Chiral ditopic receptors. Application to palladium-catalyzed allylic alkylation

Article abstract of DOI:10.1016/j.tet.2003.10.005

Chiral pyridinooxazoline, quinolinooxazoline, bis(oxazolino)pyridine (pybox), and bisoxazoline (box) derivatives containing crown ether residues were prepared. Some of the ligands were assessed in substrate binding studies and in palladium catalyzed allylic alkylations.

Full text of DOI:10.1016/j.tet.2003.10.005

Tetrahedron 59 (2003) 9583–9589
Chiral ditopic receptors. Application to palladium-catalyzed
allylic alkylation
Jean Bourguignon,a Ulf Bremberg,b Georges Dupas,a Kristina Hallman,b Lars Hagberg,b
Laurent Hortala,a Vincent Levacher,a Serghey Lutsenko,b Emmanuel Macedo,b
a
b
Christina Moberg,b Guy Queguiner and Fredrik Rahm
,
*
´
a
´ ´
IRCOF, INSA, Laboratoire de Chimie Organique Fine et Heterocyclique, UMR 6014, BP 08, F 76131 Mt St Aignan, France
bDepartment of Chemistry, KTH, Organic Chemistry, SE 100 44 Stockholm, Sweden
Received 5 May 2003; revised 9 September 2003; accepted 2 October 2003
Abstract—Chiral pyridinooxazoline, quinolinooxazoline, bis(oxazolino)pyridine (pybox), and bisoxazoline (box) derivatives containing
crown ether residues were prepared. Some of the ligands were assessed in substrate binding studies and in palladium catalyzed allylic
alkylations.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
a multifunctional substrate,9 or selective transformation of
one particular substrate out of a mixture of substrates.10 We
have previously found that a dipyridylmethanol derivative
substituted with a crown ether ring exhibits selective
complexation of v-olefinic carboxylic acids, although no
chemical transformation using that system was demon-
strated.11
Ligands capable of simultaneously being involved in two
binding interactions are attracting current interest due to
their applications in various situations involving molecular
recognition.1 Bifunctional ligands may also have versatile
properties in stereoselective catalysis due to their ability to
be engaged in secondary interactions with the substrate
undergoing reaction. Such interactions may enhance the
reactivity as well as the selectivity of the catalytic system.2
Several Lewis acid–Lewis base bifunctional catalysts were
recently presented by Shibasaki et al.3 A ferrocene
derivative with planar chirality endowed with a crown
ether function was used in palladium-catalyzed allylic
alkylations by Ito et al.4 Higher enantioselectivity and
higher yield were observed with the bifunctional catalyst
than with one lacking the crown ether moiety, indicating
formation of a ternary complex. Similar ferrocenylphos-
phines with pendant crown ether moieties were also
designed for rhodium-catalyzed hydrogenations.5 Hydro-
genation employing rhodium complexes of ligands capable
of simultaneously coordinating to boron was also reported.6
Furthermore, a salen ligand with binding sites for titanium
and palladium was synthesized;7 another bimetallic com-
plex with the same ligand, containing titanium and rhodium,
was later employed in hydroformylations.8
In order to enable studies of the possibility to achieve
selective substrate binding as well as increased stereo-
selectivity and reactivity in catalytic reactions we needed
ligands containing a binding site with chelating nitrogen
donors and a crown ether moiety. Several crown ethers with
nitrogen binding sites have been reported,12 but since they
are achiral they did not serve our purpose. The preparation
of chiral nitrogen ligands with pendant crown ether rings is
described here together with preliminary binding studies of
v-carboxylic acid olefins and preliminary studies of the use
of some of the new compounds in palladium-catalyzed
allylic alkylations.
2. Results and discussion
2.1. Preparation of ligands
Ligands 1–6, having the oxazoline and crown ether rings as
common structural features, were selected as suitable
ditopic ligands. Pyridinooxazoline ligand 1 was obtained
by esterification of (40R)-2-(40,50-dihydro-40-phenyl-20-oxa-
zolyl)-6-(hydroxymethyl)pyridine13 (7) with 4-carboxy-
benzo-18-crown-6 (8) using 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (EDCI), and quinoline
Another possible application of this type of ligands consists
of the selective transformation of one functional group in
Keywords: chiral; ligand; ditopic; crown ether; oxazoline; copper;
palladium.
