Poly(ethylene glycol)-Linked Dioxocyclams
J . Org. Chem., Vol. 65, No. 24, 2000 8305
1.97-2.02 (m, 2H); 1.32, (s, 6H); 1.20, (s, 6H); 1.14 (s, 6H); 13
NMR (d6-acetone) δ 172.7, 80.3, 71.6, 71.3, 63.6, 58.2, 57.1,
53.5, 26.7, 25.0, 20.1; IR (thin film) ν 1667 cm-1. Anal. Calcd
C: 57.62, H: 9.23, N: 12.22. Found: C: 57.44, H: 9.10, N:
12.27.
Dioxocycla m 5a . 1H NMR δ 7.07 (s, 4H); 3.45-3.72 (m,
24H); 2.88 (d, J ) 12.0 Hz, 4H); 2.62 (d, J ) 12.3 Hz, 4H);
2.12 (d, J ) 11.1 Hz, 4H); 1.42 (s, 12H); 1.32 (s, 12H); 1.25 (s,
12H); 13C NMR δ 171.9, 80.1, 70.8, 70.7, 62.7, 56.9, 56.4, 52.9,
26.8, 25.2, 19.3; IR (thin film) ν 1670 cm-1. This solid was
recrystallized from MeOH:H2O to give X-ray quality crystals.
mp 134 °C.
Dioxocycla m 4b, 5b. The dimerization and reduction of
3b were accomplished using the general conditions for 4a , 5a .
Using 0.64 g (1.3 mmol) of free azapenam 3b, after the
reduction and purification, 0.23 g (0.45 mmol, 35%) of 4b as a
white solid and 0.097 g (0.10 mmol, 15%) of 5b as a white solid
were obtained.
Dioxocycla m 4b. 1H NMR δ 7.05 (s, 2H); 3.72-3.85 (m,
2H); 3.67-3.70 (m, 12H); 3.57-3.66 (m, 4H); 2.92 (d, J ) 11.7
Hz, 2H); 2.57 (d, J ) 11.7 Hz, 2H); 2.04 (d, J ) 10.8 Hz, 2H);
1.43 (s, 6H); 1.33 (s, 6H); 1.29 (s, 6H); 13C NMR δ 172.1, 80.2,
71.0, 70.6, 70.3, 63.0, 57.3, 56.5, 53.1, 27.2, 25.4, 19.4; IR (thin
film) ν 1668 cm-1; HRMS FAB (M + 1) C24H47N4O7 Calcd
503.3445. Found: 503.3434. This solid was recrystallized from
MeOH:H2O to give X-ray quality crystals.
Dioxocycla m 5b. 1H NMR δ 6.96 (s, 4H); 3.59-3.71 (m,
28H); 3.45-3.54 (m, 8H); 2.84 (d, J ) 12.0 Hz, 4H); 2.53 (d, J
) 12.3 Hz, 4H); 2.07 (d, J ) 10.8 Hz, 4H); 1.38 (s, 12H); 1.29
(s, 12H); 1.22 (s, 12H); 13C NMR δ 172.0, 80.4, 71.0, 70.8, 70.7,
63.0, 57.3, 56.4, 53.1, 27.0, 25.4, 19.3; IR (thin film) ν 1668
cm-1; HRMS FAB (M + 1) C48H93N8O14 Calcd 1005.6811.
Found: 1005.6781.
was freeze-pump-thaw degassed three times and flushed
with CO (the pressure tube was filled with 80 psi of CO and
slowly released) three times. The pressure tube was filled with
80 psi CO and irradiated (4 × 500 W halogen lamps) at 55 °C.
After 7 h, the reaction was removed from the 55 °C bath and
irradiated at room temperature (450 W Conrad-Hanovia 7825,
Pyrex well) for 2 days. The solvent was removed under
vacuum, and methanol was added to precipitate the Cr(CO)6.
This was removed by filtration, and the methanol was removed
under vacuum. The residue was dissolved in 1:1 hexane:ethyl
acetate and placed into sunlight to oxidize any residual
chromium complexes (usually 1 day), the mixture was filtered,
and the solvent was removed under vacuum. Purification was
accomplished using column chromatography (silica gel) eluting
with 3:1 hexane:ethyl acetate until the unreacted imidazoline
was off and then with ethyl acetate to obtain 0.916 g (1.3 mmol,
74%) as a clear oil.
