Synthesis of chiral macrocycles by cyclodimerization of diamines with stepwise nucleophilic aromatic substitution of 1,5-difluoro-2,4-dinitrobenzene

Article abstract of DOI:10.1055/s-2004-835633

Chiral cyclophanes were synthesized by cyclodimerization of 2,7-diaza-1,2,3,6,7,8-hexahydropyrene N-acylated with L-amino acids through stepwise nucleophilic aromatic substitution of 1,5 -difluoro-2,4-dinitrobenzene.

Full text of DOI:10.1055/s-2004-835633

LETTER
2517
Synthesis of Chiral Macrocycles by Cyclodimerization of Diamines
with Stepwise Nucleophilic Aromatic Substitution of 1,5-Difluoro-2,4-
dinitrobenzene
C
hira
l
Cyc
ö
lophanes thr
r
ough Cy
g
clodimeriza
e
D
iam
n
ines Toftered, Ulf J. Nilsson*
Organic and Biooorganic Chemistry, Lund University, P.O. Box 124, 221 00 Lund, Sweden
Fax +46(46)2228209; E-mail: ulf.nilsson@bioorganic.lth.se
Received 9 August 2004
recently been reported (Scheme 1).20 Upon following the
reported synthesis, we found that the time-consuming
Soxhlet extraction for purification of crude 2 could be re-
placed by a considerably faster flash chromatography.
The diamine 2 has a limited stability and is not suited for
long-term storage. Consequently, the subsequent acyla-
tion of diamine with Boc-protected amino acids produce
better yields of 3 with a freshly prepared 2.
Abstract: Chiral cyclophanes were synthesized by cyclodimeriza-
tion of 2,7-diaza-1,2,3,6,7,8-hexahydropyrene N-acylated with L-
amino acids through stepwise nucleophilic aromatic substitution of
1,5-difluoro-2,4-dinitrobenzene.
Key words: macrocycles, chiral, nucleophilic aromatic substitu-
tion, cyclophanes, diazapyrene
The study of supramolecular properties of macrocyclic
molecules has been particularly successful over the years
in providing detailed insight into the mechanisms of mo-
lecular recognition. This is largely due to that macrocy-
cles are inherently more or less fairly rigid and pre-
organized and can, if properly designed, despite their rel-
atively small size, present organized grooves or cavities
for the binding of other small(er) molecules. Within this
context, cyclophanes1–8 appear attractive as their aromatic
nature allow for interactions with guest molecules e.g. via
p-p, hydrophobic, p-hydrogen bonding, and cation-p forc-
es. Although nature’s receptors are chiral and have often
been mimicked for molecular recognition studies, rela-
tively few chiral macrocycles have been reported as mod-
el systems for biomimetic molecular recognitions.2,9–18
Small macrocycles are typically more flexible than pro-
tein binding sites unless the building blocks used for the
macrocycle assembly are designed to confer conforma-
tional rigidity. The conformational flexibility of a macro-
cycle intended to mimic protein binding sites has to be
lowered in order not to loose entropy upon ligand binding,
yet high enough to adjust to the ligand structure, i.e. allow
for induced fit. One way of modulating the flexibility of
macrocycles is to vary the number and the structure of
small rings (aromatic or aliphatic) in the macrocycle.
Herein, we disclose a macrocyclization reaction sequence,
which results in the introduction of two dinitroaniline
rings into chiral cyclophanes. The reaction sequence in-
volves cyclodimerizations of L-amino acid-functionalized
2,7-diaza-1,2,3,6,7,8-hexahydropyrenes through stepwise
nucleophilic aromatic substitution of 1,5-difluoro-2,4-
dinitrobenzene.
Scheme 1
Initially, acylation of 2 was found to be difficult due to
poor solubility of 2 in solvents normally used in peptide
couplings (i.e. CH2Cl2, DMF and THF). The diamine 2
dissolves well in a mixture of CH2Cl2 and MeOH, but this
solvent mixture did however produce large amounts of
amino acid methyl esters upon attempted acylation of 2
with amino acids. A reliable procedure for acylating the
diamine 2 was finally found by using regular coupling
agents, such as EDC or DIC, in chloroform. The bis-acy-
lated compounds 3a–c were obtained in good yields and
were also found to be stable upon long-term storage.
