added via the septum using a syringe during 30 min. After a further
20 min, trimethylborate (34.2 mL, 306 mmol) was added slowly
during 15 min, so turning the solution into a yellow emulsion.
The flask and its contents were removed from the cooling bath,
and allowed to equilibrate to room temperature slowly, during
which time the emulsion dissolved to yield a clear yellow solution.
After stirring a◦t room temperature for 2 h, the solution was again
cooled to -78 C, and treated with a 1 : 1 mixture of 15% H2O2
and 1.5 M NaOH (300 mL) to give a viscous, white emulsion.
The solution was allowed to warm to room temperature and
stirred for 18 h. Na2S2O5 (60 g) was carefully added to the stirring
solution, resulting in the formation of two layers. The THF layer
was subsequently removed in vacuo to yield a yellow solid in the
residual water, which was filtered and air dried. The mixture of
alcohols was pre-adsorbed onto silica before chromatography on
silica. The chromatography column was gradient eluted, starting
with 1 : 2 EtOAc–hexane, accompanied by slow addition of EtOAc
towards a final EtOAc–hexane of 8 : 2. Compound 9 was isolated
as the most polar fraction (Rf 0.30, by TLC in 8 : 2 EtOAc–hexane)
and found to be pure (6.60 g, 53%); mp 188–190 ◦C; 1H NMR: d =
6.60 (s, 4 H, ArH), 5.94 (d, J = 6.9 Hz, 4 H, outer of OCH2O), 5.35
(s, 4 H, ArOH), 4.68 (t, J = 8.1 Hz, 4 H, CH (methine)), 4.42 (d,
J = 6.9 Hz, 4 H, inner of OCH2O), 2.17 (m, 8 H, CH2(CH2)9CH3),
1.30–1.52 (m, 72 H, CH2(CH2)9CH3), 0.88 (t, 12 H, CH3) ppm;
13C NMR: d = 141.95, 140.77, 138.52, 110.17, 99.79, 36.79, 31.94,
29.84, 29.76, 29.72, 29.60, 29.40, 27.86, 22.70, 14.12 ppm; FT-
IR/ATR: 3425, 2921, 2851 cm-1.
(t, J = 7.9 Hz, 4 H, CH (methine)), 4.44 (s, 8 H, ArOCH2), 4.27 (d,
J = 7.5 Hz, 4 H, inner of OCH2O), 2.29 (m, 8H, CH2(CH2)9CH3),
1.21–1.42 (m, 72 H, CH2(CH2)9CH3), 0.87 (t, 12 H, CH3) ppm;
13C NMR [DMSO-d6]: d = 171.95, 146.24, 143.44, 138.63, 115.38,
99.62, 69.40, 36.86, 31.30, 29.20, 29.05, 28.73, 27.64, 22.06, 21.00,
13.86 ppm; FT-IR/ATR: 3353, 2922, 2852, 1665 cm-1.
General procedure for the synthesis of amino acid cavitand
derivatives (1 and 2)37. To a suspension of 11 (0.50 g, 0.35 mmol)
in dry CH2Cl2 (20 mL) was added freshly distilled oxalyl chloride
(0.60 mL, 7.00 mmol), and the mixture was refluxed for 18 h
at 40 ◦C under N2. Unreacted oxalyl chloride and solvent were
removed in vacuo, and the product was dried under vacuum for
1 h, dissolved in dry CH2Cl2 (10 mL), and slowly added to a
◦
cooled solution (0 C) of amino acid methyl ester hydrochloride
(1.75 mmol) and Et3N (0.25 mL, 1.75 mmol) in dry CH2Cl2
(20 mL). The reaction mixture was allowed to warm up to room
temperature and stirred under N2 for 18 h. The solution mixture
was treated with 1 N HCl (20 mL), and the organic layer was
separated, washed with water (30 mL), and brine (30 mL). The
organic layer was dried (Na2SO4), filtered, and the solvent was
removed under reduced pressure, yielding a sticky residue. The
residue obtained was purified silica gel using a 3% MeOH in
CHCl3. Evaporation of the solvent followed by addition of MeOH
afforded the product after filtration and drying under vacuum.
