Glycotriazolophane synthesis via click chemistry

Article abstract of DOI:10.1055/s-0029-1217534

A glycotriazolophane (carbohydrate-triazole-cyclophane hybrid) has been synthesized from a sugar amino acid via copper-catalysed azide-alkyne cycloaddition. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217534

LETTER
1949
Glycotriazolophane Synthesis via Click Chemistry
G
lycotriazolopha
o
ne
S
ynthesissaria Leyden,a Paul V. Murphy*b
a
School of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland
School of Chemistry, National University of Ireland, Galway, Ireland
Fax +353(91)525700; E-mail: paul.v.murphy@nuigalway.ie
b
Received 31 March 2009
and sodium ascorbate in acetonitrile–water gave the de-
sired cyclophane derivative 5 in 56% yield (Scheme 1).13
Formation of the macrocyclic product 5 as opposed to oli-
gomeric products was supported by NMR and MS
{725.2549 [M + H]+}.14 A low energy structure for 5 was
generated using a conformational search (SUMM meth-
od) in Macromodel (Figure 1).15 The low solubility of the
macrocycle precluded an investigation of its molecular-
recognition phenomena in water.
Abstract: A glycotriazolophane (carbohydrate–triazole–cyclo-
phane hybrid) has been synthesized from a sugar amino acid via
copper-catalysed azide–alkyne cycloaddition.
Key words: cyclophane, carbohydrates, macrocycle, 1,2,3-tri-
azole, azide–alkyne cycloaddition
Macrocyclic compounds incorporating carbohydrates
have been of interest as they have application in bioorgan-
ic and supramolecular chemistry. Such compounds have
been investigated as inhibitors of carbohydrate–protein or
carbohydrate–RNA interactions where the embedded car-
bohydrate structures are involved in binding to a recep-
tor.1 Macrocyclic carbohydrates have also found
application in host–guest chemistry. This includes the use
of glycophanes (carbohydrate–cyclophane hybrids) for
studying carbohydrate–carbohydrate interactions2 or of
cyclodextrins3 and cyclodextrin mimetics and their appli-
cation. The incorporation of carbohydrates into macro-
cycles4 facilitates modification of properties through
modification of the reactive functional groups of the sac-
charide. Saccharides and their derivatives have thus found
wide application as scaffolds for novel bioactive molecule
design and synthesis.5 Macrocyclic compounds, such as
cyclophanes and their analogues, have also displayed
properties as scaffolds in bioactive molecule develop-
ment.6 Herein we describe the synthesis of a new class of
cyclophane7 derivatives from sugar amino acid building
blocks.
Sugar amino acids8 (SAA) are monosaccharide-based
building blocks that feature a carboxylic acid and an
amine (or azide) functional group, and they have found
application in peptidomimetic9 and foldamer10 synthesis.
The use of SAA 111 was investigated as a building block
to generate novel macrocycles. Thus treatment of 1 with
oxalyl chloride in the presence of DMF in dichloro-
methane gave the acid chloride, which was reacted with
p-xylene-1,4-diamine 2 in the presence of DIPEA in
dichloromethane followed by de-O-acetylation gave the
bisazide 3 in 37% yield from 1.
In summary a new application for sugar amino acids lead-
ing to glycotriazolophanes has been outlined. It is envis-
O
OH
1. ClCOCOCl,
DMF (cat.), CH2Cl2
O
AcO
AcO
N3
2. DIPEA, 4 Å MS
CH2Cl2,
OAc
1
NH2
H2N
2
3. NaOMe, MeOH–CH2Cl2
N3
O
O
OH
OH
HN
OH
O
NH
3 (37%)
O
HO
HO
N3
O
O
OH
4
CuSO4
sodium ascorbate
MeCN–H2O (1:1)
OH
O
HO
N
O
N
N
OH
HN
O
p-Bispropargyloxybenzene 4 was prepared as described
previously,12 and its reaction with 3 was investigated.
Thus reaction of 3 and 4 in the presence of copper sulfate
O
HN
O
N
O
N
N
HO
OH
SYNLETT 2009, No. 12, pp 1949–1950
x
x
.x
x
.2
0
0
9
5 (56%)
Advanced online publication: 01.07.2009
DOI: 10.1055/s-0029-1217534; Art ID: D08409ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1

