Synthesis of Di- and trivalent carbohydrate mimetics with oxepane substructure by employing copper-catalyzed [3+2] cycloadditions of alkynes with azidooxepanes

Article abstract of DOI:10.1002/ejoc.201402191

A series of enantiopure poly(hydroxy)aminooxepanes was converted into the corresponding azidooxepanes by a safe and efficient copper(II)-catalyzed diazo transfer reaction employing nonafluorobutanesulfonyl azide as nitrogen donor. These azidooxepanes underwent smooth copper(I)-catalyzed [3+2] cycloadditions with alkynes (click reaction) to provide a series of simple triazoles. With dialkynes and a trialkyne, bis- and tristriazoles containing oxepane substructures were prepared. Due to the polyhydroxylated end groups, these compounds are regarded as carbohydrate mimetics with potential biological activities, for example, as selectin inhibitors. In addition, unsymmetrical systems and macrocyclic compounds were prepared, again by employing [3+2] cycloadditions as key steps. Copyright

Full text of DOI:10.1002/ejoc.201402191

Job/Unit: O42191
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Date: 05-05-14 18:56:14
Pages: 8
FULL PAPER
DOI: 10.1002/ejoc.201402191
Synthesis of Di- and Trivalent Carbohydrate Mimetics with Oxepane
Substructure by Employing Copper-Catalyzed [3+2] Cycloadditions of Alkynes
with Azidooxepanes
Léa Bouché[a] and Hans-Ulrich Reissig*[a]
Keywords: Cycloaddition / Click chemistry / Macrocycles / Alkynes / Azides / Carbohydrate mimetics
A series of enantiopure poly(hydroxy)aminooxepanes was
converted into the corresponding azidooxepanes by a safe
and efficient copper(II)-catalyzed diazo transfer reaction em-
ploying nonafluorobutanesulfonyl azide as nitrogen donor.
These azidooxepanes underwent smooth copper(I)-catalyzed
[3+2] cycloadditions with alkynes (click reaction) to provide
a series of simple triazoles. With dialkynes and a tri-
alkyne, bis- and tristriazoles containing oxepane substruc-
tures were prepared. Due to the polyhydroxylated end
groups, these compounds are regarded as carbohydrate mi-
metics with potential biological activities, for example, as se-
lectin inhibitors. In addition, unsymmetrical systems and
macrocyclic compounds were prepared, again by employing
[3+2] cycloadditions as key steps.
Introduction
As reported in previous studies, enantiopure 3,6-dihydro-
2H-1,2-oxazines are versatile building blocks for the synthe-
sis of highly functionalized compounds,[1] in particular of
natural products[2] and of compounds to be considered as
carbohydrate mimetics.[3] The key heterocycles are easily
obtained in a stereocontrolled fashion by [3+3] cyclizations
of nitrones derived from chiral pool compounds and lithi-
ated alkoxyallenes.[4] In Scheme 1 we illustrate the synthesis
of poly(hydroxy)aminooxepanes D and their precursors C,
which were smoothly prepared with varying configurations
and functional groups starting from nitrones A and lithi-
ated (2-trimethylsilyl)ethoxyallene via 1,2-oxazines B with a
Lewis-acid-mediated rearrangement as the crucial step.[5]
The similarity of compounds such as D to carbohydrates
prompted us to regard them as carbohydrate mimetics[6]
and to study their influence on biological processes. Very
promising results have already been obtained with related
aminopyrans that were connected by amide bonds to gold
nanoparticles and subsequently O-sulfated. The achieved
multivalent presentation (ca. 1000–1200 ligands on one
nanoparticle) of the sulfated pyrans resulted in extremely
high binding affinities in sub-nanomolar concentrations
towards L- and P-selectins.[7] Sialyl Lewis X (sLex) ana-
logues of this type have the potential to be used for treat-
ment of diseases such as chronic inflammations.[8] The pres-
entation of multivalent structures is a strategy frequently
Scheme 1. General approach to enantiopure poly(hydroxy)amino-
oxepanes D by [3+3] cyclization of nitrones A and lithiated
TMSEO-allene followed by Lewis-acid-induced rearrangement of
3,6-dihydro-2H-1,2-oxazines B; TBS
TMSE = 2-(trimethylsilyl)ethyl.
