Ring Opening of Pyroglutamic Diketopiperazine
J . Org. Chem., Vol. 67, No. 6, 2002 1825
1,7-Diazatr icyclo[7.3.0.0]dodecan e-2,6,8,12-tetr on e (P y-
r oglu ta m ic Dik etop ip er a zin e) (3). To a 1000 mL round-
bottom flask were added acetic anhydride (345 mL), pyridine
(64 mL), and a magnetic stirring bar. A reflux condenser was
attached, and the flask was lowered into an oil bath preheated
to 110 °C. S-Pyroglutamic acid (77.4 g) was added to the
solvent mixture when the temperature reached 110 °C. Pyro-
glutamic diketopiperazine began to precipitate from solution
as a white solid after 5 min. Heating was continued for an
additional 15 min. The reaction mixture was cooled in an ice
bath, and the product was collected by vacuum filtration and
washed with cold methanol. The product was transferred to
an Erlenmeyer flask, covered with methanol, and collected by
filtration. This was repeated with distilled water. The product
was dried overnight under vacuum: yield 39.7 g (60%); mp
290 °C dec; 1H NMR (DMSO-d6 with TMS) δ 4.84 (dd, J )
8.86, 7.87 Hz, 2H), 2.84-2.11 (m, 8H); 13C NMR (DMSO-d6
with TMS) δ 172.7, 165.7, 58.4, 31.2, 18.9. Anal. Calcd for
2.25-2.08 (m, 4H), 1.98-1.80 (m, 4H); 13C NMR (DMSO-d6
with TMS) δ 171.6, 167.7, 53.6, 41.5, 30.9, 29.3. Anal. Calcd
for C14H24N4O6: C, 48.83; H, 7.02; N, 16.27. Found: C, 48.57;
H, 7.19; N, 16.05.
Methanol was removed in vacuo from the filtrate obtained
above to give 5c as a white solid: yield 3.086 g (94.3%); mp
165-169 °C; 1H NMR (DMSO-d6 with TMS): δ: 7.91 (s, 1H),
7.75 (s, 1H), 4.68 (s, 1H), 3.98 (m, 1H), 3.41 (t, J ) 5.88 Hz,
2H), 3.17-3.11 (m, 2H), 2.27-1.84 (m, 4H); 13C NMR (DMSO-
d6 with TMS) δ 177.1, 172.4, 60.0, 55.9, 41.6, 29.4, 25.4.
P yr oglu ta m ylglycin e (5d ). To a 50 mL round-bottom flask
were added pyroglutamic diketopiperazine (2.07 g, 0.0093 mol),
glycine (1.43 g, 0.0191 mol), 2,2,2-trifluoroethanol (20 mL), and
a stir bar. The reaction vessel was purged with nitrogen gas
and cooled to 0 °C in an ice bath, and triethylamine (1.98 g,
0.0196 mol) was added via syringe. The reaction was allowed
to warm slowly to room temperature and stirred for 12
additional h. The reaction flask was capped with a reflux
condenser and placed in an 80 °C oil bath for 2 h. The solvent
was removed in vacuo to give a milky white liquid. Methanol
was added, and the insoluble white solid was removed by
gravity filtration. Methanol was removed from the filtrate in
vacuo to give a viscous yellow oil. The oil was dissolved in 2
M NaOH (10 mL) and stirred for 1 h. The aqueous solution
was transferred to a separatory funnel and washed twice with
CHCl3 (10 mL). HCl (5 M, 3.9 mL) was added, and the solvent
was then removed in vacuo. Ethanol was added to the resulting
white slurry and the salt that formed was removed by vacuum
filtration. The solvent was removed in vacuo to give 5d as a
white solid: yield 2.74 g (81%); mp 168-171 °C; 1H NMR
(DMSO-d6 with TMS) δ 8.23 (t, J ) 5.88 Hz, 1H), 7.88 (s, 1H),
4.05 (q, 1H), 3.73 (d, 2H), 2.34-1.84 (m, 4H); 13C NMR (DMSO-
d6 with TMS) δ 177.6, 173.0, 171.2, 55.6, 40.7, 29.2, 25.4.
D iis o p r o p y l-2,5-d ik e t o p ip e r a zin e -3,6-d ip r o p a n a -
m id e (4e) a n d N-Isop r op ylp yr oglu ta m id e (5e). To a 100
mL round-bottom flask were added pyroglutamic diketopip-
erazine (1.02 g, 0.0048 mol), CHCl3 (25 mL), and a magnetic
stir bar. Isopropylamine (1.95 mL, 0.0229 mol) was added and
the reaction mixture was stirred for 12 h at room temperature.
