1,6-Dideoxy-D-mannitol-based 20-crown-6 ethers: Synthesis and influence of the substituents upon complexing properties toward phenylglycinium methyl esters

Article abstract of DOI:10.1039/a804873h

Ten novel homotopic 20-crown-6-ethers have been prepared from 1,3:4,6-di-O-benzylidene-D-mannitol. Substituents could be introduced on the alditol framework after the macrocyclisation in order to modify their complexing abilities. In one case, a low but significant enantiomeric excess (32% ee) in favour of L(S)-phenylglycine methyl ester could be ascertained when two bulky vic-triazole substituents were associated into the vicinity of the cavity. The formation of an adjacent trans-fused ring on C-3/C-4 of the mannitol framework mediated the complexing abilities of these macrocycles toward-2-phenylglycine methyl ester perchlorates.

Full text of DOI:10.1039/a804873h

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1,6-Dideoxy-D-mannitol-based 20-crown-6 ethers: synthesis and
influence of the substituents upon complexing properties toward
phenylglycinium methyl esters
Mostafa Nazhaoui,a Jean-Pierre Joly,*a Saïd Kitaneb and Mohamed Berradac
a Groupe SUCRES, UMR CNRS 7565, Université Henri Poincaré-Nancy I, Case Officielle 79,
BP 239, F-54506 Vandœuvre-lès-Nancy, France; e-mail: joly@meseb.u-nancy.fr
b Ecole Nationale de l’Industrie Minérale, BP 753, Agdal, Rabat, Maroc
c Faculté des Sciences Ben M’Sik, Université Hassan II, Casablanca, Maroc
Received (in Cambridge) 26th June 1998, Accepted 28th September 1998
Ten novel homotopic 20-crown-6-ethers have been prepared from 1,3:4,6-di-O-benzylidene--mannitol. Substituents
could be introduced on the alditol framework after the macrocyclisation in order to modify their complexing abilities.
In one case, a low but significant enantiomeric excess (32% ee) in favour of (S)-phenylglycine methyl ester could be
ascertained when two bulky vic-triazole substituents were associated into the vicinity of the cavity. The formation of
an adjacent trans-fused ring on C-3/C-4 of the mannitol framework mediated the complexing abilities of these
macrocycles toward 2-phenylglycine methyl ester perchlorates.
Apart from macrocycles 4, but only to a small extent, these
homotopic hosts did not extract enantiomers of racemic phenyl-
glycinium methyl ester (our standard-guest) from molar lithium
perchlorate in deuterium oxide into deuterochloroform. This
Introduction
In a recent paper1 we reported the synthesis of several C2-
symmetric macrocycles prepared from technical -mannitol.
All these crown ethers were built from a common C2-symmetric
chiral 1,3-dioxepane scaffold obtained by methylenation of
absence of extraction of the 2-phenylglycinium methyl ester
perchlorates was also established for the corresponding [20-6]-
1,3(R):4,6(R)-di-O-benzylidene--mannitol under basic condi-
macrocycle 7 incorporating a flexible 2,2Ј-biphenyl moiety in
tions. The regioselective opening of this nicely crystalline trans-
the cavity. This rather surprising lack of interaction with salts
of primary amino acid derivatives should be connected with the
rigidity of the 1,3-dioxepane framework which presumably
adopts a stable twist–chair (TC) conformation in solution. We
fused tricyclic acetal, either with N-bromosuccinimide (NBS)
under free-radical conditions2 or by reductive cleavage with
sodium cyanoborohydride (NaBH3CN) in acidic medium,3 led,
after bis-O-alkylation and cyclisation with dihydroxyaromatics,
concluded that this thermodynamically favoured TC conform-
to macrocycles 1–5 with various functionalities on C-1/C-6
ation, which could be confirmed in the solid state for two
(e.g., H, N3, triazole, OBn) of the 1,6-dideoxy--mannitol, or to
macrocycles 6 and 7 with different aromatic moieties.
derivatives, hinders the rotation around the C-3/C-4 axis neces-
sary to create a regular co-ordination polyhedron into the vicin-
ity of the ammonium cation. To ascertain this hypothesis, we
decided to synthesise less rigid structures from 1,3(R):4,6(R)-
R
O
di-O-benzylidene--mannitol. In this paper, which is the
eleventh from our laboratory in the field,2,4 we present the
O
O
O
O
O
O
results of this work whose aim was the development of acid-
stable hosts for enantiospecific complexation of primary
ammonium cations.
O
R
Results and discussion
2,5-O-Methylene-D-mannitol crown ethers 1–5
Synthesis
N
1 R = H
2 R = N3
5 R = OBn
3, 4 R =
3 R' = CO2Me
4 R' = Ph
N
N
The synthesis of the first crown ether 10 in this series pro-
ceeded as outlined in Scheme 1. The easily obtainable 1,3(R):
4,6(R)-di-O-benzylidene--mannitol 8 was converted into the
half-crown 9, which was first cyclised to the crown ether 10 by
standard chemistry.4a
As the previously mentioned trans-fused tricyclic acetal, the
C2-symmetric chiral 20-crown-6-ether 10 was treated with NBS
(2.2 mol equiv.) under free-radical conditions. After 1 h at
reflux, TLC (n-hexane–ethyl acetate, 1:1) of the resulting
crude solution showed two main products (Rf 0.67 and 0.58
respectively) besides unchanged starting material. The follow-
ing asymmetric structures A and B (Scheme 2) are in fair
agreement with the 1H NMR and electron-impact mass
(EI-MS) spectra of the two main products isolated from the
reaction mixture by conventional chromatography.
