Synthesis of peptidyl ureas using p-nitrophenyl-(9-fluorenylmethoxy carbonylamino)methyl carbamate derivatives

Article abstract of DOI:10.1081/SCC-120039483

An efficient synthesis of p-nitrophenyl-(9-fluorenylmethoxy carbonylamino) methyl carbamates using isocyanates derived from Fmoc-amino acid azides and p-nitrophenol in presence of an equimolar quantity of N-ethyldiisopropyl amine is described. All the carbamates have been isolated as crystalline solids and are fully characterized. Further, their utility for the synthesis of dipeptidyl ureas has been demonstrated.

Full text of DOI:10.1081/SCC-120039483

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Synthesis of
Peptidyl Ureas Using
p‐Nitrophenyl‐(9‐fluorenylmethox
Carbonylamino)methyl
Carbamate Derivatives
Basanagoud S. Patil a , Ganga‐Ramu
Vasanthakumar a & Vommina V. Suresh Babu a
a Department of Studies in Chemistry , Central
College Campus, Bangalore University , Dr. B. R.
Ambedkar Veedhi, Bangalore, 560 001, India
Published online: 30 Mar 2009.
To cite this article: Basanagoud S. Patil , Ganga‐Ramu Vasanthakumar
& Vommina V. Suresh Babu (2004) Synthesis of Peptidyl Ureas Using
p‐Nitrophenyl‐(9‐fluorenylmethoxy Carbonylamino)methyl Carbamate Derivatives,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 34:13, 2313-2321, DOI: 10.1081/SCC-120039483
To link to this article: http://dx.doi.org/10.1081/SCC-120039483
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 13, pp. 2313–2321, 2004
Synthesis of Peptidyl Ureas Using
p-Nitrophenyl-(9-fluorenylmethoxy
Carbonylamino)methyl Carbamate
Derivatives
Basanagoud S. Patil, Ganga-Ramu Vasanthakumar,
*
and Vommina V. Suresh Babu
Department of Studies in Chemistry, Central College Campus,
Bangalore University, Bangalore, India
ABSTRACT
An efficient synthesis of p-nitrophenyl-(9-fluorenylmethoxy carbonyl-
amino) methyl carbamates using isocyanates derived from Fmoc-
amino acid azides and p-nitrophenol in presence of an equimolar
quantity of N-ethyldiisopropyl amine is described. All the carbamates
have been isolated as crystalline solids and are fully characterized.
*
Correspondence: Vommina V. Suresh Babu, Department of Studies in Chemistry,
Central College Campus, Bangalore University, Dr. B. R. Ambedkar Veedhi, Bangalore
560 001, India; E-mail: hariccb@rediffmail.com.
2313
DOI: 10.1081/SCC-120039483
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

2314
Patil, Vasanthakumar, and Suresh Babu
Further, their utility for the synthesis of dipeptidyl ureas has been
demonstrated.
Key Words: Peptidyl ureas; N-Ethyldiisopropyl amine; Equimolar quantity;
Isocyanate derivative.
INTRODUCTION
The peptide backbone provides a framework for constructing large
folded polymers with a wide range of functions as well as smaller oligomeric
agonists, antagonists, enzyme inhibitors, etc. The problems associated
with the therapeutic utility of peptides have led to develop new oligomeric
backbones (carbamates, peptoids, ureas, sulfonamides, azatides), which
have improved pharmacokinetic properties relative to native peptides.[1]
The general procedures for the synthesis of peptidyl ureas involve the
reaction of an isocyanate and primary amine. Isocyanates are usually prepared
by bubbling phosgene gas through a solution of an amine at elevated tempera-
ture[2] or in the presence of a base at room temperature (r.t).[3] Although the
use of triphosgene is a viable substitute,[4] its utility is reported to be not satis-
factory in the case of isocyanate derivatives derived from Na-protected amino
acids.[5] Alternative methods for the preparation of peptidyl ureas are
involve the use of a carbonic acid derivative. In general, the carbamates have
been prepared using p-nitrophenyl chloroformate,[6] 2,4,5-trichlorophenyl
chloroformate,[7] (phenoxycarbonyl) tetrazole,[8] N,N0-carbonyldiimidazole,[9]
1,10-carbonylbisbenzotriazole,[10] etc., and mono protected diamines which
have to be obtained in about four to five steps.[3a,11–13] The present communi-
cation describes the synthesis of p-nitrophenyl-(9-fluorenylmethoxy carbonyl-
amino)methyl carbamate derivatives using p-nitrophenol and isocyanates
derived from Fmoc-amino acid azides in presence of a base (Sch. 1) and
their utility for the synthesis of several peptidyl ureas.
