Efficient synthesis of O-succinimidyl-(tert-butoxycarbonylamino)methyl carbamates derived from α-amino acids accelerated by ultrasound: Application to the synthesis of ureidodipeptides

Article abstract of DOI:10.1080/00397910802026386

The synthesis of O-succinimidyl-(tert-butoxycarbonylamino)methyl carbamates employing isocyanates made through the Curtius rearrangement of Boc-amino acid azides in the presence of N-hydroxysuccinimide under the influence of ultrasound is described. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802026386

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Efficient Synthesis of
O-Succinimidyl-(tert-
Butoxycarbonylamino)methyl
Carbamates Derived from α-
Amino Acids Accelerated by
Ultrasound: Application to the
Synthesis of Ureidodipeptides
Vommina V. Sureshbabu a , Naremaddepalli S.
Sudarshan a & Kantharaju a
a Department of Studies in Chemistry , Central
College Campus, Bangalore University , Bangalore,
India
Published online: 18 Aug 2008.
To cite this article: Vommina V. Sureshbabu , Naremaddepalli S.
Sudarshan & Kantharaju (2008) Efficient Synthesis of O-Succinimidyl-(tert-
Butoxycarbonylamino)methyl Carbamates Derived from α-Amino Acids Accelerated
by Ultrasound: Application to the Synthesis of Ureidodipeptides, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 38:13, 2168-2184, DOI: 10.1080/00397910802026386
To link to this article: http://dx.doi.org/10.1080/00397910802026386
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Synthetic Communications1, 38: 2168–2184, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802026386
Efficient Synthesis of O-Succinimidyl-
(tert-Butoxycarbonylamino)methyl
Carbamates Derived from a-Amino
Acids Accelerated by Ultrasound: Application
to the Synthesis of Ureidodipeptides
Vommina V. Sureshbabu, Naremaddepalli S. Sudarshan,
and Kantharaju
Department of Studies in Chemistry, Central College Campus,
Bangalore University, Bangalore, India
Abstract: The synthesis of O-succinimidyl-(tert-butoxycarbonylamino)methyl
carbamates employing isocyanates made through the Curtius rearrangement
of Boc-amino acid azides in the presence of N-hydroxysuccinimide under the
influence of ultrasound is described.
Keywords: Boc-amino acid azide; Boc-amino acid isocyanate; N-hydroxysuccini-
mide; Ultrasonic irradiation
INTRODUCTION
Ureidopeptides are an important class of peptidomimetics by virtue of
their applications as drugs with more elevated biological properties than
the parent peptides[1,2] as well as structural motifs for conformational
analysis.[3,4] Therefore, development of new methods to synthesize these
compounds has gained attention. Recently, Fishcer et al. have reported
the synthesis of six O-succinimidyl-(tert-butoxycarbonylamino)methyl
carbamates[5] through the Curtius rearrangement of corresponding acid
azides under high-temperature reflux. In this case, the product yields have
Received August 20, 2007
Address correspondence to Vommina V. Sureshbabu, Department of Studies
in Chemistry, Central College Campus, Dr B. R. Ambedkar Veedhi, Bangalore
University, Bangalore 560 001, India. E-mail: hariccb@rediffmail.com
2168

Synthesis of O-Su(Boc)methylcarbamates and Ureidodipeptides
2169
shown to be less then satisfactory, presumably because of the decompo-
sition of Boc-protected derivatives at the elevated temperature used for
the reaction. Consequently, the preparation of isocyanates derived from
Boc amino acids requires an alternative strategy. We herein demonstrate
the Curtius rearrangement of Boc amino acid azides under ultrasonica-
tion at ambient temperature.
RESULTS AND DISCUSSION
Boc-=Z-amino acid azides are known for their instability even at room
temperature.[6] Their utility as peptide coupling agents at ambient tem-
perature was accompanied by the formation of the reactive isocyanates
leading to several side products. Recently, Guichard et al. reported an
efficient stepwise synthesis of N,N0-linked oligoureas [HN-CHR-CH2-
NH-CO]n in solution and on solid support utilizing O-succinimidyl
carbamates derived from N-Boc-=Fmoc-b3-amino acids as well as
Boc-=Z-=Fmoc-a -amino acids and dipeptides as activated monomers.[7,8]
Further, they have explained the short-range interaction of the cis–trans
urea motif in urea peptides Boc-L-gSer(Bzl)-CONHMe=NMe2, Piv-L-
Pro-L-gLeu-CONHMe=NMe2, Boc-L-gSer(Bzl)-CO-L-Leu-NHMe, and
Boc-L-gSer(Bzl)-CO-D-Leu-NMe2.[9] Subsequently, they have also
described solution-phase synthesis of hexahydro-1,3,5-triazepine-2,6-
diones, novel rigid, highly substituted, seven-membered ring urea-based
scaffolds.[10]
In the present study, the Boc-a -amino acid 1 (1 equiv) was dissolved
in THF (5 mL) and cooled to ꢀ 15ꢁC. After the addition of ethyl chlor-
oformate (EtOCOCl, 1.1 equiv) and N-methylmorpholine (NMM, 1.1
equiv), the mixture was stirred at ꢀ 15ꢁC for 20 min. The resulting white
suspension was allowed to warm to ꢀ 5ꢁC, treated with an aqueous sol-
ution (1 mL) of NaN3 (2.5 equiv), and stirred for 10 min. After usual
aqueous workup, the resulting Boc-a -amino acid azide in toluene was
exposed to ultrasound at ambient temperature in the presence of an
equimolar quantity of N-hydroxysuccinimide and NMM. Initially they
rearranged to the corresponding isocyanates, which are trapped by
Scheme 1. Synthesis of O-Succinimidyl(Boc)methylcarbamates.

