Macrocyclic derivatives with a sucrose scaffold: insertion of a long polyhydroxylated linker between the terminal 6,6′-positions

Article abstract of DOI:10.1039/c8nj02808g

A series of five new macrocyclic hybrids with a sucrose scaffold were prepared by the reaction of activated 1′,2,3,3′,4,4′-hexa-O-methylsucrose with diversely functionalized d-mannitols. The 21-, 25-, and 31-membered representatives containing mannitol units were prepared by a macrocyclization of 6,6′-di-O-propargylated sucrose with protected 1,6-diazido-d-mannitol or 6,6′-di-azidosucrose with propargylated d-mannitol (a “click” approach), whereas 23-membered representatives were prepared by double N-alkylation of 1′,2,3,3′,4,4′-hexa-O-methyl-6,6′-di-aminosucrose with 1,6-di-bromoacyl d-mannitol. All sucrose derivatives were tested as putative hosts for chiral recognition of α-phenylethylammonium (α-PEA) cations. In one case, in striking contrast to all sucrose-based macrocyclic hosts previously reported by us, unexpected reverse preference for the R-enantiomer was observed (K_R/K_S = 1.5).

Full text of DOI:10.1039/c8nj02808g

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Macrocyclic derivatives with a sucrose scaffold:
insertion of a long polyhydroxylated linker
between the terminal 6,60-positions†
Cite this: New J. Chem., 2018,
42, 18578
´
Bartosz Chaciak,
Kajetan Da˛browa,
Paweł Swider
and Sławomir Jarosz
*
A series of five new macrocyclic hybrids with a sucrose scaffold were prepared by the reaction of activated
10,2,3,30,4,40-hexa-O-methylsucrose with diversely functionalized D-mannitols. The 21-, 25-, and 31-membered
representatives containing mannitol units were prepared by a macrocyclization of 6,60-di-O-propargylated
sucrose with protected 1,6-diazido-D-mannitol or 6,60-di-azidosucrose with propargylated D-mannitol
(a ‘‘click’’ approach), whereas 23-membered representatives were prepared by double N-alkylation of
10,2,3,30,4,40-hexa-O-methyl-6,60-di-aminosucrose with 1,6-di-bromoacyl D-mannitol. All sucrose derivatives
were tested as putative hosts for chiral recognition of a-phenylethylammonium (a-PEA) cations. In one case,
in striking contrast to all sucrose-based macrocyclic hosts previously reported by us, unexpected reverse
preference for the R-enantiomer was observed (KR/KS = 1.5).
Received 6th June 2018,
Accepted 15th October 2018
DOI: 10.1039/c8nj02808g
rsc.li/njc
Introduction
Carbohydrates are important platforms for the preparation of a
broad array of functionalized chiral crown, aza-, and thia-crown
ethers and their analogs.1,2 Monosaccharides are mostly used,3
however, as such chiral scaffolds, whereas application of dis-
accharides is much less explored.4
During our studies on the preparation of functional materials
from simple carbohydrates, we turned our attention to chiral
crown and aza-crown ethers5 incorporating the most common
disaccharide – sucrose (Fig. 1, type I).
Fig. 1 Examples of the macrocyclic hosts incorporating a sucrose back-
bone developed in our group.
Results and discussion
We observed that these relatively simple 16- and 19-membered Although most of the macrocyclic sucrose-derivatives prepared by
macrocyclic systems could be employed for the demanding enantio- us to date were built on benzylated sucrose, in this study we
selective recognition of chiral ammonium cations.6 We have pre- decided to employ their per-methylated analogues. The O-methyl
pared also larger macrocyclic structures bearing one (e.g. II, Fig. 1)7 protection offers lower molecular weight, reduced steric hindrance,
or two sucrose units (III, Fig. 1).8,9 Recently we have reported a new and increased stability under a range of conditions (e.g. catalytic
type of a 21-membered macrocyclic sucrose diamide (Fig. 1, type III) hydrogenation) as compared to benzyl protection. In addition, the
in which the terminal positions of this disaccharide are linked via a 1H NMR spectra of targeted macrocyclic products would be less
longer polyhydroxylated-bridge.10
complex; hence determination of their complexation properties by
In this paper we extend our studies to the synthesis of a series 1H NMR titration experiments should be facilitated, in particular
of five structurally related derivatives with the macrocyclic cavity with the guest molecules containing protons resonating at
ranging from 21 to 31 atoms. In addition, enantiodiscriminating 6–8 ppm.
properties of these macrocycles towards model phenylethyl
Hexa-O-methyl-sucrose 1 and its di-amino analog 3 were
ammonium (a-PEA) cations were also examined.
thus chosen as suitable disaccharide backbones (Scheme 1).
Compound
1
was prepared as described previously11
(Scheme 1, conditions a), whereas new diamine synthon 3
was prepared from free sucrose in the four-step synthesis,
involving: selective chlorination under Appel conditions,12
SN2-type substitution of both chlorine atoms with sodium
azide, methylation of the remaining free hydroxyl groups, and
Institute of Organic Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44/52
01-224 Warsaw, Poland. E-mail: sljar@icho.edu.pl
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c8nj02808g
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Scheme 1 Synthesis of sucrose intermediates 1–3; conditions: (a) 1. TrCl,
py; 2. MeI, KOH, TBAB, DMF; 3. Na, NH3/THF, see ref. 11; (b) 1. PPh3, CCl4,
py; 2. NaN3, DMF; 3. MeI, KOH, TBAB, DMF; 4. H2, Pd/C, MeOH.
subsequent hydrogenation of the azide groups (Scheme 1,
conditions b).
Scheme 3 Synthesis of acyclic sugar intermediates 6, 8 and 9, conditions:
(a) propargyl bromide, KOH, TBAB DMF (65% for 6 and 69% for 10);
(b) BrCH2COBr, K2CO3, CH2Cl2, 80%; (c) NaN3, DMF, 65%.