An insoluble white solid was collected by gravity filtration and
C
10H10N2O4: C, 54.05; H, 4.54; N, 12.61; O, 28.80. Found: C,
54.10; H, 4.57; N, 12.62; O, 28.99.
Dip r op yl-2,5-d ik etop ip er a zin e-3,6-d ip r op a n a m id e (4a )
a n d N-P r op ylp yr oglu ta m id e (5a ). To a 50 mL round-bottom
flask were added pyroglutamic diketopiperazine (1.00 g, 0.0045
mol), CHCl3 (10 mL), and a magnetic stir bar. Propylamine
(0.59 g, 0.0099 mol) was added, and the reaction mixture was
stirred for 4 h. The white solid was collected by filtration and
dried in vacuo to give 4a : yield 0.078 g (5.1%); mp 290 °C dec;
1H NMR (DMSO-d6 with TMS) δ 7.97 (s, 1H), 7.64 (s, 1H),
3.82 (t, J ) 5.15 Hz, 2H), 3.03-2.96 (m, 4H), 2.27-2.10 (m,
4H), 1.46-1.34 (m, 4H), 0.84 (t, J ) 7.35 Hz, 6H); 13C NMR
(DMSO-d6 with TMS) δ 171.1, 167.5, 53.5, 40.1, 30.9, 30.5,
22.0, 11.0. Anal. Calcd for C16H28N4O4: C, 56.45; H, 8.29; N,
16.46. Found: C, 56.39; H, 8.23; N, 16.46.
CHCl3 was removed from the filtrate in vacuo to give 5a as
a white solid: yield 1.424 g (92.7%); mp 103-106 °C; 1H NMR
(DMSO-d6 with TMS) δ 7.93 (s, 1H), 7.77 (s, 1H), 3.98-3.93
(m, 1H), 3.06-2.99 (m, 2H), 2.30-2.05 (m, 3H), 1.89-1.78 (m,
1H), 1.48-1.36 (m, 2H), 0.84 (t, J ) 7.35 Hz, 3H); 13C NMR
(DMSO-d6 with TMS) δ 177.4, 172.2, 55.9, 40.6, 29.3, 25.4,
22.5, 11.2. Anal. Calcd for C8H14N2O2: C, 56.45; H, 8.29; N,
16.46. Found: C, 56.00; H, 8.27; N, 16.27.
1
was identified as 4e: yield 0.034 g (2.2%); mp 274 °C dec; H
Diben zyl-2,5-d ik etop ip er a zin e-3,6-d ip r op a n a m id e (4b)
a n d N-Ben zylp yr oglu ta m id e (5b). To a 50 mL round-
bottom flask were added pyroglutamic diketopiperazine (0.989
g, 0.0045 mol), CHCl3 (20 mL), and a magnetic stir bar.
Benzylamine (1.00 g, 0.0093 mol) was added and the reaction
mixture was stirred for 12 h. The white precipitate was
collected by vacuum filtration, mixed with DMF, and filtered
once more. The white solid was dried in vacuo to give 4b: yield
0.132 g (6.8%); mp 264 °C dec; 1H NMR (DMSO-d6 with
TMS): δ: 8.33 (s, 2H), 8.16 (s, 2H), 7.33-7.23 (m, 10H), 4.26
(d, 4H), 3.87 (m, 2H), 2.32-2.17 (m, 4H), 2.03-1.88 (m, 4H);
13C NMR (DMSO-d6 with TMS) δ 171.5, 167.7, 139.5, 128.3,
NMR (DMSO-d6 with TMS) δ 8.15 (s, 2H), 7.69 (d, 2H), 3.86-
3.78 (m, 4H), 2.17-2.05 (m, 4H), 1.92-1.85 (m, 4H), 1.02 (d,
12H); 13C NMR (DMSO-d6 with TMS) δ 170.3, 167.7, 167.6,
53.5, 31.0, 30.5, 29.2, 28.5, 22.4. Anal. Calcd for C16H28N4O4:
C, 56.45; H, 8.29; N, 16.46. Found: C, 55.89; H, 8.10; N, 16.32.