R'
R'
N3
O
O
O
O
O
Ar
O
O
O
N3
2,5-O-Methylene-D-mannitol crown ethers 6 and 7
6 Ar =
7 Ar =
J. Chem. Soc., Perkin Trans. 1, 1998, 3845–3850
3845

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Ph
Ph
O
O
Ph
O
Ph
O
O
O
O
O
O
O
O
O
Cl
Cl
O
O
OH
OH
O
O
i
O
O
O
O
i
9
Ph
Ph
O
O
Ph
O
12
Di-O-benzylidene-D-mannitol 8
9
ii
ii
Br
O
O
O
BzO
O
O
O
O
O
O
O
O
O
O
BzO
O
Ph
O
Br
13
10
Scheme 4 Synthesis of the symmetric crown ethers 12 and 13 from
dichloride 9. Reagents: i, pyrocatechol, M2CO3 (M = K or Cs), BunOH
or CsF, MeCN; ii, NBS, Bz2O2, hν, CCl4, CaCO3.
Scheme 1 Synthesis of crown ether 10 from 1,3(R):4,6(R)-di-O-
benzylidene--mannitol 8. Reagents: i, (ClCH2CH2)2O, aq. NaOH; ii,
2,3-dihydroxynaphthalene, Cs2CO3, BunOH.
The 1,6-dibromo-1,6-dideoxy--mannitol derivative 13 was
isolated in only 36% after tedious purification. This rather poor
result may be attributed mainly to the high polarity of this
macrocycle towards the stationary phase (kieselgel). The two
bromine atoms could then be easily displaced by sodium azide
in DMF at 100 ЊC to give the diazide 14 in almost quantitative
yield (Scheme 5).
Br
O
Br
BzO
O
i
O
O
10
O
BzO
O
Br
N3
A (~40%)
O
+
BzO
O
O
O
i
Ph
O
13
O
O
Br
O
BzO
O
O
O
ii
O
O
N3
O
BzO
O
14
N
Br
O
B (~20%)
O
O
BzO
O
O
O
O
Scheme 2 Synthesis of A and B from crown ether 10. Reagents:
i, NBS, Bz2O2, hν, CCl4, CaCO3.
BzO
O
In order to obviate this difficulty and to obtain true homo-
topic hosts, we synthesised a macrocycle without an aromatic
moiety, from the diol 8 and tetraethylene glycol ditosylate
readily obtainable in the laboratory (Scheme 3).5
N
O
15
Ph
O
Scheme 5 Synthesis of crown ethers 14 and 15 from crown 13.
Reagents: i, NaN3, NH4Cl, DMF; ii, K-phthalimide, DMF.
O
O
O
O
O
O
i
O
8
Alternatively, the two bromine atoms could be displaced by
potassium phthalimide in the same solvent to give the
corresponding bis-phthalimide 15 in 30% yield. The first
step of this Gabriel synthesis was not optimised. From
the diazide 14, the C2-symmetric triazoles 16, 17 and 18
could be isolated after cyclisation with an excess of neat
diphenylacetylene, followed by saponification and acetylation
(Scheme 6).
Ph
O
11
Scheme 3 Synthesis of the 17-crown-5 11 from 1,3(R):4,6(R)-di-O-
benzylidene--mannitol 8. Reagents: i, NaH, tetraethylene glycol
ditosylate, DMF.
The trans-fused polycyclic crown ethers 19 and 20 were syn-
thesised to check the influence of conformational restriction on
complexation behaviour of the macrocycles (Schemes 7 and 8).
The last two syntheses were not optimised but afforded suf-
ficient amounts of purified macrocycles to allow us to check
their extraction behaviour toward /-phenylglycinium methyl
esters by monoplate partitioning.
Because of the poor yield of this reaction (~30%) and the
very poor complexing properties of the 17-crown-5 11, we tried
to optimise the cyclisation step of the dichloride 9 with pyro-
catechol under different conditions (solvent and base) (see
Scheme 4). The best yield (56%) was measured with caesium
fluoride as base6 in acetonitrile.
3846
J. Chem. Soc., Perkin Trans. 1, 1998, 3845–3850

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Table 1 Extraction data of the enantiomers of phenylglycine methyl ester perchlorate as guests by crown ethers 10–20 in CDCl3 at 273 K
Crown ether
(as host)
R (G/H)
(quotient of guest to host)
CRF
∆δ Hb
(Chiral Recognition Factor)
(ppm) = Hb Ϫ Hb
10
11
12
13
14
15
16
17
18
19
20
1.0
nmb
0.9
1.2
1.1
1.0
0.8
0.5
1.20 ()a
ϩ0.20
b
1.50 ()
1.30 ()
1.35 ()
1.30 ()
1.95 ()
1.20 ()
ϩ0.16
ϩ0.33
ϩ0.26
ϩ0.33
ϩ0.37
0c
0.55
1.85 ()
ϩ0.31
b
b
0.5
1.60 ()
ϩ0.19
a The prominent enantiomer is in parentheses. b nm = non-measurable (~0). c Superimposed.