1950
R. Leyden, P. V. Murphy
LETTER
Chem. Int. Ed. 2002, 41, 231. (c) Risseeuw, M. D. P.;
Overhand, M.; Fleet, G. W. J.; Simone, M. I. Tetrahedron:
Asymmetry 2007, 18, 2001.
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M.; Kessler, H. J. Am. Chem. Soc. 1996, 118, 10156.
(10) Szabo, L.; Smith, B. L.; McReynolds, K. D.; Parrill, A. L.;
Morris, E. R.; Gervay, J. J. Org. Chem. 1998, 63, 1074.
(11) Tosin, M.; O’Brien, C.; Fitzpatrick, G. M.; Müller-Bunz, H.;
Glass, W. K.; Murphy, P. V. J. Org. Chem. 2005, 70, 4096.
(12) Srinivasan, M.; Sankararaman, S.; Hopf, H.; Dix, I.; Jones,
P. G. J. Org. Chem. 2001, 66, 4299.
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2007, 26, 1115. (b) Kolb, H. C.; Finn, M. G.; Sharpless,
K. B. Angew. Chem. Int. Ed. 2001, 40, 2004. (c) Meldal,
M.; Tornoe, C. W. Chem. Rev. 2008, 108, 2952.
(14) Preparation of 3 and 5
To ice-cold 1 (0.95 g, 2.75 mmol) in CH2Cl2 (anhyd, 20 mL)
was added oxalyl chloride (0.25 mL, 3.03 mmol), followed
by DMF (0.005 mL) under N2 and the mixture stirred for 0.5
h. p-Xylenediamine (0.169 mg, 1.24 mmol) and DIPEA
(0.48 mL, 2.75 mmol) were stirred together in the presence
of 4 Å MS in CH2Cl2 (anhyd, 10 mL) until complete
dissolution of the amine. The solution containing the acid
chloride was added, and the mixture was stirred for a further
2 h at 0 °C. The mixture was extracted with CH2Cl2 (20 mL),
washed with NaHCO3 (2 × 15 mL), HCl (2 × 15 mL), brine
(2 × 15 mL), H2O (2 × 15 mL), dried (Na2SO4), filtered, and
the solvent removed to give a pale brown foam. Silica gel
chromatography (EtOAc–Cy, gradient elution, 1:1 to 2:1)
gave the protected diamide as a white foam (0.359 g, 37%).
This diamide (74.9 mg, 0.095 mmol) was dissolved in
MeOH–CH2Cl2 (3.5 mL, 6:1) to which was added NaOMe
in MeOH (0.1 mL of 1.09 M) and the mixture left to stir for
3 h at r.t. The solvent was removed and the residue dissolved
in H2O. Lyophilization gave 3 as an off-white powder (51
mg, quant.); [a]D –30.81 (c 0.37 g, H2O). 1H NMR (500
MHz, D2O): d = 7.24 (s, 4 H, ArH), 4.73 (d, J = 8.8 Hz, 2 H,
H-1), 4.37 (s, 4 H, PhCH2), 3.93 (d, J = 9.3 Hz, 2 H, H-5),
3.55–3.46 (m, 4 H, overlapping of H-3, H-4), 3.25 (m, 2 H,
H-2). 13C NMR (125 MHz, CDCl3): d = 170.2 (CONH),
136.9 (ArC), 127.7 (CH), 90.4, 77.1, 75.6, 72.6, 71.3 (each
CH), 42.7 (NHCH2Ph). LRMS: m/z found: 561.1 [M + Na]+,
537.2 [M – H]–. HRMS (ES): m/z calcd for C20H27O10N8:
539.1850; found: 539.1865 [M + H]+.
The bisazide 3 (60 mg, 0.111 mmol) was dissolved in a
solution of MeCN–H2O (1:1, 4.5 mL) to which was added
alkyne 4 (20 mg, 0.111 mmol) and the reactants stirred
before the addition of sodium ascorbate (2 mg, 0.011 mmol)
followed by CuSO4·5H2O (0.55 mL of a 0.01 M solution,
0.0055 mmol) and then stirred for a further 13 h. The
resulting precipitate was 5 (45 mg, 56%). 1H NMR (300
MHz, DMSO–HOD, 9:1): d = 8.38 (s, 2 H, C=CHN), 7.13
(s, 4 H, ArH), 6.95 (s, 4 H, ArH), 5.58 (d, J = 9.3 Hz, 2 H,
H-1), 5.04 (s, 4 H, PhOCH2), 4.20 (s, 4 H, PhCH2), 3.92 (d,
J = 9.7 Hz, 2 H, H-5), 3.85 (dd, J = 9.9, 8.1 Hz, 2 H, H-2),
3.55–3.51 (m, 2 H, H-4), 3.41 (dd, J = 9.5, 8.7 Hz, 2 H, H-
2). LRMS: m/z found: 747.1 [M + Na]+, 723.2 [M – H]–.
HRMS (ES): m/z calcd for C32H37O12N8: 725.2531; found:
725.2549 [M + H]+.
Figure 1 A low-energy structure of 5 (macromodel)
aged that a variety of novel chiral cyclophane16
derivatives could be generated by the concise approach
described herein.
References and Notes
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Synlett 2009, No. 12, 1949–1950 © Thieme Stuttgart · New York

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