Synthesis of sucrose macrocycles by azide–alkyne cycloaddition
From a variety of possible ways to link both terminal positions
of glucose and fructose units (C6 and C60), the ‘click’ approach
was chosen. It was based on the reaction of di-azido-sucrose 2 with
appropriate di-propargylic linkers: 4, 6, and 10 or the reaction
performed in a reverse manner (the appropriate propargylic sucrose
derivative and azido linker).
The model reaction of diazide 2 with O-propargylated derivative
of D-mannitol 413 allowed preparing macrocyclic sucrose-triazole-
mannitol hybrid 5 in a satisfactory 28% yield (Scheme 2).
This encouraging result prompted us to perform a more
detailed study on the preparation of other sucrose-containing
macrocycles by this ‘click’ approach. The required propargylated
intermediates 6 and 10, as well as azide 9, were obtained from
hexa-O-methyl-sucrose 1 and tetra-O-methyl-D-mannitol 7 14 as
shown in Scheme 3.
Finally, the reaction between O-propargylated D-mannitol 10
and sucrose-azide 2 under the ‘click’ conditions, provided
macrocycle 11 in 34% yield, while the reverse reaction between
O-propargylated sucrose 6 and D-mannitol azide 9 furnished 12
in a 26% yield (Scheme 4).
Scheme 4 Synthesis of the 25- and 31-membered sucrose-triazole-
mannitol hybrids 11 and 12, respectively; conditions: (a) CuSO4ꢀH2O,
sodium ascorbate, t-BuOH/CH2Cl2/H2O, 4 : 1 : 1 (v/v/v).
Synthesis of sucrose macrocycles by N-alkylation
Two macrocyclic hosts: 16 and 17 containing the amide and ester
motifs were synthetized by the reaction of sucrose diamine 3 with
the corresponding linker 8 or its nitrogen analog 15 (Scheme 5).
The required dibromo-linker 15 was readily prepared from
diol 7 by an activation of both hydroxyl groups (as mesylates),
the SN2-type substitution with sodium azide, and subsequent
hydrogenation to amines which were subjected to the reaction with
bromoacetyl bromide. The macrocyclization between diamine 3
Scheme 5 Synthesis of 23-membered sucrose-amide-mannitol hybrids
16 and 17; conditions: (a) 1. MsCl/pyridine; 2. NaN3; (b) Pd/C/H2, MeOH;
(c) BrCH2COBr, DMAP, Et3N, CH2Cl2, (65% over two steps); (d) DIPEA, MeCN.
and dibromide 8 performed in MeCN under high dilution
conditions afforded macrocycle 16 in 27% yield. The analogous
process carried out for compounds 3 and 15 furnished the
corresponding macrocycle 17 in 49% yield. The near two times
higher yield of the cyclization observed for 17, as compared to
16, suggests some kind of preorganization effect that favors the
ring-closing in the former case. Presumably, the amide groups,
which – in contrast to ester groups – are both hydrogen-bond
Scheme 2 Synthesis of the 21-membered sucrose-triazole-mannitol
hybrid 5; conditions: (a) CuSO4ꢀH2O, sodium ascorbate, t-BuOH/CH2Cl2/
H2O, 4 : 1 : 1 (v/v/v).
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Fig. 3 Part of the 1H NMR spectra of host 17 and its complexes with
2.2 equiv. of a-PEA-HCl in CDCl3: free 17 (a), 17 + S-a-PEA-HCl (b), and
17 + R-a-PEA-HCl (c).
Fig. 2 The lowest-energy structures of the linear intermediate exemplifying
facilitation of the ring-closure step by intramolecular hydrogen bonds; non-
acidic protons have been omitted for clarity; energies are given in kcal molꢂ1
.
donors and acceptors, preorganize the linear intermediate as very
recently observed for C2-symmetric macrocyclic urea-sucrose
derivatives.9 This assumption is supported by DFT calculations
(B3LYP-D3/6-31G(d)/C-PCM/MeCN, see Experimental section for
details) which suggest that both amide groups actively participate
in folding of the linear intermediate, hence facilitating the ring-
closure step over oligomerization (Fig. 2).
Chiral recognition properties of sucrose-derived hosts
With macrocyclic hosts in hand we aimed to test their recognition
properties toward a model chiral cationic guest, i.e. hydrochloride
salt of 1-phenylethylamine (a-PEA).15 We noticed, however, that
addition of either the S- or R-enantiomer of a-PEA does not cause
any significant changes of the chemical shifts in the NMR spectra
of macrocycles: 5, 11, 12, and 16 in CDCl3. This experimental
observation, surprisingly for us, indicates that these macrocyclic
host molecules are unable to form sufficiently strong complexes
with protonated a-PEA.
Fig. 4 Experimental chemical shift changes of the anomeric proton (a)
and distribution of residual errors (b) for titration of host 17 with hydro-
chloride of S-a-PEA (red squares) and R-a-PEA (blue triangles) in CDCl3 at
303 K; calculated binding isotherms (gray lines).
Comparison of the structures of hosts: 5, 11, 12, and 16 with method is now, however, recognized as out-dated and erroneous,
structurally related aza-crown hosts of type I (see Fig. 1) in particular for the analysis of host–guest complexes with
suggests that the macrocyclic cavity is too big to accommodate moderate stability, such as observed here.17
the a-PEA guest. In addition, good chiral recognition properties
To further test the recognition properties of host 17 towards
of sucrose-macrocycles reported earlier might result from a-PEA cations we conducted ESI-MS and computational studies
the additional dispersion interaction between aromatic rings (Fig. 5).
originating from the sugar O-benzyl protection and phenyl ring
of the a-PEA guest, respectively. Moreover, the presence of
triazole and ether groups in hosts 5, 11, and 12 introduces
additional steric hindrance which might inhibit the binding of
the guest within the macrocyclic cavity.
