(1f2)-Type Helical Turns
A R T I C L E S
Methyl 2-(1-(2-(1-(2-(tert-Butoxycarbonylamino)benzoyl)pyr-
rolidine-2-carboxamido)benzoyl) pyrrolidine-2-carboxamido)-
benzoate 2e. Boc-Ant-OH 8 (0.24 g, 1 mmol, 1 equiv) was coupled
with 2c (0.5 g, 1 mmol, 1 equiv) using TBTU (0.385 g, 1.2 mmol,
1.2 equiv) and DIEA (0.4 mL, 2.5 mmol, 2.5 equiv). Workup, as
described in the case of 1a, followed by column chromatographic
purification (eluent: pet. ether/ethyl acetate: 40:60, Rf 0.6) yielded
the pentapeptide 2e (0.49 g, 72%); as a fluffy solid, mp: 116-118
°C; [R]26D: -108° (c 0.5, CHCl3); IR (CHCl3) ν (cm-1) 3273, 3018,
2995, 1724, 1686, 1624, 1589, 1522, 1452, 1412, 1393, 1298, 1267,
dichloromethane (10 mL), and the product was extracted into
organic layer (2 × 15 mL). The organic layer was dried over
anhydrous sodium sulfate, evaporated, and dried, and the residue
obtained was taken in dry dichloromethane (10 mL). The reaction
mixture was cooled to 0 °C, pivaloyl chloride (0.1 mL, 0.8 mmol,
1.3 equiv) was added followed by Et3N (0.17 mL, 1 mmol, 2 equiv),
and the reaction mixture was allowed to stir at room temperature
for 4 h. The reaction mixture was diluted with more dichlo-
romethane (10 mL) and washed sequentially with potassium
hydrogen sulfate solution, sat. sodium bicarbonate solution, and
water. The organic layer was dried over anhydrous sodium sulfate,
and the crude product obtained on the removal of solvent under
reduced pressure was subjected to column purification (eluent: 90%
AcOEt/pet. ether, Rf 0.3) yielded 2g (0.37 g, 75%) mp: 110-112
°C; [R]25D: -60.47° (c 0.43, CHCl3); IR (ν) CHCl3 (cm-1): 3286,
3018, 2880, 1695, 1686, 1636, 1623, 1618, 1589, 1541, 1531, 1522,
1518, 1508, 1473, 1452, 1437, 1416, 1296, 1267, 1215, 1164, 1143,
1091, 1047; 1H (400 MHz, CDCl3) δ: 11.52 (s, 1H), 10.01 (s, 1H),
9.66 (s, 1H), 8.73-8.71 (d, J ) 8.40 Hz, 1H), 8.27-8.22 (t, J )
8.67 Hz, 1H), 8.04-8.02 (d, J ) 7.42 Hz, 1H), 7.66-7.65 (d, J )
7.42 Hz, 1H), 7.57-7.52 (m, 2H), 7.42-7.34 (m, 2H), 7.18-7.08
(m, 3H), 4.86-4.83 (t, J ) 7.26 Hz, 1H), 4.79-4.76 (t, J ) 6.39
Hz, 1H), 4.65-4.62 (m, 1H), 3.91 (s, 3H), 3.81-3.65 (m, 4H),
3.60-3.54 (m, 1H), 3.36-3.31 (m, 1H), 2.45-2.36 (m, 2H),
2.22-1.77 (m, 10 H), 1.25 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ: 176.96, 171.8, 171.2, 171.9, 169.4, 169.2, 168.7, 141.1, 135.97,
135.7, 134.5, 130.8, 130.7, 130.5, 127.4, 126.1, 123.7, 123.6, 122.8,
122.6, 122.4, 120.3, 115.1, 63.0, 62.1, 61.6, 52.3, 50.1, 49.9, 48.5,
38.8, 30.1, 30.0, 27.3, 25.3; ESI MS 765.43 (M + H)+, 782.47 (M
+ Na)+, 737.39 (M + K)+. Elemental analyses calculated for
C42H48N6O8: C, 65.95; H, 6.33; N, 10.99. Found: C, 66.24; H, 6.15;
N, 10.78.