*
Corresponding author. Tel.: þ46-8-790-9036; fax: þ46-8-791-2333;
e-mail: kimo@kth.se
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.10.005

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J. Bourguignon et al. / Tetrahedron 59 (2003) 9583–9589
Chart 1.
derivative 2 by O-alkylation of (40R)-2-(40,50-dihydro-
40-phenyl-20-oxazolyl)-8-hydroxyquinoline13 (9) with
4-(chloromethyl)benzo-18-crown-6 (10).14 The synthesis
of pybox derivative 3 was achieved by O-alkylation of
chelidamic acid dimethyl ester (11) with 10 to give 12,
which was transformed to amide 13 using (R)-phenyl-
glycinol. Tosylation of the alcohol functions and final ring
closure gave 3. For the preparation of bisoxazoline 4 two
routes were considered. The first involved initial alkylation
of dimethyl methylmalonate with a protected 3-hydroxy-
benzyl halide followed by transformation of the ester groups
to oxazoline rings, whereas the second involved alkylation
of a preformed bisoxazoline with the phenolic compound.
The first route was recently employed for the preparation of
a polymer-bound bisoxazoline ligand.15 However, we found
the second route to be more convenient, affording the
product with the same yield but involving fewer reaction
steps. Thus, amide 14 was prepared from dimethyl
methylmalonate and (R)-phenylglycinol. This was followed
by cyclization of 14 to form bisoxazoline 15. Alkylation
of bisoxazoline 15 with allyl-protected 3-(bromomethyl)-
phenol 16 using butyl lithium as the base resulted in the
formation of alkylated bisoxazoline 17, which was depro-
tected using palladium acetate and triphenylphosphine in
ethanol to yield 18. Final esterification gave the desired
ligand 4. The C2-symmetric ligand 5, incorporating two
crown ether groups, was obtained from the known
bisoxazoline 1916 via esterification. Ligand 6 was obtained
by an analogous procedure starting from 20 (Chart 1 and
Scheme 1).17
2.2. Catalytic reactions
In order to study the effect of the presence of a crown ether
function on the selectivity and reactivity of the catalytic
system, ligand 1 was assessed in palladium-catalyzed
alkylations of rac-1,3-(E)-diphenyl-2-propenyl acetate
with the sodium salt of dimethyl malonate, prepared
employing sodium hydride, under a variety of different
reaction conditions using bis[(p-allyl)palladium chloride]
as the palladium source. The cation of the nucleophile
was assumed to be trapped by the crown ether, resulting
in close proximity of the nucleophile to the electro-
philic allylic group. In order to judge whether this would
affect the reactivity and selectivity of the catalytic reac-
tion, the results were compared to those obtained using
ligand 21 together with 1 equiv. of benzo-18-crown-6
(Scheme 2).

J. Bourguignon et al. / Tetrahedron 59 (2003) 9583–9589
9585
Scheme 1.
At low substrate concentration (0.024 M) in dichloro-
methane, slightly higher reactivity was observed for a
catalyst containing ligand 1 than for a catalyst with ligand
21 and 1 equiv. of benzo-18-crown-6 (reactivity ratio 2:1).
At higher substrate concentration (0.24 M) equal rates were
observed for the two catalytic systems. In THF, a 2.5:1 ratio
of the rates of reactions using ligands 1 and 21 (in the
Scheme 2.

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J. Bourguignon et al. / Tetrahedron 59 (2003) 9583–9589
absence of benzo-18-crown-6) was achieved at a substrate
concentration of 0.1 M, whereas equal rates were observed
at higher concentrations. The enantioselectivity was some-
what higher for reactions employing ligand 21 and benzo-
18-crown-6 than for those with ligand 1 (75 and 67%,
respectively). Comparison of ligands 6 and 22 in dichloro-
methane under slightly different conditions, where the
nucleophile was generated in situ using BSA/KOAc,
indicated no enhancement of selectivity or reactivity of
the crown ether-containing ligand.
crown ether analogue, and suggest that a Cu(I) olefin
complex was obtained only with the acid having a longer
alkyl chain (Fig. 1).11
3. Conclusions
Chiral bidentate or tridentate nitrogen ligands containing at
least one oxazoline ring as well as a crown ether residue,
thereby capable of coordinating two metal ions, were
prepared. The ligands were used in preliminary studies of
enantioselective palladium-catalyzed allylic alkylations and
substrate-selective binding of potassium salts of carboxylic
acids containing a terminal olefinic group.