Fortunately, a considerable change of the chemical shift of
an anomeric proton of sucrose was observed upon addition of
2.2 equiv. of chloride salt of either R- or S-a-PEA to a CDCl3
solution of host 17 (Fig. 3).
The non-linear curve fitting algorithm (as implemented in
HypNMR software)16 allowed us to determine the following
association constants for the 1 : 1 (host : guest) complexes of 17
with S-a-PEA (Ka = 79 ꢁ 7 Mꢂ1) and R-a-PEA (Ka = 119 ꢁ 9 Mꢂ1),
respectively. This data indicates that host 17 exhibits a moderate
preference toward the R-enantiomer of a-PEA (Ka,R/Ka,S = 1.50 ꢁ 0.24)
Fig. 5 Energy-minimized structures of complexes of host 17 with
S-a-PEA (a) and R-a-PEA (b) calculated at the DFT/B3LYP-D3/6-31G(d)/
C-PCM:CHCl3 level of theory; non-acidic protons have been omitted for
(see Fig. 4a).
The validity of an assumed 1 : 1 binding model was confirmed
by a random distribution of residuals, whereas a Job plot
suggests a higher binding stoichiometry (Fig. 4b). The latter
clarity; binding energies of complexes (D(D(G) = DGcomplex ꢂ (DGhost
+
DGa-PEA+))) are given in kcal molꢂ1
.
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1
TMS (d 0.00) for H NMR spectra and residual solvent (CDCl3:
d 77.23; DMSO-d6: d 39.51; acetone-d6: d 206.7; benzene-d6:
d 128.4) for the 13C NMR spectra. All resonances for the carbon
skeletons were assigned by COSY (1H–1H), HSQC (1H–13C), and
HMBC (1H–13C) correlations. Reagents were purchased from
Sigma-Aldrich, Alfa Aesar, or ABCR, and were used without
purification. Hexanes (65–80 1C fraction from petroleum) and
EA were purified by distillation. TLC was carried out on silica
gel 60 F254 (Merck). Chromatography was performed on Buchi
glass columns packed with silica gel 60 (230–400 mesh, Merck),
or GraceResolvTM (40 mm) columns and Reveleriss from
GRACE. Specific rotation was measured with a Jasco DIP-360
digital polarimeter for solutions in CH2Cl2 (c B 0.5 M) at rt.
Fig. 6 Exemplification of the CHꢀ ꢀ ꢀp interactions in the 17*S-a-PEA
complex.
Seemingly, in the positive (+) ion mode, we were unable to
observe the signals corresponding to the complexes of 17 with
R- and S-enantiomers of a-PEA. This might indicate that under
ESI-MS experimental conditions (high dilution of the sample
in competitive methanol used as the carrier solvent) these
complexes are at the undetectable level since in considerably
less polar and competitive CDCl3 the Kas derived from the
1H NMR titration experiments are rather small.
Nevertheless, in line with the titration experiments in
solution, the DFT calculations suggest a preference for the R- over
S-enantiomer of a-PEA (D(DG) = ꢂ12.2 vs. ꢂ10.9 kcal molꢂ1). The
energy-minimized structures of both complexes demonstrate a
similar binding mode in which the guest molecule is bound above
the macrocyclic cavity by three OhostꢀꢀꢀH–N (d = 2.75–2.87 Å) and
one NhostꢀꢀꢀH–N (d = 3.00 Å) hydrogen bonds, respectively (Fig. 5).
In addition, in both cases the conformation of the complex is
stabilized by three albeit rather weak intramolecular hydrogen
bonds (d = 2.91–3.25 Å).
DFT calculations
All calculations were performed using the Spartan’16 Parallel
Suite18 program at the B3LYP-D3/6-31G(d) level of theory. The
C-PCM implicit solvent model was used to simulate the MeCN
or CHCl3 environment. A DFT functional with dispersion
(B3LYP-D3)19 was chosen for a better description of noncovalent
interactions. The detailed calculation procedure is similar to that
described in ref. 20.
General procedure A for macrocyclization via 1,3-dipolar
cycloaddition. The corresponding di-azide (0.4 mmol) was
dissolved in a mixture of solvents: t-BuOH : CH2Cl2 : H2O
(4 : 1 : 1, v/v/v) to make a final concentration of 0.01 M. To this
solution were added CuSO4ꢀ5H2O (0.8 mmol, 2 equiv.) and
sodium ascorbate (1.6 mmol, 1.4 equiv.). The di-propargyl
partner (0.4 mmol) in the same mixture of solvents (c = 0.01 M)
was then added dropwise within 2 h and the reaction was stirred
for an additional 12 h at rt. After this time the solvent was
evaporated under vacuum and the crude product was purified by
column chromatography.
The analysis of the complex of 17 with S-a-PEA indicates that
one OMe group from a mannitol linker and a phenyl ring from
a PEA guest are positioned in close proximity. This, in turn,
might generate a steric hindrance resulting in a lower stability
of a complex, as compared to the R-a-PEA guest in which the
phenyl ring is positioned above a macrocyclic cavity (Fig. 6).
General procedure
B for macrocyclization via double
N-alkylation. To a solution of diamine 3 (170 mg, 0.4 mmol,
1 equiv.) in ACN (40 mL, c = 0.01 M) was added DIPEA (4.2 equiv.),
followed by dropwise addition of a solution of either dibromide 8 or
15 (0.4 mmol, 1 equiv.) in ACN (40 mL, c = 0.01 M) over 1 h. The
reaction was then stirred for 18 h at 60 1C and the solvent was
evaporated under vacuum yielding the crude product as an oil
which was purified by column chromatography.
