5366 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 26
Alfaro-Lopez et al.
was cooled to 0 °C, and then ice-water was added to form an
insoluble material. To the mixture were added 30 mL of 2 N
NaOH and 50 mL of EtOAc. The organic phase was separated
and the aqueous phase extracted two times with EtOAc. The
combined organic phases were washed with brine, dried over
MgSO4, and concentrated in vacuo. The residual oil was
purified by flash chromatography (EtOAc/hexane, 4:1 to 3:1)
to yield 7.67 g (94.3%) of compound 10 as a colorless oil. 1H
NMR (CDCl3, 200 MHz): δ 7.40-7.10 (m, 10H), 6.92-6.80 (m,
2H), 6.67 (dd, J ) 1.7, 7 Hz, 1H), 3.77 (s, 3H), 3.49 (s, 2H),
3.44 (d, J ) 11 Hz, 1H), 2.84 (br d, J ) 12 Hz, 2H), 2.20-1.83
(m, 3H), 1.65-1.20 (m, 4H), 1.27 (s, 9H). 13C NMR (CDCl3, 50
MHz): δ 160.07, 149.22, 146.38, 141.01, 138.87, 129.77, 129.67,
128.54, 128.06, 127.31, 125.77, 121.03, 114.88, 111.14, 78.12,
63.82, 58.96, 55.56, 54.28, 40.16, 34.76, 31.84. FAB/MS calcd
for C30H38NO [M+H]+ ) 428.63; found 428.29.
P r ep a r a t ion of N-Ben zyl-4-(4-ter t-b u t yl-3′-h yd r oxy-
ben zh yd r yl)p ip er id in e (11). Compound 10 (0.24 g, 0.56
mmol) was dissolved in 1.15 mL of 0.1 M BBr3/DCM solution
at -10 °C, and the mixture was allowed to stir at room
temperature for 1 h. To the solution was added an excess
amount of ice-cooled NaHCO3 solution, and then the mixture
was extracted two times with DCM. The combined organic
phases were dried over MgSO4 and concentrated in vacuo. The
residue was purified by flash chromatography (CHCl3/MeOH,
50:1). The purified free amine was dissolved in 0.20 mL of 4
N HCl/dioxane, and the hydrochloride salt was precipitated
by adding ether to this solution. The resulting solid was filtered
off and dried in vacuo to yield 78 mg (31.0%) of compound 11
as an off-white solid: mp ) 186-190 °C (decomp). 1H NMR
(CDCl3, 200 MHz): δ 7.70-7.30 (m, 4H), 7.20-6.90 (m, 7H),
6.80-6.65 (m, 2H), 4.20-3.85 (m, 2H), 3.45-3.00 (m, 3H),
(m, 8H), 7.11-7.01 (m, 2H), 5.27 (dd, 1H, J ) 4.38 Hz), 4.75-
4.61 (m, 1H), 4.56-4.48 (m, 1H), 4.22-4.06 (m, 2H), 3.14-
2.91 (m, 2H), 1.38 (s, 9H), 1.28-1.18 (m, 5H). 13C NMR (CDCl3,
50 MHz): δ 172.71, 168.74, 135.95, 129.63, 128.68, 128.57,
128.43, 127.94, 127.65, 127.27, 126.76, 79.72, 61.63, 61.12,
51.88, 51.67, 48.21, 47.02, 39.62, 28.24, 14.01. ESI/MS calcd
for C25H33N2O5 [M + 1]+ ) 441.23; found 441.26.