Fmoc protected amino acids were first converted to the corresponding
azides 1 by the acid chloride method or by the mixed anhydride method
using isobutyloxycarbonylchloride (IBC-Cl) and N-methyl morpholine
(NMM) at 08C (in the case of amino acids bearing acid labile side chain
protecting groups).[14,15] The resulting acyl azides 1 were converted to the
corresponding isocyanates 2 by the Curtius rearrangement (toluene, 658C,
10 min), which were then reacted with p-nitrophenol (1 equiv.) in presence
of N-ethyldiisopropylamine (DIEA, 1 equiv.) at r.t. to afford the carbamates
3 as crystalline solids in about 88–94% yield. All the carbamates 3 prepared
have been separated as solids that were filtered and isolated. Their recrystal-
lization using dimethylformamide (DMF)–dichloromethane (DCM) gave

Synthesis of Peptidyl Ureas
2315
Scheme 1.
analytically pure samples. When stored at 48C for long periods, neither notice-
able degradation nor any change in their spectral behavior (1H NMR recorded
after several weeks of storage) has been observed.
The utility of the carbamates 3 has been demonstrated by the synthesis of
a series of dipeptidyl ureas 5 (Sch. 2). The acylation of amino acid ester hydro-
chloride salt in presence of DIEA with the carbamate 3 in DCM at r.t. has
resulted in the separation of the peptidyl ureas 5 as solids. As in the case
with the carbamates 3, the recrystallization of the peptidyl ureas 5 using
dimethylsulfoxide (DMSO)–water mixture led to obtain analytically pure
samples in about 90–96% of yield.
In summary, a simple method for the preparation of p-nitrophenyl-
(9-fluorenylmethoxycarbonylamino)methyl carbamates and their utility for
the synthesis of peptidyl ureas has been demonstrated. All the compounds
prepared have been fully characterized.
Scheme 2.

2316
Patil, Vasanthakumar, and Suresh Babu
EXPERIMENTAL
Melting points were determined using capillary method and are uncor-
rected. IR spectra were recorded on a Nicolet model impact 400D FT-IR
spectrometer (KBr pellets, 3 cm21 resolution). Specific rotations were
recorded on Rudolf Research Autopol IV automatic polarimeter. Elemen-
tary analyses were carried out using Perkin Elmer Analyzer and the
1
samples were dried for 24 hr under vacuum before analysis. H and 13C
NMR spectra were recorded on a Bruker AMX 400 MHz spectrometer.
Mass spectra were recorded on MALDI-TOF (KRATOS) and PE-SCIEX
150 EX LCMS. All solvents were freshly distilled prior to use. Amino
acid methyl ester hydrochlorides were prepared by using methanol and
thionyl chloride. Fmoc-amino acid azides were prepared by the procedures
reported by us.[14,15]
General Procedure for the Preparation of p-Nitrophenyl-
(9-fluorenylmethoxy Carbonylamino)methyl Carbamate 3
The Fmoc-amino acid azide 1 (1 mmol) was converted to the respective
isocyanate 2 by the Curtius rearrangement (in toluene at 658C for 20 min).
The solution was cooled to r.t. and p-nitrophenol (1 mmol) and DIEA
(1 mmol) were added. It was stirred at r.t. till the completion of the reaction.