Synthesis of 1,6-dipropargyl-2,3,4,5-tetra-O-methyl-D-mannitol
(10). To a solution of 7 (650 mg, 2.73 mmol, 1 equiv.) and propargyl
bromide (0.35 mL, 3 equiv.) in toluene (40 mL), was added 50%
aqueous NaOH (30 mL) followed by TBAB (50 mg). The hetero-
geneous mixture was vigorously stirred for 4 h at rt. Then it
was partitioned between water (50 mL) and ether (30 mL). The
layers were separated, and the aqueous one extracted with ether
(2 ꢃ 20 mL). Combined organic solutions were washed with water
(30 mL) and brine (30 mL), dried and concentrated, and the crude
product was purified by column chromatography (hexanes : EA,
1 : 1 v/v) to give 10 (592 mg, 69%) as a yellow oil. 1H NMR
(500 MHz, CDCl3) d 4.24 (dd, J = 2.4, 1.8 Hz, 4H), 3.93 (dd, J =
Conclusion
We have prepared five new macrocyclic hosts with a sucrose
scaffold in which the terminal positions of the disaccharide are
connected via a mannitol bridge of various lengths. Only one
21-membered host, bearing two amide groups (17), has shown
complexing ability towards a-PEA cations, the model chiral
ammonium guest. In striking contrast to all sucrose-based
macrocyclic hosts previously prepared by us, this host shows
the unexpected reverse preference for the R-enantiomer of
a-PEA (KR/KS = 1.5 in CDCl3).
Experimental section
Materials and methods
NMR spectra were recorded in CDCl3, DMSO-d6, acetone-d6, 10.7, 2.4 Hz, 2H), 3.70 (dd, J = 10.7, 4.0 Hz, 2H), 3.58 (dt, J = 1.9,
and benzene-d6 with a Varian AM 500 or AM-600 spectrometer 1.2 Hz, 2H), 3.51 (dd, J = 5.3, 4.3 Hz, 2H), 3.49 (s, 6H), 3.43 (s, 6H),
at 303 K. Chemical shifts (d) are reported in ppm as relative to 2.44 (t, J = 2.4 Hz, 2H). 13C NMR (125 MHz, CDCl3) d 79.66, 79.62,
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79.01, 74.54, 67.20, 60.60, 58.41, 56.92. HR-MS ESI (m/z): calc. for and saturated NaHCO3 solution (10 mL) were added, the layers
[M(C16H26O6) + Na+]: 337.1627, found: 337.1629. Anal.: calc. for were separated, and the aqueous one extracted with CH2Cl2
C16H26O6: C, 61.13; H, 8.24; O, 30.53, found: 61.03, H 8.16. [a]20
+5.7. IR (film): 3453, 2938, 2833, 2115, 1724, 1643, 1464, 1446, 1137, H2O (30 mL) and brine (30 mL), dried and concentrated, and
1220, 1186, 1104, 848, 770, 665, 639, 507 cmꢂ1
the product was purified by column chromatography (hexanes :
=
(2 ꢃ 10 mL). Combined organic solutions were washed with
.
1,6-Di-O-(2-bromoacetyl)-2,3,4,5-tetra-O-methyl-D-mannitol (8). EA, 4 : 1 to 100% EA) to give 15 (170 mg, 0.35 mmol, 69%) as a
To a stirred solution of 7 (185 mg, 0.78 mmol, 1 equiv.) in CH2Cl2 transparent oil. 1H NMR (600 MHz, C6D6) d 6.67 (s, 2H), 3.60–3.55
(15 mL) containing powdered K2CO3 (430 mg, 3.12 mmol, (m, 2H), 3.45 (dd, J = 3.8, 1.4 Hz, 2H), 3.41 (s, 6H), 3.39 (s, 4H), 3.34
4 equiv.), bromoacetyl bromide (0.35 mL, 2.34 mmol, 3 equiv.) (td, J = 5.0, 1.2 Hz, 2H), 3.12 (s, 6H). 13C NMR (150 MHz, C6D6) d
was added dropwise within 15 min and the mixture was stirred for 164.89, 81.11, 79.36, 60.42, 56.47, 38.69, 28.97. MS (ESI): calcd for
18 h at rt. Then, it was partitioned between 10% citric acid (50 mL) m/z = 499.0055 [M(C14H26N2O6Br2) + Na+]; found: 499.0048
and CH2Cl2 (30 mL), the layers were separated, and the aqueous [M(C14H26N2O6Br2) + Na+]; anal. calcd for C14H26N2O6: C, 35.17;
one extracted with CH2Cl2 (2 ꢃ 15 mL). Combined organic H, 5.48; N, 5.86; Br, 33.42. Found: C, 35.18; H, 5.66; N, 5.90; Br,
solutions were washed with H2O (30 mL) and brine (30 mL), 33.45. [a]20 = ꢂ19.0; IRr (film) = 3076, 2980, 2935, 2830, 1657,
dried and concentrated, and the crude product was purified 1538, 14 62, 1442, 1333, 1302, 1211, 1188, 1105, 1008, 886, 845,
by column chromatography using a gradient of hexanes and EA 754, 697, 664, 545 cmꢂ1
(1 : 0 - 1:1 v/v) to afford 8 (296 mg, 80%) as a pale yellow oil.
Synthesis of 6.60-di-O-propargyl-2,3,4,10,30,40-hexa-O-methyl-
.