P r ep a r a tion of 1-Ben zyl-3-ben zyloxym eth yl-2,5-d ik e-
top ip er a zin e (13a ). Compound 12a (1.15 g, 2.61 mmol) was
treated with 14 mL of 95% TFA-DCM at room temperature
and was monitored by TLC (MeOH/AcOEt, 4:6). After 1 h TLC
indicated total consumption of starting material. The reaction
was evaporated off, and the residue (a yellow oil) was dried
under high vacuum for 2 h to remove most of the TFA. The
residue was redissolved in 10 mL of DCM, and 2 mL of TEA
was added at room temperature; upon addition of TEA the
clear solution became cloudy. The reaction was stirred at room
temperature for 2 h. The reaction was monitored by TLC by
spraying the TLC with an ethanolic solution of ninhydrin and
heating; the product was ninhydrin inactive. The mixture was
evaporated off and the residue purified with two solvent
systems of increasing polarity (hexanes/AcOEt, 4:6) until all
the hydrophobic contaminant was eliminated and then (MeOH/
AcOEt, 4:6) to elute the desired compound. Concentration of
the collected pure fractions gave 0.853 g of compound 13a as
a white solid (96% yield): mp ) 149-150 °C. 1H NMR (CDCl3,
200 MHz): δ 7.32-7.20 (m, 10H), 4.75 (d, 1H, J ) 14.6 Hz),
4.52 (s, 2H), 4.43 (d, 1H, J ) 14.6 Hz), 3.97-3.88 (m, 2H),
3.79-3.68 (m, 2H). 13C NMR (CDCl3, 50 MHz): δ 166.34,
164.43, 137.20, 134.90, 128.83, 128.49, 128.17, 127.97, 127.58,
73.59, 71.98, 55.93, 49.67, 49.13. ESI/MS calcd for C13H21N2O3
[M + 1]+ ) 325.08; found 325.00.
2.70-1.40 (m, 8H), 1.18 (s, 9H). FAB/HRMS calcd for C29H36
-
P r ep a r a tion of 1-Ben zyl-3-m eth yl-2,5-d ik etop ip er a -
zin e (13b). Following the same procedure outlined above for
13a , but using 12b, led to 13b, after flash chromatography
purification (MeOH/AcOEt, 4:6), as a white solid (75% yield):
NO [M + H]+ ) 414.2797; found 414.2796. Anal. Calcd for
C29H35NO-HCl: C, 77.39; H, 8.06; N, 3.11. Found: C, 77.15;
H, 7.66; N, 3.11.
1
P r epar ation of Nr-Boc-Ser (OBzl)-Nr-ben zylglycin e Eth -
yl Ester (12a ). Into a solution of N-benzylglycine ethyl ester
(1 g, 5.17 mmol), N-Boc-Ser(OBzl)-OH (1.52 g, 5.17 mmol), and
HOBT (1.46 g, 10.8 mmol) dissolved in 20 mL of DCM and at
0 °C was added dropwise dicyclohexylcarbodiimide (DCC) (1.12
g, 5.40 mmol) dissolved in 5 mL of DCM. The reaction was
stirred and allowed to warm to room temperature overnight.
TLC (hexanes/AcOEt, 4:6) showed total consumption of the
benzylglycine ester. The crude mixture was diluted with 100
mL of DCM, filtered twice to eliminate most of the urea
byproduct to yield, after evaporation of the solvent, a slightly
green oil. Flash chromatography purification gave 1.96 g
mp ) 137-138 °C. H NMR (CD3OD, 200 MHz): δ 7.36-7.26
(m, 5H), 4.60 (d, 2H, J ) 3.1 Hz), 4.11 (q, 1H, J ) 7 Hz), 3.88
(s, 2H), 1.45 (d, 3H, J ) 6.96 Hz). 13C NMR (CD3OD, 50
MHz): δ 169.46, 167.95, 136.96, 129.92, 129.11, 128.99, 128.91,
52.02, 19.84. ESI/MS calcd for C12H15N2O2 [M + 1]+ ) 219.10;
found 219.01.
P r epar ation of 1,3-Diben zyl-2,5-diketopiper azin e (13c).
Following the same procedure outlined above for 13a , but
using 12c, led to 13c, after flash chromatography purification,
as a white solid (96% yield): mp ) 172-173 °C. 1H NMR
(CDCl3, 200 MHz): δ 7.32-7.15 (m, 10H), 4.46 (s, 2H), 4.3 (bs,
1H), 3.49 (d, 1H, J ) 17.6 Hz), 3.17 (m, 2H), 2.92 (d, 1H, J )
17.6 Hz). 13C NMR (DMSO, 50 MHz): δ 165.49, 165.00, 135.70,
130.14, 128.54, 128.35, 128.12, 127.58, 126.83, 55.60, 48.49,
48.25, 39.24. ESI/MS calcd for C18H19N2O2 [M + 1]+ ) 295.13;
found 295.10.