4. Experimental
4.1. General
4-(Chloromethyl)benzo-18-crown-614 (10), chelidamic acid
dimethyl ester18 (11) and bisoxazoline 1916 were prepared
according to literature procedures. 3-Allyloxybenzyl bro-
mide (16) was synthesized according to a procedure
described for the 4-substituted isomer.19 Other chemicals
were purchased from Lancaster and used as received.
Solvents were distilled according to standard procedures.
Liquid chromatography was carried out using silica gel 60
(Merck 230–400 mesh). 1H NMR spectra were recorded at
400 or 300 MHz and 13C NMR spectra at 100.6 or
75.5 MHz in CDCl3 with the solvent as internal standard,
unless otherwise stated. HRMS spectra were recorded on a
spectrometer of EB geometry equipped with FAB and EI/CI
sources.
2.3. Binding studies
A copper(I) complex of 4 was synthesized by treating 4 with
1 equiv. of [Cu(MeCN)4]PF6 in methanol under argon.
When the resulting copper(I) complex was treated with the
1
potassium salt of 10-undecanoic acid, the H NMR signals
4.1.1. Ligand 1. Pyridinooxazoline 713 (40.5 mg, 0.159
mmol), 4-carboxybenzo-18-crown-6 (8, 58.5 mg, 0.159
mmol) and DMAP (2.6 mg, 0.021 mmol) were dissolved
in CH2Cl2 (0.5 mL). EDCI (35.2 mg, 0.180 mmol) was
added and the reaction mixture was stirred at room
temperature. After 6.5 h, additional CH2Cl2 (4 mL) was
added and the mixture was extracted with brine (5 mL),
0.2 M HCl (5 mL) and saturated aqueous Na2CO3 (5 mL).
The organic phase was dried (Na2SO4) and the solvent was
evaporated in vacuo to give ester 1 (75 mg, 80%) as a thick
oil. HRMS (FAB) calcd for C32H37N2O9 (MHþ), 593.2500.
Found, 593.2497; [a]2D0¼þ22.5 (c 1.17 in CH2Cl2); IR
of the olefinic protons shifted upfield indicating a complex
being formed. Preliminary investigations showed that the
same complex was not formed when the shorter 6-heptenoic
acid was used, which suggests a 1:1 complex being formed
with 10-undecanoic acid. Due to overlapping signals from
the olefinic and oxazoline ring protons, quantitative
determination of the binding could unfortunately not be
made. The chemical shift of the terminal olefinic protons in
CD3OD shifted gradually when increasing the concentration
of the olefin, from about d 4.72 for a 0.5:1:1 olefin/metal/
ligand mixture to d 5.49 for a 5:1:1 olefin/metal/ligand
mixture, whereas for analogous experiment with 6-hepte-
noic acid signals for the olefinic protons at about d 5.30 were
observed at all olefin/metal/ligand ratios. These results are
in accordance with those previously found for a bispyridine-
1
(film): 1711, 1641 cm21; H NMR (400 MHz): d 8.12 (d,
J¼6.8 Hz, 1H), 7.83 (t, J¼8.0 Hz, 1H), 7.74 (dd, J¼8.4,
2.0 Hz, 1H), 7.60 (d, J¼2.0 Hz, 1H), 7.57 (d, J¼7.2 Hz,
1H), 7.38–7.28 (m, 5H), 6.88 (d, J¼8.4 Hz, 1H), 5.57 (s,
2H), 5.45 (dd, J¼10.2, 8.6 Hz, 1H), 4.91 (dd, J¼10.4,
8.4 Hz, 1H), 4.41 (t, J¼8.4 Hz, 1H), 4.22–4.19 (m, 4H),
3.96–3.91 (m, 4H), 3.79–3.76 (m, 4H), 3.73–3.70 (m, 4H),
3.68 (s, 4H); 13C NMR (100.6 MHz): d 165.8, 163.6, 156.7,
153.3, 148.3, 146.2, 141.7, 137.5, 128.8, 127.7, 126.8,
124.2, 123.6, 123.4, 122.2, 114.6, 112.1, 75.5, 70.94, 70.91,
70.8, 70.69, 70.65, 70.60, 70.3, 69.4, 69.3, 69.1, 68.9, 66.8.