Ph
estimate the enantiomeric excess (ee) directly in the organic
layer, but analytical HPLC with an appropriate chiral column is
perhaps the best method especially for measuring high or low
ee-values.8 When complexation occurred, R was the molar quo-
tient of guest to host in the organic phase, CRF (for Chiral
Recognition Factor) the ratio of the pre-eminent enantiomer to
the less complexed enantiomer in the organic phase, and ∆δ the
chemical-shift difference in ppm between the diastereotopic
benzylic protons of the guest.7 Our results for the extraction
of aq. racemic phenylglycine methyl ester perchlorate (see
Experimental section and ref. 1) by eleven chiral homotopic
hosts dissolved in CDCl3 at 273 K are summarised in Table 1.
Apart from host 11, which is a 17-crown-5 without any
measurable affinity in the test, most of the 20-crown-6 com-
pounds described here were able to extract the phenylglycinium
methyl esters perchlorates from D2O at 0 ЊC. The temperature
was decreased from ambient to slightly improve chiral recog-
nition.9 Complexation produced marked chemical shifts and
Ph
N
N
N
N
O
O
RO
O
O
i
O
O
14
RO
N
N
16 R = Bz
17 R = H
18 R = Ac
ii
Ph
Ph
iii
Scheme 6 Synthesis of crown ethers 16, 17 and 18 from diazide 14,
Reagents: i, diphenylacetylene; ii, MeONa, MeOH; iii, Ac2O, Pyr.
N3
O
1
O
O
O
O
multiplicity changes of H NMR spectral bands of both host
O
O
i
and guest, the more obvious one being the splitting of the benz-
ylic proton of phenylglycine into two well separated singlets
(see last column, Table 1) which allowed the estimation of
CRF.4f High extraction (~1:1) ratios were related with lower
enantioselectivity (hosts 10, 12, 13, 14 and 15). We observed
that the introduction of a phthalimide moiety on C-1 and C-6
of -mannitol in compound 15 reversed the enantioselectivity
from - and -phenylglycine methyl ester. In compounds 16, 17
and 18, the best result was observed with the largest substitu-
ents (benzoate) on C-3 and C-4. From this point of view, it
might be worth noting that another co-ordination site on C-3/
C-4 as a second binding site endowed with a different selectivity
could induce positive or negative allosteric co-operation.10 The
formation of an adjacent trans-fused ring on C-3/C-4 of the
mannitol framework dramatically reduced the complexing abil-
ities of the macrocycle 19, even with small azide functions on
C-1/C-6. We believe that this behaviour is likely to be relevant to
those of the previously described 2,5-O-methylene--mannitol
trans-fused crown ethers.1 However, the trans-fused dioxane
moiety restored the extraction capacity of macrocycle 20 with
a medium enantioselectivity (CRF20 > CRF17). A solid-state
structure of compound 20 would need to be ascertained for us
to understand the origin of this difference.
14
O
N3
19
Scheme 7 Synthesis of crown ether 19 from compound 14. Reagents:
i, CH2Br2, NBu4HSO4, 50% aq. NaOH.
Ph
Ph
N
N
N
O
O
O
O
O
i
16
O
O
O
N
N
N
Ph
20
Ph
Scheme 8 Synthesis of crown ether 20 from compound 16. Reagents:
i, ClCH2CH2Cl, NBu4HSO4, 50% aq. NaOH.
Conclusions
Extraction experiments of phenylglycinium methyl ester
perchlorates from LiClO4 M (D2O) to CDCl3 at 273 K
Homotopic 20-crown-6 ethers were successfully synthesised
from -mannitol and tested under conditions of monoplate
partitioning near 0 ЊC with phenylglycinium methyl esters as
guests. These hosts displayed much higher extraction capacities
than did former [18-6] derivatives incorporating a chiral 1,3-
dioxepane framework.1 The enantioselectivity (CRF) of these
new [20-6] macrocycles seemed to be more dependent on the
nature of the substituents on C-3 and C-4 than those on C-1
Liquid–liquid extraction, also called monoplate partitioning,
provides one of the fastest methods to evaluate the ability of
an optically pure host to distinguish between enantiomers as
guests. The guest salt is dissolved in the aqueous buffered phase
first as a pure enantiomer and then as a racemic mixture.7 A
1
spectroscopic method (most often H NMR) may be used to
J. Chem. Soc., Perkin Trans. 1, 1998, 3845–3850
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and C-6. In the extreme, the formation of a methylene acetal
between C-3 and C-4 completely froze the -mannitol frame-
work and also the trans-fused cavity, which lost its complexing
behaviour. At least enantioselectivities were in the range of
values actually found in the literature for especially designed
receptors.11 Further investigations with these macrocycles
and related structures will be undertaken under HPLC
conditions in order to evaluate their enantiomeric recognition
of un-derivatised amino acids at various pH-values.4d,4e
solved in a mixture of CH2Cl2 (50 cm3) and water (30 cm3). The
aqueous phase was extracted twice with CH2Cl2 (30 cm3), and
the organic phases were combined, washed with water (5 cm3),
dried over MgSO4, and concentrated under reduced pressure.
Chromatography with hexane–AcOEt (7:3) yielded the crown
ether 10 (0.760 g, 49%) as a solid, mp 78–80 ЊC; [α]D 71.7 (c 1.6,
CHCl3); m/z 658 (Mϩ); δH(250 MHz; CDCl3) 3.64–4.17 (16 H,
m, 6 × OCH2, 2-, 5-H, 1-, 6-Ha), 4.21 (2 H, d, J2,3 9, 3-, 4-H),
4.28–4.36 (4 H, m, 2 × OCH2), 4.45 (2 H, dd, J1e,1a 10, J1e,2 5,
1-, 6-He), 5.54 (2 H, s, 2 × OCHPhO), 7.19 (2 H, s, 1-, 4-H
naphth.), 7.31–7.40 (8 H, m, 6 × ArH, 6-, 7-H naphth.), 7.50
(m, 4 H, ArH) and 7.69 (2 H, m, 8-, 5-H naphth.).
