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obtain an analyte solution (typically 1 mL and near 500 μM
macrocycle in CDCl3) and a titrant solution (typically 5 mM in MA
and always of identical macrocycle concentration as present in the
analyte solution; also in CDCl3), thus ensuring that the macrocycle
concentration remained constant over the course of the experiment.
Titrations of a given macrocycle with enantiomeric MA samples were
performed in parallel. The observed chemical shift changes were fitted
with the computer program NMRTit HGG.26 The macroscopic 2:1
binding constants reported in Table 1 have been statistically
corrected30 from those reported by NMRTit HGG to account for
the fact that the program returns microscopic binding constants.
Crystallographic Data Collection and Refinement. Crystals of
(R,R)-2 and (R,R)-3 were grown by evaporation from concentrated
Et2O solutions, whereas crystals of (R,R)-4 and (R,R)-7 were obtained
by slow evaporation from solutions in CDCl3. X-ray diffraction data
were collected on a CCD platform diffractometer (Cu Kα (λ = 1.541
78 Å)) at 125 K. Crystals were mounted in a nylon loop with
cryoprotectant oil. The structures were solved using direct methods
and standard difference map techniques and were refined by full-
matrix least-squares procedures on F2 with SHELXTL (Version
6.14).31 All non-hydrogen atoms were refined anisotropically.
Hydrogen atoms on carbon were included in calculated positions
and were refined using a riding model. Hydrogen atoms on nitrogen
were located in the difference map and refined semifreely with the help
of a distance restraint. PLATON32 was used to verify all stereo-
chemical configuration designations. ORTEP-333 was used to generate
Figures 2 and 3. Crystallographic data for the structures reported in
this paper are given in the Supporting Information.
Typical Procedure for Synthesis of Dialdehydes. To a flame-
dried 250 mL round-bottom flask was added solution of ditosylated
ethylene glycol (10 mmol) in freshly distilled acetonitrile (60 mL),
followed by the phenol derivative (22 mmol), anhydrous K2CO3 (4.14
g, 30 mmol), and NaI (ca. 50 mg). The reaction was stirred at reflux
for 12 h, allowed to cool to room temperature, and concentrated under
reduced pressure. The resulting residue was partitioned between
CH2Cl2 (150 mL) and 1 M NaOH (50 mL). The organic phase was
washed with an additional portion of 1 M NaOH (50 mL) and
saturated brine (50 mL), dried over Na2SO4, and concentrated to yield
the product, which was of sufficient purity to be used in the
subsequent macrocyclization step but could be further purified by
column chromatography or recrystallization. Yields refer to material
obtained directly after extraction.
Diethylene Glycol Di(1-formyl-2-naphthyl) Ether (17). Yellow
solid (3.296 g, 82%); Rf (1.5:1 EtOAc:hexanes): 0.53. H NMR (300
1
MHz, CDCl3): δ 10.90 (s, 1H), 9.21 (d, J = 8.7 Hz, 1H), 7.98 (d, J =
9.0 Hz, 1H), 7.72 (bd, J = 7.9 Hz, 1H), 7.60−7.55 (m, 1H), 7.41−7.36
(m, 1H), 7.26−7.23 (m, 1H), 4.39 (t, J = 4.6 Hz, 2H), 3.99 (t, J = 4.6
Hz, 2H). 13C NMR (75 MHz, CDCl3): 192.3, 163.4, 137.7, 131.6,
131.6, 130.0, 129.0, 128.4, 125.2, 117.5, 114.2, 70.3, 69.6.
Triethylene Glycol Di(1-formyl-2-naphthyl) Ether (18). Yellow
1
solid (4.305 g, 94%); Rf (2:1 EtOAc:hexanes): 0.47. H NMR (300
MHz, CDCl3): δ 10.91 (s, 1H), 9.24 (d, J = 8.8 Hz, 1H), 7.98 (d, J =
9.2 Hz, 1H), 7.72 (bd, J = 8.1 Hz, 1H), 7.61−7.56 (m, 1H), 7.42−7.37
(m, 1H), 7.24 (d, J = 9.2 Hz, 1H), 4.35 (t, J = 4.6 Hz, 2H), 3.90 (t, J =
4.6 Hz, 2H), 3.74 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 192.5,
163.7, 137.7, 131.7, 130.0, 128.9, 128.4, 125.2, 125.1, 117.4, 114.3,
71.2, 69.9, 69.5.
