3628 J . Org. Chem., Vol. 64, No. 10, 1999
Ranganathan et al.
of dry CH3CN containing 2 mmol of DMAP, and the reaction
mixture was stirred for 12 h at room temperature. Workup as
for 3a -c and purification of the residue on a short column of
silica gel using EtOAc/hexane as eluent afforded the titled bis
Tyr compound 9 in 82% yield.
a column of silica gel using a mixture of CHCl3/MeOH as
eluents to afford the bis-Tyr-depsipeptides 14a -d in good
yields.
14a : yield 88%; syrup; [R]30D +4.48 (c 0.54, CHCl3); IR (neat)
3324, 1735, 1702, 1671, 1648, 1620, 1557 cm-1; 1H NMR (300
MHz, CDCl3) δ 0.88 (d, J ) 3.7 Hz, 12H), 1.50-2.37 (m, 20H),
3.07 (m, 4H), 3.70 (s, 6H), 4.43 (m, 2H), 4.54 (m, 2H), 5.08 (s,
4H), 5.40 (d, J ) 7.6 Hz, 2H), 6.29 (d, J ) 7.2 Hz, 2H), 6.97 (d,
J ) 8.2 Hz, 4H), 7.20 (d, J ) 7.8 Hz, 4H), 7.33 (brs, 10H);
FAB MS m/z 1073 (MH)+.
9: mp 110-112 °C; IR (KBr) 3345, 1751, 1700, 1534 cm-1
;
1H NMR (300 MHz, CDCl3) δ 1.38-1.74 (m, 12H), 2.54 (m,
4H), 3.10 (m, 4H), 3.71 (s, 6H), 4.65 (m, 2H), 5.09 (s, 4H), 5.23
(d, J ) 7.8 Hz, 2H), 6.98 (d, J ) 8.3 Hz, 4H), 7.09 (d, J ) 8.3
Hz, 4H), 7.34 (brs, 10H).
14b: yield 78%; mp 40-42 °C; [R]30D +14.14 (c 1.52, CHCl3);
(b) Con d en sa tion of Nr-Dep r otected 1,ω-Seba coyl Bis-
Tyr d er iva tive 9 w ith 1,3-Ben zen ed ica r bon yl Dich lor id e
(1b). To a well-stirred and ice-cooled solution of NR-deprotected
bis Tyr derivative (1 mmol in ∼100 mL of dry EtOAc)
containing 2 mmol of triethylamine was added dropwise a
solution of 1,3-benzenedicarbonyl dichloride (1 mmol in 50 mL
of dry CH2Cl2) over a period of 0.5 h, and the mixture was
stirred at room temperature for 12 h. Workup as for macro-
cycles 5-8 and purification of the residue on a short column
of silica gel using EtOAc/hexane as eluent afforded the
sebacoyl-bridged macrocycle 10 in 30% yield; mp 102-104 °C;
IR (KBr) 3333, 1751, 1673, 1555 cm-1 1H NMR (300 MHz,
;
CDCl3) δ 0.99 (d, J ) 4.5 Hz, 12H), 1.50-2.41 (m, 20H), 3.18
(m, 4H), 3.80 (s, 6H), 4.22 (m, 2H), 4.93 (m, 2H), 5.19 (brs,
6H), 6.57 (brd, 2H), 7.02 (d, J ) 8.4 Hz, 4H), 7.17 (d, J ) 7.4
Hz, 4H), 7.43 (brs, 10H); FAB MS m/z 1073 (MH)+.
14c: yield 85%; mp 146-148 °C; [R]30D -37.26 (c 1.0, CHCl3);
IR (KBr) 3320, 1756, 1749, 1714, 1668, 1652, 1584, 1544 cm-1
;
1H NMR (300 MHz, CDCl3) δ 0.97 (d, J ) 4.5 Hz, 24H), 1.57-
2.44 (m, 26H), 3.15 (m, 4H), 3.79 (s, 6H), 4.21 (m, 2H), 4.61
(m, 2H), 4.74 (m, 2H), 5.17 (m, 6H), 6.50 (br, 2H), 6.77 (br,
2H), 7.00 (d, J ) 8.4 Hz, 4H), 7.28 (d, J ) 8.1 Hz, 4H), 7.42
(brs, 10H); FAB MS m/z 1299 (MH)+.
IR (KBr) 3371, 1752, 1671, 1648, 1538 cm-1 1H NMR (400
;
MHz, CDCl3) δ 1.37 (m, 6H), 1.72 (m, 6H), 2.50 (m, 4H), 3.09
(m, 2H), 3.44 (dd, J ) 4.5, 9.7 Hz, 2H), 3.83 (s, 6H), 5.11 (m,
2H), 6.83 (d, J ) 7.6 Hz, 2H), 6.97 (d, J ) 8.5 Hz, 4H), 7.14 (d,
J ) 8.5 Hz, 4H), 7.44 (t, J ) 7.7 Hz, 1H), 7.85 (dd, J ) 1.7, 6.0
Hz, 2H), 8.05 (t, J ) 1.6 Hz, 1H); FAB MS m/z 687 (MH)+.