Experimental
Preparative chromatography was performed on kieselgel from
E. Merck, particle size 0.040–0.063 mm (230–400 mesh). Mps
were determined on a Büchi apparatus in capillary tubes and
are uncorrected; optical rotations were measured on a Perkin-
Elmer 141 automatic polarimeter in a 1 dm cell at room temp.;
[α]D-values are given in units of 10Ϫ1 deg cm2 gϪ1. IR spectra
were recorded on a Perkin-Elmer 1000 spectrometer at room
temp. Mass spectra were recorded on a Nermag R1010 instru-
ment at 70 eV unless otherwise stated. Enantioselectivity in the
complexation of the enantiomers of phenylglycine methyl
esters by crown ethers was estimated with the help of 250 MHz
1H NMR spectroscopy (Bruker AC 250). For this purpose, the
crown ether (~50 µM) was dissolved in 1.0 cm3 of CDCl3 and
shaken for 1 min with 1.0 cm3 of 1 M LiClO4 in D2O containing
4 mol equiv. of racemic phenylglycine methyl ester hydro-
chloride at 0 ЊC. The mixture was allowed to settle for 30 min in
crushed ice and the organic layer was then carefully separated,
dried over anhydrous Na2SO4, filtered through a small cotton
1,3:4,6-Di-O-benzylidene-2,5-O-[oxybis(ethyleneoxyethyl]-D-
mannitol 11
To a solution of 1,3:4,5-di-O-benzylidene--mannitol 8 (3.58
g, 10 mmol) in abs. THF (125 cm3) under argon was added 60%
NaH (1.2 g, 1.5 mol equiv.) and the resulting mixture was mag-
netically stirred at room temp. until the solution turned white
(ca. 1 h). Tetraethylene glycol ditosylate [37860-51-8] (6.03 g,
1.2 mol equiv.) was added in small portions and the mixture was
stirred for 80 h under argon. The reaction was monitored by
TLC (hexane–AcOEt, 1:1; Rf 0.22) and stopped by dilution
with water (50 cm3). The solvents were evaporated off under
reduced pressure, and the residue was dissolved in CH2Cl2 (100
cm3) and washed with water (2 × 25 cm3). These aqueous
phases were re-extracted with CH2Cl2 (2 × 15 cm3). The organic
phases were combined, dried over MgSO4, and concentrated
under reduced pressure. Chromatography of the residue on
silica with CH2Cl2–EtOH (9:1) yielded the crown ether 11 (1.91
g, 37%) as a syrup; [α]D Ϫ30.1 (c 2.2, CHCl3); m/z 515
(M Ϫ H)ϩ; δH(400 MHz; CDCl3) 3.5–3.85 (18 H, m, 8 × OCH2,
1-, 6-Ha), 3.82–4.10 (2 H, m, 2-, 5-H), 4.21 (2 H, d, J3,4 8.8, 3-,
4-H), 4.41 (2 H, dd, J1e,2 5, J1e,1a 10.8, 1-, 6-He), 5.55 (2 H, s,
2 × OCHPhO), 7.33 (6 H, d, ArH) and 7.52 (4 H, d, ArH).
1
pad, and its H NMR spectrum was immediately recorded at
27 ЊC. The CRFs were estimated by comparison of integrals of
the separated benzylic protons of phenylglycine between δ 4.5
and 5.0. The molar ratio R of guest to host in the organic phase
was estimated by comparison of suitable expanded aromatic
signals. NMR J-values are given in Hz.
2,5-O-[Benzene-1,2-diylbis(oxyethyleneoxyethyl)]-1,3:4,6-di-
O-benzylidene-D-mannitol 12
1,3:4,6-Di-O-benzylidene-2,5-bis-O-[(2-chloroethoxy)ethyl]-D-
mannitol 9
The same procedure was used as described for compound 10
except that pyrocatechol was used instead of 2,3-dihydroxy-
naphthalene and the reaction time was 48 h. From 0.81 g (3 mol
equiv.) of catechol, 2.40 g (3 mol equiv.) of Cs2CO3, and 1.40 g
(2.45 mmol) of dichloride 9 was obtained 1.00 g (67%) of crown
ether 12 as a gum after chromatography on silica with n-
hexane–AcOEt (1:1), [α]D Ϫ47.3 (c 3.1, CHCl3); m/z 608 (M)ϩ;
δH(400 MHz; CDCl3) 3.61–3.71 [8 H, m, 2 × (OCH2 ϩ
OCHH), 2-, 5-H], 3.72–3.81 (2 H, m, 2 × OCHH), 3.85 (2 H,
dd, J1e,1a 11, J1e,2 4.5, 1-, 6-Ha), 3.87–3.98 (4 H, m, 2 × OCH2),
4.14–4.22 (6 H, m, 2 × OCH2, 3-, 4-H), 4.39 (2 H, dd, J1e,1a 11,
1-, 6-He), 5.46 (2 H, s, 2 × OCHPhO), 6.91 (4 H, br s, catechol
ring), 7.25–7.40 (6 H, m, ArH) and 7.48 (4 H, m, ArH).