= tert-butyldimethylsilyl,
realized by nature.[9] In the context of our aminopyran and
aminooxepane compounds, we were interested in finding
smaller inhibitors to study the influence of their multivalent
presentation more systematically.[10] We therefore wanted to
prepare carbohydrate mimetics derived from compounds D
(Scheme 1) in mono-, di- and trivalent fashion. For this
purpose, an efficient and flexible method was required that
would allow the use of easily accessible spacer molecules
with varying length and flexibility. An obvious choice to
achieve this goal was the use of the well-developed copper-
catalyzed [3+2] cycloaddition of alkynes and azides
(Huisgen–Sharpless–Meldal reaction also known as the
click reaction).[11] We also present a simple, safe, and reli-
able method to prepare azidooxepanes from the corre-
sponding amines D, which should have general importance.
[a] Institut für Chemie und Biochemie, Freie Universität Berlin,
Takustr. 3, 14195 Berlin, Germany
E-mail: hans.reissig@chemie.fu-berlin.de
http://www.bcp.fu-berlin.de/en/chemie/chemie/forschung/
OrgChem/reissig/index.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402191.
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Table 1. Synthesis of enantiopure azidooxepanes 2, 4, 6, 8, 10, and
12 by copper(II)-catalyzed diazo transfer employing nonafluoro-
butanesulfonyl azide; Nf = nonafluorobutylsulfonyl.
Results and Discussion
Starting from poly(hydroxy)aminooxepanes D, we first
developed a safe and efficient method to prepare the corre-
sponding azidooxepanes. The azido group is a versatile
functional moiety that allows many chemical transforma-
tions.[12] For the amino to azido conversion, the copper(II)-
catalyzed diazo transfer reaction was selected. This process
has been known for a long time[13] and was further devel-
oped by Wong through the use of metal catalysis.[14] The
reaction has frequently been used in carbohydrate chemis-
try and, in 2007, our group successfully applied it to gener-
ate azidopyrans.[3b,15] The crucial feature of our new proto-
col is the use of freshly prepared nonafluorobutanesulfonyl
azide (NfN3),[16] which is less explosive and probably less
toxic than the conventionally applied trifluoromethane-
sulfonyl azide (TfN3). A systematic evaluation of NfN3 in
the copper(II)-catalyzed diazo transfer reactions and other
processes were later reported by the group of Chiara.[17] The
very mild conditions of the diazo transfer reaction allowed
the preparation of azides with complete retention of config-
uration. A practical advantage of this protocol is that the
completion of the reaction can be followed by the color
change of the reaction mixture.
By using our method with NfN3, poly(hydroxy)amino-
oxepanes[5] 1, 3, 5, 7, 9, and 11, containing an amino group
at C-4, were smoothly converted into the new azidooxe-
panes 2, 4, 6, 8, 10, and 12, respectively, in yields ranging
from 59 to 90% (Table 1, entries 1–6). Due to the diversity
of the precursor amines, azides bearing variable substitu-
ents at C-2, C-5, and C-7 were accessible. Of particular
interest is bis(azido)oxepane 10 (entry 5), which was ob-
tained through a twofold diazo transfer reaction in very
good yield. The recorded yields do not strongly depend on
the structure or configuration of the starting materials, and
there was no indication of chemical instability of the re-
sulting azidooxepanes or of an erosion of their configura-
tional homogeneity.