Anal. Calcd for C38H42N2O10: C, 66.47; H, 6.12; N, 4.08.
Found: C, 66.19; H, 5.91; N, 3.92.
14d : yield 32%; sticky solid; IR (KBr) 3486, 3347, 3041,
1734, 1702, 1678, 1614, 1557, 1534 cm-1; 1H NMR (300 MHz,
CDCl3) δ 1.76-2.38 (m, 14H), 2.99 (brm, 8H), 3.68 (brs, 6H),
4.57 (m, 4H), 4.99 (brs, 4H), 5.38 (br, 2H), 5.81 (br, 2H), 6.69
(d, J ) 7.8 Hz, 8H), 6.90 (d, J ) 8.0 Hz, 8H); 7.31 (brs, 10H),
7.83 (br, 2H).
(b) Con d en sa tion of Nr-Dep r otected 1,3-Ad a m a n ta n e
Bis-Tyr -d ep sip ep tid es 14a -d w ith 1,3-Ad a m a n ta n ed i-
ca r bon yl Dich lor id e (1a ). To a well-stirred and ice-cooled
solution (1 mmol in ∼100 mL of dry EtOAc) of NR-deprotected
14a -c (Pd/C/H2 as described for 5-8) containing 2 mmol of
triethylamine was added dropwise a solution of freshly pre-
pared 1,3-adamantanedicarbonyl dichloride (1 mmol in 50 mL
of dry CH2Cl2) over a period of 0.5 h, and the mixture was
stirred at room temperature for 12 h. Workup as described
for 5-8 and purification of the residue on a column of silica
gel using a mixture of CHCl3/MeOH as eluent afforded
adamantane-constrained Tyr cyclodepsipeptides 15-18 in low
to moderate yields.
Rever se Ad d ition Rea ction : P r ep a r a tion of Seba coyl
Cyclic Am id e 11 a n d Ca ten a ted Molecu le 12. A solution
of 1,ω-sebacoyldicarbonyl dichloride (1 mmol) in dry CH2Cl2
(50 mL) was added dropwise to a well-stirred and ice-cooled
solution of N-deprotected (Pd/C, 5%, H2) 1,3-benzene bis-Tyr-
depsipeptide (3b, 1 mmol) in dry ethyl acetate (100 mL)
containing 2 mmol of triethylamin, and the reaction mixture
was stirred for 12 h. The solvents were removed in vacuo, and
the residue was dissolved in CH2Cl2 (100 mL), washed with
5% NaHCO3 (20 mL), dried (anhydrous MgSO4), and evapo-
rated in vacuo. The residue showing two spots on TLC was
chromatographed on a column of silica gel. Elution with a
mixture of CHCl3/MeOH yielded two compounds, identified as
a [1 + 1] cyclization product (11) and [1 + 1 + 1 + 1] catenane
(12).
11: yield 25%; mp 286-288 °C; IR (KBr) 3307, 1741, 1655,
1546 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.20 (s, 8H), 1.41 (m,
4H), 2.06 (m, 4H), 2.94 (m, 2H), 3.33 (dd, J ) 4.7, 9.1 Hz, 2H),
3.80 (s, 6H), 4.93 (m, 2H), 5.77 (d, J ) 8.3 Hz, 2H), 7.19 (s,
8H), 7.69 (t, J ) 7.9 Hz, 1H), 8.42 (dd, J ) 1.7, 6.2 Hz, 2H),
9.06 (s, 1H); FAB MS m/z 687 (MH)+.
12: yield 5%; mp 208-210 °C; IR (KBr) 3308, 1747, 1649,
1621, 1601 (sh), 1541 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.25
(m, 16H), 1.40 (m, 4H), 1.57 (m, 4H), 2.10 (m, 8H), 2.94 (m,
2H), 3.08 (m, 2H), 3.21 (m, 2H), 3.33 (m, 2H), 3.74 (s, 6H),
3.80 (s, 6H), 4.91 (m, 4H), 5.74 (d, J ) 8.4 Hz, 2H), 6.02 (d, J
) 7.9 Hz, 2H), 7.09 (s, 8H), 7.19 (m, 8H), 7.68 (m, 2H), 8.42
(d, J ) 6.5 Hz, 4H), 8.95 (s, 1H), 9.07 (s, 1H); FAB MS m/z
1395 (M + Na+), 1373 (MH)+, 709 (M/2 + Na+), 687 (M/2 +
H)+.