The separated solid was filtered and washed with DCM and toluene to get the
title compound as a solid in almost quantitative yield.
p-Nitrophenyl-f1-f[(9H-fluorenyl-9-ylmethoxy)carbonyl]aminog-methylg
1
carbamate 3a. Yield: 91%; m.p.: 1718C; IR: 1734, 3328 cm21; H NMR
(d, DMSO): 3.2 (2H, br), 4.2 (1H, t), 4.4 (2H, d), 6.7 (1H, s), 7.25–8.16
(13H, m); 13C NMR (d, DMSO): 41.5, 48.5, 66.6, 120.2, 122.5, 125.5,
126.0, 127.6, 128.5, 142.4, 145.4, 145.5, 154.2, 157.5, 157.6; MS (MALDI-
TOF) m/z observed: 455.8 [M þ Na]þ, 471.9 [M þ K]þ; Anal. Calcd. for
C23H19N3O6: C, 63.74; H, 4.42; N, 9.69. Found: C, 63.61; H, 4.35; N, 9.57.
p-Nitrophenyl-f1-f[(9H-fluorenyl-9-ylmethoxy)carbonyl]aminog-ethylg
carbamate 3b. Yield: 92%; m.p.: 1198C; IR: 1734, 3317 cm21; [a]D25 (c ¼ 1,
DMSO), 212.4; 1H NMR (d, DMSO): 1.14 (3H, d), 3.85 (1H, m), 4.2 (1H, t),
4.35 (2H, m), 6.6 (1H, d), 7.2–8.1 (13H, m); 13C NMR (d, DMSO): 18.3, 48.0,
48.5, 66.6, 120.2, 122.4, 125.6, 125.8, 127.6, 128.2, 141.9, 145.1, 145.7,
154.5, 157.1, 157.9; MS (MALDI-TOF) m/z observed: 469.8 [M þ Na]þ,
485.8 [M þ K]þ; Anal. Calcd. for C24H21N3O6: C, 64.42; H, 4.73; N, 9.39.
Found: C, 64.31; H, 4.68; N, 9.29.
p-Nitrophenyl-f1-f[(9H-fluorenyl-9-ylmethoxy)carbonyl]aminog-2-
methylpropylg carbamate 3c. Yield: 93%; m.p.: 1398C; IR: 1734,

Synthesis of Peptidyl Ureas
2317
3312 cm21; [a]2D5 (c ¼ 1, DMSO), 24.5; 1H NMR (d, DMSO): 0.95 (7H, m),
3.8 (1H, m), 4.2 (1H, t), 4.4 (2H, m), 6.4 (1H, d), 7.3–8.15 (13H, m);
13C NMR (d, DMSO): 18.2, 19.5, 30.6, 47.4, 56.8, 66.9, 120.1, 121.9,
124.8, 125.0, 127.2, 127.9, 141.5, 143.8, 144.7, 153.8, 155.9, 157.5; MS
(MALDI-TOF) m/z observed: 497.7 [M þ Na]þ, 514.0 [M þ K]þ; Anal.
Calcd. for C26H25N3O6: C, 65.67; H, 5.30; N, 8.84. Found: C, 65.53; H,
5.21; N, 8.72.
p-Nitrophenyl-f1-f[(9H-fluorenyl-9-ylmethoxy)carbonyl]aminog-3-
methylbutylg carbamate 3d. Yield: 92%; m.p.: 1168C; IR: 1733, 3320 cm21
;
[a]2D5 (c ¼ 1, DMSO), 232.2; H NMR (d, DMSO): 0.95 (6H, m), 1.25–1.4
(3H, m), 3.8 (1H, m), 4.12 (1H, t), 4.35 (2H, m), 6.45 (1H, d), 7.25–8.12
(13H, m); 13C NMR (d, DMSO): 22.0, 23.2, 24.8, 41.9, 47.4, 49.9, 66.6,
120.0, 121.9, 125.0, 125.1, 127.1, 127.9, 141.4, 143.6, 144.8, 153.7, 155.9,
157.1; MS (MALDI-TOF) m/z observed: 511.9 [M þ Na]þ, 528.1 [M þ K]þ;
Anal. Calcd. for C27H27N3O6: C, 66.24; H, 5.56; N, 8.58. Found: C, 66.12;
H, 5.41; N, 8.45.
