) afforded
13 (0.675 g, 66.29%) as a white solid: mp 153-155 °C; [R]D
)
-69.54 (c1.07, CHCl3); IR (KBr) 3269, 2982, 2930, 1732, 1695,
1
1673, 1551, 1365, 1282, 1254, 1021, 858 cm-1; H NMR (500
MHz, CDCl3) δ 9.30 (s, 1H, NH-2), 5.85 (d, J ) 3.6 Hz, 1H, C1H-
1), 5.50 (d, J ) 9.7 Hz, 1H, NH-1), 4.54 (d, J ) 3.6 Hz, 1H, C2H-
1), 4.44 (s, 2H, CRH-2), 4.32 (m, 1H, CꢀH-1), 4.25 (dd, J ) 2.2,
4.7 Hz, 1H, C4H-1), 4.22 (m, 2H, -CH2), 3.71 (d, J ) 2.2 Hz,
1H, C3H-1), 3.41 (s, 3H, OCH3-1), 2.51 (dd, J ) 5.7, 14.5 Hz,
1H, CRH(pro-S)-1), 2.43 (dd, J ) 4.8, 14.5 Hz, 1H, CRH(pro-R)-
1), 1.46, 1.31 (2s, 6H, acetonide-CH3), 1.43 (s, 9H, BOC), 1.30 (t,
J ) 6.2 Hz, 3H, -CH3); 13C NMR (150 MHz, CDCl3, 278 K) δ
169.5, 169.0, 155.2, 111.7, 104.7, 83.4, 81.3, 80.0, 79.4, 72.1, 61.3,
57.8, 45.6, 39.4, 28.2, 26.6, 26.2, 14.0; HRMS (ESI+) m/z calcd
for C20H35N2O10 (M+ + H) 463.2291, found 463.2270.
Boc-(R)-ꢀ-Caa-Ama-(R)-ꢀ-Caa-Ama-OEt (5a). A solution of
13 (0.2 g, 0.43 mmol) as described for 9 gave Boc-(R)-ꢀ-Caa-Ama-
OH (14; 0.18 g, 96.2%) as a white solid, which was used for the
further reaction.
A solution of 14 (0.18 g,0.41 mmol), HOBt (0.067 g, 0.49 mmol),
and EDCI (0.095 g, 0.49 mmol) in dry CH2Cl2 (2 mL) was stirred
at 0 °C for 15 min and treated with the above-obtained amine TFA
salt 15 [prepared from the ester 13] and DIPEA (0.102 mL, 0.62
mmol) under nitrogen atmosphere for 5 h. Workup as described
for 9 and purification by column chromatography (silica gel, 1.8%
CH3OH in CHCl3) afforded 5a (0.17 g, 53.12%) as a white solid:
Boc-(R)-ꢀ-Caa-(R)-Ama-(R)-ꢀ-Caa-(R)-Ama-OEt (3a). A so-
lution of 9 (0.2 g, 0.42 mmol) as described for 8 gave Boc-(R)-ꢀ-
Caa-(R)-Ama-OH (10; 0.17 g, 90.4%) as a white solid, which was
used for the further reaction.
A solution of 9 (0.18 g, 0.38 mmol) and CF3COOH (0.4 mL) in
CH2Cl2 (2 mL) was stirred at 0 °C to rt for 2 h. Solvent was
evaporated under reduced pressure, and the resulting salt 11 was
dried under high vacuum and used as such for further reaction.
A solution of 10 (0.17 g,0.38 mmol), HOBt (0.062 g, 0.456
mmol), and EDCI (0.087 g, 0.456 mmol) in dry CH2Cl2 (2 mL)
was stirred at 0 °C for 15 min and treated with the above-obtained
amine TFA salt 11 and DIPEA (0.098 mL, 0.57 mmol) under
nitrogen atmosphere for 5 h. Workup as described for 9 and
purification by column chromatography (silica gel, 1.8% CH3OH
in CHCl3) afforded 3a (0.16 g, 52.3%) as a white solid: mp 84-85
°C; [R]20D ) +143.66 (c 0.3 in CHCl3); IR (KBr) 3431, 2985, 1683,
mp 80-82 °C; [R]20 ) -19.89 (c 1.25, CHCl3); IR (KBr) 3431,
D
2923, 2853, 1686, 1463, 1376, 1261, 1021, 855; 13C (150 MHz,
CDCl3, 278 K) δ 183.2, 169.7, 168.8, 168.2, 155.9, 111.8, 104.8,
83.7, 83.6, 81.3, 81.2, 80.2, 80.0, 79.9, 75.6, 72.1, 61.3, 58.1, 57.8,
46.2, 45.1, 35.8, 35.5, 31.9, 29.7, 28.3, 27.0, 26.7, 26.2, 16.3, 14.1;
HRMS (ESI+) m/z calcd for C33H55N4O17 (M+ + H) 779.3562,
found 779.3561.
Boc-(R)-ꢀ-Caa-Ama-(R)-ꢀ-Caa-Ama-(R)-ꢀ-Caa-Ama-OEt (5b). A
solution of 5a (0.15 g, 0.19 mmol) as described for 8 gave Boc-
(R)-ꢀ-Caa)-Ama-(R)-ꢀ-Caa)-Ama-OH (16; 0.13 g, 90.27%) as a
white solid, which was used for further reaction without any
purification.
