Synthesis of Cystinophanes
J. Am. Chem. Soc., Vol. 120, No. 12, 1998 2701
ester (5 mmol, prepared by N-deprotection of the bis-Boc derivative
with 25% TFA in 15 mL of dry CH2Cl2, followed by neutralization
with saturated sodium carbonate, extraction with CH2Cl2, and drying
of the organic layer with anhydrous MgSO4). The reaction mixture
was further diluted with ∼150 mL of dry CH2Cl2 and left stirred at
room temperature for 12 h, and washed with 20 mL, each, of ice-cold
2 N H2SO4, water and bicarbonate solution, and the organic extract
was dried (anhydrous MgSO4) and evaporated in vacuo. The residue
was chromatographed on a column of silica gel and products eluted
with CHCl3/MeOH (95:5) eluent.
(2). Selected Data of Cystinophanes. 3a: Yield 52%; mp 132-
134 °C; [R]26 -36.33 (c 1.94, CHCl3); IR (KBr) 3385, 3072, 2959,
D
1750, 1680, 1671 (sh), 1648, 1586 (sh), 1556, 1538, 1515, 1481, 1442
1
cm-1; H NMR (300 MHz, DMSO-d6) δ 2.88 (4H, dd, J ) 5.1, 8.7
Hz), 3.19 (4H, dd, J ) 6.3, 7.5 Hz), 3.59 (12H, s), 4.74 (4H, m), 7.31
(2H, t, J ) 7.8 Hz), 7.71 (4H, d, J ) 7.8 Hz), 7.95 (2H, s), 8.99 (4H,
d, J ) 7.5 Hz); FAB-MS m/z (%) 797 (95) [M + H]+.
3b: Yield 51%; mp 102-104 °C; [R]26 +177.92 (c 4.0, CHCl3);
D
IR (KBr) 3404, 2959, 1751, 1689, 1559 (sh), 1528, 1443, 1354 cm-1
;
1H NMR (300 MHz, CDCl3) δ 3.31 (4H, dd, J ) 4.5, 15 Hz), 3.51
(4H, dd, J ) 4.5, 14.4 Hz), 3.73 (12H, s), 5.09 (4H, m), 8.08 (2H, t,
J ) 7.5 Hz), 8.37 (4H, d, J ) 7.8 Hz), 8.82 (4H, d, J ) 8.1 Hz);
FAB-MS m/z (%) (100) 799 [M + H]+.
4: Yield 12%; semisolid; [R]26D -28.80 (c 1.70, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 3.27 (12H, m), 3.72 (18H, brs), 4.97 (6H, m),
8.04 (3H, t, J ) 7.5 Hz), 8.36 (6H, d, J ) 7.8 Hz), 8.84 (6H, d, J )
5.1 Hz); IR (KBr) 3361, 2962, 2934, 1751, 1681, 1559 (sh), 1524,
1444, 1355 cm-1; FAB-MS m/z (%) 1198 (100) [(M + H)+], 799 (80)
[M+ - 3b + H].
Figure 7. The hydrogen bond environment about the water molecule
W1 and the symmetry related W1a. The cystinophane molecules are
connected into an infinite chain by the water molecules. The orientation
of 3a on the left shows the parallel planes near which most of the
backbone atoms lie.
26
5: Yield 4%; mp 136-138 °C; [R]D -65.29 (c 1.1, CHCl3); IR
(KBr) 3360, 2959, 1749, 1681, 1534, 1444, 1355 cm-1; 1H NMR (300
MHz, CDCl3) δ 3.29 (16H, m), 3.71 (24H, brs), 4.97 (8H, m), 8.03
(4H, t, J ) 7.5 Hz), 8.33 (8H, d, J ) 7.5 Hz), 8.88 (8H, d, J ) 8.1
Hz); FAB-MS m/z (%) 1597 (60) [M + H]+, 1198 (43) [M+ - 3b +
H], 799 (100) [M+ - 2 × 3b + H].
6a: Yield 62%; mp 71-72 °C; [R]26 +26.32 (c 4.40, CHCl3); IR
D
(KBr) 3332, 2967, 1751, 1718, 1687, 1661, 1533, 1514 cm-1; 1H NMR
(90 MHz, CDCl3) δ 0.93 (12H, d, J ) 5 Hz), 1.46 (18H, m), 1.67 (6H,
m), 3.18 (4H, m), 3.77 (6H, s), 4.25 (2H, m), 4.88 (2H, m), 5.39 (2H,
d, J ) 7.5 Hz), 7.62 (2H, brd); FAB-MS m/z (%) 717 (8) [M + Na]+,
695 (20) [M + H]+, 595 (44) [M -Boc + H]+, 495 (100) [M -2 ×
Boc + H]+.