1
p-Nitrophenyl-f1-f[(9H-fluorenyl-9-ylmethoxy)carbonyl]aminog-2-
methylbutylg carbamate 3e. Yield: 94%; m.p.: 1598C; IR: 1734, 3322 cm21
;
[a]2D5 (c ¼ 1, DMSO), 214.7; H NMR (d, DMSO): 0.95 (6H, m), 1.2–1.5
(3H, m), 3.75 (1H, m), 4.2 (1H, t), 4.35 (2H, m), 6.5 (1H, d), 7.25–8.1
(13H, m); 13C NMR (d, DMSO): 11.5, 15.8, 26.1, 37.9, 48.4, 56.5, 66.6,
120.2, 122.6, 125.7, 125.9, 127.6, 128.2, 142.3, 144.5, 144.6, 153.7, 156.2,
157.3; MS (MALDI-TOF) m/z observed: 512.1 [M þ Na]þ, 528.0
[M þ K]þ; Anal. Calcd. for C27H27N3O6: C, 66.24; H, 5.56; N, 8.58.
Found: C, 66.14; H, 5.43; N, 8.48.
1
p-Nitrophenyl-f1-f[(9H-fluorenyl-9-ylmethoxy)carbonyl]aminog-2-
phenylethylg carbamate 3f. Yield: 93%; m.p.: 1438C; IR: 1734, 3317 cm21
;
[a]2D5 (c ¼ 1, DMSO), 25.4; H NMR (d, DMSO): 2.85 (2H, d), 4.1 (1H, t),
4.25–4.45 (3H, m), 6.58 (1H, d), 7.1–8.15 (18H, m); 13C NMR (d,
DMSO): 38.8, 47.2, 52.6, 66.6, 120.1, 121.9, 125.0, 125.1, 127.1, 127.2,
127.8, 128.7, 129.2, 136.9, 141.2, 143.5, 144.5, 53.7, 155.8, 156.4; MS
(MALDI-TOF) m/z observed: 545.9 [M þ Na]þ, 562.1 [M þ K]þ; Anal.
Calcd. for C30H25N3O6: C, 68.82; H, 4.81; N, 8.02. Found: C, 68.71; H,
4.70; N, 7.89.
1
p-Nitrophenyl-f1-f[(9H-fluorenyl-9-ylmethoxy)carbonyl]aminog-1-
phenylethylg carbamate 3g. Yield: 89%; m.p.: 1648C; IR: 1735, 3319 cm21
;
[a]2D5 (c ¼ 1, DMSO), 211.2; 1H NMR (d, DMSO): 4.2 (1H, t), 4.3–4.45 (3H,
m), 6.6 (1H, d), 7.1–8.16 (18H, m); 13C NMR (d, DMSO): 47.2, 54.1, 66.6,
120.0, 122.0, 125.0, 125.1, 126.9, 127.2, 127.8, 128.7, 129.3, 136.8, 141.2,
143.9, 144.5, 153.8, 155.9, 156.6; MS (MALDI-TOF) m/z observed: 531.8
[M þ Na]þ, 547.9 [M þ K]þ; Anal. Calcd. for C29H23N3O6: C, 68.36; H,
4.55; N, 8.25. Found: C, 68.23; H, 4.44; N, 8.16.

2318
Patil, Vasanthakumar, and Suresh Babu
p-Nitrophenyl-fD-1-f[(9H-fluorenyl-9-ylmethoxy)carbonyl]aminog-1-
phenylmethylg carbamate 3gꢀ. Yield: 88%; m.p.: 1618C; IR: 1734,
3318 cm21; [a]2D5 (c ¼ 1, DMSO), þ11.3; H NMR (d, DMSO): 4.1 (1H, t),
1
4.25–4.35 (3H, m), 6.65 (1H, d), 7.15–8.1 (18H, m); 13C NMR (d,
DMSO): 47.3, 54.1, 66.5, 119.9, 122.1, 125.0, 125.2, 127.0, 127.2, 127.7,
128.8, 129.2, 136.7, 141.2, 143.8, 144.6, 153.8, 155.9, 156.6; MS (MALDI-
TOF) m/z observed: 531.9 [M þ Na]þ, 547.9 [M þ K]þ; Anal. Calcd. for
C29H23N3O6: C, 68.36; H, 4.55; N, 8.25. Found: C, 68.25; H, 4.47; N, 8.13.