Having the highly substituted enantiopure azidooxe-
panes 2, 4, 6, 8, 10 and 12 in hand, we first studied the
[3+2] cycloaddition of model compounds 2 and 4 with sev-
eral simple terminal alkynes (Table 2). The conditions intro-
[a] Yield of purified compound.
duced by Sharpless et al. employing copper(I) iodide and ined (entries 2–4). Azidooxepane 4 furnished cycloadduct
the ligand tris(benzyltriazolylmethyl)amine (TBTA)[18,19] 14 in nearly quantitative yield (entry 2). Similarly, the reac-
were carefully screened in our laboratory and have been fre- tion of 2 with an alkyne bearing a methoxycarbonyl
quently used.[20] The copper(I)-catalyzed cycloadditions group[21] gave the expected triazolinyl-substituted oxepane
were efficient at room temperature and no sideproducts 15 in reasonable efficiency (entry 3). In addition, the click
could be detected. For the synthesis of the simple triazoles, protocol reported by Lipshutz[22] was examined with 2 and
1.5–3.0 equiv. of the alkynes were used. Because we wanted cyclopropylethyne, but, in our case, the reaction required
to examine the biological activity of our products, the cop- longer and the yield of 16 was significantly lower (entry 4);
per catalyst needed to be removed as completely as possible. however, we did not perform this reaction under the stan-
Addition of ammonia solution to the crude product mix- dard conditions. All presented transformations show the
tures before filtration and chromatography was a simple usefulness of the applied conditions for the copper(I)-cata-
procedure that reliably achieved this goal.
lyzed [3+2] cycloaddition and we were thus encouraged to
Addition of phenylacetylene (Table 2, entry 1) led to the apply these conditions to the preparation of di- and tri-
smooth conversion of azidooxepane 2 into the correspond- valent structures.
ing 1,2,3-triazole derivative 13 in excellent yield (96%).
For the synthesis of divalent compounds, the required
Three other alkynes with functional groups were also exam- dialkynes were combined with a slight excess of the corre-
2
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Synthesis of Di- and Trivalent Carbohydrate Mimetics
Table 2. Copper(I)-catalyzed [3+2] cycloadditions of azidooxepanes
2 and 4 with terminal alkynes to give the corresponding triazoles
13–16; TBTA = tris(1-benzyl-1H-1,2,3-triazol-4-yl)methylamine.
Table 3. Copper(I)-catalyzed [3+2] cycloadditions of azidooxepane
2 with three different dialkynes to give the corresponding bistri-
azoles 17–19 with flexible and rigid spacer moieties.
[a] Yield of purified compound.
Scheme 2. Synthesis of divalent compound 20 from azidooxepane
12 and nona-1,8-diyne. Reagents and conditions: (a) CuI, Et3N,
TBTA, nona-1,8-diyne, MeCN, r.t., 17 h.
[a] Yield of purified compound. [b] Reaction conditions: Cu/C,
Et3N, dioxane, 60 °C.[22]
catalysis, which could be successfully applied to our prob-
lematic transformation. After addition of copper(I) iodide
sponding azidooxepane (ca. 2.1 equiv.) to avoid formation and equimolar amounts of acetic acid and of Hünig base,
of the mono-cycloaddition products. We used dialkynes we isolated the tristriazole derivative 21 in pure form and
with aliphatic or aromatic central units to obtain divalent in an acceptable yield of 58%. It should be mentioned that
oxepane derivatives either with flexible (Table 3, entries 1 the obtained carbohydrate mimetic 21 bears twelve hydroxy
and 2) or with rigid (entry 3) spacer units. Gratifyingly, the groups and therefore intense purification by column
desired bistriazoles 17–19 were isolated in good yields.