1H NMR (500 MHz, CDCl3) d 4.84 (dd, J = 12.2, 2.2 Hz, 1H), 4.18 sucrose (6). To a solution of 10,2,3,30,4,40-hexa-O-methylsucrose
(dd, J = 12.2, 3.4 Hz, 1H), 3.90 (d, J = 1.7 Hz, 2H), 3.59–3.55 (1; 628 mg, 1.47 mmol, 1 equiv.) in toluene (15 mL) containing
(m, 1H), 3.52 (dd, J = 8.2, 3.0 Hz, 1H), 3.49 (s, 3H), 3.43 (s, 3H). TBAB (50 mg), aqueous 50% NaOH was added followed by
13C NMR (125 MHz, CDCl3) d 167.07, 78.78, 78.08, 62.84, 60.80, propargyl bromide (0.35 mL, 4.41 mmol, 3 equiv.), and the
57.11, 25.65. HR-MS ESI (m/z): calc. for [M(C14H24Br2O8) + Na+]: mixture was vigorously stirred for 6 h at rt. Then it was
500.9736, found: 500.9730. Anal.: calc. for C14H24Br2O8: C, 35.02; partitioned between water (15 mL) and Et2O (15 mL), the layers
H, 5.04; Br, 33.28, found: C, 35.04; H, 5.04; Br, 33.13. [a]D = +27.0. were separated, and the aqueous one extracted with Et2O
IR (film): 3501, 2939, 2833, 1739, 1460, 1424, 1365, 1336, 1284, (2 ꢃ 10 mL). Combined organic solutions were washed with
1184, 1171, 1111, 1090, 1023, 937, 890, 849, 713, 665, 621, 548, H2O (30 mL) and brine (30 mL), dried and concentrated, and
512 cmꢂ1
.
the product was purified by column chromatography (100%
1,6-Di-O-(2-azido-acetyl)-2,3,4,5-tetra-O-methyl-D-mannitol (9). hexane to hexanes : EA, 1 : 1 v/v) to give 6 (480 mg, 0.96 mmol,
To a solution of dibromide 8 (135 mg, 0.28 mmol, 1 equiv.) in 65%) as a pale yellow oil. 1H NMR (600 MHz, CDCl3) d 5.54
DMF (5 mL) NaN3 (55 mg, 0.84 mmol, 3 equiv.) was added and (d, J = 3.7 Hz, 1H), 4.28 (dd, J = 15.9, 2.4 Hz, 1H), 4.24 (dd,
the mixture was stirred for 2 h at rt. It was then partitioned J = 15.9, 2.4 Hz, 1H), 4.20 (dd, J = 4.4, 2.4 Hz, 2H), 4.18 (dd,
between water (15 mL) and ether (15 mL), the layers were J = 4.4, 2.4 Hz, 1H), 4.04 (d, J = 7.8 Hz, 1H), 3.99–3.95 (m, 2H),
separated, and the aqueous one extracted with ether (2 ꢃ 10 mL). 3.85 (d, J = 7.7 Hz, 1H), 3.81 (dd, J = 10.2, 3.8 Hz, 1H), 3.79–3.74
Combined organic solutions were washed with water (30 mL) and (m, 2H), 3.67 (dd, J = 10.4, 2.0 Hz, 1H), 3.62 (s, 3H), 3.58
brine (30 mL), dried and concentrated, and the crude product was (dd, J = 10.6, 2.6 Hz, 2H), 3.47 (d, J = 2.5 Hz, 3H), 3.46 (s, 3H),
purified by column chromatography (hexanes : EA, 1 : 1 v/v) to afford 3.45 (d, J = 7.0 Hz, 1H), 3.44 (s, 3H), 3.39 (dd, J = 10.9, 4.6 Hz,
9 (74 mg, 65%) as a transparent oil. 1H NMR (600 MHz, CDCl3) d 5H), 3.21 (dd, J = 10.2, 9.0 Hz, 1H), 3.14 (dd, J = 9.7, 3.7 Hz, 1H),
4.92 (dd, J = 12.2, 2.2 Hz, 1H), 4.17 (dd, J = 12.2, 3.1 Hz, 1H), 3.94 2.43 (t, J = 2.4 Hz, 2H). 13C NMR (150 MHz, CDCl3) d 104.16,
(d, J = 2.4 Hz, 2H), 3.54 (d, J = 8.4 Hz, 1H), 3.51 (ddd, J = 8.3, 3.0, 89.25, 85.07, 83.73, 83.09, 81.55, 79.68, 79.58, 79.32, 79.22,
2.3 Hz, 1H), 3.48 (s, 3H), 3.41 (s, 3H). 13C NMR (150 MHz, CDCl3) 77.00, 74.65, 74.63, 73.95, 71.16, 70.20, 68.25, 60.64, 60.48,
d 168.13, 78.68, 77.95, 62.06, 60.75, 57.02, 50.36. HR-MS ESI 59.37, 58.52, 58.50, 58.47, 58.41, 58.24. HR-MS ESI (m/z): calc.
(m/z): calc. for [M(C14H24N6O8)
+
Na+]: 427.1553; found: for [M(C24H38O11) + Na+]: 525.2312, found: 525.23070. Anal.:
427.1540. Anal.: calc. for C14H24N6O8: C, 41.57; H, 5.98; N, calc. for M(C24H38O11) + H2O: C, 55.37; H, 7.75, found: C, 55.37;
20.78, found: C, 41.58; H, 5.91; N, 20.55. [a]20 = +23.7. IR (film): H, 7.51. [a]20 = +43.7; IR (film): 3454, 3263, 2981, 2935, 2833,
2981, 2938, 2835, 2108, 1747, 1460, 1426, 1367, 1346, 1292, 1239, 2117, 1724, 1643, 1450, 1374, 1270, 1185, 1148, 1099, 1018, 982,
1190, 1112, 1089, 1038, 1023, 944, 839, 771, 733, 648, 553, 512 cmꢂ1
1,6-N-di-(2-bromoacetylo)-2,3,4,5-tetra-O-methyl-D-mannitol
(15)
.
873, 836, 736, 701, 562 cmꢂ1
.