p-Nitrophenyl-f1-f[(9H-fluorenyl-9-ylmethoxy)carbonyl]aminog-2-
[(tert-butoxy)carbonyl]ethylg carbamate 3h. Yield: 87%; m.p.: 1368C; IR:
1734, 3316 cm21; [a]2D5 (c ¼ 1, DMSO), 210.7; H NMR (d, DMSO): 1.45
1
(9H, s), 2.45 (2H, m), 4.2–4.35 (4H, m), 6.65 (1H, d), 7.2–8.14 (13H, m);
13C NMR (d, DMSO): 28.0, 37.9, 47.3, 49.1, 66.7, 81.6, 120.1, 121.8,
125.1, 125.3, 127.0, 127.7, 141.4, 143.8, 144.6, 153.7, 155.6, 156.8, 171.3;
MS (MALDI-TOF) m/z observed: 570.0 [M þ Na]þ, 586.2 [M þ K]þ;
Anal. Calcd. for C29H29N3O8: C, 63.61; H, 5.34; N, 7.67. Found: C, 63.52;
H, 5.22; N, 7.56.
p-Nitrophenyl-f1-f[(9H-fluorenyl-9-ylmethoxy)carbonyl]aminog-3-[(tert-
butoxy)carbonyl]ethylg carbamate 3i. Yield: 89%; m.p.: 1408C; IR: 1734,
3319 cm21; [a]2D5 (c ¼ 1, DMSO), 212.3; H NMR (d, DMSO): 1.5 (9H, s),
1
2.3–2.6 (4H, m), 4.2–4.4 (4H, m), 6.68 (1H, d), 7.1–8.1 (13H, m); 13C
NMR (d, DMSO): 28.0, 31.0, 37.8, 47.3, 48.7, 66.7, 81.6, 120.1, 121.8,
125.1, 125.3, 127.0, 127.7, 141.4, 143.8, 144.6, 153.7, 155.6, 156.8, 171.1;
MS (MALDI-TOF) m/z observed: 583.8 [M þ Na]þ, 599.8 [M þ K]þ;
Anal. Calcd. for C30H31N3O8: C, 64.16; H, 5.56; N, 7.48. Found: C, 64.03;
H, 5.42; N, 7.39.
p-Nitrophenyl-f1-f[(9H-fluorenyl-9-ylmethoxy)carbonyl]aminog-2-
[4-(tert-butoxy)phenyl]ethylg carbamate 3j. Yield: 88%; m.p.: 1448C; IR:
1
1736, 3314 cm21; [a]2D5 (c ¼ 1, DMSO), 213.8; H NMR (d, DMSO): 1.3
(9H, s), 2.8 (2H, d), 3.95–4.35 (4H, m), 6.55 (1H, d), 7.1–8.16 (17H, m);
13C NMR (d, DMSO): 28.8, 38.2, 47.3, 52.7, 66.6, 78.6, 120.0, 122.0,
124.5, 125.0, 125.1, 127.2, 127.7, 129.6, 131.4, 141.5, 143.6, 144.6, 153.8,
154.5, 155.8, 156.8; MS (MALDI-TOF) m/z observed: 618.0 [M þ Na]þ,
634.1 [M þ K]þ; Anal. Calcd. for C34H33N3O7: C, 68.56; H, 5.58; N, 7.05.
Found: C, 68.42; H, 5.43; N, 6.89.
p-Nitrophenyl-f1-f[(9H-fluorenyl-9-ylmethoxy)carbonyl]aminog-2-
[benzyloxy]ethylg carbamates 3k. Yield: 91%; m.p.: 1298C; IR: 1734,
1
3317 cm21; [a]2D5 (c ¼ 1, DMSO), 24.2; H NMR (d, DMSO): 2.85 (2H, s),
3.35 (2H, d), 3.85 (1H, m), 4.2 (1H, t), 4.35 (2H, m), 6.5 (1H, d), 7.15–8.15
(18H, m); 13C NMR (d, DMSO): 38.6, 47.2, 50.7, 61.5, 66.8, 120.0, 121.8,
124.9, 125.0, 127.0, 127.1, 127.7, 128.8, 129.3, 136.8, 141.3, 143.8, 144.7,
153.6, 155.9, 156.8; MS (MALDI-TOF) m/z observed: 576.1 [M þ Na]þ,

Synthesis of Peptidyl Ureas
2319
591.9 [M þ K]þ; Anal. Calcd. for C31H27N3O7: C, 67.26; H, 4.91; N, 7.59.