Tetra-alanyl methyl ester cavitand 1. L-Alanine methyl ester
hydrochloride (0.25 g, 1.75 mmol) was used as described in
the general procedure. Compound 1 was obtained as a white,
crystalline solid (0.42 g, 68%), Rf 0.42 (3% MeOH/CH3Cl), mp
76–79 ◦C; 1H NMR: d = 8.08 (d, J = 7.6 Hz, 4 H, NH), 6.81 (s, 4
H, ArH), 6.03 (d, J = 7.1 Hz, 4 H, outer of OCH2O), 4.62 (t, 4 H,
CH (methine)), 4.62 (m, 4 H, Ala-a H), 4.50 (d, J = 5.0 Hz, 8 H,
ArOCH2), 4.39 (d, J = 7.1 Hz, 4 H, inner of OCH2O), 3.71 (s, 12 H,
OCH3), 2.07 (m, 8 H, CH2(CH2)9CH3), 1.38 (d, 12 H, Ala-CH3),
Tetraester cavitand 1027. To a stirring solution of tetrol, 9
(3.10 g, 2.55 mmol) and oven-dried (110 ◦C) K2CO3 (3.50 g,
25.50 mmol) in dry CH3CN (350 mL), methylbromoacetate
(1.50 mL, 12.75 mmol) was added and the reaction mixture
refluxed at 82 ◦C for 24 h under a nitrogen atmosphere, then
the reaction mixture was cooled to room temperature and the
solvent was removed in vacuo. The residue was dissolved in CH2Cl2
(200 mL). The organic layer was washed with 1N HCl (50 mL)
followed by water (100 mL, 3¥), and then washed with saturated
brine (100 mL), and dried over anhydrous MgSO4. After filtration,
the solution was evaporated under reduced pressure to yield the
title compound, which was triturated in methanol to give a white,
crystalline solid. (3.80 g, 98%), mp 184–187 ◦C, 1H NMR: d = 6.77
(s, 4 H, ArH), 5.70 (d, J = 7.4 Hz, 4 H, outer of OCH2O), 4.67 (t,
J = 8.0 Hz, 4 H, CH (methine), 4.52 (s, 8 H, ArOCH2), 4.39 (d,
J = 7.4 Hz, 4 H, inner of OCH2O), 3.76 (s, 12 H, OCH3), 2.18 (m,
8 H, CH2(CH2)9CH3), 1.27–1.40 (m, 72 H, CH2(CH2)9CH3), 0.88
(t, 12 H, CH3) ppm; 13C NMR: d = 169.75, 147.35, 143.93, 138.86,
114.37, 99.91, 69.99, 51.91, 36.85, 31.94, 29.90, 29.86, 29.75, 29.72,
29.41, 27.41, 22.69, 14.11 ppm; FT-IR/ATR: 2919, 2851, 1758,
1737 cm-1.
1.20–1.28 (m, 72 H, CH2(CH2)9CH3), 0.84 (t, 12 H, CH3) ppm; 13
C
NMR: d = 173.24, 168.66, 147.03, 143.98, 139.30, 114.83, 99.64,
73.05, 52.52, 47.64, 36.91, 31.94, 29.86, 29.74, 29.72, 29.40, 27.87,
22.69, 18.56, 14.11 ppm; FT-IR/ATR: 3355, 2923, 2852, 1742,
1680 cm-1. MS (ESI-TOF) Calcd for C100H148O24N4: 1789.2916.
Found: 1790.0560. [a]2D0 = 41.7◦ (c = 0.12, CHCl3).
Tetra-phenylalanyl methyl ester cavitand 2. L-Phenylalanine
methyl ester hydrochloride (0.38 g, 1.75 mmol) was used as
described in the general procedure. Compound 2 was obtained
as a white, crystalline solid (0.51 g, 70%), Rf 0.52 (3% MeOH–
◦
1
CHCl3), mp 72–74 C. H NMR: d = 8.06 (d, J = 8.2 Hz, 4 H,
NH), 7.19–7.10 (m, 20 H, Phe-ArH). 6.82 (s, 4 H, ArH), 5.69 (d,
J = 7.1 Hz, 4 H, outer of OCH2O), 4.97 (m, 4 H, Phe-a H), 4.67
(t, 4 H, CH (methine)), 4.51 (d, J = 7.0 Hz, 8 H, ArOCH2), 4.28
(d, J = 7.1 Hz, 4 H, inner of OCH2O), 3.68 (s, 12 H, OCH3), 3.21
(dd, 4 H, Phe-ArCH2), 3.11 (dd, 4 H, Phe-ArCH2), 2.17 (m, 8
H, CH2(CH2)9CH3), 1.20–1.28 (m, 72 H, CH2(CH2)9CH3), 0.87 (t,
12 H, CH3) ppm; 13C NMR: d = 171.80, 168.59, 146.96, 146.68,
143.89, 139.15, 138.88, 135.92, 129.32, 128.40, 126.97, 114.70,
99.30, 72.85, 52.93, 52.34, 38.42, 36.93, 31.93, 29.97, 29.80, 2976,
29.71, 29.41, 28.01, 22.69, 14.11 ppm; FT-IR/ATR: 3355, 2923,
2852, 1742, 1680 cm-1. MS (ESI-TOF) Calcd for C124H164O24N4:
2093.4444. Found: 2094.1762. [a]2D0 = 36.42◦ (c = 0.11, CHCl3).
Tetrahydroxycarbonyl cavitand 11. To a solution of compound
10 (1.5 g, 1 mmol) in THF (70 mL) was added 2 M KOH (30 mL),
and the reaction mixture was stirred at room temperature for 24 h.
The reaction mixture was acidified with 2 M HCl (60 mL), and the
THF was removed in vacuo. The precipitate formed was filtered
and thoroughly washed with water. The solid obtained was dried
at 80 ◦C under vacuum for 3 h, and then suspended in THF and
filtered. The solution was evaporated to dryness to yield 11 as white
◦
1
solid. (1.38 g, 96%), mp 214–216 C, H NMR [DMSO-d6]: d =
7.23 (s, 4 H, ArH), 5.70 (d, J = 7.5 Hz, 4 H, outer of OCH2O), 4.54
4504 | Org. Biomol. Chem., 2011, 9, 4498–4506
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The Royal Society of Chemistry 2011
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