2170
V. V. Sureshbabu, N. S. Sureshbabu, and Kantharaju
N-hydroxysuccinimide, giving the desired O-succinimidyl-(tert-
butoxycarbonylamino) methyl carbamate 3a–t (Scheme 1) in high yields.
The entire course of the reaction was complete in about 15–20 min.
The methyl carbamates 3 precipitated directly from the toluene solution
were simply collected by filtration and washed with toluene. All the
1
methyl carbamates 3 were characterized by IR, H, 13C NMR, and mass
spectrometry. Their IR spectrum contains a characteristic sharp peak of
methyl carbamate urethane stretching vibrational frequency at around
Table 1. Physical constants of O-succinimdyl-(tert-butoxycarbonylamino)methyl
carbamates
MALDI mass
Compound
3
Calculated
Yield (%) Mp (ꢁC) [M]þ
Found
[M þ Na]þ
R
R1
a
b
c
d
e
H
H
H
H
H
H
H
H
H
H
H
CH3
H
CH(CH3)2
CH2CH(CH3)2
CH(CH3)C2H5
CH2C6H5
C6H5
C6H5
CH2OBzl
CH2COOBzl
(CH2)2COOBzl
87
82
85
84
82
86
87
85
83
84
80
82
80
75
72
76
152
166
107
125
129
143
126
122
141
122
140
127
125
149
151
142
301.3
287.3
329.4
343.4
343.4
377.4
363.4
363.4
407.4
435.4
449.5
327.3
347.4
492.5
393.4
331.3
324.2
310.2
352.3
366.3
366.2
400.3
386.3
386.3
430.2
458.5
472.2
350.3
370.3
515.2
416.3
354.3
f
g
hꢂ
i
j
k
l
m
n
o
p
R ¼ R1 -(CH2)3-
`
(CH2)2SCH3
H
H
H
H
(CH2)4NHZ
CH2C6H5OH
CH(CH3)OH
q
H
70
168
550.5
573.2
r
s
H
H
(CH2)2CONH2
CH2CONH2
72
75
136
141
358.3
344.3
381.3
367.1
t
H
70
149
501.4
524.3
ꢂ
Notes: Phg ¼ phenylglycine; D-configuration.

Synthesis of O-Su(Boc)methylcarbamates and Ureidodipeptides
2171
Table 2. Comparison of Boc-gPhe-COOSu (3f) formation under
different methods
Methods
Time (min)
Yield (%)
Thermal
Microwave
Ultrasound
45
2
25
43
49
86
1735–1745 cmꢀ1. The physical constants as well as yields 70–85% of
methyl carbamates are given in the Table 1. Almost all the proteniogenic
amino acids including Ser, Thr, Tyr, Asp, Glu, Asn, Gln, His, Trp, and
Cys have been prepared. The methyl carbamates 3 were stable white crys-
talline solids. When stored at rt for long periods, neither noticeable
degradation nor any change in their spectral behavior was observed.
A comparative study for the synthesis of O-succinimidyl-{1-(tert-
butoxycarbonylamino)-2-phenyl}methylcarbamate using Boc-Phe-N3
and N-hydroxysuccinimide was carried out under different conditions.
It was found that the formation of 3 through Curtius rearrange-
ment assisted by ultrasound under ambient temperature results in better
yields then the classical thermal method or microwave irradiation, and
results are furnished in Table 2.
To demonstrate the use of the activated carbamates, the synthesis of
Boc-dipeptidyl urea esters has been carried out. The reaction of methyl-
carbamate 3 with amino acid esters 4 in THF–DMF (2:1) in the presence
of NMM at rt gave the corresponding ureas 5 in good yields (Scheme 2).
The reaction proceeds rapidly and was found to be completed within
30 min at rt. A routine workup and recrystallization with DMSO–water
resulted in analytically pure dipeptidyl urea esters 5a–j. The only by-
product formed during the reaction was N-hydroxysuccinimide, which
was easily removed during aqueous wash. All the dipeptidyl ureas pre-
pared are characterized by 1H and 13C NMR and mass spectral methods.
The carbamates were further reacted with the in situ generated N,
O-bis(trimethylsilyl)amino acids 7 to synthesize Boc-dipeptidyl urea acids
Scheme 2. Synthesis of ureidopeptide esters from 3.

2172
V. V. Sureshbabu, N. S. Sureshbabu, and Kantharaju
Table 3. List of ureidopeptide esters prepared through scheme 2
Urea ester 5
R
R1
Y
a
b
c
d
e
f
CH(CH3)2
CH2C6H5
H
CH2C6H5
CH2OBzl
CH2COOBzl
(CH2)2COOBzl
CH(CH3)C2H5
CH2C6H4OH
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH(CH3)2
CH2C6H5
CH3
H
H
CH2CH(CH3)2
CH2C6H5
CH3
g
h
i
j
CH(CH3)2
CH3
(Scheme 3). A simple workup of the reaction mixture followed by their
recrystallization resulted in pure dipeptidyl urea acids 8a–d, which were
fully characterized.
Racemization Study for Methylcarbamates 3
To demonstrate the stereospecificity of both the carbamates 3 prepared
and their use as urea coupling agents, the carbamate 3f derived from
Boc-Phe was coupled with R-( þ ), S-( ꢀ ), and R,S-( ꢃ )-1-phenylethyla-
mines 9a–c to obtain the white solid ureas 10a, 10b, and 10c respectively
(Scheme 4, Figure 1), and their recrystallization resulted in analytically
Scheme 3. Synthesis of ureidopeptide acids 8 (Y-H) from 3.