Found: C, 62.13; H, 4.80; N, 7.47.
General Procedure for the Synthesis of Dipeptidyl Ureas 5
To a stirred solution of amino acid methyl ester hydrochloride salt 4
(1 mmol) in DMF (5 mL) and DIEA (2 mmol), carbamate 3 (1 mmol) was
added and stirred at r.t. till the completion of the reaction. The separated
solid was filtered and crystallized using DMSO and water (70 : 30) to get
the dipeptidyl urea 5 as a crystalline off-white solid.
Fmoc-Ileu-Gly-Ome (5a). Yield: 96%; m.p.: 1438C; 1H NMR
(d, DMSO): 0.8 (6H, m), 1.1–1.65 (3H, m), 2.5 (2H, m), 3.6 (3H, s), 3.8
(1H, m), 4.2–4.4 (3H, m), 5.0 (1H, d), 6.3–6.5 (2H, m), 7.3–7.9 (8H, m);
13C NMR (d, DMSO): 11.0, 14.3, 25.0, 40.4, 41.2, 46.7, 51.5, 61.5, 65.1,
120.0, 125.2, 127.0, 127.6, 140.7, 143.8, 155.0, 156.8, 171.5; ES MS m/z
observed: 440.2; Anal. Calcd. for C24H29N3O5: C, 65.59; H, 6.65; N, 9.56.
Found: C, 65.38; H, 6.52; N, 9.38.
Fmoc-Pheu-Leu-OMe (5b). Yield: 94%; m.p.: 1488C; 1H NMR (d,
DMSO): 0.95 (6H, d), 1.35 (2H, s), 1.6 (1H, m), 2.82 (2H, d), 3.65 (3H, m),
3.8 (1H, m), 4.1–4.4 (4H, m), 5.1 (1H, d), 6.5–6.7 (2H, m), 7.2–7.85
(13H, m); 13C NMR (d, DMSO): 22.0, 23.0, 24.5, 37.2, 47.3, 51.4, 54.2,
61.3, 66.6, 120.1, 125.0, 126.5, 127.0, 127.5, 128.5, 129.2, 137.5, 141.3,
144.0, 155.8, 156.5, 171.6; MS (MALDI-TOF) m/z observed: 552.6
[M þ Na]þ, 568.7 [M þ K]þ; Anal. Calcd. for C31H35N3O5: C, 70.30; H,
6.66; N, 7.93. Found: C, 70.18; H, 6.57; N, 7.81.
Fmoc-Pheu-Phe-OMe (5c). Yield: 90%; m.p.: 1848C; 1H NMR (d,
DMSO): 2.85 (4H, d), 3.65 (3H, s), 3.96–4.1 (2H, m), 4.2 (1H, t), 4.4
(2H, m), 6.0 (1H, d), 6.7–6.9 (2H, m), 7.1–7.85 (18H, m); 13C NMR (d,
DMSO): 37.2, 37.3, 47.4, 54.1, 54.3, 61.3, 66.6, 120.1, 125.0, 126.5, 126.6,
127.0, 127.6, 128.4, 128.6, 129.1, 129.3, 137.5, 137.6, 141.2, 144.0, 155.8,
156.5, 171.1; MS (MALDI-TOF) m/z observed: 586.6 [M þ Na]þ, 602.7
[M þ K]þ; Anal. Calcd. for C34H33N3O5: C, 72.45; H, 5.90; N, 7.45.
Found: C, 72.38; H, 5.81; N, 7.39.
Fmoc-Phgu-Phe-OMe (5d). Yield: 91%; m.p.: 1678C; 1H NMR
(d, DMSO): 2.85 (2H, d), 3.60 (3H, s), 3.95–4.1 (2H, m), 4.2 (1H, t), 4.4
(2H, m), 6.1 (1H, d), 6.6–6.9 (2H, m), 7.1–7.9 (18H, m); 13C NMR
(d, DMSO): 37.2, 47.4, 54.1, 54.6, 61.3, 66.6, 120.1, 125.0, 126.7, 127.0,
127.2, 127.6, 128.2, 128.6, 129.0, 129.3, 137.5, 137.8, 141.3, 144.0, 155.4,
156.3, 171.1; MS (MALDI-TOF) m/z observed: 572.1 [M þ Na]þ, 588.1
[M þ K]þ; Anal. Calcd. for C33H31N3O5: C, 72.11; H, 5.68; N, 7.64.