chromatography was required. To the best of our knowl-
This established method was also applied to phenyl-sub- edge, this example represents the first trivalent carbohydrate
stituted azidooxepane 12 and nona-1,8-diyne, which pro- mimetic bearing an oxepane moiety.[25]
vided the divalent oxepane 20 in comparable efficiency
(Scheme 2). This latter compound, bearing hydrophilic and
hydrophobic groups, was more difficult to purify due to its
lower solubility. The divalent structure, the long flexible
spacer, and the terminal aryl groups of product 20 show, in
part, resemblance to the known selectin inhibitor Bimosia-
mose. This compound is a carbohydrate mimetic that was
developed in industry and has already been investigated in
clinical studies.[23]
The preparation of trivalent compound 21 from azido-
oxepane 2 and 1,3,5-tri(ethynyl)benzene was found to be
challenging (Scheme 3). Difficulties were encountered in the
separation of TBTA from the final product, showing the
Scheme 3. Synthesis of the tristriazole derivative 21 from azidooex-
limitation of the applied protocol. Gratifyingly, Wang re-
pane 2 and 1,3,5-tri(ethynyl)benzene by employing Wang’s acid/
cently reported an alternative method,[24] using acid/base base protocol.[24]
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Taking into account that simple triazoles are very easily
formed, we also planned to prepare unsymmetrically substi-
tuted divalent compounds. Bicyclic azidooxepane 8 was
therefore treated with an excess of nona-1,8-diyne
(2.4 equiv.) under standard conditions (Scheme 4). After
stirring overnight, the desired alkynyl-substituted oxepane
22 was isolated in moderate yield; the corresponding bistri-
azole could not be detected in the crude reaction mixture. A
second copper(I)-catalyzed cycloaddition of alkyne 22 with
azidooxepane 2 (1.2 equiv.) under the same conditions pro-
vided the unsymmetrical divalent bistriazole 23 in excellent
yield. This example demonstrates that our concept also al-
lows the synthesis of unsymmetrically substituted divalent
carbohydrate mimetics with reasonable overall efficacy.
Scheme 5. Two-step synthesis of unsymmetrical trivalent tristri-
azole derivative 25 with dialkynyl-substituted triazole 24 and azido-
oxepane 2 as building blocks.
Scheme 4. Synthesis of unsymmetrical divalent oxepane derivative
23 by two sequential [3+2] cycloadditions starting from nona-1,8-
diyne and two different azidooxepanes.
The procedure described above was also applied to the
construction of more complex architectures. Cycloaddition
of bis(azido)oxepane 10 with an excess of hepta-1,6-diyne
(7.4 equiv.) furnished dialkynyl-substituted triazole 24 in
68% yield (Scheme 5). Two subsequent [3+2] cycloadditions
of 24 with azidooxepane 2 allowed successful isolation of
the unsymmetrical trivalent tristriazole derivative 25, which
contains eleven hydroxy groups. This example shows the
potential of our approach for the preparation of new oligo-
meric oxepane derivatives connected by triazole units.
A final challenging goal was the use of azidooxepane/
alkyne cycloadditions for the construction of novel macro-
cycles. Fascinating examples of macrocycles containing
carbohydrate substructures are known.[26] Gratifyingly,
macrocycle 26 was obtained from bis(azido)oxepane 10 and
nona-1,8-diyne in 39% yield after two days stirring at room
temperature under high dilution conditions and final ultra-
sonication (0.007 mmol/mL) (Scheme 6). Hence, both the
intermolecular and subsequent intramolecular [3+2] cyclo-
addition proceed with reasonable efficacy.
Scheme 6. Syntheses of two macrocyclic carbohydrate mimetics 26
and 27 (proposed constitution) bearing oxepane units prepared
from bis(azido)oxepane 10.
