An efficient and convergent route towards water-soluble, chiral and amphiphilic macrocycles

Article abstract of DOI:10.1016/S0040-4039(01)00301-X

A practical procedure for the synthesis of water-soluble, chiral and amphiphilic macrocyclic molecules is described. Acylation of p-xylylene diamine with Fmoc-protected glycine and aspartic acid, followed by removal of the Fmoc moiety afforded amino acid:

Full text of DOI:10.1016/S0040-4039(01)00301-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2873–2875
An efficient and convergent route towards water-soluble, chiral
and amphiphilic macrocycles
Tapes Bhattacharyya and Ulf J. Nilsson*
Department of Organic Chemistry 2, Lund University, POB 124, SE-221 00 Lund, Sweden
Received 29 January 2001; revised 15 February 2001; accepted 20 February 2001
Abstract—A practical procedure for the synthesis of water-soluble, chiral and amphiphilic macrocyclic molecules is described.
Acylation of p-xylylene diamine with Fmoc-protected glycine and aspartic acid, followed by removal of the Fmoc moiety afforded
amino acid:p-xylene conjugates as free diamines. These diamines were converted to symmetrical and unsymmetrical macrocycles
via stepwise urea formation using p-nitrophenyl chloroformate. © 2001 Elsevier Science Ltd. All rights reserved.
Macrocyclic structures have received much attention in
the search for artificial receptors, mainly because of
their inherent reduced flexibility and higher degree of
pre-organization as compared to their acyclic counter-
parts. Consequently, several elegant and efficient
macrocyclic receptors for biomolecules in organic sol-
vents, as well as some in aqueous environment, have
been reported.1,2 Within our ongoing research activities
towards receptors for biomolecules, we sought a
straightforward, yet flexible, method for the synthesis
of water-soluble and chiral macrocyclic structures dis-
playing diverse functionalities capable of taking part in
different types of intermolecular interactions (hydrogen
bonds, charge–charge, van der Waals, hydrophobic,
etc.). In this respect, macrocyclizations based on urea
formation between diamines appeared to be an attrac-
tive approach. Syntheses of achiral,3–10 as well as chi-
ral,11,12 macrocyclic ureas have been reported and some
have been shown to function as receptors for cations3–7
or anions.10,12
O
O
NH
NH2
HN
H2N
a, b
H2N
NH2
R
R
O
O
NH
NH
HN
HN
1
R
O
R
2a R=H
2b R=CH2COOtBu
NH
NH
HN
HN
d
O
c
R'
R'
OPNP
PNPO
O
R'
O
O
O
NH
NH
HN
HN
R'
4 R=R'=H
O
O
5 R=R'=CH2COOtBu
6 R=R'=CH2COOH
7 R=H, R'=CH2COOtBu
8 R=H, R'=CH2COOH
e
e
3a R=H
3b R=CH2COOtBu
Scheme 1. (a) Fmoc-amino acid, DIC, HOBt, THF. (b) Piperidine, DMF. (c) p-Nitrophenyl chloroformate, pyridine, DMF. (d)
2a+3a“4, 2b+3b“5 or 2a+3b“7 pyridine, DMAP, DMF. (e) TFA, H2O.
* Corresponding author. Fax: +46 46 222 8218; e-mail: ulf.nilsson@orgk2.lth.se
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00301-X