Deprotection of 3a–c to diamines 4a–c proceeded
smoothly with HCl or TFA (Scheme 2). The hydrochlo-
ride salts corresponding to 4a–c showed poor solubility,
which limited their use as nucleophiles in subsequent
The synthesis of 2,7-diaza-1,2,3,6,7,8-hexahydropyrene 2
from 1,4,5,8-naphthalenetetracarboxylic diimide19 (1) has
SYNLETT 2004, No. 14, pp 2517–2520
2
2
.1
1
.2
0
0
4
Advanced online publication: 10.11.2004
DOI: 10.1055/s-2004-835633; Art ID: D23004ST
© Georg Thieme Verlag Stuttgart · New York

2518
J. Toftered, U. J. Nilsson
LETTER
reactions. Treatment of the crude bis-ammonium TFA Monte-Carlo conformational searches22 of 6a (side-chains
salts 4a–c with 1,5-difluoro-2,4-dinitrobenzene in the protected as methyl ethers in order to simplify calcula-
presence of cesium carbonate in THF afforded 5a–c dou- tions) gave the one dominating group of closely related
bly equipped with monofluorobenzene moieties ready for conformers (150–200 similar conformers within 5 kcal/
cyclodimerization in a second nucleophilic aromatic sub- mol) with cleft-like collapsed structures in which the two
stitution with 4a–c. Substitution of the second fluoride re- naphthalene units were face-to-face stacked (Figure 1).
quired harsher conditions. Refluxing equimolar amounts The two dinitroaniline units were oriented perpendicular
of 4 and 5 and 6 equivalents of cesium carbonate in THF to the naphthalene units in opposite directions. The main
for 20 hours furnished the target macrocycles 6a–f in rel- group conformers differed by small changes in the angle
atively good yields of 15–25% after purification with between the naphthalene and dinitroaniline units and the
flash chromatography followed by precipitation. At- conformations of the flexible amino acid side chain,
tempts to increase the cyclodimerization yields and to which suggests that the macrocycles indeed are conforma-
shorten reactions times by adding copper iodide to the re- tionally well-defined. A few minor conformers with either
action mixtures failed.21 The purities of 6a–f were ana- a naphthalene sandwiched between the dinitroanilines or
lyzed with RP-HPLC and macrocycles 6a,b,e,f yielded a dinitroaniline sandwiched between two naphthalenes
chromatograms with one peak corresponding to a purity were found, however, with higher energies than the main
of >95%. Macrocycles 6c,d were of lower purity and gave group conformers.
unfortunately less satisfactory chromatograms, though
the identity of 6c–d were confirmed with FAB-HRMS.
FAB-HRMS and 13C-NMR analysis of the macrocycles
6a–f confirmed their structures, whereas 1H NMR analy-
ses of 6a–f proved difficult due to poor resolution presum-
ably caused by slow conformational exchange. High-
temperature NMR experiments in deuterated DMSO were
unsuccessful as the macrocycles 6a–f decomposed
spontaneously at elevated temperatures.
Figure 1 Stereo representation of the global energy minimum con-
formation of an analog of 6a with side-chains protected as methyl
ethers in order to simplify calculations
In summary, we have developed a short synthesis of
cyclophanes via step-wise nucleophilic aromatic substitu-
tion of 1,5-difluoro-2,4-dinitrobenzene with diamines ob-
tained
by
acylation
of
2,7-diaza-1,2,3,6,7,8-
hexahydropyrene with amino acids. The method is versa-
tile as variation of the diamine component opens up for
the construction of a range of related 1,5-difluoro-2,4-
dinitrobenzene derived cyclophanes as receptors with po-
tential of mimicking biomolecule recognition.
