Modular Synthesis of π-Acceptor Cyclophanes
J . Org. Chem., Vol. 66, No. 9, 2001 3033
was performed to ensure complete coupling.23 The procedure
was repeated for (S)-Val-N-t-BOC. After the DMF wash, the
resin was washed with MeOH and allowed to air-dry. The
BOC-protected tripeptide was cleaved from the resin by
potassium carbonate with a phase transfer reagent.24 (S)-Val-
(N-t-BOC)-Leu-Ala (2.70 g, yield 40%) was isolated as de-
scribed previously:111H NMR (DMSO-d6) δ [8.13 (d, 1H, J )
6.7 Hz), 7.75 (d, 1H, J ) 7.9 Hz), 6.75 (d, 1H, J ) 8.2 Hz)]
(three NHCO), [4.38 (m, 1H), 4.15 (m, 1H), 3.73 (m, 1H)] (CH
amino acid chiral centers), 1.90 (m, 1H) (CH valine), 1.62 (m,
1H) (CH leucine), 1.45 (m, 2H) (CH2 valine), 1.33 (s, 9H) (BOC),
1.22 (d, 3H, J ) 7.0 Hz) (CH3 alanine), 0.81 (m, 12H) (two
CH3 valine and two CH3 leucine); 13C NMR (DMSO-d6) δ
[174.02, 171.82, 171.21, 155.58] (carbonyl), [78.23, 28.33] (BOC
carbons), [60.13, 50.57, 47.58] (chiral center carbons), [24.08,
23.32, 21.72, 19.42, 18.38, 17.23] (amino acid side chains).
Anal. Calcd (found): C, 56.91% (57.05%); H, 8.73% (8.78%);
N, 10.47% (10.38%)
of the solvent resulted in an orange solid. The solid was
purified by silica gel chromatography (MeOH/CHCl3, 1:9).
Removal of the solvent gave an orange-yellow product (0.224
1
g, 76%). H NMR showed minor impurities in the range 2.3-
1
2.8 ppm (see Supporting Information). H NMR (DMSO-d6) δ
8.64 (br, 4H) (naphthalene), [8.41 (m, 1H), 8.13 (m, 2H), 7.80
(m, 1H)] (four NHCO), [7.19-7.40 (br, 4H), 7.10 (m, 4H)]
(phenyls), 5.46-5.28 (br, 4H)) (methylene groups next to
imides), 4.52-3.71 (br, 5H) (CH2NH and three amino acid
chiral centers), 2.08 (m, 1H) (CH valine), 1.40-1.10 (br, 6H)
(CH leucine, CH2 valine, CH3 alanine), 0.87-0.52 (br, 12H)
(two CH3 valine and two CH3 leucine); 13C NMR (DMSO-d6) δ
[171.89, 171.80, 171.64, 170.23, 166.81] (carbonyl), [138.96,
138.72, 134.64, 131.12, 129.46, 128.97, 128.11, 127.98, 127.73,
127.36, 126.64] (phenyl and naphthalene rings), [59.53, 51.98,
50.21] (chiral carbon centers), 48.65 (-CH2NH), 42.53 (two
methylenes next to imides), [24.11, 23.21, 21.84, 19.82, 18.45,
18.11] (amino acid side chains); positive ion MALDI HRMS:
C
44H44O8N6 MH+ ) 785.3299 ( 10 ppm. Anal. Calcd (found):
{N-[(p-Car boxyph en yl)m eth yl]-N′-[(p-((S)-Val(N-t-BOC)-
Leu -Ala -a m in om et h yl)p h en yl)m et h yl]-1,4,5,8-n a p h t h a -
len etetr acar boxylic diim ide}. (S)-Val-Leu-Ala-N-t-BOC was
coupled to {N-[(p-carboxyphenyl)methyl]-N′-[p-(N-t-BOC-ami-
nomethyl)phenyl)methyl]-1,4,5,8-naphthalenetetracarboxylic
diimide} using a modified amino acid coupling procedure.25 {N-
[(p-Carboxyphenyl)methyl]-N′-[p-(N-t-BOC-aminomethyl)phe-
nyl)methyl]-1,4,5,8-naphthalenetetracarboxylic diimide} (0.63
g, 1.0 mmol) was dissolved in TFA/CHCl3 (15 mL, 1:3) and
stirred for 45 min. The solvent was removed under vacuum.