Synthesis of O-Su(Boc)methylcarbamates and Ureidodipeptides
Table 4. List of ureidopeptide acids obtained via scheme 3
2173
Urea acid 8
R
R1
CH3
CH3
H
a
b
c
CH2CH(CH3)2
CH2C6H5
CH2CH(CH3)2
CH(CH3)2
d
CH2C6H5
pure compounds. Their 1H NMR analysis revealed that the methyl group
resonances of 10a (d, 1.28 and 1.30) and 10b (d, 1.26 and 1.28) are clearly
separated by 0.02 ppm in DMSO-d6 solution. In addition, the H NMR
1
spectrum of the racemic urea 10c was observed as a doublet of doublet
for the methyl group resonances at (d, 1.25, 1.27, 1.28, and 1.30). This
clearly confirms that both the carbamates’ preparation as well as the
coupling reaction to obtain the peptidyl ureas are completely free from
racemization.
EXPERIMENTAL
The melting points were recorded in open capillary tubes and are uncor-
rected. The reactions were carried out using a sonic bath (35 kHz, Elma,
T 310=H German make) at ambient temperature. Infrared spectra were
recorded on a Nicolet Impact 400D FT-IR spectrometer (KBr pellets,
3 cmꢀ1 resolution). Elementalanalyses were carried out using a Perkin-
Elmer analyzer, and the samples were dried for 24 h under vacuum before
analysis. 1H and 13C NMR spectra were recorded on a Bruker AMX 400-
MHz spectrometer. Mass spectra were recorded on Maldi, PE-Sciex 150
EX LC-MS, and Jeol-JMS-600H spectrometers in FABþ mode using
3-nitrobenzyl alcohol as a liquid matrix. All solvents were freshly distilled
prior to use. Amino acid methyl ester hydrochlorides were prepared using
methanol and thionyl chloride.
Scheme 4. Preparation of urea adducts for racemization studies.

2174
V. V. Sureshbabu, N. S. Sureshbabu, and Kantharaju
Figure 1. 1H NMR spectra of Boc-Phe-w(NH-CO-NH)-R-( þ )-1-phenylethyla-
mine: Inset figure shown splitting pattern of CH3 group of 1-phenylethylamine
in urea adducts R-( þ )-1-phenylethylamine (10a), S-( ꢀ )-1-phenylethylamine
(10b), and R,S-( ꢃ )-1-phenylethylamine (10c).
General Procedure for the Synthesis of O-Succinimidyl-
(tert-butoxycarbonylamino)methylcarbamates 3a–t
Boc-a-amino acid 1 (1 mmol) was dissolved in THF (5 mL) and cooled
to –20 ꢁC. After addition of ethylchloroformate (1.1 mmol) aꢁnd N-
methylmorpholine (1.1 mmol), the mixture was stirred at –20 C for
15 min and allowed to warm to ꢀ 5ꢁC. It was treated with an aqueous
solution of NaN3 (2.5 mmol in 2 mL of water) for 5 min. After concen-
tration of the solvent under reduced pressure, the resulting residue was
diluted with CH2Cl2 (15 mL); washed with 5% citric acid solution
(3 ꢄ 5 mL), 5% sodium bicarbonate solution (3 ꢄ 5 mL), and brine;
dried over anhydrous Na2SO4; and concentrated under reduced pressure
to give the acyl azide 2, which was used without further purification.
The acyl azide was taken in toluene (5 mL), and N-hydroxy succinimide
(1 mmol) and NMM (1.1 mmol) were successively added. The mixture
was sonicated in an ultrasound bath for about 15–25 min at ambient
temperature. After the completion of the reaction, carbamates crystal-
lized from the toluene solution were collected by filtration. All the car-
bamates 3 have been fully characterized. The physical and spectral data
are furnished in Table 1.

Synthesis of O-Su(Boc)methylcarbamates and Ureidodipeptides
2175
Data
Boc-gAla-COOSu (3a)
1
White solid,IR: 1715, 1745, 1780 cmꢀ1; H NMR (DMSO): d 1.16 (3H,
s), 1.36 (9H, s), 2.8 (4H, s), 3.8 (1H, m), 5.2 (1H, m), 8.5 (1H, d); 13C
NMR (DMSO): d 18.3, 28.6, 59.6, 70.1, 72.2, 78.4, 151.2, 154.7, 170.8.
Anal. calcd. for C12H19N3O6: C, 47.84; H, 6.36; N, 13.95. Found: C,
47.12; H, 6.62; N, 13.24%.
Boc-gGly-COOSu (3b)
1
White solid,IR: 1710, 1750, 1775 cmꢀ1; H NMR (DMSO): d 1.36 (9H,
s), 2.5 (2H, m), 2.8 (4H, s), 5.2 (1H, br), 8.2 (1H, br); 13C NMR (DMSO):
d 27.8, 40.4, 69.6, 72.0, 79.1, 151.2, 155.7, 170.5. Anal. calcd. for
C11H17N3O6: C, 45.99; H, 5.96; N, 14.63. Found: C, 45.12; H, 5.62; N,
14.50%.
Boc-gVal-COOSu (3c)
White solid,IR: 1705, 1745, 1770 cmꢀ1; 1H NMR (DMSO): d 0.93 (6H, t),
1.35 (9H, s), 1.9 (1H, m), 2.7 (4H, s), 3.9 (1H, m), 5.3 (1H, br), 8.4 (1H,
d); 13C NMR (DMSO): d 18.5, 19.7, 28.4, 29.6, 58.6, 69.7, 72.1, 79.0,
150.7, 155.2, 170.8. Anal. Calcd. for C14H23N3O6: C, 51.06; H, 7.04; N,
12.76. Found: C, 51.12; H, 7.62; N, 12.24%.
Boc-gLeu-COOSu (3d)
1
White solid,IR: 1715, 1755, 1780 cmꢀ1; H NMR (DMSO): d 0.93 (6H,
d), 1.25–1.35 (11H, m), 1.62 (1H, m), 2.7 (4H, s), 3.7 (1H, m), 5.2 (1H,
br), 8.5 (1H, br); 13C NMR (DMSO): d 22.1, 23.4, 24.8, 41.0, 51.6,
70.1, 72.2, 78.7, 151.2, 154.7, 171.0. Anal. calcd. for C15H25N3O6: C,
52.47; H, 7.34; N, 12.24. Found: C, 52.12; H, 7.62; N, 12.50%.
Boc-gIle-COOSu (3e)
1
White solid,IR: 1715, 1755, 1780 cmꢀ1; H NMR (DMSO): d 0.91 (6H,
m), 1.12 (1H, m), 1.3 (9H, s), 1.52 (2H, m), 3.7 (1H, m), 4.94 (1H, m),
5.2 (1H, br); 13C NMR (DMSO): d 11.5, 15.7, 25.2, 26.2, 28.6, 34.4,
56.6, 78.2, 151.2, 153.7, 170.5. Anal. calcd. for C15H25N3O6: C, 52.47;
H, 7.34; N, 12.24. Found: C, 53.12; H, 7.0; N, 12.10%.