Macrocyclic host 11. Following the general procedure A the
crude product was purified by flash chromatography using
This reaction was carried out under Ar atmosphere. To a stirred EA : MeOH (9 : 1 v/v) to afford 11 (102 mg, 34%) as a white
and cooled to ꢂ78 1C solution of 1,6-diamino-2,3,4,5-tetra-O- amorphous foam. 1H NMR (600 MHz, DMSO-d6) d 8.01 (s, 1H),
methyl-D-mannitol 14 (120 mg, 0.52 mmol, 1 equiv.) in CH2Cl2 7.88 (s, 1H), 5.25 (d, J = 3.4 Hz, 1H), 4.68 (dd, J = 14.7, 5.2 Hz,
(20 mL) containing DMAP (3 mg) and Et3N (0.151 mL, 1.08 mmol, 1H), 4.63 (d, J = 12.7 Hz, 1H), 4.57 (dd, J = 14.7, 2.8 Hz, 1H),
2.1 equiv.), bromoacetyl bromide (0.092 mL, 1.06 mmol, 2.06 equiv.) 4.49 (d, J = 12.7 Hz, 1H), 4.42 (dd, J = 14.4, 2.5 Hz, 1H), 4.17 (dd,
was added dropwise within 1 h. The cooling bath was removed J = 14.4, 9.3 Hz, 1H), 4.11 (ddd, J = 10.0, 5.1, 3.0 Hz, 1H), 4.03
and the solution was stirred until all starting material disappeared (dd, J = 16.7, 2.6 Hz, 1H), 3.95–3.91 (m, 1H), 3.82 (t, J = 7.6 Hz,
(TLC monitoring in hexanes : ethyl acetate, 3 : 1). Water (10 mL) 1H), 3.60–3.56 (m, 2H), 3.54 (d, J = 11.0 Hz, 3H), 3.49–3.43
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(m, 7H), 3.41 (s, 3H), 3.39 (dt, J = 7.9, 2.6 Hz, 2H), 3.36–3.34 3.40 (d, J = 2.3 Hz, 2H), 3.38 (t, J = 3.2 Hz, 6H), 3.37 (s, 3H), 3.34
(m, 4H), 3.32 (d, J = 1.7 Hz, 3H), 3.30–3.27 (m, 4H), 3.26 (s, 4H), 3.32 (s, 3H), 3.32 (s, 3H), 3.30 (d, J = 3.8 Hz, 1H), 3.28
(d, J = 5.3 Hz, 3H), 3.25 (s, 3H), 3.24–3.20 (m, 5H), 2.91 (dd, (s, 5H), 3.27 (d, J = 2.2 Hz, 5H), 3.26–3.20 (m, 3H), 3.07 (t, J =
J = 9.8, 3.4 Hz, 1H). 13C NMR (150 MHz, DMSO-d6) d 144.74, 9.4 Hz, 2H), 2.97 (dd, J = 9.7, 3.5 Hz, 1H), 2.83–2.63 (m, 5H).
144.50, 125.41, 125.03, 104.29, 89.52, 84.39, 83.97, 83.06, 81.14 13C NMR (150 MHz, DMSO-d6) d 172.59, 172.01, 103.16, 88.53,
(double intensity), 81.09, 81.07, 80.49, 79.41, 78.47, 73.04, 84.31, 84.17, 82.53, 81.00, 80.32, 79.74, 79.62, 79.42, 79.33,
69.57, 69.33, 68.63, 64.64, 63.90, 60.39, 60.25, 60.06, 59.93, 79.18, 73.63, 70.69, 62.22, 61.36, 59.98, 59.93, 59.71, 59.66,
59.07, 58.69, 58.40, 58.38, 57.57, 57.36, 53.24, 50.32. HR-MS 58.77, 57.84, 57.76, 57.68, 56.91, 56.84, 51.18, 50.72, 50.03,
ESI (m/z): calc. for [M(C34H58O15N6) + Na+]: 813.3858, found: 48.82. HR-MS ESI (m/z): calc. for [M(C32H58O17N2) + H+]:
813.3832. Anal.: calc. for M(C34H58O15N6) + H2O: C, 50.49; 743.3774, found: 743.3799. Anal.: calc. for M(C32H58O17N2) +
H, 7.48; N, 10.39, found: C, 50.32; H, 7.40; N 10.16. [a]D = +29.7. H2O: C, 50.52; H, 7.95; O, 37.85; N, 3.68, found: C, 50.67;
Macrocyclic host 5. Following the general procedure A the H, 7.88; N, 3.66. [a]D = +50.4.