In a second example, precursor 10 was combined with ultrasound were advantageous to promote the conversion
unsymmetrical bisalkyne 24 containing an oxepane core. In of the precursors.[27] Due to the asymmetry of 24 the forma-
this case, high dilution (0.0043 mmol/mL) and the use of tion of two regioisomeric macrocycles is possible. The pri-
4
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Synthesis of Di- and Trivalent Carbohydrate Mimetics
J = 3.5, 6.1, 9.8 Hz, 1 H, 6-H), 3.50–3.57 (m, 4 H, 2-CH2, 3-H, 4-
H), 3.64–3.67 (m, 3 H, 2-H, 6-CH2), 3.89 (t, J ≈ 9.8 Hz, 1 H, 5-
H) ppm. 13C NMR (175 MHz, CD3OD): δ = 21.0, 31.5 (2q, Me),
59.9 (d, C-6), 63.4 (t, 2-CH2), 64.2 (t, 6-CH2), 72.3 (d, C-5), 73.6
(d, C-2), 74.8, 76.8 (2d, C-3, C-4), 77.0 (s, C-7) ppm. IR (ATR):
mary azide moiety of 10 will certainly undergo the first cy-
cloaddition, however the two alkyne units of 24 should have
very similar reactivity. Therefore, it was hard to predict
which isomer would be favored. One compound was iso-
lated after chromatography in pure form in 23% yield,
whereas a minor fraction consisting of an inseparable mix-
ture of this compound, a second isomer, and unknown im-
purities (possibly oligomers) was also obtained. Currently
it is not clear which product was actually isolated as the
major product. The drawn structure of 27 is C2-symmetric
whereas the alternative regioisomer (not shown) has an in-
version center. This does not allow a distinction to be made
based on the existing NMR spectroscopic data.
ν = 3355 (OH), 2990–2835 (C–H), 2120 (N ), 1645 (C=C), 1265
˜
3
(C–O), 1015 (C–O–C) cm–1. HRMS (ESI-TOF): m/z calcd. for
C10H19N3O5Na [M + Na]+ 284.1217; found 284.1225. C10H19N3O5
(261.3): calcd. C 45.97, H 7.33, N 16.08; found C 46.03, H 7.15, N
15.99.
Typical Procedure for Copper(I)-Catalyzed [3+2] Cycloaddition with
TBTA as Ligand (Procedure 2); Bistriazole 20: Azide 12 (66 mg,
0.21 mmol), nona-1,8-diyne (15.7 μL, 0.104 mmol), Et3N (6.3 μL,
0.046 mmol), TBTA (24.3 mg, 0.046 mmol), and CuI (8.7 mg,
0.046 mmol) were dissolved in MeCN (6 mL). The yellow mixture
was stirred at room temp. for 17 h and, upon completion of the
reaction, a solution of 7 n NH3 in MeOH (10:1) was added. The
mixture was stirred for a further 10 min, filtered through a small
column (silica gel), and the solvents were removed in vacuo. The
crude product (yellow solid, 117 mg) was purified by column
chromatography (silica gel; CH2Cl2/MeOH, 25:1 to 10:1) to give
bistriazole 20 (58 mg, 75%) as a yellow solid; melting range 185–
192 °C; [α]2D2 = +20.8 (c = 0.27, DMF); Rf = 0.14 (silica gel;
CH2Cl2/MeOH, 7:1). 1H NMR (700 MHz, [D7]DMF): δ = 1.47,
1.70 (2mc, 2 H, 4 H, CH2), 2.65 (mc, 2 H, 6-H), 2.66 (t, J = 7.6 Hz,
Conclusions
By using a safe and efficient diazo transfer method, poly-
(hydroxy)aminooxepanes were converted into azidooxep-
anes, including one bisazide. Subsequent copper(I)-cata-
lyzed cycloaddition (click reaction) of these azides with
mono-, bis-, and trisalkynes allowed the flexible synthesis
of triazole derivatives with oxepane end groups that can be
regarded as new multivalent carbohydrate mimetics. Both
symmetrically and unsymmetrically substituted systems
were prepared. Other architectures were also constructed by
this method, for example, macrocycles with oxepane sub-
units. No protective groups were required to achieve the
transformations. Together, these experiments demonstrate
the versatility and efficacy of the cycloaddition approach to
new multivalent carbohydrate mimetics with poly(hydroxy)-
oxepane end groups. In a future publication we shall report
on the sulfation of the reported multivalent polyols and of
related compounds prepared in our group and on an evalu-
ation of their biological activity.