Cbz-protected 3a (0.866 g, 1.2 mmol), 500 mg of 10% Pd/C,
60 mL of dry methanol, and 60 drops of triethylamine were
added to an oven dried 125 mL Ace pressure tube. This was
pressured with 80 psi H2 and stirred at room temperature for
2 h. The mixture was filtered and the solvent removed under
vacuum. The residue was dissolved in CH2Cl2 and washed one
time with 5% NaHCO3 (aq). The aqueous layer was extracted
three times with CH2Cl2, and the combined organic layers were
dried over Na2SO4. The solvent was removed under vacuum
to yield 0.545 g (1.2 mmol, 100%) of free azapenam 3a as a
clear oil. 1H NMR δ 4.75 (s, 2H); 3.79-3.84 (m, 4H); 3.62-
3.75 (m, 8H); 3.05 (d, J ) 11.1 Hz, 2H); 2.65 (d, J ) 11.4 Hz,
2H); 2.35 (bs, 2H); 1.54 (s, 6H); 1.30 (s, 6H); 1.08 (s, 6H); 13C
NMR δ 175.5, 89.5, 77.9, 70.4, 65.3, 61.9, 60.8, 24.8, 21.6, 14.7;
IR (thin film) ν 1747 cm-1; HRMS FAB (M + 1) C22H39N4O6
Calcd 455.2870. Found 455.2864.
C
Bis-a za p en a m 3b. Using a procedure similar to that of 3a ,
1.3 g (2.1 mmol) of bis-carbene complex 2b, 0.94 g (4.1 mmol)
of 4,4′-dimethyl-4,5-dihydroimidazole-1-carboxylic acid benzyl
ester, and 70 mL of CH2Cl2 were irradiated (4 × 500 W halogen
lamps) at 55 °C for 5 h and then at room temperature (450 W
Conrad-Hanovia 7825, Pyrex well) for 2 days, followed by
isolation as with 3a to give 1.4 g (1.8 mmol, 83%) of Cbz-
protected azapenam 3b. The Cbz group was removed under
standard conditions using 1.1 g (1.4 mmol) of azapenam, 560
mg of 10% Pd/C, 70 mL of methanol, and 2 mL of triethylamine
to yield 1.4 g (1.3 mmol, 91%) of free azapenam 3b as a clear
Nick el Com p lex 6a . Into a flame-dried, 100 mL round-
bottom flask under Ar were placed 114 mg (0.249 mmol) of
basket cyclam 4a , 544 mg (1.2 mmol) of NiBr2‚3DMF, one drop
of triethylamine, and 30 mL of MeOH. This mixture was
heated to reflux overnight. The solution was cooled to room
temperature and filtered through Celite, and the solvent was
removed under vacuum. The residue was dissolved in CH2Cl2
and washed once with water. The aqueous layer was extracted
with 3 × 50 mL of CH2Cl2. The combined organic layers were
dried over MgSO4 and filtered, and the solvent was removed
under vacuum. Purification was accomplished using column
chromatography (silica gel) eluting with 8:1 ethyl acetate:
methanol to yield 71 mg (0.138 mmol, 55%) of 6a as a pink
solid: 1H NMR δ 4.18-4.11 (m, 2H); 3.99-3.75 (m, 8H); 3.54
(d, J ) 10.4 Hz, 2H); 3.22 (t, J ) 12.6 Hz, 2H); 2.78 (dd, J )
10.8 Hz, 13.8 Hz, 2H); 2.52 (t, J ) 11.6 Hz, 2H); 2.13 (dd J )
11.1, 1.6 Hz, 2H); 1.84, (dd, J ) 10.5, 2.7 Hz, 2H); 1.40 (s, 6H);
1.29, (s, 6H); 1.20, (s, 6H); 13C NMR δ 172.7, 70.3, 69.5, 65.6,
1
oil. H NMR δ 4.82 (s, 2H); 3.88 (m, 2H); 3.70-3.81 (m, 14H);
3.10 (d, J ) 11.4 Hz, 2H); 2.66 (d, J ) 11.1 Hz, 2H); 2.38 (bs,
2H); 1.60 (s, 6H); 1.36 (s, 6H); 1.14 (s, 6H); 13C NMR δ 175.5,
170.8, 89.5, 77.8, 70.5, 70.4, 70.3, 69.0, 65.2, 63.5, 61.9, 60.8,
24.9, 21.7, 20.9, 14.8. IR (thin film) ν 1745 cm-1; HRMS FAB
(M + 1) C24H43N4O7 Calcd 499.3132. Found 499.3121.