tert-Butyl 2-(2-(2-(2-(2-(2-(2-(2-(Methoxycarbonyl)phenylcar-
bamoyl)pyrrolidine-1-carbonyl) phenylcarbamoyl)pyrrolidine-
1-carbonyl)phenylcarbamoyl)pyrrolidine-1-carbonyl)phenyl-
carbamoyl)pyrrolidine-1-carboxylate 3a. The acid 2b (0.6 g, 1.1
mmol, 1 equiv) was coupled with amine 2c (0.55 g, 1.1 mmol, 1
equiv) using TBTU (0.42 g, 1.3 mmol, 1.2 equiv) and DIEA (0.48
mL, 2.7 mmol, 2.5 equiv), and the reaction was allowed to proceed
for 12 h, at room temperature. Workup, as described in the case of
1a, followed by column chromatographic purification (eluent: ethyl
acetate/MeOH: 98:2, Rf 0.3), afforded 3a (0.73 g, 67%) as a fluffy
solid; mp: 145-146 °C; [R]24D: -60° (c 0.2, CHCl3); IR (CHCl3)
ν (cm-1) 3271, 3124, 3016, 2980, 1693, 1682, 1626, 1589, 1528,
1454, 1416, 1296, 1276, 1215, 1165, 1092; 1H (400 MHz, CDCl3)
δ: 11.56 (s, 1H), 10.12 (s, 1H), 10.03 (s, 1H), 9.81rotamer (0.8H),
9.73rotamer (0.2H), 8.74 (d, J ) 8.31 Hz, 1H), 8.51-8.35 (m, 3H),
8.07 (d, J ) 7.71 Hz, 1H), 7.70-7.47 (m, 4H), 7.46-7.32 (m,
3H), 7.25-7.10 (m, 4H), 5.05-4.7 (m, 3H), 4.48rotamer (0.2H),
4.30rotamer(0.8H), 3.94 (s, 3H), 3.9-3.2 (m, 8H), 2.5-1.6 (m, 16H),
1.46rotamer (3H), 1.35rotamer (6H); 13C NMR (100 MHz, CDCl3) δ:
172.13, 171.5, 168.85, 168.8, 168.7, 154.1, 141.1, 136.7, 135.9,
134.7, 130.96, 130.92, 130.6, 127.2, 127.16, 127.1, 123.98, 123.9,
122.98, 122.9, 121.7, 121.6, 121.1, 120.9, 115.3, 62. 0, 61.97, 61.37,
61.1, 50.31, 49.9, 47.2, 46.7, 31.3, 30.19, 30.01, 29.7, 24.9, 25.43,
25.2, 23.9; ESI Mass: 998.04 (M + H)+, 1019.99 (M + Na)+,
1035.95 (M + K)+. Anal. Calcd for C54H60N8O11: C, 65.05.; H,
6.07.; N, 11.24. Found: C, 65.28.; H, 6.20.; N, 11.10.
1
1248, 1219, 1092, 1047; H (400 MHz, CDCl3) δ: 11.55 (s, 1H),
10.15 (s, 1H), 8.75-8.73 (m, 2H), 8.52-8.49 (d, J ) 8.04 Hz,
1H), 8.17-8.15 (d, J ) 8.30 Hz, 1H), 8.04-8.02 (d, J ) 6.96 Hz,
1H), 7.73-7.71 (d, J ) 7.23 Hz, 1H), 7.66-7.64 (d, J ) 7.50 Hz,
1H), 7.56-7.52 (m, 1H), 7.43-7.36 (m, 2H), 7.14-7.08 (m, 3H),
4.85-4.83 (m, 1H), 4.69-4.66 (m, 1H), 3.91 (s, 3H), 3.87-3.80
(m, 1H), 3.71-3.65 (m, 1H), 3.58-3.53 (m, 1H), 3.50-3.45 (m,
1H), 2.47-2.39 (m,1H), 2.37-2.30 (m,1H), 2.14-1.76 (m, 6H),
1.48 (s, 9H); 13C NMR (100 MHz, CDCl3) δ: 170.8, 170.6, 170.1,
169.6, 168.7, 153.1, 141.1, 137.6, 136.8, 134.6, 131.2, 130.9, 128.3,
127.7, 123.96, 123.1, 122.9, 122.8, 121.7, 121.4, 120.3, 120.1,
115.2, 80.1, 62.3, 61.9, 52.4, 50.7, 50.4, 30.0, 29.98, 28.3, 25.5,
25.4; ESI Mass: 684.16 (M + H)+, 706.11 (M + Na)+, 722.07 (M
+ K)+. Anal. Calcd for C37H41N5O8: C, 64.99; H, 6.04; N, 10.24.
Found: C, 65.10; H, 6.18; N, 10.16.
tert-Butyl 2-(2-(2-(2-(2-(2-(methoxycarbonyl)phenylcarbam-
oyl)pyrrolidine-1-carbonyl)phenylcarbamoyl)pyrrolidine-1-car-
bonyl)phenylcarbamoyl)pyrrolidine-1-carboxylate 2f. A solution
containing the tetrapeptide 2a (1.2 g, 2.1 mmol) in dichloromethane
(8 mL) was subjected to Boc deprotection using DCM/TFA (50%,
2 mL). After completion of the reaction (1 h), the reaction mixture
was stripped of the solvent, neutralized with saturated sodium
bicarbonate solution, and diluted with dichloromethane (10 mL),
and the product was extracted into the organic layer (2 × 15 mL).