2,7-Diaza-1,2,3,6,7,8-hexahydropyrene (2):
1,4,5,8-Naphthalenetetracarboxylic diimide (1, 3.00 g, 11.3 mmol)
was suspended in dry THF (75 mL, dried over MS 4Å) in an oven-
dried and nitrogen-flushed 250 mL three-necked flask. To this mix-
ture BF3·THF (5.0 mL, 45 mmol) was added, followed by
BH3·DMS in THF (70 mL, 2 M). The reaction was refluxed for 64
h, cooled to 0 °C and slowly quenched with MeOH (15 mL) while
immersed in an ice-bath. (CAUTION: Excessive foaming may oc-
cur at this moment). Then, 6 M HCl (25 mL) was added and the re-
action was refluxed for another 3 h. After cooling to ambient
temperature, the reaction was adjusted to pH 13 with 50% NaOH.
The organic solvents were evaporated and the remaining aqueous
suspension was filtered. Filtered solids were dried in vacuo and fur-
ther purified by flash chromatography (SiO2, CH2Cl2–MeOH–Et3N
20:0:1 → 20:1:1 → 20:2:1 gradient) yielding 1.55 g (65%) of 2 as a
1
pale solid. TLC (EtOAc–MeOH–Et3N 16:4:1): Rf = 0.2. H NMR
(400 MHz, CDCl3): d = 7.15 (s, 4 H), 4.20 (s, 8 H).
Scheme 2
Synlett 2004, No. 14, 2517–2520 © Thieme Stuttgart · New York

LETTER
Chiral Cyclophanes through Cyclodimerization of Diamines
2519
Typical Acylation of 2: [S,S]-N,N¢-Bis-[3-benzyloxy-2-(N-t-but-
oxycarbonylamino)-propionyl]-2,7-diaza-1,2,3,6,7,8-hexahy-
dropyrene (3a):
[S,S]-N,N¢-Bis-[3-(benzyloxycarbonyl)-2-(N-5-fluoro-2,4-dini-
trophenylamino)-propionyl]-2,7-diaza-1,2,3,6,7,8-hexahydro-
pyrene (5b):
Compound 2 (0.60 g, 2.9 mmol) was suspended and sonicated for 5
min at ambient temperature in CHCl3 (150 mL, purified on basic
Al2O3). To the suspension was added BOC-Ser(OBn)-OH (2.53 g,
8.6 mmol), EDC (2.19 g, 11.4 mmol), HOBt (0.88 g, 5.7 mmol),
DMAP (1.44 g, 11.4 mmol) and NaHCO3 (0.96 g, 11.4 mmol) and
the resulting mixture was stirred for 18 h. The reaction was washed
with 5% HCl (2 × 200 mL), sat. NaHCO3 (3 × 200 mL), and sat.
NaCl (3 × 200 mL). The organic phase was dried (MgSO4), filtered,
and evaporated into a pale solid (2.50 g), which was purified by
flash chromatography (SiO2, heptane–EtOAc 1:1) to give 3a (1.57
g, 72%). A sample of analytical purity was prepared by precipita-
tion from MeOH–H2O (9:1). TLC (heptane–EtOAc 1:1): Rf = 0.25.
TLC (heptane–EtOAc 1:1): Rf = 0.21. [a]D25 +35 (c 0.5, CH2Cl2). 1H
NMR (400 MHz, CDCl3): d = 9.34–9.20 (br, 2 H), 8.94–8.86 (br, 2
H), 7.32–7.07 (m, 10 H), 6.64 (m, 2 H), 5.25–4.93 (m, 14 H), 3.00–
2.87 (m, 2 H), 2.85–2.74 (m, 2 H). 13C NMR (100 MHz, CDCl3):
d = 170.6, 167.9, 147.8, 147.7, 135.2, 135.19, 131.10, 130.0,
129.12, 129.06, 128.9, 128.3, 128.1, 127.9, 126.5, 123.7, 123.2,
122.5, 121.9, 102.3, 102.0, 68.0, 51.2, 51.1, 49.3, 46.6, 38.5. FAB-
HRMS: m/z calcd for C48H39F2N8O14 [M + H]+: 989.2555. Found:
989.2556.