To a vigorously cooled suspension of the diol 8 (7.16 g, 20.0
mmol) and Bu4NHSO4 (14.00 g, 2 mol equiv.) in bis-(2-chloro-
ethyl) ether (150 cm3) was added 50% aq. NaOH (150 cm3)
below 5 ЊC. The two-phase system was mechanically stirred for
16 h below 20 ЊC, the reaction being monitored by TLC with
hexane–AcOEt (2:3). The mixture was then diluted with both
ice-cooled water (500 cm3) and CH2Cl2 (400 cm3) and the
organic phase was isolated. The aqueous phase was extracted
twice with CH2Cl2 (150 cm3), and the organic phases were com-
bined, washed with water (2 × 75 cm3), dried over MgSO4, and
concentrated under reduced pressure to remove the solvents
and the excess of reagent. Rapid chromatography with hexane–
AcOEt (3:2) yielded the bis-chloride 9 (9.82 g, 86%) as a gum,
[α]D Ϫ30.9 (c 3.8, CHCl3); δH(250 MHz; CDCl3) 3.56–3.66
(10 H, m, 5 × OCH2), 3.67–3.74 (6 H, m, 2 × OCHHCl,
2 × OCHH, 2- and 5-H), 3.79 (2 H, dd, J1e,1a 10, 1-, 6-Ha),
3.84–3.96 (2 H, m, 2 × OCHHCl), 4.08 (2 H, d, J2,3 9, 3-, 4-H),
4.44 (2 H, dd, J1e,2 5, 1-, 6-He), 5.55 (2 H, s, OCHPhO),
7.31–7.42 (6 H, m, ArH) and 7.51 (4 H, m, ArH).
2,5-O-[Benzene-1,2-diylbis(oxyethyleneoxyethyl)]-3,4-di-
O-benzoyl-1,6-dibromo-1,6-dideoxy-D-mannitol 13
To a stirred solution of compound 12 (0.65 g, 1.07 mmol) in
anhydrous CCl4 (50 cm3) under argon were added successively
dried CaCO3 (235 mg, 2.2 mol equiv.), NBS (420 mg, 2.35 mol
equiv.) and a few crystals of Bz2O2. The resulting dispersion
was immediately heated to reflux by an incandescent 500 W
lamp for 30 min, cooled to 5 ЊC, and filtered through sintered
glass under a fume board. The remaining succinimide and cal-
cium salts were rinsed with CH2Cl2 (~50 cm3) and the combined
organic phases were washed successively with 0.2 M aq. Na2S2-
O5 (10 cm3), 5% aq. NaHCO3 (10 cm3) and water (10 cm3), dried
over MgSO4, and finally evaporated under reduced pressure.
The residue was chromatographed with n-hexane–AcOEt (4:1)
to yield the dibromide 13 (0.48 g, 59%) as a gum, [α]D ϩ34.0 (c
1.5, CHCl3); νmax(neat/NaCl)/cmϪ1 1724; δH(250 MHz; CDCl3)
1,3:4,6-Di-O-benzylidene-2,5-O-[naphthalene-2,3-diylbis-
(oxyethyleneoxyethyl)]-D-mannitol 10
A solution of 2,3-dihydroxynaphthalene (1.14 g, 3.0 mol equiv.)
in freshly distilled BunOH (30 cm3) was stirred for 20 min at
room temp. under argon. To this solution were added, first,
dried powdered Cs2CO3 (3.47 g, 4.5 mol equiv.) and then, after
the mixture had been heated to a gentle reflux, the half-crown 9
(1.35 g, 2.36 mmol). The resulting suspension was boiled for 40
h, allowed to cool to room temp., and the BunOH was evapor-
ated off under reduced pressure. The remaining solids were dis-
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3.48 (2 H, dd, Jgem 12, J1,2 6, 1-, 6-H), 3.72 (2 H, dd, J1Ј,2 3, 1-,
6-HЈ), 3.78–4.07 (14 H, m, 2-, 5-H, 6 × OCH2), 4.21 (4 H, m,
2 × CH2 near catechol ring), 5.69 (2 H, dd, J2,3 6.5, 3-, 4-H),
6.92 (4 H, br s, catechol ring), 7.32 (4 H, t, ArH), 7.49 (2 H, t,
ArH) and 7.92 (4 H, d, ArH).