The residue was washed with hexane (15 mL × 3) which was
removed under vacuum. The deprotected diimide was dissolved
in DMF (50 mL), and DIEA (0.348 mL, 2.0 mmol) was added.
In a separate flask under Ar, (S)-Val(N-t-BOC)-Leu-Ala (0.40
g, 1.0 mmol) was dissolved in DMF (20 mL). DIEA (0.174 mL,
1.0 mmol) and BOP (0.442 g, 1.0 mmol) were added, and the
solution was allowed to react for 20 min. The deprotected
diimide solution was then added dropwise to the activated (S)-
Val(N-t-BOC)-Leu-Ala solution, and the solution was stirred
for 6 h. The solvent was removed by evaporation at 50 °C at
atmospheric pressure. The residue was washed with MeCN,
water, and acetone and dried under vacuum to yield a yellow
powder (0.471 g, 52%): 1H NMR (DMSO-d6) δ 8.69 (s, 4H)
(naphthalene), [8.25 (m, 1H), 7.94 (m, 1H), 7.78 (m, 1H), 6.70
(m, 1H)] (four NHCO), [7.87 (d, 2H, J ) 8.2 Hz), 7.50 (d, 2H,
J ) 8.3 Hz), 7.32 (d, 2H, J ) 8.1 Hz), 7.17 (m, 2H)] (phenyls),
5.28 (d, 4H, J ) 30.5 Hz) (methylene groups next to imides),
4.21 (m, 4H) (CH2NH and two amino acid chiral centers), 3.70
(m, 1H) (amino acid chiral center), 1.84 (m, 1H) (CH valine),
1.55 (m, 1H) (CH leucine), 1.40 (m, 2H) (CH2 valine), 1.32 (s,
9H) (BOC), 1.17 (d, 3H, J ) 7.2 Hz) (CH3 alanine), 0.78 (m,
12H) (two CH3 valine and two CH3 leucine); 13C NMR (DMSO-
d6) δ [172.37, 172.21, 172.08, 156.01] (carbonyl), 167.49 (car-
boxylic), [163.30, 163.20] (carbonyl), [142.43, 138.91, 135.85,
131.28, 130.15, 129.98, 128.18, 127.75, 127.59, 126.96, 126.89]
(phenyl and naphthalene rings), 48.73 (-CH2NH), 43.81 (two
methylenes next to imides), 28.66 (BOC carbons), [24.56, 23.40,
22.16, 19.64, 18.75, 18.48] (amino acid side chains); positive
ion MALDI: C49H54O11N6 [M + Na]+ ) 925.
C, 67.33% (64.22%); H, 5.65% (6.06%); N, 10.71% (10.55%).
{N-[(p-((S)-Val(N-t-BOC)-Leu -Ala-am in om eth yl)ph en yl)-
m eth yl]-N′-[(p-ca r boxyp h en yl)m eth yl]-1,5-d in itr on a p h -
th alen e-3,7-diam ide}. {N-[(p-(N-t-BOC-aminomethyl)phenyl)-
methyl]-N′-[(p-carboxyphenyl)methyl]-1,5-dinitronaphthalene-
3,7-diamide} (1.10 g, 1.67 mmol) was dissolved in TFA/CHCl3
(15 mL, 1:3) and stirred for 45 min. The solvent was removed
under vacuum. The residue was washed with hexane (15 mL
× 3) which was removed under vacuum. The deprotected
dinitronaphthalene was dissolved in DMF (50 mL), and DIEA
(0.295 mL, 1.6 mmol) was added. In a separate flask under
Ar, (S)-Val(N-t-BOC)-Leu-Ala (0.65 g, 1.62 mmol) was dis-
solved in DMF (50 mL). DIEA (0.582 mL, 3.2 mmol) and BOP
(0.723 g, 1.64 mmol) were added, and the solution was allowed
to react for 20 min. The deprotected dinitronaphthalene
solution was then added dropwise to the activated (S)-Val(N-
t-BOC)-Leu-Ala solution, and the solution was stirred for 6 h.