[S,S]-N,N¢-Bis-[4-(benzyloxycarbonyl)-2-(N-5-fluoro-2,4-dini-
trophenylamino)-butanoyl]-2,7-diaza-1,2,3,6,7,8-hexahydropy-
rene (5c):
23
[a]D –3.9 (c 1, CH2Cl2). 1H NMR (400 MHz, CDCl3): d = 7.30–
21
7.00 (m, 14 H), 5.50 (d, 2 H, J = 8 Hz), 5.17–4.92 (m, 10 H), 4.37
(s, 4 H), 3.67–3.52 (m, 4 H), 1.41 (s, 18 H). 13C NMR (100 MHz,
CDCl3): d = 169.4, 155.3, 137.7, 130.5, 130.2, 128.4, 127.7, 127.6,
122.7, 122.5, 122.1, 121.8, 80.0, 77.4, 73.3, 71.2, 50.5, 48.9, 45.4,
28.5. FAB-HRMS: m/z calcd for C44H53N4O8 [M + H]+: 765.3864.
Found: 765.3859.
TLC (heptane–EtOAc 1:1): Rf = 0.16. [a]D +58 (c 0.5, CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 9.10 (dd, 2 H, J = 7, 23 Hz), 8.98
(d, 2 H, J = 8 Hz), 7.34–7.20 (m, 14 H), 6.43 (t, 2 H, J = 14 Hz),
5.19–4.91 (m, 14 H), 2.49–2.39 (br, 4 H), 2.25–2.10 (br, 2 H), 1.98–
1.85 (br, 2 H). 13C NMR (100 MHz, CDCl3): d = 173.5, 173.4,
168.6, 168.5, 161.4, 158.7, 148.5, 148.4, 135.4, 131.0, 130.3, 130.1,
129.3, 128.9, 128.63, 128.56, 128.2, 127.9, 126.3, 126.2, 123.5,
123.0, 122.5, 122.0, 101.6, 101.4, 67.3, 52.7, 48.8, 46.2, 29.0, 28.0.
FAB-HRMS: m/z calcd for C50H42F2N8O14Na [M + Na]+:
1039.2687. Found: 1039.2675.
In a similar manner were prepared:
[S,S]-N,N¢-Bis-[3-(benzyloxycarbonyl)-2-(N-t-butoxycarbonyl-
amino)-propionyl]-2,7-diaza-1,2,3,6,7,8-hexahydropyrene (3b):
TLC (heptane–EtOAc 1:1): Rf = 0.17. [a]D21 –4.6 (c 1, CH2Cl2). 1H
NMR (400 MHz, CDCl3): d = 7.35–7.17 (m, 14 H), 5.42 (d, 2 H,
J = 7 Hz), 5.23–4.60 (m, 14 H), 2.95–2.75 (m, 2 H), 2.67–2.59 (br,
2 H), 1.42 (s, 18 H). 13C NMR (100 MHz, CDCl3): d = 170.9, 169.4,
155.0, 135.8, 130.7, 130.2, 129.9, 128.7, 128.4, 128.3, 127.7, 127.4,
122.5, 122.0, 80.4, 77.4, 66.8, 47.9, 45.5, 38.0, 28.5. FAB-HRMS:
m/z calcd for C46H53N4O10 [M + H]+: 821.3762. Found: 821.3759.
Typical Synthesis of Macrocycles 6a–f: Macrocycle 6a:
Compound 3a (84 mg, 0.11 mmol) was dissolved in CH2Cl2 (5 mL).
Triethylsilane (75 mL, 0.40 mmol) was added, followed by TFA
(270 mL, 3.3 mmol). The solution was stirred at ambient tempera-
ture for 16 h and then evaporated into a syrup. This syrup was dis-
solved in THF (130 mL, dried over MS) to which was added
Cs2CO3 (215 mg, 0.70 mmol) and compound 5a (102 mg, 0.11
mmol). The resulting suspension was refluxed for 20 h and then
evaporated. Flash chromatography (SiO2, heptane–EtOAc 1:4) fol-
lowed by precipitation from CHCl3–MeOH (1:2) yielded 6a as a
yellow solid (36 mg, 22%). TLC (heptane–EtOAc 1:4): Rf = 0.10.