being monitored by TLC with n-hexane–AcOEt (1:1). After 48
h, the reaction mixture being cooled to room temp., the DMF
was evaporated off in vacuo, and the residue was purified by
chromatography on silica with n-hexane–AcOEt (7:3) to yield
title compound 16 (0.357 g, 76%) as a solid; mp 103–105 ЊC;
[α]D ϩ38.1 (c 1.5, CHCl3); νmax(KBr)/cmϪ1 1724; m/z 1047 (M)ϩ;
δH(2D; 250 MHz; CDCl3) 3.28 (2 H, m, 2 × OCHH), 3.45–3.72
(6 H, m, 2 × OCH2, 2 × OCHH), 3.77 (4 H, br t, 2 × OCH2),
3.98–4.18 (4 H, m, 2 × OCH2), 4.23–4.40 (4 H, m, J1,2 ~8, 2-,
5-H, 1-, 6-HЈ), 4.53 (2 H, m, Jgem 10.5, 1-, 6-H), 5.49 (2 H, d,
J2,3 3.5, 3-, 4-H), 6.86 (4 H, m, catechol ring), 7.17–7.31 (20 H,
m, 4 × ArH ϩ 16 H Ph on triazole), 7.42–7.53 (6 H, m,
2 × ArH ϩ 4 H Ph on triazole) and 7.72 (4 H, d, ArH);
1,6-Diazido-2,5-O-[benzene-1,2-diylbis(oxyethyleneoxyethyl)]-
3,4-di-O-benzoyl-1,6-dideoxy-D-mannitol 14
To a solution of the dibromide 13 (0.35 g, 0.46 mmol) in DMF
(25 cm3) were added sodium azide (0.12 g, 4 mol equiv.) and
ammonium chloride (0.102 g, 4 mol equiv.). The resulting mix-
ture was stirred and heated to 100 ЊC for 12 h, the reaction
being monitored by TLC with n-hexane–AcOEt (1:1) since
diazide 14 produced a typical brownish colour after charring
with dil. sulfuric acid (H2SO4–MeOH, 1:1); the reaction prod-
uct was cooled to room temp., DMF was evaporated off in
vacuo, and the residue was dissolved in CH2Cl2 (50 cm3). The
solution was washed with distilled water (2 × 15 cm3), decanted,
dried over MgSO4, and purified by chromatography on silica
with n-hexane–AcOEt (3:1) to yield title compound 14 (0.300
g, 95%) as a homogeneous wax, [α]D ϩ57.3 (c 1.3, CHCl3);
νmax(NaCl)/cmϪ1 1724 and 2102; δH(250 MHz; CDCl3) 3.28
(2 H, dd, Jgem 13, J1,2 6, 1-, 6-H), 3.59 (2 H, dd, J1Ј,2 3, 1-, 6-HЈ),
3.76–4.06 (14 H, 6 × OCH2, 2-, 5-H), 4.22 (4 H, m, 2 × OCH2
near catechol ring), 5.66 (2 H, d, J2,3 6, 3-, 4-H), 6.73 (4 H, br s,
catechol ring), 7.32 (4 H, t, ArH), 7.5 (2 H, t, ArH) and 7.91
δ (62.896 MHz; CDCl ) 165.25 (2 × PhC᎐O), 148.96 (C-1, -2,
᎐
C
3
catechol ring), 143.98 (2 × C-1, triazole), 134.69 (2 × C1Ј,
triazole), 133.31 (2 × C-4, Ph), 130.21 (2 × C-2, -6, Ph), 129.74
(C-1, -1Ј, Ph), 129.57 (2 × C-3, -5, Ph), 129.41 (2 × C-4, Ph on
triazole), 129.09 (2 × C-2, -6, Ph on triazole), 128.56 (2 × C᎐C),
᎐
128.23 (2 × C-3, -5, -3Ј, -5Ј, Ph on triazole), 127.46 (2 × C-4Ј,
Ph on triazole), 127.39 (2 × C᎐C), 126.59 (2 × C-2Ј, -6Ј, Ph
᎐
on triazole), 121.51 (C-4, -5, catechol ring), 114.81 (C-3, -6,
catechol ring), 78.19 (C-2, -5), 70.99 (2 × OCH2), 70.57 (C-3,
-4), 70.36, 69.64 and 68.89 (6 × OCH2) and 48.99 (C-1, -6).
2,5-O-[Benzene-1,2-diylbis(oxyethyleneoxyethyl)]-1,6-dideoxy-
1,6-bis(4,5-diphenyl-1,2,3-triazol-1-yl)-D-mannitol 17
To a solution of dibenzoate 16 (110 mg, 0.105 mmol) in abs.
MeOH (25 cm3) was added MeONa (~5 mg, 0.5 mol equiv.) and
the mixture was magnetically stirred for 1 h at room temp.
under argon. The reaction, which was monitored by TLC
(n-hexane–AcOEt, 1:1), was stopped by addition of Amberlyst
15 resin (~300 mg). After 30 min of gentle stirring, the beads
were removed by filtration on sintered glass, rinsed with meth-
anol (~25 cm3), and the solvents were evaporated off under
reduced pressure. The residue was purified by elution through a
neutral alumina column (EtOH–CH2Cl2, 1:1; 75 cm3) to
yield the diol 17 (79 mg, 90%) as a waxy solid from which an
analytical sample could be obtained by preparative TLC (SiO2;
AcOEt); [α]D ϩ25.7 (c 0.6, CHCl3); m/z 838 (M)ϩ; δH(2D; 250
MHz; CDCl3) 1.27 (2 H, br s, 2 × OH), 3.16–3.28 (2 H, m,
2 × OCHH), 3.39–3.45 [m, 6 H, 2 × (OCH2, OCHH)], 3.63–
3.88 (6 H, m, 2 × OCH2, 3-, 4-H), 3.94–4.10 (4 H, m, 2-, 5-H,
2 × OCH2), 4.22 (2 H, dd, J1,1Ј 14, 1-, 6-HЈ), 4.58 (2 H, dd, J1,2 3,
1-, 6-H), 6.86 (4 H, m, catechol ring), 7.19–7.30 (6 H, m, Ph on
triazole), 7.31–7.48 (10 H, Ph on triazole) and 7.52 (4 H, dd, Ph
on trazole); δC(62.896 MHz; CDCl3) 148.86 (C-1, -2, catechol
ring), 144.08 (2 × C-1, Ph on triazole), 135.19 (2 × C-1Ј, Ph on
(4 H, d, ArH); δ (62.896 MHz; CDCl ) 165.54 (2 × PhC᎐O),
᎐
C
3
149.27 (C-1, -2 catechol ring), 133.47 (C-4, -4Ј, Ph), 129.76
(C-2, -2Ј, -6, 6Ј, Ph), 129.12 (C-1, -1Ј, Ph), 128.49 (C-3, -3Ј, -5,
-5Ј, Ph), 121.76 (C-4, -5, catechol ring), 115.11 (C-3, -6, catechol
ring), 78.80 (C-2, -5), 70.78 (2 × OCH2), 70.45 (C-3, -4), 70.34,
70.13 and 69.18 (6 × OCH2) and 50.71 (C-1, -6).