The organic layer was dried over anhydrous sodium sulfate,
evaporated, and dried, and the residue obtained was taken in dry
acetonitrile (10 mL). The reaction mixture was cooled to 0 °C. To
this stirring solution, the acid 1b was added followed by HBTU
(1.2 g, 3.2 mmol, 1.5 equiv) and DIEA (0.76 mL, 4.2 mmol, 2
equiv). The reaction mixture was allowed to stir at room temperature
for 12 h. Workup as described in the case of tetrapeptide 2a and
purification of the crude product by column chromatographic
purification (eluent: 80% AcOEt/pet. ether, Rf 0.3) yielded 2f (1.24
g, 75%) as a fluffy compound; mp: 119-121 °C; [R]27D: -85.71°
(c 1.4, CHCl3); IR (ν) nujol (cm-1): 3264, 1687, 1625, 1586, 1520,
1
1456; H (400 MHz, CDCl3) δ: 11.54 (s, 1H), 10.07-10.02rotamer
(1H), 9.90rotamer (0.6H), 9.84rotamer (0.4H), 8.75-8.73 (d, J ) 8.51
Hz, 1H), 8.47-8.26 (m, 2H), 8.06-8.04 (d, J ) 7.96 Hz, 1H),
7.75-7.53 (m, 3H), 7.41 (b, 2H), 7.20-7.10 (m, 3H), 4.94rotamer
(0.55H), 4.87rotamer (0.45H), 4.76 (b, 1H), 4.43rotamer (0.45H),
4.27rotamer (0.55 H), 3.93 (s, 3H), 3.87 (b, 1H), 3.69 (b, 1H), 3.55
(b, 3H), 3.34 (b, 1H), 2.45-2.36 (m, 2H), 2.25-1.8 (m, 10H),
1.46rotamer (3H), 1.32rotamer(6H); 13C NMR (100 MHz, CDCl3) δ:
172.0, 171.9, 171.0, 170.8, 169.9, 169.6, 169.3, 169.0, 168.7, 155.0,
154.0, 141.1, 136.8, 136.4, 136.1, 135.9, 135.8, 134.5, 131.2, 130.9,
130.8, 127.95, 127.6, 127.5, 125.7, 124.95, 123.7, 123.6, 123.3,
122.9, 122.3, 122.1, 121.1, 120.8, 120.3, 115.2, 79.7, 62.1, 61.5,
61.4, 61.1, 52.4, 50.6, 50.0, 47.1, 46.7, 31.4, 30.1, 29.9, 28.4, 28.2,
25.4, 25.3, 24.3, 23.8; ESI MS 781.84 (M + H)+, 803.84 (M +
Na)+, 819.82 (M + K)+. Elemental analyses calculated for
C42H48N6O9: C, 64.60; H, 6.20; N, 10.76. Found: C, 64.25; H, 6.37;
N, 11.02.
Methyl 2-(1-(2-(1-(2-(1-(2-(1-Pivaloylpyrrolidine-2-carboxa-
mido)benzoyl) pyrrolidine-2-carboxamido)benzoyl)pyrrolidine-
2-carboxamido)benzoyl) pyrrolidine-2-carboxamido)benzoate
3b. A solution containing the octapeptide 3a (0.3 g, 0.3 mmol) in
dichloromethane (5 mL) was subjected to Boc deprotection using
DCM/TFA (50%, 2 mL). After completion of the reaction (1 h),
the reaction mixture was stripped of the solvent, neutralized with
saturated sodium bicarbonate solution, and diluted with dichlo-
romethane (10 mL), and the product was extracted into the organic
layer (2 × 15 mL). The organic layer was dried over anhydrous
sodium sulfate, evaporated, and dried, and the residue obtained was
Methyl 2-(1-(2-(1-(2-(1-Pivaloylpyrrolidine-2-carboxamido)-
benzoyl)pyrrolidine-2-carboxamido)benzoyl)pyrrolidine-2-car-
boxamido)benzoate 2g. A solution containing the hexapeptide 2f
(0.5 g, 0.6 mmol) in dichloromethane (5 mL) was subjected to Boc
deprotection using DCM/TFA (50%, 2 mL). After completion of
the reaction (1 h), the reaction mixture was stripped of the solvent,
neutralized with saturated sodium bicarbonate solution, diluted with
9
J. AM. CHEM. SOC. VOL. 130, NO. 52, 2008 17753