Modular Approach to Self-Assembling Capsules
J. Am. Chem. Soc., Vol. 123, No. 47, 2001 11523
isomer was isolated and characterized from this reaction; the axial
isomer was present in trace amounts. 1H NMR (CDCl3, 600 MHz): δ
(ppm) 7.09 (d, J ) 8.5 Hz, 4H), 7.01 (d, J ) 8.6 Hz, 2H), 6.91 (d, J
) 8.6 Hz, 2H), 6.86 (d, J ) 8.5 Hz, 2H), 6.82 (d, J ) 8.7 Hz, 4H),
6.68 (d, J ) 8.5 Hz, 2H), 4.45 (dd, J ) 14.2 Hz, 4.4 Hz, 2H), 4.37 (d,
J ) 16.3 Hz, 2H), 3.91 (d, J ) 16.3 Hz, 2H), 4.78 (s, 6H), 3.67 (s,
3H), 3.08 (m, 2H), 2.86 (m, 1H), 1.16 (s, 9H), 1.14 (s, 9H). 13C NMR
(CDCl3, 150 MHz): δ (ppm) 170.99, 159.27, 158.55, 152.27, 151.87,
129.84, 129.55, 128.95, 128.62, 127.97, 127.10, 125.15, 124.90, 113.90,
88.32, 80.67, 55.19, 52.04, 45.71, 40.16, 38.08, 34.34, 31.10. HRMS
(FAB) calcd for [M + Na]+ C45H52N4O6‚Na+, 767.3784; found,
767.3755.
55.36, 46.25, 39.45, 36.21, 35.45, 35.34, 31.92, 31.88, 31.44, 31.36,
29.23, 29.20, 29.13, 22.77, 22.75, 14.17, 14.15. IR (CDCl3): 2927.04,
2855.03, 1735.84, 1710.15, 1612.81, 1513.21, 1458.05, 1417.67,
1284.28, 1246.83, 1175.69 cm-1. HRMS (FAB) calcd for [M + Cs+]
C57H68N4O6‚Cs+, 1037.4193; found, 1037.4248.
Methyl Ester 18a. Glycoluril 16a (8.14 g, 9.8 mmol) was dissolved
in 230 mL of CH3CN. While heating gently, water (45 mL) was added,
and the solution was allowed to cool to room temperature slowly. CAN
(23.68 g, 43.2 mmol) was added to the slightly cloudy solution, and
this mixture was allowed to stir overnight. When TLC indicated
complete disappearance of 7a, the flask’s contents were poured into
600 mL of EtOAc. This phase was washed with 1 M HCl (3 × 100
mL), 0.5 M KOH (2 × 100 mL), saturated NaHCO3 solution (100 mL),
and brine (2 × 100 mL). The organic phase was dried over Na2SO4,
filtered, and concentrated in vacuo. The residue was dissolved in a
minimum amount of hot ether, and after refrigeration overnight, a white
precipitate was collected by filtration. Yield 1.33 g (23%); mp 160 °C.
1H NMR (CDCl3, 600 MHz): δ (ppm) 7.09 (d, J ) 8.3 Hz, 2H), 6.95
(d, J ) 8.3 Hz, 2H), 6.88 (m, 4H), 5.91 (s, 2H), 4.35 (dd, J ) 14.4,
4.6 Hz, 2H), 3.64 (s, 3H), 2.98 (m, 2H), 2.72 (m, 1H), 2.41 (m, 4H),
1.42 (m, 4H), 1.24 (m, 16H), 0.88 (m, 6H). 13C NMR (CDCl3, 151
MHz): δ (ppm) 171.20, 159.20, 144.36, 144.27, 133.37, 129.94, 128.85,
128.46, 127.68, 127.40, 83.52, 78.67, 52.22, 39.89, 37.85, 35.47, 35.39,
31.94, 31.40, 29.24, 29.22, 29.16, 29.12, 22.81, 22.79, 14.20. IR
(CDCl3): 3255.88, 2951.54, 2925.14, 2854.42, 1736.43, 1691.82,
1465.60, 1432.07 cm-1. HRMS (FAB) calcd for [M + H]+ C35H48N4O4,
589.3754; found, 589.3738.
PMB-Protected Module 16c. Glycoluril 5c (2.00 g, 2.36 mmol)
and Cs2CO3 (1.69 g, 5.19 mmol) were suspended in MeCN (30 mL).
After the reaction was refluxed for 30 min, 3-bromo-2-(bromomethyl)-
propanoic acid methyl ester (0.37 mL, 2.60 mmol) was added, and the
reaction was refluxed for 20 h. The resulting reaction mixture was
cooled to rt, poured into 100 mL of water, and partioned between water
and dichloromethane (100 mL). After separation of the phases, the
aqueous layer was further extracted with dichloromethane (2 × 100
mL). The combined organic extracts were washed with brine, dried
(MgSO4), and evaporated. Flash column chromatography (SiO2, eluent
EtOAc-hexane 1:3) gave the desired diastereomeric products in a
combined yield of 630 mg (28%).