2874
T. Bhattacharyya, U. J. Nilsson / Tetrahedron Letters 42 (2001) 2873–2875
In this letter we describe a simple synthetic route
towards water-soluble and chiral macrocyclic
amphiphiles, using predictable and high-yielding amide
and urea bond forming reactions between amino acids
and a diamino-functionalized hydrophobic scaffold.
The amide and urea moieties are expected to induce
rigidity in the final products, as well as providing sites
for hydrogen bonding. In addition, the use of amino
acids as building blocks allows for convenient introduc-
tion of charged and polar functionalities, which pro-
motes water-solubility and provides sites for
charge–charge or hydrogen bonding interactions. The
methodology is demonstrated with the synthesis of
three macrocycles based on the amino acids glycine and
References
1. Hartley, J. H.; James, T. D.; Ward, C. J. J. Chem. Soc.,
Perkin Trans. 1 2000, 3155–3184.
2. Zhang, X. X.; Bradshaw, J. S.; Izatt, R. M. Chem. Rev.
1997, 97, 3313–3361.
3. Kaplan, L. J.; Weisman, G. R.; Cram, D. J. J. Org.
Chem. 1979, 44, 2226–2233.
4. Stewart, K. D.; Miesch, M.; Knobler, C. B.; Maverick, E.
F.; Cram, D. J. J. Org. Chem. 1986, 51, 4327–4337.
5. Rosser, M.; Parker, D.; Ferguson, G.; Gallagher, J. F.;
Howard, J. A. K.; Yufit, D. S. J. Chem. Soc., Chem.
Commun. 1993, 1267–1269.
6. Cordier, D.; Coulet, P. R. J. Chem. Soc., Perkin Trans. 2
L
-aspartic acid.
1994, 891–894.
7. Cordier, D.; Dumaine-Bouaziz, M.; Coulet, P. R. Anal.
Lett. 1995, 28, 959–969.
8. Dave, P. R.; Doyle, G.; Axenrod, T.; Yazdekhasti, H.;
Ammon, H. L. J. Org. Chem. 1995, 60, 6946–6952.
9. Shargi, H.; Niknam, K.; Massah, A. R. J. Heterocycl.
Chem. 1999, 36, 601–606.
10. Snellink-Rue¨l, B. H. M.; Antonisse, M. M. G.; Eng-
bersen, J. F. J.; Timmerman, P.; Reinhoudt, D. N. Eur. J.
Org. Chem. 2000, 165–170.
As a building block for the hydrophobic part of the
amphiphilic macrocycles, the readily available p-
xylylene diamine 1 was selected (Scheme 1). Carbodi-
imide/hydroxybenzotriazole-promoted acylation with
Fmoc-protected amino acids, followed by Fmoc-cleav-
age, afforded the bis-glycine and aspartic acid deriva-
tives 2a and 2b in 95 and 90% yields, respectively.13 The
choice of an amino-reactive cross-linking reagent for
macrocyclizations of 2a and 2b fell on p-nitrophenyl
chloroformate, because it allows selective reaction with
one amine component at a time via an intermediate
p-nitrophenyl carbamate. Thus, treatment of 2a and 2b
with an excess of p-nitrophenyl chloroformate yielded
the p-nitrophenyl carbamates 3a and 3b in 50 and 67%
yields.
11. Didier, E.; Horwell, D. C.; Pritchard, M. C. Tetrahedron
1992, 48, 8471–8490.
12. Tejeda, A.; Oliva, A. I.; Simo´n, L.; Grande, M.;
Cabarello, M. C.; Mora´n, J. R. Tetrahedron Lett. 2000,
41, 4563–4566.
1
13. All compounds were characterized by H NMR (1D and
1
2D), MALDI-TOF MS, and FAB-HRMS: 2a: H NMR
(300 MHz, CD3OD) l 7.27 (s, 4H, ArH), 4.40 (bs, 4H,
ArCH2), (d, 4H, J 1.6 Hz, CH2CO); MALDI-TOF-MS
m/z calcd for C12H18N4NaO2 (M+Na): 273.1, found
274.0; FAB-HRMS m/z calcd for C12H19N4O2 (M+H):
251.1508, found 251.1459. 2b: 1H NMR (300 MHz,
CD3OD) l 7.26 (s, 4H, ArH), 4.37 (d, 4H, J 4.4 Hz,
ArCH2), 3.64 (t, 2H, J 6.0 Hz, CHCO), 2.67 (dd, 2H, J
5.7, 16.3 Hz, CH2CO), 2.55 (dd, 2H, J 6.8, 16.3 Hz,
CH2CO), 1.45 (s, 18H, CH3); MALDI-TOF-MS m/z
calcd for C24H38N4NaO6 (M+Na): 501.3, found 501.7;
FAB-HRMS m/z calcd for C24H39N4O6 (M+H):
479.2870, found 479.2874. 3a: 1H NMR (300 MHz, d6-
DMSO) l 8.55 (t, 2H, J 5.6 Hz, ArCH2NH), 8.27 (d, 4H,
J 9.0 Hz, ArH), 7.42 (d, 4H, J 9.0 Hz, ArH), 7.22 (s, 4H,
ArH), 4.27 (d, 4H, J 5.5 Hz, ArCH2), 3.75 (d, 4H, J 5.8
Macrocyclizations were accomplished under high dilu-
tion conditions (1.4 mM) with amines 2, p-nitrophenyl
carbamates 3, pyridine and DMAP in N,N-dimethyl-
formamide over 12 h. The macrocyclic compounds 4, 5
and 7 precipitated as the major products (38, 53 and
28%, respectively).14 t-Butyl esters in compounds 5 and
7 were removed with trifluoroacetic acid to give the
final macrocycles 6 and 8 in 80 and 75% in purities of
>95% according to NMR spectroscopy. The glycine-
based macrocycle 4 was insoluble in PBS buffer (pH
7.2), while the -aspartate-containing compounds 6 and
L
8 proved to be highly soluble, thus fulfilling a funda-
mental prerequisite for biomimetic receptors.
1
In summary, we have developed a simple and high-
yielding procedure for the synthesis of water-soluble
and chiral amphiphilic macrocycles. A particularly
attractive feature of our simple and flexible procedure is
that it is amenable for diversification of the amino acid
and/or the hydrophobic diamine components, which
would give rapid access to libraries of water-soluble
and chiral amphiphilic macrocycles.
Hz, CH2CO). 3b: H NMR (400 MHz, CD3OD) l 8.65
(t, 2H, J 5.4 Hz, CH2NH), 8.26 (d, 4H, J 9.2 Hz, ArH),
7.37 (d, 4H, J 9.2 Hz, ArH), 7.26 (s, 4H, ArH), 4.57 (m,
2H, CHCO), 4.40 (m, 4H ArCH2), 2.87 (dd, 2H, J 5.6,
16.2 Hz, CH2CO), 2.68 (dd, 2H, J 8.1, 16.2 Hz, CH2CO),
1
1.46 (s, 18H, CH3). 4: H NMR (400 MHz, d6-DMSO) l
8.49 and 8.42 (2s, 2H each, ArCH2NH), 7.29 (s, 8H,
ArH), 6.60 (bs, 4H, COCH2NH), 4.35 (bs, 8H, ArCH2),
3.77 (d, 8H, J 15.8 Hz, CH2CO); MALDI-TOF-MS m/z
calcd for C26H32N8NaO6 (M+Na): 575.2, found 575.8. 5:
1H NMR (400 MHz, d6-DMSO)
l 8.16 (s, 4H,
Acknowledgements
ArCH2NH), 7.12 (s, 8H, ArH), 6.55 (bs, 4H, CHNH),
4.10–4.42 (m, 10H, ArCH2, CH), 1.37 (s, 36H, CH3);
MALDI-TOF-MS m/z calcd for C50H72N8NaO14 (M+
Na): 1031.5, found 1031.2. 6: 1H NMR (400 MHz,
d-PBS, pD 7.2) l 7.17 (s, 8H, ArH), 4.27 (ABq, 8H, J
15.9, 22.2 Hz, ArCH2), 4.24 (dd, 4H, J 4.6, 8.3 Hz,
This work was supported by grants from The Swedish
Natural Science Research Council and The Swedish
Strategic Research Foundation.