4.1.2. Ligand 2. 8-Hydroxyquinoline-2-oxazoline13 (9,
200 mg, 0.69 mmol), K2CO3 (290 mg, 2.1 mmol) and 10
(218 mg, 0.70 mmol) were heated at 608C in DMF (4 mL)
under nitrogen for 24 h. Water (2 mL) was added after
Figure 1. Complexation of 10-undecenoic acid to a Cu(I)–K(I) complex
of 4.

J. Bourguignon et al. / Tetrahedron 59 (2003) 9583–9589
9587
cooling, the aqueous phase extracted twice with CH2Cl2 and
the organic phases dried (MgSO4) to give a crude product,
which was chromatographed on silica (eluent CHCl3/MeOH
98:2). The slightly yellow product obtained was triturated
with ether to give 2 as a white solid (100 mg, 25%). Anal.
calcd for C33H34N2O7: C, 69.47; H, 5.96; N, 4.91. Found: C,
69.19; H, 5.85; N, 4.85%; [a]2D0¼þ34.6 (c 0.25 in CH2Cl2);
1H NMR (300 MHz): d 8.23 (d, J¼8.6 Hz, 1H), 8.12 (d,
J¼8.6 Hz, 1H), 7.39 (d, J¼8.2 Hz, 1H), 7.36–7.35 (m, 1H),
7.30–7.23 (m, 5H), 7.09 (s, 1H), 7.01 (d, J¼7.1 Hz, 1H),
6.94 (d, J¼8.2 Hz, 1H), 6.77 (d, J¼8.2 Hz, 1H), 5.41 (dd,
J¼10.2, 8.8 Hz, 1H), 5.29 (s, 2H), 4.87 (dd, J¼10.2, 8.4 Hz,
1H), 4.35 (t, J¼8.6 Hz, 1H), 4.06–4.03 (m, 4H), 3.83–3.75
(m, 4H), 3.66 (d, 8H); 13C NMR (37.6 MHz): d 166.5,
157.0, 151.2, 150.5, 147.4, 143.9, 141.9, 138.6, 132.1,
132.0, 130.8, 130.4, 129.7, 128.9, 123.5, 121.9, 121.6,
115.8, 114.9, 113.0, 77.4, 73.0, 72.4, 71.5, 71.0, 70.7.
3.90 (m, 4H), 3.76 (s, 8H); 13C NMR (37.6 MHz): d 166.1,
164.0, 149.8, 148.7, 142.1, 129.2, 128.4, 128.2, 127.3,
121.2, 114.3, 113.9, 113.5, 76.0, 71.5, 70.9, 70.7, 70.0, 69.4.
4.1.6. Diamide 14. A mixture of dimethyl methylmalonate
(2.00 g, 13.7 mmol) and (R)-2-phenylglycinol (3.76 g,
27.4 mmol) was stirred at 1108C for 16 h. The solid
obtained was crystallized from EtOH/CHCl3 giving 4.12 g
(84%) of the corresponding diamide 14 as a white solid:
[a]2D0¼237.8 (c 1.66 in DMSO); mp 1588C; 1H NMR
(400 MHz, DMSO-d6): d 7.32–7.21 (m, 10H), 5.31–5.29
(m, 2H), 3.86 (m, 2H), 3.79 (m, 2H), 3.27 (q, J¼7.0 Hz, 1H)
1.53 (d, J¼7.0 Hz, 3H); 13C NMR (100.6 MHz, DMSO-d6):
d 170.23, 170.15, 141.4, 141.3, 128.5, 128.4, 127.5, 127.4,
127.2, 127.1, 65.1, 65.0, 55.4, 55.2, 46.9, 15.3.