The solvent was removed by evaporation at 50 °C at atmo-
spheric pressure. The residue was washed with 0.5 N NaHCO3,
water, MeCN, and hexane to yield a yellow product (1.30 g,
85%): 1H NMR (DMSO-d6) δ 9.75 (m, 2H) (two -NHCO), [9.18
(m, 2H), 8.90 (m, 2H)] (naphthalene), [8.32 (m, 1H), 8.02 (m,
1H), 7.80 (m, 1H), 6.75 (m, 1H)] (four NHCO], [7.95 (d, 2H, J
) 8.3 Hz), 7.50 (d, 2H, J ) 8.3 Hz), 7.20 (dd, 4H, J ) 13.81
Hz, 8.0 Hz)] (phenyls), [4.65 (d, 2H, J ) 4.79), 4.52 (d, 2H, J
) 4.33)] (methylenes next to naphthalene), [4.30 (m, 1H), 3.70
(m, 1H), 3.00 (m, 1H)] (CH amino acid chiral centers), 4.20
(m, 2H) (CH2NH), 1.95 (m,1H) (CH valine), 1.60 (m, 1H) (CH
leucine), 1.42 (m, 11H) (CH2 valine and BOC), 1.17 (d, 3H, J
) 7.4 Hz) (CH3 alanine), 0.80 (m, 12H) (two CH3 valine and
two CH3 leucine); positive ion MALDI: C47H56N8O13 [M + Na]+
) 963. Anal. Calcd (found): C, 60.0% (58.14%); H, 5.96%
(5.95%); N, 11.91% (11.60%).
Cyclop h a n e 4. {N-[(p-((S)-Val(N-t-BOC)-Leu-Ala-amino-
methyl)phenyl)methyl]-N′-[(p-carboxyphenyl)methyl]-1,5-di-
nitronaphthalene-3,7-diamide} (0.455 g, 0.48 mmol) was depro-
tected as described above. DMF (40 mL) and DIEA (0.085 mL,
0.48 mmol) were added to the deprotected dinitronaphthalene.
In a separate flask under Ar, BOP (0.243 g, 0.55 mmol) and
DIEA (0.17 mL, 0.96 mmol) were combined with DMF (30 mL)
and stirred for 20 min. The deprotected dinitronaphthalene
solution was slowly added to the BOP solution and stirred for
24 h. The solvent was removed by evaporation at 50 °C at
atmospheric pressure. The residue was washed with 0.5 N
NaHCO3, water, MeCN, and hexane. Further purification was
carried out by silica gel column chromatography (MeOH/
CHCl3, 1:10) to yield a yellow product (0.038 g, 10%): 1H NMR
(DMSO-d6) δ 9.65 (m, 2H) (two NHCO), [9.12 (m, 2H), 8.85
(m, 2H)] (naphthalene), [8.20 (m, 1H), 7.95 (m, 1H), 7.75 (m,
1H), 7.55 (m, 1H)] (four NHCO), [7.50 (m, 4H), 7.25 (dd, 4H,
J ) 13.8 Hz, 8.0 Hz)] (phenyls), [4.65 (s, 2H), 4.55 (s, 2H)]
(methylenes next to naphthalene), 4.40 (m, 2H) (CH2NH), [4.25
(m, 2H), 3.60 (m, 1H)] (CH amino acid chiral centers), 2.05
(m, 1H) (CH valine), 1.45 (m,1H) (CH leucine), 1.35 (m, 2H)
(CH2 valine), 1.20 (m, 3H) (CH3 alanine), 0.80 (m, 12H) (two
CH3 valine and two CH3 leucine); positive ion MALDI HRMS:
Cyclop h a n e 3. {N-[(p-Carboxyphenyl)methyl]-N′-[(p-((S)-
Val(N-t-BOC)-Leu-Ala-aminomethyl)phenyl)methyl]-1,4,5,8-
naphthalenetetracarboxylic diimide} (0.345 g, 0.38 mmol) was
deprotected as described above. It was then dissolved in DMF
(50 mL) and transferred to a syringe. In a separate flask under
Ar, BOP (0.252 g, 0.57 mmol) and DIEA (0.199 mL, 1.1 mmol)
were combined with DMF (250 mL). The diimide solution was
then added to the BOP solution via a syringe pump (4.2 mL/
h). The solution was stirred for 4 d. The solvent was removed
by rotary evaporation. The residue was washed with aqueous
NaHCO3 and water. It was then dissolved in CHCl3, filtered
to remove the insoluble solid, and dried over Na2SO4. Removal
(23) Sarin, V. K.; Kent, B. H.; Tam, J . P.; Merrifield, R. B. Anal.
Biochem. 1981, 117, 147.
(24) Anwer, M. K.; Spatola, A. F. Tetrahedron Lett. 1992, 33, 3121.
(25) Nguyen, D. L.; Seyer, R.; Heitz, A.; Castro, B. J . Chem. Soc.,
Perkin Trans. 1 1985, 1025.