2176
V. V. Sureshbabu, N. S. Sureshbabu, and Kantharaju
Boc-gPhe-COOSu (3f)
1
White solid, IR: 1715, 1755, 1780 cmꢀ1; H NMR (DMSO): d 1.36 (9H,
m), 2.7 (4H, s), 2.8 (2H, d), 3.9 (1H, m), 5.0 (1H, d), 5.4 (1H, m), 7.25–7.3
(5H, m); 13C NMR (DMSO): d 26.1, 28.9, 62.2, 79.1, 126.9, 127.6, 128.9,
129.0, 129.1, 130.2, 137.9, 151.4, 155.2, 171.6. Anal. calcd. for
C18H23N3O6: C, 57.29; H, 6.14; N, 11.13. Found: C, 57.12; H, 6.20; N,
11.24%.
Boc-gPhg-COOSu (3g)
White solid, IR: 1715, 1755, 1780 cmꢀ1; 1H NMR (DMSO): d 1.3 (9H, s),
2.68 (4H, s), 3.9 (1H, m), 4.9 (1H, d), 5.2 (1H, br), 7.25–7.3 (5H, m); 13
C
NMR (DMSO): d 26.6, 28.6, 57.8, 78.2, 125.8, 127.1, 127.9, 129.7, 151.2,
154.7, 171.5. Anal. calcd. for C17H21N3O6: C, 56.19; H, 5.83; N, 11.56.
Found: C, 56.12; H, 5.62; N, 11.24%.
Boc-g(D)Phg-COOSu (3hꢂ)
1
White solid, IR: 1715, 1755, 1780 cmꢀ1; H NMR (DMSO): d 1.28 (9H,
m), 2.7 (4H, s), 3.88 (1H, m), 4.8 (1H, m), 5.1 (1H, br), 7.25–7.3 (5H, m);
13C NMR (DMSO): d 26.7, 28.8, 58.6, 79.0, 125.6, 127.1, 127.9, 129.7,
151.8, 155.7, 170.9. Anal. calcd. for C17H21N3O6: C, 56.19; H, 5.83; N,
11.56. Found: C, 56.10; H, 5.66; N, 11.20%.
Boc-gSer(Bzl)-COOSu (3i)
White solid, IR: 1715, 1755, 1785 cmꢀ1; 1H NMR (DMSO): d 1.3 (9H, s),
3.6 (2H, d), 3.8 (1H, m), 4.8 (2H, s), 5.1 (1H, d), 5.3 (1H, br), 7.25–7.30
(5H, m); 13C NMR (DMSO): d 25.6, 27.8, 51.4, 62.6, 78.2, 124.5, 125.1,
127.1, 127.9, 151.2, 153.9, 171.5. Anal. calcd. for C19H25N3O7: C, 56.01;
H, 6.18; N, 10.31. Found: C, 56.10; H, 6.62; N, 10.70%.
Boc-gAsp(Bzl)-COOSu (3j)
White solid, IR: 1715, 1755, 1780 cmꢀ1; 1H NMR (DMSO): d 1.3 (9H, s),
3.6 (2H, d), 3.8 (1H, m), 4.0 (2H, s), 4.9 (1H, d), 5.1 (1H, m), 7.25–7.35
(5H, m); 13C NMR (DMSO): d 26.0, 28.6, 37.2, 48.4, 57.6, 78.6, 125.1,
127.1, 127.9, 129.7, 151.2, 153.7, 154.8, 170.5. Anal. calcd. for
C20H25N3O8: C, 59.19; H, 4.59; N, 5.11. Found: C, 59.12; H, 4.62; N,
5.24%.