4.1.7. Bisoxazoline 15. A solution of p-toluene sulfonyl
chloride (846 mg, 4.4 mmol) in dry CH2Cl2 (4 mL) was
added to a solution of diamide 14 (712 mg, 2.0 mmol), Et3N
(2.2 mL, 16.5 mmol) and DMAP (24.4 mg, 0.2 mmol) in
dry CH2Cl2 (6 mL). The resulting mixture was stirred for
48 h and then partitioned between EtOAc and 0.025 M
aqueous HCl. The phases were separated, the organic layer
was washed with saturated aqueous Na2CO3 and brine, and
dried over Na2SO4. After evaporation of the solvent, the
residue was purified by flash chromatography (eluent
hexane/EtOAc/Et3N 50:50:1) to give compound 15
(423 mg, 66%) as a yellow oil. HRMS (FAB) calcd for
C20H21N2O2 (MHþ), 321.1604. Found, 321.1603; [a]2D0¼
4.1.3. Compound 12. K2CO3 (314 mg, 2.28 mmol) was
added to the chelidamic acid dimethyl ester (11) (160 mg,
0.76 mmol) in dry DMF (5 mL). After stirring for 20 min at
608C the mixture was cooled and, after portionwise addition
of compound 10 (241 mg, 0.76 mmol), again heated at 608C
for 4 h. The reaction was quenched by the addition of water
(2 mL), the DMF was evaporated, and CH2Cl2 (5 mL) was
added. The organic phase was washed with water and
brine, and dried (MgSO4). Evaporation of the solvent and
trituration with ether gave 12 as a white solid (220 mg,
60%). Anal. calcd for C24H29NO10: C, 58.65; H, 5.95; N,
2.85. Found: C, 58.08; H, 6.26; N, 2.81%; 1H NMR
(300 MHz): d 7.84 (s, 2H), 6.97–6.84 (m, 3H), 5.12 (s, 2H),
4.14–4.11 (m, 4H), 3.98 (s, 6H), 3.89–3.87 (m, 4H), 3.73
(s, 8H); 13C NMR (37.6 MHz): d 167.6, 164.2, 151.2, 149.5,
139.6, 129.1, 128.3, 128.0, 127.2, 114.1, 114.0, 111.9, 71.2,
70.9, 70.5, 69.7, 69.1, 66.0, 56.4.
1
þ69 (c 0.92 in CH2Cl2); IR (film): 1659 cm21; H NMR
(400 MHz): d 7.35–7.25 (m, 10H), 5.24 (m, 2H), 4.743
(dd, J¼10.2, 8.4 Hz, 1H), 4.741 (dd, J¼10.2, 9.4 Hz, 1H),
4.24 (dd, J¼8.3, 7.8 Hz, 1H), 4.23 (dd, J¼9.3, 8.9 Hz,
1H), 3.82 (q, J¼7.3 Hz, 1H), 1.70 (d, J¼7.3 Hz, 3H); 13C
NMR (100.6 MHz): d 168.8, 168.5, 143.82, 143.81, 130.3,
129.2, 128.3, 128.2, 128.1, 76.92, 76.90, 71.2, 71.1, 35.7,
17.0.
4.1.4. Compound 13. Diester 12 (200 mg, 0.4 mmol) and
(R)-phenylglycinol (446 mg, 3.26 mmol) were heated at
reflux in anhydrous toluene (4 mL) for 18 h. The solvent
was evaporated, the residue dissolved in ethyl acetate, the
organic phase washed with HCl (1 M) and NaHCO3, and
dried (MgSO4) to give diamide 13 as a white solid (292 mg,
100%). HRMS (FAB) calcd for C38H44N3O10 (MHþ),
4.1.8. Bisoxazoline 17. n-BuLi (0.6 mL, 2.5 M in hexane,
1.50 mmol) was added to a solution of 15 (423 mg,
1.32 mmol) in dry THF (10 mL) at 2788C under nitrogen
over a period of 5 min. The mixture was allowed to warm to
08C and was then stirred for 0.5 h. At this temperature
compound 16 (340 mg, 1.50 mmol) in THF (5 mL) was
added dropwise. Stirring was continued for 20 min at 08C
followed by 5 h at room temperature. The reaction was
quenched with brine and the reaction mixture extracted with
EtOAc. The two phases were separated, the aqueous layer
was extracted with EtOAc and the combined organic phases
were dried over Na2SO4. Evaporation in vacuo gave a
yellow oil that was purified by flash chromatography on
silica gel (eluent hexane/EtOAc 1:1) to give 17 (482 mg,
78%) as a yellow oil. 1H NMR (400 MHz): d 7.31–7.24 (m,
10H), 7.16 (m, 2H), 6.84 (m, 2H), 6.12–6.02 (m, 1H), 5.42
(d, J¼17.3 Hz, 1H), 5.33–5.30 (m, 2H), 5.26 (d, J¼
10.1 Hz, 1H), 4.77 (dd, J¼10.1, 8.6 Hz, 2H), 4.50 (d, J¼
5.3 Hz, 2H), 4.24–4.18 (m, 2H), 3.47 (s, 2H), 1.69 (s, 3H);
13C NMR (100.6 MHz): d 171.9, 171.7, 161.1, 144.9,
144.75, 140.6, 136.0, 131.7, 131.35, 131.25, 130.2, 130.1,
129.4, 125.9, 120.2, 119.9, 115.7, 78.4, 78.0, 77.95, 72.3,
72.2, 71.3, 46.4, 44.8, 24.3.