2,5-O-[Benzene-1,2-diylbis(oxyethyleneoxyethyl)]-3,4-di-O-
dibenzoyl-1,6-dideoxy-1,6-diphthalimido-D-mannitol 15
To a stirred solution of crown ether 13 (0.285 g, 0.37 mmol) in
abs. DMF (20 cm3) was added 0.206 g (1.37 mmol, 6 mol equiv.)
of potassium phthalimide and the reaction mixture was heated
immediately to 120 ЊC for 2.5 h, the reaction being monitored
by TLC with n-hexane–AcOEt (1:1). After the mixture had
cooled to room temp., the DMF was evaporated off in vacuo
and the residue was dissolved in CH2Cl2 (50 cm3). The solution
was washed with distilled water (3 × 15 cm3), decanted, dried
over MgSO4, and purified by chromatography on silica with
n-hexane–AcOEt (2:1) to yield title compound 15 (0.100 g,
30%) as a waxy solid; [α]D ϩ49.3 (c 1.4, CHCl3); νmax(NaCl)/
cmϪ1 1715; m/z 900 (M ϩ 2H)ϩ; δH(2D; 250 MHz; CDCl3)
3.57–3.71 (8 H, br t, 4 × OCH2), 3.76–3.87 (2 H, m,
2 × OCHH), 3.88–4.03 (6 H, m, 2 × OCHH, 2 × OCH2), 4.16
(2 H, Jgem 13.5, J1,2 4, 1-, 6-H), 4.28 (2 H, m, 2-, 5-H), 4.38 (2 H,
dd, J1Ј,2 6.5, 1-, 6-HЈ), 5.76 (2 H, s, 3-, 4-H), 6.78 (2 H, m,
catechol ring), 6.87 (2 H, m, catechol ring), 7.22 (4 H, m,
ArH), 7.38 (2 H, m, ArH), 7.63 (4 H, m, phthal.), 7.74 (4 H, m,
phthal.) and 7.83 (4 H, d, ArH); δC(62.896 MHz; CDCl3) 168.18
triazole), 131.01 (2 × C᎐C), 130.50 (2 × C-2, -6, Ph on triazole),
᎐
129.66 (2 × C-4, Ph on triazole), 129.27 (2 × C-3, -5, Ph on
triazole), 128.49 (2 × C-3Ј, -5Ј, Ph on triazole), 129.09 (2 × C-2,
-6, Ph on triazole), 127.85 (2 × C᎐C), 127.71 (2 × C-4Ј, Ph on
᎐
triazole), 126.88 (2 × C-2Ј, -6Ј, Ph on triazole), 121.92 (C-4, -5,
catechol ring), 115.00 (C-3, -6, catechol ring), 80.18 (C-2, -5),
70.64, 70.23 and 69.75 (6 × OCH2), 69.09 (C-3, -4), 68.81
(2 × OCH2) and 48.66 (C-1, -6).
(4 × NC᎐O), 165.87 (2 × PhC᎐O), 149.13 (C-1, -2, catechol
᎐
᎐
ring), 133.76 (C-4, -4Ј, Ph), 132.97 (C-4, -4Ј, -5, -5Ј, phthal.),
132.15 (C-1, -1Ј, -2, -2Ј, phthal.), 129.66 (C-2, -2Ј, -6, -6Ј, Ph),
129.38 (C-1, -1Ј, Ph), 128.15 (C-3, -3Ј, -5, -5Ј, Ph), 123.14 (C-3,
-3Ј, -6, -6Ј, phthal.), 121.52 (C-4, -5, catechol ring), 114.89 (C-3,
-6, catechol ring), 77.7 (C-2, -5), 71.03 (2 × OCH2), 70.75 (C-3,
-4), 69.87, 69.64 and 69.0 (6 × OCH2) and 30.38 (C-1, -6).
3,4-Di-O-acetyl-2,5-O-[benzene-1,2-diylbis(oxyethylene-
oxyethyl)]-1,6-dideoxy-1,6-bis(4,5-diphenyl-1,2,3-triazol-1-yl)-
D-mannitol 18
To a solution of the diol 17 (35 mg, 42 mm3) in abs. pyridine
(0.5 cm3) were added acetic anhydride (1.5 cm3) and 4-DMAP
(~1 mg) and the mixture was stirred at room temp. under argon
for 1 h. Usual work-up1 and chromatography on silica gel with
n-hexane–AcOEt (3:7) yielded diacetate 18 (40 mg, 95%) as a
homogeneous wax, mp < 50 ЊC; [α]D ϩ23.4 (c 0.6, CHCl3); m/z
922 (M)ϩ; δH(250 Hz; CDCl3) 2.01 (6 H, s, 2 × CH3), 3.12–
3.27 (2 H, m, 2 × OCHH), 3.4–3.62 [6 H, m, 2 × (OCH2 ϩ
OCHH)], 3.71 (4 H, t, 2 × OCH2), 4.0–4.12 (6 H, m, 2-, 5-H,
2 × OCH2), 4.22 (2 H, dd, J1,1Ј 14, 1Ј-, 6Ј-H), 4.43 (2 H, dd, J1,1Ј
2,5-O-[Benzene-1,2-diylbis(oxyethyleneoxyethyl)]-3,4-di-O-
benzoyl-1,6-dideoxy-1,6-bis(4,5-diphenyl-1,2,3-triazol-1-yl)-D-
mannitol 16
To a stirred solution of diphenylacetylene (0.81 g, 5 mol equiv.)