T. Bhattacharyya, U. J. Nilsson / Tetrahedron Letters 42 (2001) 2873–2875
2875
CHCH2), 2.56 (dd, 4H, J 4.6, 16.0 Hz, CHCH2), 2.47
(dd, 4H, J 8.3, 16.0 Hz, CHCH2); MALDI-TOF-MS m/z
calcd for C34H41N8O14 (M+H): 785.3, found 784.0. 7: H
4.27 (d, 2H, J 15.7 Hz, ArCH2), 4.17 (d, 2H, J 15.5 Hz,
ArCH2), 4.15 (d, 2H, J 15.7 Hz, ArCH2), 4.10 (d, 2H, J
15.5 Hz, ArCH2), 3.90 (d, 2H, J 17.5 Hz, CH2CO), 3.62
(d, 2H, J 17.5 Hz, CH2CO), 2.58 (dd, 2H, J 4.6, 15.7 Hz,
1
NMR (400 MHz, d6-DMSO) l 8.32 (bs, 4H, ArCH2NH),
7.14 (s, 4H, ArH), 7.12 (s, 4H, ArH), 6.52 (dd, 2H, J 8.2,
14.4 Hz, NHCOCH), 6.43 (t, 2H, J 7.0 Hz, NHCOCH2),
4.41 (dd, 2H, J 8.2, 14.4 Hz, CH), 4.16–4.32 (m, 8H,
ArCH2), 3.78 (dd, 2H, J 6.9, 16.7 Hz, COCH2NH), 3.44
(dd, 2H, J 16.1 Hz, COCH2NH), 2.59–2.63 (m, 4H,
CHCH2), 1.36 (s, 18H, CH3); MALDI-TOF-MS m/z
CHCH2), 2.46 (dd, 2H,
J 8.6, 15.7 Hz, CHCH2);
MALDI-TOF-MS m/z calcd for C30H37N8O10 (M+H):
669.3, found 669.6; FAB-HRMS m/z calcd for
C30H37N8O10 (M+H): 669.2633, found 669.2647.
14. Typical procedure for macrocyclization: To a solution of
pyridine (8.6 mL) and DMAP (1 mg) in DMF was added
2a (27.5 mg, 110 mmol) and 3a (63.8 mg, 110 mmol). After
12 h, the white precipitate formed was filtered off and
washed with DMF and MeOH to give 4 (23 mg, 38%).
1
calcd for C30H37N8O10 (M+H): 669.3, found 669.8. 8: H
NMR (400 MHz, d-PBS, pD 7.2) l 7.05 (s, 4H, ArH),
7.01 (s, 4H, ArH), 4.35 (dd, 2H, J 4.6, 8.6 Hz, CHCH2),
.