1
702.3027. Found, 702.2990; H NMR (300 MHz): d 8.69
(d, J¼7.3 Hz, 2H), 7.81 (s, 2H), 7.27–7.36 (m, 10H), 6.91–
6.83 (m, 3H), 5.20 (m, 2H), 5.05 (s, 2H), 4.10–3.97 (m, 4H),
3.95–3.87 (m, 8H), 3.74 (s, 8H); 13C NMR (37.6 MHz): d
167.6, 164.2, 151.2, 149.5, 139.6, 129.1, 128.3, 128.0,
127.2, 114.1, 114.0, 111.9, 71.2, 70.9, 70.5, 69.7, 69.1, 66.0,
56.4.
4.1.5. Ligand 3. p-Toluene sulfonyl chloride (170 mg,
0.89 mmol) was added to diamide 13 (292 mg, 0.41 mmol)
and Et3N (576 mL, 4.1 mmol) in CH2Cl2 (4 mL). After
heating at reflux for 24 h, water (16 mL) was added and
heating continued for another 1 h. The organic phase was
washed with water and dried (MgSO4) to give 3 (170 mg,
60%) as a white solid. HRMS (FAB) calcd for C38H40N3O8
(MHþ), 666.2816. Found, 666.2858; [a]2D0¼þ28.0 (c 0.25
1
in CH2Cl2); IR (film): 1641 cm21; H NMR (300 MHz): d
7.94 (s, 2H), 7.40–7.30 (m, 10H), 6.94–6.88 (m, 3H), 5.45
(app t, J¼8.8 Hz, 2H), 5.13 (s, 2H), 4.93 (app t, J¼8.8 Hz,
2H), 4.42 (app t, J¼8.6 Hz, 2H), 4.15–4.12 (m, 4H), 3.93–
4.1.9. Bisoxazoline 18. A solution of 17 (482 mg,

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J. Bourguignon et al. / Tetrahedron 59 (2003) 9583–9589
1.03 mmol), Pd(OAc)2 (22.4 mg, 0.1 mmol) and PPh3
(115 mg, 0.44 mmol) in ethanol (15 mL) was heated at
reflux for 90 min. Silica (2 g) was then added at room
temperature. After 15 min of stirring, the resulting mixture
was filtered through Celite and the solvent was evaporated.
The residue was purified by flash chromatography (eluent
CH2Cl2/EtOAc 7:3) to yield compound 18 (271 mg, 62%)
as a yellow oil. [a]D20¼þ115.8 (c 0.52 in CH2Cl2); 1H NMR
(400 MHz): d 8.12 (br s, 1H), 7.22–7.12 (m, 8H), 7.01 (m,
2H), 6.89 (t, J¼8.0 Hz, 1H), 6.56 (d, J¼7.6 Hz, 1H), 6.42
(m, 2H), 5.15 (dd, J¼10.0, 8.4 Hz, 1H), 5.07 (dd, J¼10.0,
7.6 Hz, 1H), 4.60 (dd, J¼10.2, 8.4 Hz, 1H), 4.59 (dd, J¼
10.2, 8.4 Hz, 1H), 4.11 (dd, J¼8.5, 7.6 Hz, 1H), 4.04 (t,
J¼8.5 Hz, 1H), 3.25 and 3.21 (AB spectrum, J¼13.5 Hz,
2H), 1.48 (s, 3H); 13C NMR (100.6 MHz): d 170.10, 170.09,
157.0, 142.3, 142.2, 137.9, 129.6, 129.2, 129.1, 128.2,
128.1, 127.21, 127.19, 122.2, 118.3, 114.7, 75.84, 75.78,
69.9, 69.7, 44.3, 42.4, 21.9.
74.3, 71.35, 71.32, 71.2, 71.12, 71.1, 71.05, 69.8, 68.9, 69.4,
69.2, 66.0, 29.1.