in CH2Cl2 (4 cm3) was added diazide 14 (0.31 g, 0.45 mmol) and
the reaction vessel was heated gradually to 120 ЊC, the reaction
J. Chem. Soc., Perkin Trans. 1, 1998, 3845–3850
3849

View Article Online
14, J1,2 4.5, 1-, 6-H), 5.13 (2 H, d, J2,3 4, 3-, 4-H), 6.85 (4 H, m,
catechol ring), 7.20–7.28 (6 H, m, Ph on triazole), 7.42 (10 H, br
s, Ph on triazole) and 7.53 (4 H, dd, Ph on triazole); δC(62.896
MHz; CDCl3) 169.77 (2 × COCH3), 149.02 (C-1, -2, catechol
ring), 144.12 (2 × C-1, Ph on triazole), 134.86 (2 × C-1Ј, Ph on
triazole), 7.44 (10 H, br s, Ph on triazole) and 7.53 (4 H, dd, Ph
on triazole); δC(62.896 MHz; CDCl3) 149.07 (C-1, -2, catechol
ring), 144.0 (2 × C-1, Ph on triazole), 135.06 (2 × C-1Ј, Ph on
triazole), 131.19 (2 × C᎐C), 130.54 (2 × C-2, -6, Ph on triazole),
᎐
129.61 (2 × C-4, Ph on triazole), 129.33 (2 × C-3, -5, Ph on
triazole), 130.87 (2 × C᎐C), 130.45 (2 × C-2, -6, Ph on triazole),
triazole), 128.48 (2 × C-3Ј, -5Ј, Ph on triazole), 127.86 (2 ×
᎐
129.64 (2 × C-4, Ph on triazole), 129.23 (2 × C-3, -5, Ph on
C᎐C), 127.66 (2 × C-4Ј, Ph on triazole), 126.86 (2 × C-2Ј, -6Ј,
᎐
triazole), 128.40 (2 × C-3Ј, -5Ј, Ph on triazole), 127.62 (2 ×
Ph on triazole), 121.74 (C-4, -5, catechol ring), 114.85 (C-3, -6,
catechol ring), 79.27 (C-2, -5), 76.28 (C-3, -4), 70.4 and 69.65
(8 × OCH2), 65.79 (2 × C, dioxane) and 48.76 (C-1, -6).
C-4Ј, Ph on triazole), 127.59 (2 × C᎐C), 126.72 (2 × C-2Ј, -6Ј,
᎐
Ph on triazole), 121.61 (C-4, -5, catechol ring), 114.85 (C-3, -6,
catechol ring), 78.25 (C-2, -5), 70.78 and 70.38 (4 × OCH2),
70.23 (C-3, -4), 69.69 and 68.98 (4 × OCH2), 48.78 (C-1, -6) and
20.62 (2 × CH3).
Acknowledgements
We thank Dr Nicolas Moitessier for critically reading the
original manuscript and making several useful remarks.
1,6-Diazido-2,5-O-[benzene-1,2-diylbis(oxyethyleneoxyethyl)]-
1,6-dideoxy-3,4-O-methylene-D-mannitol 19
References
To a solution of the diester 14 (100 mg, 0.145 mmol) in CH2Br2
(8 cm3) were added 50% aq. NaOH (6 cm3) and NBu4HSO4 (51
mg, 1 mol equiv.) and the reaction mixture was vigorously
stirred at room temp. for 12 h. Usual work-up1 and chrom-
atography on silica gel with n-hexane–AcOEt (3:1) yielded
unchanged starting material 14 (70 mg, 70% recovery) and then
title compound 19 (10 mg, 14%) as a homogeneous wax,
mp < 50 ЊC; [α]D ϩ2.1 (c 1.6, CHCl3); m/z 494 (M)ϩ; δH(250
MHz; CDCl3) 3.45 (2 H, m, J1,1Ј 13, J1,2 6.5, 1-, 6-H), 3.52–3.67
(4 H, m, 2-, 5-H, 1-, 6-HЈ), 3.71–3.80 (6 H, m, 2 × OCH2,
2 × OCHH), 3.81–4.01 (6 H, m, 2 × OCH2, 2 × OCHH), 4.07
(2 H, d, J2,3 5, 3-, 4-H), 4.18 (4 H, t, 2 × OCH2), 4.93 (2 H, s,
OCH2O) and 6.9 (4 H, s, catechol ring); δC(62.896 MHz;
CDCl3) 149.35 (C-1, -2, catechol ring), 121.84 (C-4, -5, catechol
ring), 114.47 (C-3, -6, catechol ring), 95.3 (OCH2O), 79.40 (C-2,
-5), 77.65 (C-3, -4) 70.81, 70.12 and 69.98 (6 × OCH2), 68.95
(2 × OCH2) and 50.68 (C-1, -6).
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2 × CH2 dioxane, 3-, 4-H), 4.05 (4 H, br t, 2 × OCH2), 4.18–
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Paper 8/04873H
3850
J. Chem. Soc., Perkin Trans. 1, 1998, 3845–3850