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PMB-Protected Equatorial Ester 16ceq. Yield 380 mg (17%). H
NMR (CDCl3, 300 MHz): δ (ppm) 7.08-6.46 (m, 16H), 4.43 (dd, J
) 13.8 Hz, 4.4 Hz, 2H), 4.32 (d, J ) 16.2 Hz, 2H), 3.88 (d, J ) 16.2
Hz, 2H), 3.80 (m, 4H), 1.64 (m, 4H), 3.75 (s, 6H), 3.68 (s, 3H), 3.04
(dd, J ) 13.8 Hz, 11.7 Hz, 2H), 2.84 (m, 1H), 1.26 (m, 28H), 0.87 (t,
J ) 6.4 Hz, 6H). HRMS (FAB) calcd for [M + Cs]+ C57H76N4O8‚Cs+,
1077.4717; found, 1077.4676
Module 18b. PMB-protected glycoluril 16b (6.32 g, 8.5 mmol) was
dissolved in MeCN (200 mL) and heated to 50 °C, whereupon H2O
(40 mL) was added. The resulting clear solution was allowed to cool
to room temperature with stirring, causing the solution to become turbid.
Ceric ammonium nitrate (20.55 g, 37.5 mmol) was added in one
portion, and the reaction was stirred at room temperature for 24 h,
after which it was poured into EtOAc (600 mL). The resulting solution
was washed with 1 M HCl (3 × 300 mL), NaHCO3 (2 × 300 mL),
and brine (2 × 300 mL). The organic phase was dried (Na2SO4) and
evaporated, and the resulting oil was subjected to flash column
chromatography (2.5%-7.5% MeOH in CH2Cl2). Evaporation of the
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PMB-Protected Equatorial Ester 16cax. Yield 250 mg (11%). H
NMR (CDCl3, 300 MHz): δ (ppm) 7.20-6.27 (m, 16H), 4.57 (d, J )
14.2 Hz, 2H), 4.25 (d, J ) 16.2 Hz, 2H), 3.97 (d, J ) 16.2 Hz, 2H),
3.79 (s, 6H), 3.78 (s, 3H), 3.75 (m, 1H), 3.75 (m, 4H), 3.16 (dd, J )
14.2 Hz, 4.1 Hz, 2H), 1.67 (m, 4H), 1.26 (m, 28H), 0.87 (t, J ) 6.4
Hz, 6H). HRMS (FAB) calcd for [M + Cs]+ C57H76N4O8‚Cs+,
1077.4717; found, 1077.4674.
PMB-Protected Benzyl Ester 17a. Glycoluril 5a (29.24 g, 40.0
mmol), Cs2CO3 (19.55 g, 60.0 mmol) and benzyl acrylate 14 (4.71 g,
18.5 mmol) were mixed in CH3CN (400 mL), and the resulting reaction
mixture was heated at reflux for 5 h. After cooling to room temperature,
the mixture was partitioned between CH2Cl2 (800 mL) and 1 M HCl
(400 mL). Drying over Na2SO4, filtration, and evaporation of the solvent
gave an off-white foam. This residue was subjected to flash chroma-
tography (25-50% EtOAc/hexanes) to separate the equatorial ester
isomer 10c (faster eluting isomer) from the axial isomer (slower eluting
isomer). Each was isolated as a white foam. Combined yield 31.08 g
(86%).
PMB-Protected Equatorial Benzyl Ester 17aeq. Yield 22.12 g
(61%). 1H NMR (CDCl3, 600 MHz): δ (ppm) 7.35 (m, 5H), 7.08 (m,
4H), 6.82 (m, 8H), 6.73 (m, 2H), 6.65 (m, 2H), 5.10 (bs, 2H), 4.87
(dd, J ) 14.2, 4.7 Hz, 2H), 4.34 (d, J ) 16.3 Hz, 2H), 3.90 (d, J )
16.3 Hz, 2H), 3.77 (s, 6H), 3.08 (m, 2H), 2.89 (m, 1H), 2.38 (m, 4H),
1.41 (m, 4H), 1.24 (m, 16H), 0.88 (m, 6H). 13C NMR (CDCl3, 151
MHz): δ (ppm) 170.75, 159.65, 158.96, 144.38, 144.10, 135.52, 130.21,
130.08, 129.47, 128.96, 128.81, 128.75, 128.67, 128.42, 128.35, 127.67,
114.21, 88.65, 80.97, 67.02, 55.39, 45.90, 40.31, 38.19, 35.52, 35.38,
31.95, 31.92, 31.47, 31.37, 29.26, 29.25, 29.13, 22.80, 14.20. IR
(CDCl3): 2927.16, 2854.96, 1722.64, 1710.81, 1612.81, 1513.36,
1460.06, 1247.14, 1175.94 cm-1. MS (FAB) calcd for [M + Cs]+
C57H68N4O6‚Cs+, 1037; found, 1037.