Dioxocycla m 4a , 5a . Into a 250 mL round-bottom flask
were placed 0.496 g (1.09 mmol) of azapenam 3a , 32 mg (0.14
mmol) of racemic camphor sulfonic acid, and 110 mL of dry
CH2Cl2. This was allowed to stir at room temperature for 3
days. The solution was then washed with 5% NaHCO3 (aq), and
the aqueous layer was extracted three times with CH2Cl2. The
solution was dried over Na2SO4 and the solvent removed under
vacuum. The residue was dissolved in 55 mL of CH2Cl2 and
55 mL of methanol. To this were added a small crystal of
bromocresol green and 151 mg (2.4 mmol) of NaCNBH3. The
mixture was cooled to 0 °C, and sat. HCl/MeOH was added
until a yellow-green color persisted (pH ∼ 6). The reaction was
warmed to room temperature and stirred at this temperature
overnight, adding additional HCl/MeOH as needed to keep the
pH ∼ 6. Saturated HCl/MeOH was added to give a pH ) 1.
Then, 10% NaOH(aq) was added to give a pH ) 10. The aqueous
layer was extracted three times with CH2Cl2 and dried over
Na2SO4, and the solvent was removed under vacuum. Purifica-
tion was accomplished using column chromatography (silica
gel) eluting with 95:5 CH2Cl2:MeOH to yield 0.149 g (0.33
mmol, 30%) of basket cyclam 4a as a white solid, and then
10:1 CH2Cl2:MeOH to yield 0.123 g (0.13 mmol, 25%) of bis-
cyclam 5a as a white solid.
62.1, 58.5, 57.1, 25.1, 22.7, 20.1; IR (thin film) ν 1550 cm-1
.
This solid was recrystallized from CH2Cl2:MeOH to give X-ray
quality crystals.
Nick el Com p lex 7a . Into a flame-dried, 50 mL round-
bottom flask under Ar were placed 571 mg (2.9 mmol) of
AgBF4, 634 mg (2.9 mmol) of NiBr2, and 29 mL of THF. This
solution was heated to reflux for 1 h. The resulting pale green
solution was filtered hot through Celite into an oven-dried,
125 mL Ace pressure tube containing 265 mg (0.29 mmol) of
bis-cyclam 5a , 0.15 mL of triethylamine, and 10 mL of THF.
The tube was sealed and heated to 80 °C for 2 days. The
resulting pink solution was cooled to room temperature, and
20 mL of 5% NaHCO3
was added. This solution was
(aq)
extracted with 3 × 20 mL of CH2Cl2 and dried over Na2SO4,
and the solvent was removed under vacuum to yield 180 mg
(0.175 mmol, 60%) of 7a as a pink solid. mp > 200 °C; 1H NMR
δ 3.65-3.87 (m, 28H); 3.06 (t, J ) 12.6 Hz,6H); 2.75 (dd, J )
10.8, 13.5 Hz. 4H); 2.50 (t, J ) 11.7 Hz, 4H); 2.13, (d, J ) 9.9
Hz, 4H); 1.84 (d, J ) 10.5 Hz, 4H); 1.35 (s, 12H); 1.26 (s, 12H);
1.17 (s, 12H); 13C NMR δ 172.5, 76.8, 70.9, 70.5, 65.3, 62.8,
58.4, 56.5, 24.8, 22.6, 20.3; IR (thin film) ν 1574 cm-1. This
solid was recrystallized from CHCl3:pentane to give X-ray
quality crystals.
Dioxocycla m 4a . 1H NMR (d6-acetone) δ 7.57 (s, 2H); 3.45-
3.72 (m, 12H); 3.03 (d, J ) 11.3 Hz, 2H); 2.80, (d, J ) 11.7 Hz,
2H); 2.65, (d, J ) 11.8 Hz, 2H); 2.11, (d, J ) 11.3 Hz, 2H);
Nick el Com p lex 6b. Nickel complex 6b was synthesized
under the conditions for 7a using 0.209 g (1.06 mmol) of AgBF4,