4 H, CH2), 3.35, 3.49 (AB part of ABX system, JAX = 5.3, JBX
=
7.7, JAB = 10.7 Hz, 2 H each, 6-CH2), 3.70 (dd, J = 6.0, 11.4 Hz,
2 H, 2-CH2), 3.77 (mc, 2 H, 2-H), 3.92 (dd, J = 2.2, 11.4 Hz, 2 H,
2-CH2), 4.21 (t, J ≈ 9.5 Hz, 2 H, 3-H), 4.51 (br. s, 2 H each, OH),
4.54 (dd, J = 7.7, 9.3 Hz, 2 H, 5-H), 4.78 (t, J = 9.5 Hz, 2 H, 4-
H), 4.76 (br. s, 2 H, OH), 5.05 (br. s, 2 H, OH), 5.18 (d, J = 7.6 Hz,
1 H, 7-H), 5.40 (br. s, 2 H, OH), 7.29, 7.37, 7.55 (2t, d, J ≈ 7.5 Hz,
2 H, 4 H, 4 H, ArH), 7.88 (s, 2 H, 5Ј-H) ppm. 13C NMR (175 MHz,
[D7]DMF): δ = 25.2 (d, C-6), 28.9, 29.4, 50.4 (3t, CH2), 61.2 (t, 6-
CH2), 63.7 (t, 2-CH2), 69.7 (d, C-5), 72.0 (d, C-3), 73.7 (d, C-4),
79.4 (d, C-7), 82.0 (d, C-2), 123.3 (d, C-5Ј), 127.2, 127.3, 128.0,
141.2 (3d, s, Ar), 146.2 (s, C-4Ј) ppm. IR (ATR): ν = 3350 (OH),
˜
3080–3000 (=C–H), 2930–2770 (C–H), 1600 (C=C, C=N), 1090,
1060 (C–O–C) cm–1. HRMS (ESI-TOF): m/z calcd. for
C37H50N6O10Na [M + Na]+ 761.3486; found 761.3481.
Typical Procedure for Copper(I)-Catalyzed [3+2] Cycloaddition
Employing DIPEA and AcOH (Procedure 3); Tristriazole 21:
Azide 2 (70 mg, 0.27 mmol), DIPEA (62.5 μL, 0.351 mmol), AcOH
Experimental Section
(20.1 μL,
0.351 mmol),
1,3,5-tri(ethynyl)benzene
(11.7 mg,
General Methods: See the Supporting Information.
0.078 mmol), and CuI (11.0 mg, 0.058 mmol) were dissolved in
MeCN (1 mL). The yellow solution was stirred at room temp. for
Typical Procedure for the Copper(II)-Catalyzed Diazo Transfer
(Procedure 1); (2S,3S,4R,5S,6S)-4-Azido-2,6-bis(hydroxylmethyl)- 17 h. Upon completion of the reaction, a mixture of CH2Cl2/7 n
7,7-dimethyloxepan-3,5-diol (2): Aminooxepane
1
(55 mg,
NH3 in MeOH (20:1) was added, the reaction mixture was filtered
through a small column (silica gel) and the solvents were removed
in vacuo. The crude product (94 mg, yellow solid) was then purified
by column chromatography (silica gel; CH2Cl2/MeOH, 10:1 to 4:1)
and filtered twice through a syringe filter to give tristriazole 21
(42 mg, 58%) as a colorless solid; melting range 205–210 °C; [α]2D2
= –55.1 (c = 0.56, MeOH); Rf = 0.21 (silica gel; CH2Cl2/MeOH,
0.23 mmol) dissolved in MeOH (1 mL) was stirred with
CuSO4·H2O (7.0 mg, 0.028 mmol) dissolved in H2O (0.5 mL),
K2CO3 (65 mg, 0.47 mmol), and freshly synthesized NfN3 (220 mg,
0.677 mmol) at room temp. for 17 h. Upon completion of the reac-
tion the blue solution became green, then glycine hydrochloride
(180 mg, 1.61 mmol) was added and the mixture was stirred for a
further 24 h. A solution of CH2Cl2/7 n NH3 in MeOH (30:1) was
1
4:1). H NMR (700 MHz, [D5]py/CD3OD, 2:1): δ = 1.33, 1.39 (2s,
added and the mixture was stirred for 10 min. The mixture was 9 H each, Me), 2.23 (ddd, J = 3.4, 6.1, 9.7 Hz, 3 H, 6-H), 3.82,
filtered through a short column (silica gel) and the solvents were
removed in vacuo. The crude material (55 mg, colorless solid) was