Found: C, 71.98; H, 5.57; N, 7.49.

2320
Patil, Vasanthakumar, and Suresh Babu
1
Fmoc-D-Phgu-Phe-OMe (5e). Yield: 91%; m.p.: 1818C; H NMR (d,
DMSO): 2.84 (2H, d), 3.6 (3H, s), 3.93–4.1 (2H, m), 4.2 (1H, t), 4.4 (2H,
m), 6.1 (1H, d), 6.6–6.9 (2H, d), 7.2–7.9 (18H, m); 13C NMR (d, DMSO):
37.3, 47.4, 54.2, 54.6, 61.4, 66.6, 120.2, 125.1, 126.8, 127.1, 127.2, 127.6,
128.2, 128.6, 129.0, 129.4, 137.5, 137.9, 141.4, 144.0, 155.6, 156.4, 171.0;
MS (MALDI-TOF) m/z observed: 572.1 [M þ Na]þ, 588.1 [M þ K]þ;
Anal. Calcd. for C33H31N3O5: C, 72.11; H, 5.68; N, 7.64. Found: C, 72.01;
H, 5.56; N, 7.46.
1
Fmoc-Asp(OtBu)u-Gly-Ome (5f). Yield: 90%; m.p.: 1578C; H NMR
(d, DMSO): 1.45 (9H, s), 1.9 (2H, d), 2.6 (2H, d), 3.65 (3H, s), 4.1 (1H, t),
4.3–4.4 (3H, m), 5.8 (1H, d), 6.5–6.7 (2H, m), 7.3–7.75 (8H, m);
13C NMR (d, DMSO): 27.9, 37.5, 41.5, 47.1, 50.0, 61.3, 66.8, 81.5,
120.0, 125.0, 127.5, 128.0, 141.0, 144.1, 155.5, 156.5, 170.8, 171.1; MS
(MALDI-TOF) m/z observed: 519.8 [M þ Na]þ, 536.0 [M þ K]þ; Anal.
Calcd. for C26H31N3O7: C, 62.76; H, 6.28; N, 8.44. Found: C, 62.66; H,
6.07; N, 8.29.
Fmoc-Valu-Leu-OBzl (5g). Yield: 95%; m.p.: 1848C; 1H NMR (d,
DMSO): 0.92 (12H, m), 1.32–1.85 (4H, m), 3.1 (2H, s), 3.7–3.8 (2H, m),
4.2 (1H, t), 4.42 (2H, m), 5.1 (1H, d), 6.6–6.7 (2H, m), 7.2–7.85 (13H, m);
13C NMR (d, DMSO): 18.5, 19.5, 22.0, 23.1, 24.5, 29.2, 37.2, 40.2, 47.2,
51.5, 59.0, 66.6, 120.0, 125.0, 126.5, 127.2, 128.0, 128.4, 129.3, 137.6,
141.2, 144.0, 155.4, 156.8, 176.4; MS (MALDI-TOF) m/z observed: 580.0
[M þ Na]þ, 596.1 [M þ K]þ; Anal. Calcd. for C33H39N3O5: C, 71.07;
H, 7.05; N, 7.53. Found: C, 70.96; H, 6.89; N, 7.41.
Fmoc-Leuu-Phe-OBzl (5h). Yield: 92%; m.p.: 1458C; 1H NMR
(d, DMSO): 0.95 (6H, d), 1.35 (2H, s), 1.6 (1H, m), 2.85 (2H, d), 3.1
(2H, s), 3.8 (1H, m), 4.1–4.45 (4H, m), 5.1 (1H, d), 6.5–6.7 (2H, m),
7.2–7.85 (18H, m); 13C NMR (d, DMSO): 22.0, 23.0, 24.5, 37.2, 40.2,
47.3, 51.4, 54.2, 66.6, 120.1, 125.0, 126.5, 126.6, 127.0, 127.5, 128.5,
128.7, 129.1, 129.2, 137.5, 137.6, 141.3, 144.0, 155.8, 156.5, 171.6; MS
(MALDI-TOF) m/z observed: 628.7 [M þ Na]þ, 644.8 [M þ K]þ; Anal.