Chloroform and excess isopropylamine were removed in
vacuo from the filtrate obtained above to give 5e as a white
solid: yield 1.516 g (97%); mp 126-130 °C; 1H NMR (DMSO-
d6 with TMS) δ 7.80 (m, 2H), 3.95-3.91 (m, 1H), 3.83 (m, 1H),
2.25-2.04 (m, 3H), 1.89-1.79 (m, 1H), 1.06 (dd, 6H); 13C NMR
(DMSO-d6 with TMS) δ 177.4, 171.3, 55.8, 40.4, 29.3, 25.3,
22.3, 22.2. Anal. Calcd for C8H14N2O2: C, 56.45; H, 8.29; N,
16.46. Found: C, 56.48; H, 8.42; N, 16.63.
127.2, 126.7, 53.5, 42.1, 30.8, 29.1. Anal. Calcd for C24H28
-
N4O4: C, 66.04; H, 6.47; N, 12.84. Found: C, 65.92; H, 6.35;
N, 12.71.
(S)-1-P h en yleth yl-(S)-p yr oglu ta m id e (5f). To a 50 mL
round-bottom flask were added pyroglutamic diketopiperazine
(0.50 g, 0.0023 mol), CHCl3 (10 mL) and a magnetic stir bar.
(S)-(-)-1-Phenylethylamine (1.36 g, 0.0113 mol) was added and
the reaction mixture was stirred for 12 h. A condenser was
attached to the flask and the reaction mixture was heated at
reflux for 3 h. The solution was cooled and then filtered
through Celite. The solvent was removed from the filtrate in
vacuo to give a clear oil. The oil was triturated with ether
which resulted in the formation of a white solid. This material
was washed with excess ether and dried under vacuum to give
5f as a white solid: yield 0.88 g (84%); mp 135-138 °C; 1H
NMR (DMSO-d6 with TMS) δ 8.41 (d, 1H), 7.82 (s 1H), 7.32-
7.27 (m, 5H), 4.92 (m, 1H), 4.06-4.02 (q, 1H), 2.31-2.06 (m,
3H), 1.85-1.74 (m, 1H), 1.36 (d, 3H); 13C NMR (DMSO-d6 with
TMS) δ 177.4, 171.4, 144.4, 128.3, 126.7, 125.9, 55.6, 47.8, 29.3,
25.2, 22.4. Anal. Calcd for C13H16N2O2: C, 67.22; H, 6.94; N,
12.06. Found: C, 67.14; H, 7.11; N, 12.16.
CHCl3 and DMF were removed in vacuo from the combined
filtrates obtained above to give 5b as a white solid: yield 1.671
g (86%) white solid; mp 134-137 °C; 1H NMR (DMSO-d6 with
TMS) δ 8.51 (s, 1H), 7.87 (s, 1H), 7.35-7.25 (m, 5H), 4.30 (d,
2H), 4.07-4.038 (m, 1H), 2.34-1.86 (m, 4H); 13C NMR (DMSO-
d6 with TMS) δ 177.6, 172.6, 139.3, 127.3, 127.1, 126.9, 56.1,
42.2, 29.4, 25.5. Anal. Calcd for C12H14N2O2: C, 66.04; H, 6.47;
N, 12.84. Found: C, 65.83; H, 6.55; N, 12.72.
Bis(2-h yd r oxyet h yl)-2,5-d ik et op ip er a zin e-3,6-d ip r o-
p a n a m id e (4c) a n d N-(2-H yd r oxyet h yl)p yr oglu t a m id e
(5c). To a 50 mL round-bottom flask were added pyroglutamic
diketopiperazine (2.115 g, 0.0095 mol), CHCl3 (20 mL), and a
magnetic stir bar. Ethanolamine (1.16, 0.0190 mol) was added
and the reaction mixture was stirred for 12 h. Chloroform was
removed in vacuo and methanol added to the resulting white
solid. The insoluble white solid was collected by filtration and
was identified as 4c: yield 0.123 g (3.76%); mp 257 °C dec; 1H
NMR (DMSO-d6 with TMS) δ 8.17 (s, 1H), 7.85 (s, 1H), 4.66
(t, J ) 4.41 Hz, 2H), 3.83 (s, 2H), 3.87 (m, 4H), 3.09 (q, 4H),
(R)-1-P h en yleth yl-(S)-p yr oglu ta m id e (5g). Preparation
was similar to that of (S)-1-phenylethyl-(S)-pyroglutamide (5f)
above: yield (87%); mp 151-152 °C; 1H NMR (DMSO-d6 with