HPLC (Column: Supelcosil 250 mm × 10 mm, 5 mm. Eluent: H2O–
MeCN 1:0 over 5 min, 1:0 → 0:1 over 1 h, 0:1 over 5 min. Flow: 5
mL/min) tR = 47 min. [a]D21 –38 (c 0.5, CHCl3). The 1H NMR spec-
trum showed poorly resolved broad peaks. 13C NMR (125 MHz,
CDCl3): d = 167.0, 147.4, 137.2, 130.6, 129.4, 128.7, 128.6, 128.3,
128.1, 127.7, 124.8, 123.5, 121.2, 93.0, 73.8, 67.7, 54.1, 48.7, 46.0.
FAB-HRMS: m/z calcd for C80H73N12O16 [M + H]+: 1457.5268.
Found: 1457.5251.
[S,S]-N,N¢-Bis-[4-(benzyloxycarbonyl)-2-(N-t-butoxycarbonyl-
amino)-butanoyl]-2,7-diaza-1,2,3,6,7,8-hexahydropyrene (3c):
TLC (heptane–EtOAc 1:1): Rf = 0.20. [a]D21 +41 (c 1, CH2Cl2). 1H
NMR (400 MHz, CDCl3): d = 7.45–7.20 (m, 14 H), 5.50 (d, 2 H,
J = 7 Hz), 5.35–5.15 (m, 8 H), 5.05–4.80 (m, 6 H), 2.65–2.50 (br, 2
H), 2.45–2.30 (br, 2 H), 2.10–1.90 (br, 2 H), 1.65–1.50 (br, 2 H),
1.45 (s, 18 H). 13C NMR (100 MHz, CDCl3): d = 173.2, 170.7,
156.0, 136.2, 130.8, 130.4, 130.2, 129.8, 128.8, 128.4, 127.9, 122.7,
122.7, 122.5, 79.9, 66.6, 49.8, 48.3, 45.4, 29.5, 29.0, 28.5. FAB-
HRMS: m/z calcd for C48H56N4O10Na [M + Na]+: 871.3894. Found:
871.3907.
Typical Synthesis of Bis-fluorophenyls 5a-c: [S,S]-N,N¢-Bis-[3-
benzyloxy-2-(N-5-fluoro-2,4-dinitrophenylamino)-propionyl]-
2,7-diaza-1,2,3,6,7,8-hexahydropyrene (5a):
In a similar manner were prepared:
Macrocycle 6b:
Compound 3a (100 mg, 0.13 mmol) was dissolved in CH2Cl2 (5
mL) and triethylsilane (85 mL, 0.50 mmol) was added, followed by
TFA (290 mL, 3.9 mmol). After 16 h, the solution was concentrated,
the residue dissolved in THF (5 mL, dried over MS), and Cs2CO3
(256 mg, 0.80 mmol) and 1,5-difluoro-2,4-dinitrobenzene (214 mg,
0.50 mmol) were added. The resulting suspension was stirred for 2
h and then concentrated. Flash chromatography (SiO2, heptane–
EtOAc 1:1) yielded product 5a as a yellow solid (102 mg, 84%).
TLC (heptane–EtOAc 1:1): Rf = 0.23. [a]D24 +24 (c 0.5, CH2Cl2). 1H
NMR (400 MHz, CDCl3): d = 9.62–9.55 (br, 2 H), 8.90 (d, 2 H,
J = 13 Hz), 7.29–7.10 (m, 14 H), 6.72 (d, 2 H, J = 13 Hz), 5.15–4.87
(m, 10 H), 4.43 (s, 4 H), 3.82–3.66 (m, 4 H). 13C NMR (100 MHz,
CDCl3): d = 167.0, 161.0, 158.4, 148.0, 147.9, 136.7, 130.6, 129.2,
128.7, 128.4, 127.9, 127.8, 127.6, 126.0, 125.9, 122.8, 122.4, 102.7,
102.4, 73.9, 70.9, 55.2, 48.9, 46.1. FAB-HRMS: m/z calcd for
C46H39F2N8O12 [M + H]+: 933.2656. Found: 933.2657.