Calcd. for C37H39N3O5: C, 73.36; H, 6.49; N, 6.94. Found: C, 73.21; H,
6.37; N, 6.79.
ACKNOWLEDGMENTS
We are grateful to Department of Science and Technology, Govt. of India
for financial assistance. We thank Sophisticated Instruments Facility, I. I. Sc.,
for NMR data and Hikal India Ltd., Bangalore for optical rotation
measurements.

Synthesis of Peptidyl Ureas
2321
REFERENCES
1. (a) Lowe, G. Chem. Soc. Rev. 1995, 309; (b) Gallop, M.A.; Barret, R.W.;
Dower, W.J.; Fodor, S.P.A.; Gordon, E.M. J. Med. Chem. 1994, 37, 1233;
(c) Lam, K.S.; Salman, S.E.; Hersh, E.M.; Hruby, V.J.; Kazmierski, W.M.;
Knapp, R.J. Nature 1991, 354, 82; (d) Houghten, R.A.; Pinilla, C.;
Blondelle, S.E.; Appel, J.R.; Dooley, C.T.; Cuervo, J.H. Nature 1991,
354, 84; (e) Fodor, S.P.A.; Read, J.L.; Pirrung, M.S.; Stryer, L.;
Lu, A.T.; Solas, D. Science 1991, 251, 767.
2. (a) Goldschmidt, S.; Wick, M.Z. Natureforsch. B 1950, 5, 170;
(b) Goldschmidt, S.; Wick, M. Liebigs Ann. Chem. 1952, 575, 217.
3. (a) Nowick, J.S.; Powell, N.A.; Nguyem, T.M.; Noronha, G. J. Org.
Chem. 1992, 57, 7364; (b) Burgess, K.; Ibarzo, J.; Linthicum, S.;
Russell, D.H.; Shin, H.; Shitangkoon, A.; Totani, R.; Zhang, A.J. J. Am.
Chem. Soc. 1997, 119, 1556.
4. Majer, P.; Randad, R.S. J. Org. Chem. 1994, 59, 1937.
5. Nowick, J.S.; Holmes, D.L.; Noronha, G.; Smith, E.M.; Nguyen, T.M.;
Huang, S.-L. J. Org. Chem. 1996, 61, 3929.
6. (a) Gante, J. Chem. Ber. 1965, 98, 3334; (b) Kim, J-M.; Bi, Y.;
Paikoff, S.J.; Schultz, P.G. Tetrahedron Lett. 1996, 37, 5305.
7. Lipkowski, A.W.; Tam, S.W.; Portoghese, P.S. J. Med. Chem. 1986,
29, 1222.
8. Adamiak, R.W.; Stawinski, J. Tetrahedron Lett. 1977, 1935.
9. Zhang, X.; Rodrigues, J.; Evans, L.; Hinkle, B.; Ballantyne, L.; Pena, M.
J. Org. Chem. 1997, 62, 6420.
10. Katritzky, A.R.; Pleynet, P.M.; Yang, B. J. Org. Chem. 1997, 62, 4155.
11. Boeijen, A.; van Ameijde, J.; Liskamp, R.M.J. J. Org. Chem. 2001,
66, 8454.
12. Burgess, K.; Linthicum, D.S.; Shin, H. Angew. Chem. Int. Ed. Engl. 1995,
34, 907.
13. Boeijen, A.; Liskamp, R.M. J. Eur. J. Org. Chem. 1999, 2127.
14. Suresh Babu, V.V.; Ananda, K.; Vasanthakumar, G-R. J. Chem. Soc.
Perkin Trans. 1 2000, 4328.
15. Vasanthakumar, G-R.; Ananda, K.; Suresh Babu, V.V. Ind. J. Chem.
2002, 41B, 1733.
Received in India February 16, 2004