4.1.12. Ligand 6. A solution of bisoxazoline 2017 (135 mg,
0.5 mmol), 4-carboxybenzo-18-crown-6 (8, 400 mg,
1.12 mmol), EDCI (315 mg, 1.64 mmol) and DMAP
(24.4 mg, 0.2 mmol) in CH2Cl2 (9 mL) was stirred for 3
days and then partitioned between EtOAc and 0.025 M
aqueous HCl. The phases were separated, the organic phase
was washed with water, saturated aqueous Na2CO3 and
brine, and dried over Na2SO4. After evaporation of the
solvent the residue was purified by flash chromatography
(eluent MeOH/CH2Cl2 1:10). The product was dissolved in
EtOAc (1 mL) and ether (15 mL) was added. The milky
mixture was kept for 16 h at 58C. Decantation of the clear
solution, evaporation of the solvent and recrystallization of
the solid obtained from ether gave ligand 6 (52 mg, 11%) as
a white solid. Anal. calcd for C47H66N2O18: C, 59.61; H,
7.02; N, 2.96. Found: C, 59.40; H, 7.15; N, 2.95%; mp
1
4.1.10. Ligand 4. Bisoxazoline 18 (271 mg, 0.64 mmol)
was added in one portion to a solution of EDCI (135 mg,
0.70 mmol), 4-carboxybenzo-18-crown-6 (8, 230 mg,
0.64 mmol) and DMAP (8.5 mg, 0.07 mmol) in CH2Cl2
(10 mL). After 18 h of stirring, the mixture was partitioned
between EtOAc and 0.025 M aqueous HCl. The phases were
separated, the organic phase was washed with water,
saturated aqueous Na2CO3, and brine, and dried over
Na2SO4. After evaporation of the solvent the residue was
purified by flash chromatography (eluent MeOH/CH2Cl2
1:10) followed by crystallization from ether/CH2Cl2 to
yield 4 (391 mg, 80%) as a white solid: Anal. calcd for
C44H48N2O10: C, 69.09; H, 6.33; N, 3.66. Found: C, 68.89;
H, 6.40; N, 3.54; [a]D20¼þ56 (c 0.70 in CH2Cl2); mp 588C;
1078C; H NMR (400 MHz): d 7.56 (dd, J¼8.2, 2.0 Hz,
2H), 7.45 (d, J¼2.0 Hz, 2H), 6.79 (d, J¼8.2 Hz, 2H), 4.42
(quint, J¼6.3 Hz, 2H), 4.33 (dd, J¼11.0, 4.6 Hz, 2H), 4.21
(dd, J¼11, 6.0 Hz, 2H), 4.13 (m, 8H), 3.86 (m, 10H), 3.71
(m, 8H), 3.63 (m, 16H), 1.87 (s, 6H), 1.25 (d, J¼6.3 Hz,
6H); 13C NMR (100.6 MHz): d 166.5, 166.3, 153.65, 148.8,
124.4, 122.9, 115.0, 112.6, 79.4, 72.3, 71.4, 71.3, 71.2,
71.15, 71.1, 69.9, 69.8, 69.6, 69.3, 66.4, 21.4, 14.7.
Acknowledgements
This work was supported by the Swedish Research Council
¨
and by the Goran Gustafsson Foundation for Research in
Sciences and Medicine.
1
IR (film): 1727, 1656 cm21; H NMR (400 MHz): d 7.72
(dd, J¼8.4, 2.0 Hz, 1H), 7.58 (d, J¼2.0 Hz, 1H), 7.20 (m,
10H), 7.07 (m, 4H), 6.85 (d, J¼8.6 Hz, 1H), 5.19 (dd,
J¼10.1, 7.7 Hz, 1H), 5.13 (dd, J¼10.1, 8.4 Hz, 1H), 4.640
(dd, J¼10.1, 8.1 Hz, 1H), 4.639 (dd, J¼10.3, 8.4 Hz, 1H),
4.20–4.13 (m, 6H), 3.98–3.94 (m, 4H), 3.79–3.70 (m,
12H), 3.43 and 3.38 (AB spectrum, J¼13.6 Hz, 2H), 1.59 (s,
3H); 13C NMR (100.6 MHz): d 168.4, 168.2, 164.0, 150.2,
147.8, 141.6, 141.4, 137.5, 128.3, 128.0, 127.9, 127.3,
126.9, 126.8, 126.0, 124.0, 123.2, 119.5, 114.2, 111.6, 74.7,
74.6, 70.30, 70.28, 70.15, 70.07, 70.04, 69.98, 68.96, 68.83,
68.78, 68.7, 43.0, 41.3, 21.0.
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