Typical Procedure for Synthesis of Macrocycles (R,R)-1
through (R,R)-5. To a flame-dried 1 L round-bottom flask was added
a solution of (R,R)-DACH (10.8 mmol, 1.23 g) in anhydrous MeOH
(200 mL) and a solution of the dialdehyde (10.8 mmol) in anhydrous
MeOH (200 mL). The reaction was stirred at room temperature for
16 h, after which NaBH4 (50 mmol, 1.89 g) was carefully added in
small portions over a period of 1 h. The reaction was then brought to
reflux for 4 h, concentrated under reduced pressure, and dissolved in a
bilayer of CH2Cl2 (300 mL) and 1 M NaOH (100 mL). The organic
phase was then washed sequentially with an additional portion of 1 M
NaOH (100 mL) and brine (100 mL), dried over Na2SO4, and
concentrated under reduced pressure to give the crude products
(typically foamy solids), which were purified by column chromatog-
raphy on silica gel (∼50 cm3 g−1), using 1−10% NH3-saturated
MeOH:EtOAc as the eluent.
Tri(ethyleneoxy)-o-phenylene-Linked Macrocycle ((R,R)-1). Col-
1
orless oil (2.106 g, 44%); Rf (10% NH3(sat)MeOH/EtOAc): 0.56. H
NMR (300 MHz, CDCl3): δ 7.14−7.04 (m, 2H), 6.84−6.73 (m, 2H),
4.09−4.02 (m, 1H), 3.98−3.92 (m, 2H), 3.77−3.55 (m, 6H), 2.12
(bdd, J = 5.2 Hz, J = 3.2 Hz 1H), 3.46 (d, J = 12.8 Hz, 1H), 2.18−2.10
(m, 2H), 1.89−1.85 (bm, 1H), 1.58−1.54 (bm, 1H), 1.13−1.07 (bm,
1H), 0.98−0.90 (bm, 1H). 13C NMR (75 MHz, CDCl3): δ 157.4,
130.6, 129.9, 128.2, 120.8, 111.7, 71.6, 70.0, 68.4, 62.5, 48.5, 31.7, 25.2.
HRMS (ESI, m/z) calcd for C26H37N2O4[M + H]+: 441.2748; found:
441.2751.
Di(ethyleneoxy)-m-phenylene-Linked Macrocycle ((R,R)-2).
White foamy solid (2.377 g, 55%); Rf (3% NH3(sat)MeOH/EtOAc):
1
0.39. H NMR (300 MHz, CDCl3): δ 7.16 (t, J = 7.9 Hz, 1H), 7.09
Triethylene Glycol Di(p-formylphenyl) Ether (9). Yellow solid
1
(bt, 1H), 6.79−6.73 (m, 2H), 4.14−4.11 (m, 2H), 3.95−3.88 (m, 3H),
3.56 (d, J = 12.8 Hz, 1H), 2.28−2.19 (bm, 2H), 1.84 (bd, J = 8.6 Hz,
1H), 1.28−1.21 (bm, 1H), 1.08−1.01 (bm, 1H). 13C NMR (75 MHz,
CDCl3): δ 159.3, 142.7, 129.0, 120.9, 114.6, 112.5, 71.4, 67.5, 61.3,
50.8, 31.6, 25.1. HRMS (ESI, m/z) calcd for C24H33N2O3[M + H]+:
397.2486; found: 397.2497.
(3.150 g, 88%); Rf (2:1 EtOAc:hexanes): 0.43. H NMR (300 MHz,
CDCl3): δ 9.86 (s, 1H), 7.79 (d, J = 8.9 Hz, 2H), 6.98 (d, J = 8.9 Hz,
2H), 4.18 (m, 2H), 3.87 (t, J = 4.7 Hz, 2H), 3.74 (s, 2H). 13C NMR
(75 MHz, CDCl3): 191.1, 164.0, 132.2, 130.3, 115.1, 71.1, 69.8, 67.9.
Triethylene Glycol Di(o-formylphenyl) Ether (13). Pale yellow oil
1
(3.364 g, 94%); Rf (1.5:1 EtOAc:hexanes): 0.47. H NMR (300 MHz,
Tri(ethyleneoxy)-m-phenylene-Linked Macrocycle ((R,R)-3).
CDCl3): δ 10.48 (s, 1H), 7.78 (dd, J = 7.7 Hz, J = 1.8 Hz, 1H), 7.52−
7.46 (m, 1H), 7.02−6.94 (m, 2H), 4.21 (t, J = 4.7 Hz, 2H), 3.88 (t, J =
4.6 Hz, 2H), 3.72 (s, 2H). 13C NMR (75 MHz, CDCl3): 190.1, 161.4,
136.1, 128.5, 125.3, 121.2, 113.1, 71.2, 69.8, 68.4.