crude product was purified by flash chromatography (EA :
Macrocyclic host 17. Following the general procedure B
MeOH 9 : 1, v/v) to afford 5 (91 mg, 28%) as a white amorphous the crude product was purified by flash chromatography (EA :
foam. 1H NMR (600 MHz, DMSO-d6) d 8.06 (s, 1H), 7.74 MeOH, 9 : 1 v/v) to afford 17 (138.6 mg, 47%) as a white
(s, 1H), 4.90 (d, J = 13.0 Hz, 1H), 4.87 (d, J = 3.7 Hz, 1H), 4.71 amorphous foam. 1H NMR (600 MHz, acetone-d6) d 7.72 (s,
(dd, J = 14.7, 2.5 Hz, 1H), 4.50 (dd, J = 13.9, 5.4 Hz, 1H), 4.38 1H), 7.55 (s, 1H), 5.55 (d, J = 3.5 Hz, 1H), 4.02–3.94 (m, 2H),
(dd, J = 14.7, 3.3 Hz, 1H), 4.07 (dd, J = 11.5, 6.4 Hz, 1H), 3.92–3.87 (m, 2H), 3.66 (d, J = 11.1 Hz, 1H), 3.61–3.55 (m, 2H),
4.04–3.95 (m, 5H), 3.93–3.83 (m, 4H), 3.94–3.82 (m, 4H), 3.62–3.59 3.53 (s, 1H), 3.52 (s, 3H), 3.50 (s, 3H), 3.48 (s, 3H), 3.47 (s, 3H),
(m, 1H), 3.51 (s, J = 7.6 Hz, 2H), 3.50–3.47 (m, 4H), 3.43 (s, 3H), 3.41 3.46 (d, J = 3.7 Hz, 1H), 3.45 (s, 3H), 3.44 (s, 5H), 3.42 (d, J =
(s, 3H), 3.40–3.37 (m, 2H), 3.30 (s, 3H), 3.28 (s, 3H), 3.24–3.17 9.1 Hz, 3H), 3.40 (d, J = 1.9 Hz, 4H), 3.40 (s, 3H), 3.39 (s, 4H),
(m, 2H), 2.75 (dd, J = 9.8, 3.8 Hz, 1H), 1.35 (s, 3H), 1.32 (s, 3H), 1.29 3.37 (dd, J = 6.3, 2.9 Hz, 2H), 3.33 (dd, J = 15.2, 5.1 Hz, 3H), 3.21
(s, 3H), 1.23 (s, 3H). 13C NMR (150 MHz, DMSO-d6) d 145.10, (d, J = 16.1 Hz, 2H), 3.08 (dd, J = 9.6, 3.6 Hz, 2H), 2.98 (dd, J =
126.15, 125.78, 108.72, 108.57, 104.21, 88.88, 84.55, 83.17, 83.07, 11.3, 7.6 Hz, 4H), 2.70 (dd, J = 12.0, 8.0 Hz, 1H). 13C NMR
80.50, 78.70, 78.55, 77.90, 77.68, 76.43, 75.92, 74.43, 69.09, 65.89, (150 MHz, acetone-d6) d 170.48, 170.40, 104.48, 89.47, 85.62,
65.50, 65.46, 65.25, 60.46, 60.19, 59.27, 58.47, 58.42, 58.06, 51.73, 85.00, 83.21, 81.91, 81.28, 81.20, 80.91, 80.25, 80.10, 79.17,
49.38, 26.62, 25.69, 25.06, 21.19, 14.52. HR-MS ESI (m/z): calc. for 73.57, 70.25, 59.85, 59.77, 59.75, 59.59, 58.52, 57.86, 57.54,
[M(C36H58O15N6) + Na+]: 837.3858, found: 837.3826. Anal.: calc. for 57.50, 56.43, 56.35, 52.39, 52.01, 51.77, 50.19, 37.02, 36.84.
M(C36H58O15N6) + H2O: C, 51.91; H, 7.26; N, 10.09, found: C, 52.07; MS HR-MS ESI (m/z): calc. for [M(C32H60O15N4)
H, 7.24; N, 9.91. [a]D = +33.9. 741.4133, found: 741.4142. Elemental analysis indicated that
+
H+]:
Macrocyclic host 12. Following the general procedure A the 17 formed a strong complex with methylene chloride: anal:
crude product was purified by flash chromatography (EA : calc. for M(C32H60O15N4) + CH2Cl2: C, 48.00; H, 7.57; N, 6.78,
MeOH 9 : 1, v/v) to afford 12 (83 mg, 23%) as a white amorphous found: C, 47.86; H, 7.57; N, 6.64. [a]20 = +23.1.
foam. 1H NMR (600 MHz, DMSO-d6) d 8.07 (s, 1H), 8.06 (s, 1H),
5.48–5.45 (m, 1H), 5.44 (d, J = 7.5 Hz, 2H), 5.42 (s, 2H), 5.39
(d, J = 3.5 Hz, 1H), 4.71 (dd, J = 12.2, 1.9 Hz, 1H), 4.67 (dd, J =
Conflicts of interest
12.1, 2.0 Hz, 1H), 4.62 (t, J = 9.9 Hz, 2H), 4.54 (d, J = 12.0 Hz,
2H), 4.48 (d, J = 12.3 Hz, 1H), 3.90 (ddd, J = 16.9, 10.6, 5.8 Hz,
There are no conflicts to declare.
4H), 3.83–3.68 (m, 6H), 3.65–3.56 (m, 4H), 3.44 (s, 3H), 3.39
(s, 3H), 3.38 (s, 3H), 3.32 (s, 3H), 3.36–3.28 (m, 3H), 3.28–3.22 Acknowledgements
(m, 6H), 3.23–3.18 (m, 9H), 3.16 (s, 3H), 3.09–3.06 (m, 1H),
The support from the Grant OPUS of the National Science
3.04–2.97 (m, 3H). 13C NMR (150 MHz, DMSO-d6) d 167.22,
Centre UMO-2012/05/B/ST5/00377 is acknowledged. KD thanks
167.09, 144.57, 144.43, 125.65, 125.57, 103.93, 88.75, 84.53,
the National Science Centre (UMO-2016/23/D/ST5/03301) for
83.63, 83.10, 81.24, 79.39, 79.09, 78.92, 78.74, 78.59, 73.85,
71.56, 70.44, 69.29, 64.18, 63.99, 62.85, 62.66, 60.30, 60.26,
financial support.
60.23, 60.18, 60.14, 59.20, 58.25, 58.08, 57.05, 51.09, 50.98, 21.19,
14.52. HR-MS ESI (m/z): calc. for [M(C38H62O19N6) + Na+]: 929.3967,
found: 929.3950. Anal.: calc. for M(C38H62O16N6) + H2O: C, 49.35;
Notes and references
H, 6.97; N, 9.09, found: C, 49.38; H, 7.02; N, 8.82. [a]D = +56.0.