then purified by column chromatography (silica gel; CH2Cl2 to
CH2Cl2/MeOH, 20:1) to give azidooxepane 2 (53 mg, 87%) as a
colorless solid; m.p. 146 °C; [α]2D2 = –34.2 (c = 0.04, MeOH); Rf =
3.87 (AB part of ABX system, JAX = 3.4, JBX = 6.1, JAB = 11.5 Hz,
3 H each, 6-CH2), 3.92, 3.97 (AB part of ABX system, JAX = 5.4,
JBX = 7.1, JAB = 11.4 Hz, 3 H each, 2-CH2), 4.22 (mc, 3 H, 2-H),
4.67 (t, J ≈ 9.5 Hz, 3 H, 5-H), 4.82 (dd, J = 2.8, 7.2 Hz, 3 H, 3-H),
5.06 (dd, J = 7.2, 9.5 Hz, 3 H, 4-H), 8.35 (s, 3 H, ArH), 8.49 (s, 3
0.07 (silica gel; CH2Cl2/7 n NH3 in MeOH, 20:1). 1H NMR H, 5Ј-H) ppm. 13C NMR (175 MHz, [D5]py/CD3OD, 2:1): δ = 21.5,
(700 MHz, CD3OD): δ = 1.17, 1.35 (2s, 3 H each, Me), 1.88 (ddd, 32.0 (2q, Me), 60.5 (d, C-6), 63.6 (t, 2-CH2), 63.9 (t, 6-CH2), 70.3
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(d, C-5), 74.06 (d, C-2), 74.12 (d, C-3), 76.0 (d, C-4), 77.1 (s, C-7),
122.7 (d, Ar), 124.7 (d, C-5Ј), 133.5, 147.1 (2s, Ar, C-4Ј) ppm. IR
(ATR): ν = 3375 (OH), 2980–2845 (C–H), 1545–1490 (C=C, C=N),
˜
1220 (C–O), 1065, 1020 (C–O–C) cm–1. HRMS (ESI-TOF): m/z
calcd. for C42H63N9O15Na [M + Na]+ 956.4436; found 956.4314.
[10]
[11]
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, analytical data and copies of the
NMR spectra.
Acknowledgments
This work was generously supported by the Deutsche Forschungs-
gemeinschaft (SFB 765), the Center of International Co-
operation of the Freie Universität Berlin and Bayer HealthCare,
which is most gratefully acknowledged. We also thank M. Menger
and L. Selter for experimental assistance as well as Dr. R. Zimmer,
M. Kandziora and J. Salta for valuable discussions and help during
the preparation of this manuscript.
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6
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42191
/KAP1
Date: 05-05-14 18:56:14
Pages: 8
Synthesis of Di- and Trivalent Carbohydrate Mimetics
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Received: March 4, 2014
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O42191
/KAP1
Date: 05-05-14 18:56:14
Pages: 8
L. Bouché, H.-U. Reissig
FULL PAPER
Carbohydrate Mimetics
A safe and reliable copper(II)-catalyzed
diazo transfer method leads to azido-
oxepanes that smoothly undergo copper(I)-
catalyzed [3+2] cycloadditions with alkynes
to provide triazole derivatives. This se-
quence allows the preparation of di- and
trivalent carbohydrate mimetics including
novel macrocyclic compounds.
L. Bouché, H.-U. Reissig* ................. 1–8
Synthesis of Di- and Trivalent Carbo-
hydrate Mimetics with Oxepane Substruc-
ture by Employing Copper-Catalyzed [3+2]
Cycloadditions of Alkynes with Azido-
oxepanes
Keywords: Cycloaddition / Click chemis-
try / Macrocycles / Alkynes / Azides /
Carbohydrate mimetics
8
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