6b: Yield 65%; mp 119-121 °C; IR (KBr) 3354, 2986, 2937, 1744,
1
1694, 1671, 1534 cm-1; H NMR (90 MHz, CDCl3) δ 1.42 (18H, s),
3.18 (8H, m), 3.81 (6H, s), 4.63 (2H, m), 4.92 (2H, m), 5.54 (2H, d,
J ) 7.5 Hz), 7.06-7.55 (12H, m); FAB-MS m/z (%) 763 (16) [M +
H]+, 663 (62) [M -Boc + H]+, 563 (100) [M -2 × Boc + H]+.
7a: Yield 42%; mp 254-256 °C; [R]26D -147.02 (c 3.85, CHCl3);
1
IR (KBr) 3292, 2964, 1749, 1650, 1534 cm-1; H NMR (300 MHz,
DMSO-d6) 0.90 (12H, m), 1.62 (6H, m), 2.93 (2H, dd, J ) 9.9, 12
Hz), 3.18 (2H, dd, J ) 4.2, 13.8 Hz), 3.63 (6H, s), 4.55 (4H, m), 7.49
(1H, t, J ) 7.8 Hz), 7.75 (2H, d, J ) 7.8 Hz), 7.99 (1H, s), 8.18 (2H,
d, J ) 7.8 Hz), 8.59 (2H, d, J ) 8.7 Hz); FAB-MS m/z (%) 625 (88)
[M + H]+.
26
7b: Yield 45%; mp 216-218 °C; [R]D -191.60 (c 0.57, CHCl3/
MeOH; 3:1); IR (KBr) 3291, 2941, 2684, 1744, 1732, 1674, 1653,
1537, 1442 cm-1; 1H NMR (300 MHz, DMSO-d6) 2.92 (4H, t, J ) 9.6
Hz), 3.13 (4H, m), 3.62 (6H, s), 4.65 (4H, m), 7.18-7.28 (10H, m),
7.46 (1H, t, J ) 7.5 Hz), 7.59 (2H, d, J ) 7.5 Hz), 7.99 (1H, s), 8.18
(2H, d, J ) 7.5 Hz), 8.87 (2H, d, J ) 8.7 Hz); FAB-MS m/z (%) 693
(100) [M + H]+.
Figure 8. Projection down the a axis of the cystinophane crystal.
Hydrogen bonds involving water molecules (darkened) are indicated
by dashed lines. Dotted lines indicate N2H‚‚‚O3 hydrogen bonds
between the infinite chains of molecules. Ethyl acetate molecules have
been omitted for clarity. They reside in the channels represented by
the open spaces such as between S1f, S2f and S3h, S4h.
Preparation of Tetrabutylammonium Salts of 1,ω-Alkane Di-
carboxylic Acids.19 To a stirred solution of the dicarboxylic acid (1
mmol) in dry methanol (∼2 mL) was added 2 equiv of a 0.1 N solution
of tetrabutylammonium hydroxide in methanol/toluene (SRL) in one
portion. The resulting mixture after 2 h of stirring at room temperature
was subjected to vacuum and the thick syrupy residue was dried for
24 h over P2O5 in a vacuum desiccator. The dried bis-TBA salts were
(b) Condensation of Cystine Dimethyl Ester or N-Deprotected
Cystino Bispeptides with 1,3 Aromatic Dicarbonyl Dichlorides:
Preparation of Cystinophanes 3a,b, 4, 5, and 7a,b. A solution of
1,3 aromatic dicarbonyl dichloride (1, X ) CH or N) (5 mmol) in dry
CH2Cl2 (30 mL) was added dropwise (0.5 h) to a well-stirred and ice-
cooled solution of cystine dimethyl ester (generated in situ at 0 °C
from 5 mmol of cystine dimethyl ester dihydrochloride and 10 mmol
of triethylamine in 50 mL of dry CH2Cl2) or cystino bispeptide dimethyl
1
directly used for H NMR titration experiments.
1H NMR Titration of 3b with the Bis-TBA Salt of Glutaric Acid
in CDCl3. An initial NMR spectrum of the solution of 3b (8 mg/0.5