Synthesis of O-Su(Boc)methylcarbamates and Ureidodipeptides
2177
Boc-gGlu(Bzl)-COOSu (3k)
1
White solid, IR: 1715, 1755, 1785 cmꢀ1; H NMR (DMSO): d 1.32 (9H,
s), 3.6–3.8 (5H, m), 4.9 (2H, s), 5.1 (1H, d), 5.3 (1H, m), 7.25–7.35 (5H,
m); 13C NMR (DMSO): d 25.8, 28.2, 35.6, 37.5, 48.8, 56.9, 78.6, 125.1,
127.1, 127.9, 129.7, 151.2, 153.7, 154.8, 171.5. Anal. calcd. for
C21H27N3O8: C, 56.12; H, 6.06; N, 9.35. Found: C, 56.00; H, 6.62; N,
9.24%.
Boc-gPro-COOSu (3l)
1
White solid, IR: 1710, 1745, 1780 cmꢀ1; H NMR (DMSO): d 1.2–2.2
(13H, m), 2.7 (4H, s), 3.4–3.7 (3H, m), 4.8 (1H, d), 5.1 (1H, m); 13C
NMR (DMSO): d 24.2, 25.8, 28.2, 28.4, 60.6, 78.1, 150.8, 154.7, 170.4.
Anal. calcd. for C14H21N3O6: C, 51.37; H, 6.47; N, 12.84. Found: C,
51.12; H, 6.62; N, 12.24%.
Boc-gMet-COOSu (3m)
1
White solid, IR: 1710, 1750, 1785 cmꢀ1; H NMR (DMSO): d 1.31–2.25
(11H, m), 2.7 (4H, s), 3.3–3.5 (4H, m), 4.9 (1H, d), 5.15 (1H, m); 13C
NMR (DMSO): d 26.1, 27.9, 28.5, 48.5, 49.1, 59.8, 73.9, 151.8, 154.7,
171.4. Anal. calcd. for C13H21N3O6S: C, 44.95; H, 6.09; N, 12.09. Found:
C, 45.12; H, 6.02; N, 12.06%.
Boc-gLys(Z)-COOSu (3n)
1
White solid, IR: 1715, 1750, 1785 cmꢀ1; H NMR (DMSO): d 1.37 (9H,
s), 1.6 (6H, m), 3.0 (6H, m), 4.8 (2H, s), 5.0 (1H, s), 5.4 (1H, m), 5.8 (1H,
m), 7.25–7.30 (5H, m); 13C NMR (DMSO): d 18.9, 24.1, 25.3, 27.8, 32.1,
47.4, 59.7, 69.0, 79.4, 127.7, 128.4, 137.4, 152.4, 156.6, 158.3, 172.9. Anal.
calcd. for C23H32N4O8: C, 56.09; H, 6.55; N, 11.38; O, 25.99. Found: C,
56.01; H, 6.52; N, 11.30; O, 25.91%.
Boc-gTyr-COOSu (3o)
1
White solid, IR: 1715, 1745, 1785 cmꢀ1; H NMR (DMSO): d 1.37 (9H,
s), 3.0 (4H, m), 7.1 (4H, m), 5.8 (1H, m); 13C NMR (DMSO): d 26.1, 28.1,
40.1, 63.9, 81.1, 116.0, 129.3, 129.4, 152.3, 154.8, 158.2, 172.2. Anal.
calcd. for C18H23N3O7: C, 54.96; H, 5.89; N, 10.68; O, 28.47. Found:
C, 54.90; H, 5.81; N, 10.70; O, 28.51%.

2178
V. V. Sureshbabu, N. S. Sureshbabu, and Kantharaju
Boc-gThr-COOSu (3p)
White solid, IR: 1710, 1745, 1785 cmꢀ1; 1H NMR (DMSO): d 1.2 (3H, s),
1.38 (9H, s), 3.0 (4H, m), 3.7 (1H, m), 5.2 (1H, m), 5.8 (1H, m); 13C NMR
(DMSO): d 17.9, 26.1, 28.2, 68.6, 70.8, 81.1, 153.1, 158.2, 172.8. Anal.
calcd. for C13H21N3O7: C, 47.13; H, 6.39; N, 12.68; O, 33.80. Found:
C, 47.08; H, 6.42; N, 12.70; O, 33.73%.
Boc-gTrp(Z)-COOSu (3q)
1
White solid, IR: 1719, 1745, 1785 cmꢀ1; H NMR (DMSO): d 1.37 (9H,
s), 3.0 (4H, m), 3.4 (2H, m), 5.6 (m, H), 7.0–7.9 (10H, m); 13C NMR
(DMSO): d 25.5, 28.1, 33.5, 63.4, 64.6, 81.0, 108.9, 119.2, 122.2, 122.5,
124.8, 127.6, 128.5, 127.9, 137.7, 146.8, 148.1, 153.8, 159.3, 172.2. Anal.
calcd. for C28H30N4O8: C, 61.08; H, 5.49; N, 10.18; O, 23.25. Found:
C, 61.01; H, 5.50; N, 10.10; O, 23.33%.
Boc-gGln-COOSu (3r)
1
White solid, IR: 1710, 1750, 1785 cmꢀ1; H NMR (DMSO): d 1.36 (9H,
s), 2.1 (2H, m), 2.4 (2H, t), 3.1 (4H, m), 5.0 (2H, s), 5.8 (m, 1H); 13C
NMR (DMSO): d 16.1, 25.5, 28.1, 32.6, 62.4, 81.0, 152.4, 158.6, 172.2,
172.4. Anal. calcd. for C14H22N4O7: C, 46.92; H, 6.19; N, 15.63; O,
31.25. Found: C, 46.88; H, 6.23; N, 15.67; O, 31.27%.
Boc-gAsn-COOSu (3s)
1
White solid, IR: 1715, 1750, 1785 cmꢀ1; H NMR (DMSO): d 1.36 (9H,
s), 3.0 (6H, m), 4.8 (1H, s), 5.0 (2H, s), 5.7 (m, 1H); 13C NMR (DMSO): d
25.4, 28.0, 42.2, 62.0, 81.0, 149.9, 155.9, 172.3, 174.4. Anal. calcd. for
C13H20N4O7: C, 45.35; H, 5.85; N, 16.27; O, 32.53. Found: C, 45.30;
H, 5.90; N, 16.30; O, 32.56%.
Boc-gHis(Z)-COOSu (3t)
1
White solid, IR: 1710, 1745, 1785 cmꢀ1; H NMR (DMSO): d 1.37 (9H,
s), 3.1 (6H, m), 5.2 (2H, s), 7.0 (6H, m), 7.6 (m, 1H); 13C NMR (DMSO):
d 25.4, 28.1, 31.4, 63.5, 64.6, 81.0, 107.8, 122.2, 127.88, 127.95, 128.4,
128.9, 138.1, 146.1, 152.0, 153.8, 160.1, 172.3. Anal. calcd. for
C23H27N5O8: C, 55.09; H, 5.43; N, 13.97; O, 25.52. Found: C, 55.02;
H, 5.50; N, 13.90; O, 25.55%.