P r ep a r a t ion of 1-Ben zyl-3-b en zyloxym et h ylp ip er a -
zin e (14a ). A solution of compound 13a (0.60 g, 1.85 mmol)
dissolved in 15 mL of dry THF was flushed with nitrogen for
20 min. The solution was cooled to 0 °C in an ice bath, and
LAH (0.35 g, 9.25 mmol) was added in portions (slowly at the
beginning). The reaction was stirred at room temperature for
1 h, then LAH (0.210 g, 5.5 mmol) was added, and the reaction
was stirred at room temperature for 36 h. The reaction was
cooled to -10 °C, and 0.15 mL of a 15% aqueous NaOH
solution was added. After 1 h, 2 mL of H2O was added and
the reaction stirred overnight. The white precipitate was
filtered out and washed with DCM (3 × 20 mL). The solution
was dried over MgSO4, filtered, and concentrated to give 0.46
g of a slightly green oil (84% yield). 1H NMR (CDCl3, 200
MHz): δ 7.30-7.25 (m, 10H), 4.47 (s, 2H), 3.48 (s, 2H), 3.39-
3.33 (m, 2H), 3.1-2.9 (m, 1H), 2.9-2.85 (m, 2H), 2.08 (td, 1H,
J ) 4.04 Hz), 1.82 (t, 1H, J ) 10.2 Hz). 13C NMR (CDCl3, 50
MHz): δ 137.99, 137.81, 129.08, 128.29, 128.09, 127.62, 127.58,
126.94, 73.27, 72.52, 63.30, 55.74, 54.47, 53.61, 45.03. FAB/
MS calcd for C19H25N2O [M + 1]+ ) 297.4219; found 297.1967.
1
(80.6% yield) of a colorless oil. H NMR (CDCl3, 200 MHz): δ
7.3-7.22 (m, 10H), 5.43 (d, 1H, J ) 7.9 Hz), 4.98 (d, 1H, J )
14.5 Hz), 4.73 (d, 1H, J ) 13.1 Hz), 4.51 (s, 2H), 4.42 (d, 1H,
J ) 14.7 Hz), 4.17-4.07 (m, 3H), 3.74-3.63 (m, 2H), 1.43 (s,
9H), 1.22 (t, 3H, J ) 6.9 Hz). 13C NMR (CDCl3, 50 MHz): δ
171.65, 168.90, 168.65, 155.02, 135.98, 128.79, 128.30, 128.01,
127.89, 127.82, 127.62, 127.39, 79.78, 73.38, 71.31, 61.55,
51.96, 50.14, 46.93, 28.23, 14.04. ESI/MS calcd for C26H34N2O6
[M + Na]+ ) 493.28; found 493.30.
P r ep a r a tion of Nr-Boc-Ala -Nr-ben zylglycin e Eth yl Es-
ter (12b). Following the same procedure outlined for 12a , but
using Boc-Ala-OH, led to 12b, after flash chromatography
purification (AcOEt/hexanes, 1:1), as a colorless oil (93% yield).
1H NMR (CDCl3, 200 MHz): δ 7.37-7.20 (m, 5H), 5.48 (bs,
1H), 4.80-4.50 (m, 3H), 4.18-4.11 (dd, 3H), 1.44-1.42 (bs,
9H), 1.39-1.34 (dd, 3H), 1.28-1.20 (td, 3H). 13C NMR (CDCl3,
50 MHz): δ 173.80, 168.89, 168.72, 155.11, 154.86, 136.06,
135.25, 128.87, 128.55, 128.05, 127.97, 127.54, 127.17, 79.56,
51.53, 61.07, 60.24, 51.70, 49.86, 48.23, 46.70, 46.06, 28.21,
19.21, 13.98. FAB/MS calcd for C19H29N2O5 [M + 1]+ ) 365.20;
found 365.10.
P r ep a r a tion of Nr-Boc-P h e-Nr-ben zylglycin e Eth yl
Ester (12c). Following the same procedure outlined for 12a ,
but using Boc-Phe-OH, led to 12c (2.116 g), after flash
chromatography purification (AcOEt/hexanes, 1:1), as a white
solid (93% yield). 1H NMR (CDCl3, 200 MHz): δ 7.28-7.21
P r ep a r a tion of 1-Ben zyl-3-m eth ylp ip er a zin e (14b).
Following the same procedure outlined above for 14a , but