Macrocyclic host 16. Following the general procedure B the
crude product was purified by flash chromatography (CH2Cl2 :
MeOH, 9 : 1 v/v) to afford 16 (81 mg, 27%) as a white amorphous
1 (a) J. Xie and N. Bogliotti, Chem. Rev., 2014, 114, 7678–7739;
(b) M. A. Potopnyk and S. Jarosz, Adv. Carbohydr. Chem.
Biochem., 2014, 71, 227–295.
2 (a) S. Jarosz and A. Listkowski, Curr. Org. Chem., 2006, 10,
643–662; (b) P. Bako, G. Keglevich, Z. Rapi and L. Toke, Curr.
Org. Chem., 2012, 16, 297–304.
1
foam. H NMR (600 MHz, DMSO-d6) d 5.29 (d, J = 3.4 Hz, 1H),
4.42–4.38 (m, 2H), 3.90 (dd, J = 12.1, 4.4 Hz, 1H), 3.86 (dd, J =
12.2, 5.3 Hz, 1H), 3.82 (d, J = 7.3 Hz, 1H), 3.71 (dd, J = 9.7,
5.2 Hz, 2H), 3.67–3.63 (m, 1H), 3.47–3.43 (m, 2H), 3.41 (s, 4H),
3 (a) For selected examples, see: M. Pietraszkiewicz and
J. Jurczak, J. Chem. Soc., Chem. Commun., 1983, 132–133;
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NJC
(b) M. Pietraszkiewicz and J. Jurczak, Tetrahedron, 1984, 40,
Paper
8 B. Lewandowski and S. Jarosz, Org. Lett., 2010, 12, 2532–2535.
9 K. Ł˛eczycka-Wilk, K. Dabrowa, P. Cmoch and S. Jarosz, Org.
Lett., 2017, 19, 4596–4599.
2967–2970; (c) M. Menand, J.-C. Blais, J.-M. Valery and J. Xie,
J. Org. Chem., 2006, 71, 3295–3298; (d) D. Doyle and
P. V. Murphy, Carbohydr. Res., 2008, 343, 2535–2544; 10 K. Ł˛eczycka and S. Jarosz, Tetrahedron, 2015, 71, 9216–9222.
(e) V. K. Tiwari, A. Kumar and R. R. Schmidt, Eur. J. Org. 11 N. D. Sachinvala, W. P. Niemczura and M. H. Litt, Carbohydr.
Chem., 2012, 2945–2956; ( f ) J. M. Swarbrick, R. Graeff,
C. Garnham, M. P. Thomas, A. Galione and B. V. L. Potter, 12 C. Chen, R. L. Whistler and J. R. Daniel, Carbohydr. Res.,
Chem. Commun., 2014, 50, 2458–2461; (g) S. N. Das, R. Rana, 1983, 117, 318–321.
S. Chatterjee, G. S. Kumar and S. B. Mandal, J. Org. Chem., 13 A. I. Mohammed, Z. H. Abboud and A. H. O. Alghanimi,
2014, 79, 9958–9969. Tetrahedron Lett., 2012, 53, 5081–5083.
4 For selected examples, see ref. 1 and 2; recent examples: 14 M. Mancera, I. Roffe, M. Rivas and J. A. Galbis, Carbohydr. Res.,
(a) L. Ying and J. Gervay-Hague, Carbohydr. Res., 2003, 338, 1991, 338, 1115–1119.
835–841; (b) D. Rodriguez-Lucena, C. O. Mellet, C. Jaime, 15 (a) M. A. Potopnyk and S. Jarosz, Eur. J. Org. Chem., 2013,
Res., 1991, 218, 237–245.
´
K. K. Burusco, J. M. G. Fernandez and J. M. Benito, J. Org.
Chem., 2009, 74, 2997–3008; (c) M. Pintal, B. Kryczka,
5117–5126; (b) B. Lewandowski and S. Jarosz, Chem. Com-
mun., 2008, 6399–6401; (c) M. A. Potopnyk, B. Lewandowski
and S. Jarosz, Tetrahedron: Asymmetry, 2012, 23, 1474–1479.
´
A. Marsura and S. Porwanski, Carbohydr. Res., 2014, 386,
18–22; (d) G. C. Dashkan and N. Jayaraman, Chem. Com- 16 C. Frassineti, L. Alderighi, P. Gans, A. Sabatini, A. Vacca and
mun., 2014, 50, 8554–8557. S. Ghelli, Anal. Bioanal. Chem., 2003, 376, 1041–1052.
5 For the review, see: S. Jarosz; M. A. Potopnyk and 17 (a) F. Ulatowski, K. D˛abrowa, T. Bałakier and J. Jurczak,
M. Kowalski, Carbohydrate Chemistry-Chemical and Biologi-
cal Approaches, RSC publication, 2014, vol. 40, pp. 236–256.
J. Org. Chem., 2016, 81, 1746–1756; (b) D. Brynn Hibbert and
P. Thordarson, Chem. Commun., 2016, 52, 12792–12805.
6 (a) M. A. Potopnyk and S. Jarosz, Eur. J. Org. Chem., 2013, 18 Spartan’16 Parrallel Suite, Wavefunction, Inc. Irvine.
5117–5126; (b) B. Lewandowski and S. Jarosz, Chem. Com- 19 S. Grimme, J. Antony, S. Ehrlich and H. Krieg, J. Chem. Phys.,
mun., 2008, 6399–6401; (c) M. A. Potopnyk, B. Lewandowski
2010, 132, 154104.
and S. Jarosz, Tetrahedron: Asymmetry, 2012, 23, 1474–1479. 20 (a) K. Dabrowa, P. Niedbala and J. Jurczak, Chem. Commun.,
7 M. A. Potopnyk, P. Cmoch and S. Jarosz, Org. Lett., 2012, 14,
4258–4261.
2014, 50, 15748–15751; (b) K. D˛abrowa, P. Niedbała and
J. Jurczak, J. Org. Chem., 2016, 81, 3576–3584.
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