Gen er a l P r oced u r e for th e P r ep a r a tion of 1,3-Ad a -
m a n ta n e-Br id ged Leu -Con ta in in g Tyr osin e Cyclod ep -
sip ep tid es 15-18. (a ) P r ep a r a tion of P r ecu r sor 1,3-
Ad a m a n ta n e Bis-Tyr -d ep sip ep tid es 14a -d Listed in
Sch em e 4. A solution of 1,3-adamantanedicarbonyl dichloride
(1a , 1 mmol) in dry CH2Cl2 (10 mL) was added dropwise over
a period of 0.5 h to a well-stirred and ice-cooled solution of
NR-Z-Tyr-OMe or its di- or tripeptide (2 mmol) in dry CH3CN
(30 mL) containing DMAP (2 mmol), and the reaction mixture
was stirred at room temperature for 12 h. Solvents were
removed in vacuo, the residue was triturated with ethyl
acetate (∼100 mL), the extract was washed sequentially with
20 mL each of ice cold 2 N H2SO4, H2O, and 5% aqueous
NaHCO3, and the organic layer was dried over anhydrous
MgSO4 and evaporated in vacuo. The residue was purified on
15: yield 10%; mp 145-146 °C; [R]30D +2.10 (c 0.21, CHCl3);
1
IR (KBr) 3314, 1751, 1701, 1680, 1643, 1574, 1552 cm-1; H
NMR (300 MHz, CDCl3) δ 0.89 (m, 12H), 1.25-2.30 (m, 34H),
2.97 (m, 2H), 3.21 (dd, J ) 4.3, 10.1 Hz, 2H), 3.75 (s, 6H), 4.58
(m, 4H), 5.96 (d, J ) 7.3 Hz, 2H), 6.73 (d, J ) 7.9 Hz, 2H),
7.00 (d, J ) 8.3 Hz, 4H), 7.10 (d, J ) 8.3 Hz, 4H); FAB MS
m/z 993 (MH)+. Anal. Calcd for C56H72N4O12: C, 67.74; H, 7.25;
N, 5.64. Found: C, 67.53; H, 7.03; N, 5.39.
16: yield 20%; mp 108-110 °C; [R]30D -15.82 (c 0.3, CHCl3);
IR (KBr) 3384, 3323, 1752, 1670, 1648, 1551 (sh) cm-1 1H
;
NMR (400 MHz, CDCl3) δ 0.88 (d, J ) 6.6 Hz, 12H), 1.25-
2.33 (m, 34H), 2.90 (m, 2H), 3.30 (dd, J ) 4.0, 10.4 Hz, 2H),
3.79 (s, 6H), 4.44 (m, 2H), 4.86 (m, 2H), 5.67 (d, J ) 8.4 Hz,
2H), 6.59 (d, J ) 7.8 Hz, 2H), 6.99 (d, J ) 8.4 Hz, 4H), 7.12 (d,
J ) 8.5 Hz, 4H); FAB MS m/z 993 (MH)+. Anal. Calcd for
C
56H72N4O12: C, 67.74; H, 7.25; N, 5.64. Found: C, 68.03; H,
7.35; N, 5.83.
17: yield 32%; mp 210-212 °C; [R]30D -31.40 (c 1.0, CHCl3);
IR (KBr) 3323, 1755, 1673 (sh), 1656, 1561 cm-1; 1H NMR (400
MHz, CDCl3) δ 0.89 (m, 24H), 1.36-2.40 (m, 40H), 2.99 (dd, J
) 4.6, 9.8 Hz, 2H), 3.25 (m, 2H), 3.72 (s, 6H), 4.25 (m, 2H),
4.61 (m, 2H), 4.79 (m, 2H), 5.66 (d, J ) 6.7 Hz, 2H), 6.34 (d, J
) 8.6 Hz, 2H), 6.79 (d, J ) 8.4 Hz, 2H), 6.95 (d, J ) 8.4 Hz,
4H), 7.16 (d, J ) 8.4 Hz, 4H); FAB MS m/z 1219 (MH)+. Anal.
Calcd for C68H94N6O14: C, 66.99; H, 7.71; N, 6.89. Found: C,
67.13; H, 7.92; N, 6.82.
18: yield 10%; sticky solid; 1H NMR (300 MHz, CDCl3) δ
1.56-2.36 (m, 28H), 2.99-3.08 (m, 8H), 3.71 (s, 6H), 4.56 (m,
2H), 4.74 (m, 2H), 5.08 (brs, 4H), 5.27 (d, J ) 8.17 Hz, 2H),
5.84 (br, 2H), 6.70 (d, J ) 8.0 Hz, 4H), 6.92 (d, J ) 8.1 Hz,
4H), 7.35 (brs, 10H); FAB MS m/z 1361 (MH)+.
Rea ction of 2,6-P yr id in e-Su p p or ted Bis-Tyr -a m id e
(19) w it h 1,3-Ben zen ed ica r b on yl D. R ever se r ea ct ion