Compound 4b and 5b gave 6b in 20% yield. TLC (heptane–EtOAc
1:4): Rf = 0.50. HPLC: tR = 46 min. [a]D21 +18 (c 0.5, CHCl3). 13
C
NMR (125 MHz, CDCl3): d = 171.0, 168.8, 146.5, 135.5, 135.2,
131.4, 129.8, 128.82, 128.77, 128.71, 128.65, 128.61, 128.4, 128.3,
128.0, 127.9, 127.6, 127.4, 124.5, 122.7, 92.7, 67.1, 49.0, 46.5,
37.5. FAB-HRMS: m/z calcd for C84H72N12O20Na [M + Na]+:
1591.4884. Found: 1591.4904.
Macrocycle 6c:
Compound 4c and 5c gave impure 6c. FAB-HRMS: m/z calcd for
C88H81N12O20 [M + H]+: 1625.5691. Found: 1625.5717.
Macrocycle 6d:
Compound 4a and 5b (or 4b and 5a) gave impure 6d. FAB-HRMS:
m/z calcd for C82H72N12O18Na [M + Na]+: 1535.4986. Found:
1535.4996.
In a similar manner were prepared:
Synlett 2004, No. 14, 2517–2520 © Thieme Stuttgart · New York

2520
J. Toftered, U. J. Nilsson
LETTER
(4) Hartley, J. H.; James, T. D.; Ward, C. J. J. Chem. Soc.,
Macrocycle 6e:
Compound 4a and 5c (or 4c and 5a) gave 6e in 18% yield. TLC
(heptane–EtOAc 1:4): Rf = 0.10. HPLC: tR = 49 min. [a]D21 +13 (c
0.5, CHCl3). 13C NMR (100 MHz, CDCl3): d = 173.7, 168.5, 166.9,
147.4, 147.3, 136.9, 135.2, 130.6, 130.4, 129.6, 128.9, 128.7, 128.5,
128.2, 128.0, 127.9, 127.8, 124.8, 124.7, 123.8, 123.6, 122.1, 121.l,
92.8, 73.6, 68.4, 66.7, 54.1, 51.4, 48.9, 48.2, 45.7, 29.9, 28.7, 27.1.
FAB-HRMS: m/z calcd for C84H77N12O18 [M + H]+: 1541.5480.
Found: 1541.5490.
Perkin Trans. 1 2000, 3155.
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Macrocycle 6f:
Compound 4b and 5c (or 4c and 5b) gave 6b in 20% yield. TLC
(heptane–EtOAc 1:4): Rf = 0.20. HPLC: tR = 45 min. [a]D21 +80 (c
0.5, CHCl3). 13C NMR (100 MHz, CDCl3): d = 173.3, 172.2, 168.7,
167.8, 147.3, 146.4, 135.1, 134.6, 130.7, 130.4, 130.2, 129.8,
128.88, 128.83, 128.76, 128.73, 128.59, 128.49, 127.8, 127.6,
126.5, 124.64, 124.58, 123.8, 123.7, 122.1, 122.0, 95.6, 92.6, 68.2,
67.2, 67.0, 66.8, 66.3, 51.0, 50.0, 48.5, 45.8, 28.5, 27.3, 25.8. FAB-
HRMS: m/z calcd for C86H76N12O20Na [M + Na]+: 1619.5197.
Found: 1619.5199.
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Acknowledgment
We thank for financial support the Swedish Research Council, the
Swedish Strategic Research Foundation and the program ‘Glyco-
conjugates in Biological Systems’ sponsored by the Swedish
Strategic Research Foundation.
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chloroform implemented in MacroModel; 20000
conformers were collected for each compound.
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Synlett 2004, No. 14, 2517–2520 © Thieme Stuttgart · New York