Synthesis of O-Su(Boc)methylcarbamates and Ureidodipeptides
2179
General Procedure for the Synthesis of Boc-Dipeptidyl
Urea Esters (5a–j)
To a stirred solution of amino acid methyl ester hydrochloride salt
4 (1.3 mmol) in THF–DMF (2:1, 5 mL), NMM (1.3 mmol) and O-
succinimidyl methylcarbamate 3 (1 mmol) were successively added and
stirred at rt until the completion of the reaction. After the completion
of the reaction, the solvent was evaporated under reduced pressure,
and the residue was triturated with water, filtered, and finally recrystal-
lized with DMSO–water to afford the pure urea esters 5a–j as crystal-
line off-white solids.
Data
Boc-Val-w(NH-CO-NH)-Ala-OMe (5a)
ꢁ
1
Yield: 77%; mp 170 C; H NMR (DMSO): d 0.93 (6H, t), 1.15 (3H, d),
1.35 (9H, s), 1.85 (1H, m), 3.6 (3H, s), 3.8–3.95 (2H, m), 5.15 (1H, m), 6.4
(1H, d), 6.5 (1H, d); 13C NMR (DMSO): d 18.5, 18.8, 28.6, 32.9, 48.3,
52.0, 60.6, 63.0, 78.0, 155.0, 156.6, 174.5; ESI MS: m=z 319.2 [M þ H]þ.
Anal. calcd. for C14H27N3O5: C, 52.98; H, 8.57; N, 13.24. Found: C,
53.20; H, 8.52; N, 13.38%.
Boc-Phe-w(NH-CO-NH)-Val-OMe (5b)
Yield: 72%; mp 140ꢁC; 1H NMR (DMSO): d 0.93 (6H, t), 1.3 (9H, s), 1.8
(1H, m), 2.85 (2H, d), 3.6 (3H, s), 3.8–3.95 (2H, m), 5.2 (1H, m), 6.35 (1H,
br), 6.45 (1H, d), 7.15–7.3 (5H, m); 13C NMR (DMSO): d 18.7, 19.5, 28.3,
29.5, 37.1, 54.7, 57.5, 63.1, 78.2, 126.9, 127.6, 129.1, 137.9, 155.3, 156.9,
174.5; ESI MS: m=z 406.7 [M þ H]þ. Anal. calcd. for C21H31N3O5: C,
62.20; H, 7.71; N, 10.36. Found: C, 61.90; H, 7.52; N, 10.38%.
Boc-Gly-w(NH-CO-NH)-Phe-OMe (5c)
ꢁ
1
Yield: 74%; mp 120–22 C; H NMR (DMSO): d 1.35 (9H, s), 2.85 (2H,
d), 3.6 (3H, s), 3.85 (3H, m), 5.2 (1H, m), 6.3 (1H, br), 6.5 (1H, d), 7.2–7.4
(5H, m); 13C NMR (DMSO): d 28.7, 37.2, 53.9, 63.0, 64.7, 78.1, 126.9,
127.5, 129.1, 137.7, 155.3, 156.7, 173.8; ESI MS: m=z 353.2 [M þ H]þ.
Anal. calcd. for C17H25N3O5: C, 58.11; H, 7.17; N, 11.96. Found: C,
58.38; H, 7.52; N, 11.78%.