1552, 1165, 1081, 1021, 855 cm-1 13C NMR (150 MHz, CDCl3,
;
278 K) δ 172.3, 170.7, 168.8, 168.5, 156.1, 111.8, 111.7, 104.9,
104.8, 83.9, 83.4, 81.4, 81.1, 81.0, 80.3, 80.0, 79.9, 79.8, 61.4, 58.1,
57.8, 47.2, 45.7, 36.4, 35.6, 29.7, 29.4, 28.3, 26.6, 26.1, 16.3, 15.7,
14.1; HRMS (ESI+) m/z calcd for C35H58N4O17 (M+ + Na)
829.3694, found 829.3688.
Boc-(R)-ꢀ-Caa-(R)-Ama-(R)-ꢀ-Caa-(R)-Ama-(R)-ꢀ-Caa-(R)-
Ama-OEt (4a). A solution of 3a (0.14 g, 0.173 mmol) as described
for 8 gave Boc-(R)-ꢀ-Caa-(R)-Ama-(R)-ꢀ-Caa-(R)-Ama-OH (12;
0.125 g, 92.6%) as a white solid, mp 96-97 °C.
To a solution of 16 (0.13 g, 0.17 mmol), HOBt (0.028 g, 0.207
mmol), and EDCI (0.040 g, 0.207 mmol) in dry CH2Cl2 (5 mL)
were added amine salt 15 [prepared from 13 (0.080 g, 0.17mmol)
and CF3COOH (0.2 mL) in CH2Cl2 (2 mL)] and DIPEA (0.045
mL, 0.25mmol) and the mixture stirred at room temperature for
5 h. Workup as described for 9 and purification by column
chromatography (silica gel, 2.5% CH3OH in CHCl3) furnished 5b
(0.067 g, 35.4%) as a white solid: mp 86-90 °C; [R]D ) -1.85 (c
0.09, CHCl3); IR (KBr) 3423, 2925, 2853, 1670, 1545, 1456, 1379,
1261, 1117, 1081, 888 cm-1 13C NMR (150 MHz, CDCl3, 278 K)
;
To a solution of 12 (0.125 g, 0.16 mmol), HOBt (0.026 g, 0.193
mmol), and EDCI (0.037 g, 0.193 mmol) in dry CH2Cl2 (5 mL)
was added amine salt 11 [prepared from 9 (0.077 g, 0.16 mmol)
and CF3COOH (0.2 mL) in CH2Cl2 (2 mL)] and the mixture stirred
at room temperature for 5 h. Workup as described for 9 and
purification by column chromatography (silica gel, 2.4% CH3OH
in CHCl3) furnished 4a (0.082 g, 44.3%) as a white solid: mp
97-98 °C; [R]D ) +318.59 (c 0.13, CHCl3); IR (KBr) 3423, 2986,
2925, 2852, 1669, 1537, 1456, 1374, 1253, 1218, 1165, 1117, 1081,
δ 183.3, 169.5, 169.3, 169.2, 168.8, 168.4, 155.8,139.4, 114.2,
111.9, 104.9, 83.7, 83.6, 83.5, 81.3, 81.2, 80.3, 80.2, 80.0, 75.5,
75.3, 72.0, 61.5, 57.9, 57.9, 57.8, 46.5, 45.2, 45.0, 38.4, 36.1, 35.9,
35.1, 33.9, 31.9, 29.7, 29.4, 28.4, 27.0, 26.7, 26.1, 22.7, 14.2, 14.1;
HRMS (ESI+) m/z calcd for C46H74N6O24 (M+ + Na) 1117.4652,
found 1117.4644.
Boc-(R)-ꢀ-hAla-(R)-Ama-OEt (18). A solution of 1a (0.9 g,
0.4.14 mmol) as described for 8 gave Boc-(R)-ꢀ-hAla-(R)-Ama-
OH 17; (0.83 g, 98.5%) as a white solid which was used for further
reaction without any purification.
A solution of acid 17 (0.82 g, 4.03 mmol), HOBt (0.65 g, 4.84
mmol), and EDCI (0.92 g, 4.84 mmol) in CH2Cl2 (5 mL) was stirred
at 0 °C under N2 atmosphere for 15 min, treated with the above
crude amine 2 [prepared from 7a (1.4 g, 2.665.32 mmol) and
N2H4 · H2O (0.78 mL, 15.96 mmol)] and DIPEA (0.50 mL,2.90
mmol), and stirred at room temperature for 5 h. Workup as
described for 9 and purification by column chromatography (silica
gel, 50% etthyl acetate and petroleum ether) gave 18 (0.75 g,
58.59%) as a white solid: mp 110-112 °C; [R]D ) +38.15 (c 1.065,
888, 854 cm-1 13C NMR (150 MHz, CDCl3, 278 K) δ 172.7, 170.3,
;
169.6,168.7, 168.6, 167.1, 156.7, 111.6, 111.3, 105.2, 105.0, 104.9,
84.3, 83.7, 83.1, 81.7, 81.0, 80.7, 80.6, 80.1, 80.0, 79.4, 78.9, 61.5,
58.2,57.8, 57.5, 48.6, 47.3, 45.1, 37.3, 36.0, 33.8, 29.7, 29.4, 28.3,
26.7, 26.4, 26.1, 26.0, 25.9, 24.8, 16.3, 15.4, 15.0, 14.2, 14.0; HRMS
(ESI+) m/z calcd for C49H80N6O24 (M+ + Na) 1159.5121, found
1159.5092.
Boc-(R)-ꢀ-Caa-Ama-OEt (13). A solution of acid 8 (0.80 g,
2.21 mmol), HOBt (0.360 g, 2.65 mmol), and EDCI (0.509 g, 2.65
mmol) in CH2Cl2 (5 mL) was stirred at 0 °C under N2 atmosphere
for 15 min, treated with the above crude amine 2a and DIPEA
J. Org. Chem. Vol. 73, No. 10, 2008 3697