White foamy solid (2.880 g, 61%); Rf (3% NH3(sat)MeOH/EtOAc):
1
0.29. H NMR (300 MHz, CDCl3): δ 7.15 (t, J = 7.9 Hz, 1H), 6.97
(bt, 1H), 6.80−6.76 (m, 2H), 4.04−4.01 (m, 2H), 3.90−3.82 (m, 3H),
3.72 (s, 2H), 3.58 (d, J = 12.6 Hz, 1H), 2.24−2.16 (bm, 2H), 1.72 (bd,
J = 9.8 Hz, 1H), 1.28−1.14 (bm, 1H), 1.06−0.99 (bm, 1H). 13C NMR
(75 MHz, CDCl3): δ 159.2, 142.6, 129.1, 120.9, 113.6, 113.0, 70.9,
69.9, 67.3, 60.9, 50.8, 31.5, 25.1. HRMS (ESI, m/z) calcd for
C26H37N2O4[M + H]+: 441.2748; found: 441.2761.
Diethylene glycol Di(m-formylphenyl) Ether (14). White solid
1
(2.875 g, 93%); Rf (1:1 EtOAc:hexanes): 0.53. H NMR (300 MHz,
CDCl3): δ 9.94 (s, 1H), 7.44−7.38 (m, 3H), 7.20−7.16 (m, 1H), 4.21
(t, J = 4.7 Hz, 2H), 3.95 (t, J = 4.7 Hz, 2H). 13C NMR (75 MHz,
CDCl3): 192.2, 159.5, 138.0, 130.3, 123.9, 122.3, 113.0, 70.0, 67.9.
Triethylene Glycol Di(m-formylphenyl) Ether (15). Pale yellow
Tetra(ethyleneoxy)-m-phenylene-Linked Macrocycle ((R,R)-4).
1
White foamy solid (2.682 g, 57%); Rf (3% NH3(sat)MeOH/EtOAc):
solid (3.217 g, 89%); Rf (1.5:1 EtOAc:hexanes): 0.50. H NMR (300
1
MHz, CDCl3): δ 9.91 (s, 1H), 7.42−7.35 (m, 3H), 7.17−7.13 (m,
0.28. H NMR (300 MHz, CDCl3): δ 7.13 (t, J = 7.9 Hz, 1H), 6.88
1H), 4.15 (t, J = 4.7 Hz, 2H), 3.85 (t, J = 4.7 Hz, 2H) 3.72 (s, 2H). 13
C
(bt, 1H), 6.79−6.76 (m, 2H), 4.04−3.77 (m, 5H), 3.66 (s, 4H), 3.55
(d, J = 13.0 Hz, 1H), 2.24−2.163 (bm, 3H), 1.70 (bd, J = 8.4 Hz, 1H),
1.23−1.17 (bm, 1H), 1.07−1.00 (bm, 1H). 13C NMR (75 MHz,
CDCl3): δ 159.3, 142.6, 129.2, 120.9, 113.9, 113.3, 71.0, 70.9, 69.8,
67.5 60.9, 50.8, 31.5, 25.2. HRMS (ESI, m/z) calcd for C26H37N2O4[M
+ H]+: 485.3010; found: 485.3018.
NMR (75 MHz, CDCl3): 192.2, 159.5, 137.9, 130.2, 123.8, 122.1,
113.0, 71.1, 69.8, 67.8.
Tetraethylene Glycol Di(m-formylphenyl) Ether (16). Colorless oil
1
(3.296 g, 82%); Rf (2:1 EtOAc:hexanes): 0.48. H NMR (300 MHz,
CDCl3): δ 9.93 (s, 1H), 7.44−7.36 (m, 3H), 7.19−7.15 (m, 1H), 4.16
(t, J = 4.8 Hz, 2H), 3.85 (t, J = 4.7 Hz, 2H) 3.73−3.65 (m, 4H). 13C
NMR (75 MHz, CDCl3): 192.3, 159.6, 138.0, 130.3, 123.8, 122.3,
113.1, 71.1, 70.1, 69.8, 67.9.
Tri(ethyleneoxy)-p-phenylene-Linked Macrocycle ((R,R)-5). Col-
1
orless oil (1.959 g, 41%); Rf (10% NH3(sat)MeOH/EtOAc): 0.48. H
NMR (300 MHz, CDCl3): δ 7.16 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 8.5
10028
dx.doi.org/10.1021/jo2018203 | J. Org. Chem. 2011, 76, 10020−10030