2180
V. V. Sureshbabu, N. S. Sureshbabu, and Kantharaju
Boc-Phe-w(NH-CO-NH)-Ala-OMe (5d)
Yield: 76%; mp 138–139ꢁC; 1H NMR (DMSO): d 1.15 (3H, d), 1.35 (9H,
s), 2.84 (2H, d), 3.65 (3H, s), 3.85 (2H, m), 5.15 (1H, d), 6.35 (1H, d), 6.5
(1H, d), 7.15–7.4 (5H, m); 13C NMR (DMSO): d 17.1, 28.7, 37.1, 48.7,
54.7, 63.5, 78.3, 126.7, 127.9, 129.2, 137.9, 154.8, 156.3, 174.5; ESI MS:
m=z 366.1 [M þ H]þ. Anal. calcd. for C18H27N3O5: C, 59.16; H, 7.45;
N, 11.50. Found: C, 59.30; H, 7.52; N, 11.20%.
Boc-Ser(Bzl)-w(NH-CO-NH)-Gly-OMe (5e)
ꢁ
1
Yield: 78%; mp 124–126 C; H NMR (DMSO): d 1.35 (9H, s), 3.6 (3H,
s), 3.7–3.85 (5H, m), 4.48 (2H, s), 5.25 (1H, br), 6.3 (1H, d), 6.45 (1H, d),
7.3–7.4 (5H, m); 13C NMR (DMSO): d 28.5, 51.7, 57.7, 63.7, 65.0, 71.9,
78.0, 126.6, 129.3, 130.5, 138.0, 155.3, 156.8, 174.5; ESI MS: m=z 383.1
[M þ H]þ. Anal. calcd. for C18H27N3O6: C, 56.68; H, 7.15; N, 11.02.
Found: C, 56.38; H, 7.20; N, 11.10%.
Boc-Asp(OBzl)-w(NH-CO-NH)-Gly-OMe (5f)
ꢁ
1
Yield: 70%; mp 120–121 C; H NMR (DMSO): d 1.4 (9H, s), 2.55 (2H,
d), 3.6 (3H, s), 3.85 (3H, m), 5.0 (1H, m), 5.1 (2H, s), 6.35 (1H, d), 6.5
(1H, t), 7.25–7.35 (5H, m); 13C NMR (DMSO): d 28.1, 38.0, 49.5, 61.5,
62.7, 64.7, 78.5, 127.6, 128.5, 129.3, 136.7, 155.0, 156.8, 174.5; ESI MS:
m=z 425.1 [M þ H]þ. Anal. calcd. for C20H29N3O7: C, 56.73; H, 6.90;
N, 9.92. Found: C, 56.80; H, 6.52; N, 10.38%.
Boc-Glu(OBzl)-w(NH-CO-NH)-Leu-OMe (5g)
ꢁ
1
Yield: 74%; mp 139–140 C; H NMR (DMSO): d 0.91 (6H, d), 1.3–1.45
(11H, s), 1.65 (1H, m), 2.55 (2H, m), 2.9 (2H, m), 3.65 (3H, s), 3.8–3.9
(2H, m), 5.15 (2H, s), 5.3 (1H, d), 6.35 (1H, d), 6.5 (1H, d), 7.3–7.4 (5H,
m); 13C NMR (DMSO): d 22.1, 23.1, 24.7, 28.6, 37.9, 39.7, 41.9, 50.9,
51.7, 61.9, 63.1, 78.7, 126.7, 127.6, 128.9, 137.7, 155.3, 156.8, 157.5,
178.1; ESI MS: m=z 480.2 [M þ H]þ. Anal. calcd. for C24H37N3O7: C,
60.11; H, 7.78; N, 8.76. Found: C, 59.80; H, 7.52; N, 9.10%.
Boc-Ile-w(NH-CO-NH)-Phe-OMe (5h)
Yield: 72%; mp 135–137ꢁC; 1H NMR (DMSO): d 0.91 (6H, m), 1.13 (1H, m),
1.35(9H, s), 1.55(2H,m),2.85(2H, d),3.65(3H, s), 3.85(2H,m), 5.15(1H,d),

Synthesis of O-Su(Boc)methylcarbamates and Ureidodipeptides
2181
6.35 (1H, d), 6.5 (1H, d), 7.3–7.45 (5H, m); 13C NMR (DMSO): d 11.7,
15.5, 25.5, 28.3, 37.5, 55.1, 58.7, 63.5, 78.3, 126.7, 127.9, 129.2, 137.9,
154.8, 156.3, 174.5; ESI MS: m=z 409.4 [Mþ H]þ. Anal. calcd. for
C21H33N3O5: C, 61.90; H, 8.16; N, 10.31. Found: C, 62.20; H, 8.52; N, 10.38%.
Boc-Tyr-w(NH-CO-NH)-Ala-OMe (5i)
Yield: 70%; mp 140–42ꢁC; 1H NMR (DMSO): d 1.2 (3H, s), 1.37 (9H, s),
3.1 (2H, m), 3.71 (3H, s), 3.8 (m, 1H), 6.2 (m, 2H), 7.0 (m, 4H); 13C NMR
(DMSO): d 16.1, 28.0, 40.3, 50.6, 52.1, 66.9, 81.0, 119.1, 127.1, 128.7,
128.4, 1548, 158.4, 159.6, 172.1; ESI MS: m=z 382.4 [M þ H]þ. Anal.
calcd. for C18H27N3O8: C, 56.68; H, 7.13; N, 11.02; O, 25.17. Found:
C, 56.62; H, 7.18; N, 11.06, O, 25.20%.
Boc-Trp(Z)-w(NH-CO-NH)-Val-OMe (5j)
Yield: 69%; mp 148–50ꢁC; 1H NMR (DMSO): d 0.9 (6H, s), 1.36 (9H, s),
1.8 (m, 1H), 3.4 (m, 2H), 3.7 (3H, s), 4.4 (1H, m), 5.2 (2H, s), 5.8 (m, 1H),
7.0–7.9 (10H, m); 13C NMR (DMSO): d 18.1, 28.0, 34.2, 34.3, 57.2, 29.8,
63.4, 67.7, 79.3, 108.8, 119.2, 122.2, 122.5, 123.7, 124.8, 127.6, 127.9,
128.5, 136.0, 145.4, 146.8, 159.8, 161.0, 173.1; ESI MS: m=z 567.3
[M þ H]þ. Anal. calcd. for C30H38N4O7: C, 63.59; H, 6.76; N, 9.89; O,
19.76. Found: C, 63.55; H, 6.80; N, 9.91; O, 19.80%.
Boc-Dipeptidyl Urea Acids (8a–d): General Procedure
To a stirred suspension of amino acid 6 (1 mmol) in CH2Cl2 (5 mL)
freshly distilled TMS-Cl (2.2 mmol) and TEA (2.2 mmol) were added
and refluxed for 2 h. The reaction mixture was cooled to rt, O-succinimi-
dyl methylcarbamate 3 (1 mmol) in THF–DMF (2:1, 5 mL) solution was
added, and it was stirred for 30 min at rt. After the completion of the
reaction, the solvent was evaporated under reduced pressure, and the
residue was triturated with water (to remove side product formed during
the reaction), filtered, and recrystallized using DMSO–water to afford the
pure urea acids 8a–d as crystalline off-white solids.
Data
Boc-Leu-w(NH-CO-NH)-Ala-OH (8a)
Yield: 80%; mp 140–141ꢁC; 1H NMR (DMSO): d 0.93 (6H, d), 1.15 (3H,
d), 1.3 (9H, s), 1.35 (2H, t), 1.6 (1H, m), 3.75–3.8 (2H, m), 5.2 (1H, br),