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solvent gave the product as a white powder, yield 2.59 g (61%). H
NMR (CDCl3, 600 MHz): δ (ppm) 7.06 (m, 6H), 6.94 (dd, J ) 7.0
Hz, 1.9 Hz, 2H), 6.40 (s, 2H), 4.33 (dd, J ) 14.5 Hz, 4.6 Hz, 2H),
3.62 (s, 3H), 2.98 (m, 2H), 2.71 (m, 1H), 1.14 (s, 9H), 1.13 (s, 9H).
13C NMR (CDCl3, 150 MHz): δ (ppm) 171.26, 159.59, 152.45, 133.32,
129.88, 127.56, 127.35, 125.63, 125.23, 83.62, 78.94, 52.41, 40.12,
38.10, 34.74, 31.49. HRMS (FAB) calcd for [M + Na]+ C29H36N4O4‚
Na+, 527.2634; found, 527.2634.
Module 18c. PMB-protected glycoluril 16ceq (380 mg, 0.40 mmol)
was dissolved in acetonitrile/THF/water (4/2/1, 15 mL), and cerium
ammonium nitrate (1.76 g, 3.22 mmol) was added. The reaction was
stirred at room temperature for 24 h, after which it was concentrated
and partioned between water and dichloromethane. The aqueous layer
was further extracted with dichloromethane. The combined organic
layers were washed with brine, dried over MgSO4, and concentrated.
Trituration of residue with diethyl ether gave the desired equatorial
1
methyl ester. Yield 125 mg (44%). H NMR (CDCl3, 300 MHz): δ
(ppm) 7.12-6.59 (m, 8H), 5.51 (s, 2H), 4.35 (dd, J ) 14.6 Hz, 4.1
Hz, 2H), 3.81 (m. 2H), 3.64 (s, 3H), 2.97 (dd, J ) 14.6 Hz, 11.6 Hz,
2H), 2.72 (m, 1H), 1.69 (m, 4H), 1.26 (m, 28 H, 0.87 (t, J ) 7.2 Hz,
6H). HRMS (FAB) calcd for [M + H]+ C41H61N4O4‚Na+, 705.4591;
found, 705.4622.
Benzyl Ester 19a. In a 2-L Erlenmeyer flask, glycoluril 17a (18.10
g, 20.0 mmol) was dissolved in CH3CN (670 mL). H2O (130 mL) was
added which caused turbidity. After the reaction mixture had reached
room temperature, CAN (43.86 g, 80.0 mmol) was added and the
resulting reaction mixture stirred overnight, ∼16 h. The reaction mixture
was diluted with H2O (800 mL) and extracted with CH2Cl2 (800 mL).
Drying of the organic layer over Na2SO4, filtration, and evaporation
of the solvent afforded a yellow oil. Silica gel flash chromatography
(50% EtOAc/hexanes) afforded the target molecule as a white foam.
PMB-Protected Axial Benzyl Ester 17aax. Yield 8.96 g (25%). 1H
NMR (CDCl3, 600 MHz): δ (ppm) 7.50 (m, 2H), 7.36 (m, 3H), 7.22
(d, J ) 8.6 Hz, 4H), 6.85 (m, 8H), 6.72 (d, J ) 8.3 Hz, 2H), 6.67 (d,
J ) 8.3 Hz, 2H), 5.20 (s, 2H), 4.64 (d, J ) 14.3 Hz, 2H), 4.31 (d, J )
16.3 Hz, 2H), 4.02 (d, J ) 16.3 Hz, 2H), 3.77 (s, 6H), 3.19 (dd, J )
14.3, 4.3 Hz, 2H), 2.39 (m, 5H), 1.40 (m, 4H), 1.25 (m, 16H), 0.88
(m, 6H). 13C NMR (CDCl3, 151 MHz): δ (ppm) 172.32, 159.87,
158.84, 144.05, 143.83, 136.01, 130.72, 130.54, 129.27, 129.25, 128.93,
128.82, 128.61, 128.59, 128.20, 127.81, 113.96, 88.82, 80.66, 67.54,
1
Yield 8.03 g (60%). H NMR (CDCl3, 600 MHz): δ (ppm) 7.28 (m,
5H), 7.06 (d, J ) 8.1 Hz, 2H), 6.91 (d, J ) 8.1 Hz, 2H), 6.86 (m, 4H),