2182
V. V. Sureshbabu, N. S. Sureshbabu, and Kantharaju
6.3–6.45 (2H, m), 8.4 (1H, d); 13C NMR (DMSO): d 17.4, 22.1, 23.3, 24.7,
28.5, 40.1, 49.2, 51.3, 78.1, 155.2, 156.9, 177.8; MS (FABþ): m=z 318.1.
Anal. calcd. for C14H27N3O5: C, 52.98; H, 8.57; N, 13.24. Found: C,
52.66; H, 8.57; N, 13.20%.
Boc-Phe-w(NH-CO-NH)-Ala-OH (8b)
Yield: 78%; mp 137–138ꢁC; 1H NMR (DMSO): d 1.16 (3H, d), 1.31 (9H,
s), 2.85 (2H, d), 3.8–3.9 (2H, m), 5.3 (1H, br), 6.4–6.4 (2H, m), 7.15–7.3
(5H, m), 8.35 (1H, d); 13C NMR (DMSO):d 17.3, 28.1, 37.5, 48.7, 54.1,
77.2, 126.7, 129.1, 130.2, 137.9, 155.1, 156.7, 177.5; MS (FABþ): m=z
352.2. Anal. calcd. for C17H25N3O5: C, 58.11; H, 7.17; N, 11.96. Found:
C, 58.16; H, 7.40; N, 11.70%.
Boc-Leu-w(NH-CO-NH)-Gly-OH (8c)
ꢁ
1
Yield: 75%; mp 123–125 C; H NMR (DMSO): d 0.93 (6H, d), 1.3 (9H,
s), 1.4 (2H, m), 1.65 (1H, m), 3.5 (2H, d), 3.7 (1H, m), 5.2 (1H, d), 6.1
(1H, br), 6.35 (1H, d), 8.35 (1H, d); 13C NMR (DMSO): d 22.0, 23.1,
24.7, 28.1, 40.5, 41.9, 52.0, 75.9, 155.2, 156.9, 178.8; MS (FABþ): m=z
304.2. Anal. calcd. for C13H25N3O5: C, 51.47; H, 8.31; N, 13.85. Found:
C, 51.20; H, 8.52; N, 13.78%.
Boc-Val-w(NH-CO-NH)-Phe-OH (8d)
Yield: 72%; mp 128–130ꢁC; 1H NMR (DMSO): d 0.80–0.91 (6H, t), 1.35
(9H, s), 1.85 (1H, m), 2.8 (2H, d), 4.3 (1H, m), 4.8 (1H, m), 5.5 (1H, d),
6.1–6.3 (2H, br), 7.13–7.25 (5H, m), 8.35 (1H, d); 13C NMR (DMSO): d
18.5, 19.3, 26.1, 29.2, 37.2, 54.9, 62.1, 78.1, 126.7, 128.5, 129.2, 137.5,
154.5, 156.7, 176.2; MS (FABþ): m=z 380.0. Anal. calcd. for
C19H29N3O5: C, 60.14; H, 7.70; N, 11.07. Found: C, 60.45; H, 7.57; N,
11.20%.
Test for Racemization of Methylcarbamate 3f
To a stirred solution of methylcarbamate 3f (0.377 g, 1 mmol) in THF-
DMF (5 mL), optically pure (R)-( þ )-1-phenylethylamine (0.121 g,
1 mmol) was added, and the mixture was stirred at 25ꢁC for 30 min. After
routine workup, it resulted in the diastereomer 10a. The solid was recrys-
tallized using DMSO–water. Mp 165ꢁC; [a]D25: þ 24.8 (c 1, DMSO); H
1
NMR (DMSO): d 1.2–1.4 (12H, t), 2.9 (2H, d), 3.3 (1H, m), 4.7 (1H, m),

Synthesis of O-Su(Boc)methylcarbamates and Ureidodipeptides
2183
5.1 (1H, br), 6.2 (1H, s), 6.55 (1H, m), 7.2–7.35 (10H, m); MS
(FABþ): m=z 384.1. When this experiment was repeated using 3f with
optically pure (S)-( ꢀ )-1-phenylethylamine (0.121 g, 1 mmol), the other
diastereomer 10b was isolated. Mp 160–161ꢁC; [a]D25: ꢀ25.6 (c 1,
1
DMSO); H NMR (DMSO): d 1.2–1.4 (12H, t), 2.9 (2H, d), 3.3 (1H,
m), 4.7 (1H, m), 5.1 (1H, br), 6.2 (1H, s), 6.55 (1H, m), 7.2–7.35 (10H,
m); MS (FABþ): m=z 384.1. Anal. calcd. for C22H29N3O3: C, 68.90; H,
7.62; N, 10.96. Found: C, 68.91; H, 7.23; N, 10.59%. The experiment
was repeated using 3f with racemic 1-phenylethylamine (0.121 g, 1 mmol).
The corresponding diastereomer 10c was obtained and isolated. Mp 155–
ꢁ
1
157 C; H NMR (DMSO): d 1.2–1.4 (12H, dd), 2.9 (2H, d), 3.3 (1H, m),
4.7 (1H, m), 5.1 (1H, br), 6.2 (1H, s), 6.55 (1H, m), 7.2–7.35 (10H, m); MS
(FABþ): m=z 384.0. Anal. calcd. for C22H29N3O3: C, 68.90; H, 7.62; N,
10.96. Found: C, 68.81; H, 7.29; N, 10.60%.
ACKNOWLEDGMENTS
Authors thank the Department of Science and Technology, Government
of India, for financial assistance. Authors also thank Sophisticated
Instruments Facility, Indian Institute of Science (IISc), for NMR data
and P. Balaram, Molecular Biophysics Unit (MBU), IISc, Bangalore,
for mass spectral data.
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