Carbonyldiimidazole (CDI) mediated synthesis of Nα- protected amino acid azides: Application to the one-pot preparation of ureidopeptides

Article abstract of DOI:10.2174/092986611797200922

Synthesis of N^α-protected amino acyl azides starting from corresponding acids via the carbonyldiimidazole (CDI) activation is described. The protocol is extended for a one-pot preparation of ureido peptides that circumvents the isolation of acy

Full text of DOI:10.2174/092986611797200922

Protein & Peptide Letters, 2011, 18, 1093-1098
1093
Carbonyldiimidazole (CDI) Mediated Synthesis of Nꢀ-Protected Amino
Acid Azides: Application to the One-pot Preparation of Ureidopeptides
B. Vasantha, T. M. Vishwanatha and Vommina V. Sureshbabu*
#109, Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Dr. B. R. Ambedkar
Veedhi, Bangalore University: Bangalore-560 001, India
Abstract: Synthesis of Nꢀ-protected amino acyl azides starting from corresponding acids via the carbonyldiimidazole
(CDI) activation is described. The protocol is extended for a one-pot preparation of ureido peptides that circumvents the
isolation of acyl azide and isocyanate intermediates. The reaction was accomplished without using any additives and base.
The protocol is simple, clean, high yielding and free from racemization.
Keywords: Acyl azide, CDI, one-pot reaction, ureidopeptides.
INTRODUCTION
by a reaction of NaN3 with aldehydes using Dess-Martin
periodinane [10]. Katritzky’s group developed a method for
the synthesis of acyl azides from corresponding acyl ben-
zotriazole intermediate [11]. Sureshbabu et al., reported the
preparation of Fmoc-amino acid azides from corresponding
acid chlorides or mixed anhydrides [7,12]. However the acid
chloride method is obsolete in case of Boc/Z amino acids
because the corresponding acid chlorides degrade to Leuch’s
anhydride [9] and most of the other protocols are less advan-
tageous due to multi-step reactions, long duration, and use of
toxic reagents. On the other hand, though a plethora of pro-
tocols are available for the synthesis of urea derivatives such
as reaction of amines with carbonyl transfer agents, active
carbamates or the generation of isocyanates using phos-
gene/phosgene equivalents followed by reaction with an
amine [13], the one involving generation of isocyanates
through curtius rearrangement of acyl azides followed by
their aminolysis is of much synthetic interest. This is the
protocol of choice especially for N-protected ꢀ-ureido pepti-
domimetics. Previously, we had demonstrated one pot prepa-
ration of ureido peptides from corresponding acids using
diphenylphosphoryl azide (DPPA) and Deoxoflour/TMSN3
[14]. The in situ generated acyl azides have played a key role
in these experiments. Recently our group reported the syn-
thesis of acyl azides employing peptide-coupling reagents
such as EDC, HBTU in high yields [15]. In view of the wide
spread applications of acyl azides, development of a mild
protocol for their preparation is still of interest.
N-Protected amino acid azides are well known and effi-
cient acylating agents in peptide chemistry. They were first
reported by Curtius during his efforts to develop mild, race-
mization free route for peptide synthesis [1]. Acid azide
method, frequently used in the segment condensation of pep-
tide fragments by the divergent approach, is still practiced by
the peptide chemists especially for the coupling of bifunc-
tional amino acids His, Thr, Trp and Ser [2]. The total syn-
thesis of bovine pancreatic ribonuclease (RNase) A with 124
amino acids was carried out using acid azide method by Ha-
ruaki Yajima [3]. They are the building blocks for the syn-
thesis of partially modified retro-inverso peptides, gem-
diaminoalkylamines, ꢁ-amino acids, ꢁ-amino alcoholss [4].
In general, acyl azides are extensively used in organic syn-
thesis for the preparation of amides, nitriles, and heterocy-
cles and also in cycloaddition reactions [5].
Curtius rearrangement is an important application of acyl
azides, which describes their degradation into isocyanate
through a concerted mechanism. Isocyanates are reactive
intermediates employed in the synthesis of polyurethanes,
used as precursors to agrochemicals, adhesives, etc [6]. In
particular, amino acid derived isocyanates are useful inter-
mediates for the synthesis of artificial ꢁ-sheets, various
pharmacologically important scaffolds such as ureas, carba-
mates, and formamides [7]. Insertion of urea moiety in place
of amide bond has lead to ureidopeptidomimetics some of
which are screened as HIV-1 protease inhibitors, [Leu]5
enkephalin analogs, angiotensins, ꢂ-secretaries that have
shown increased metabolic stability [8].
With the continued interest in this area and our knowl-
edge over various classes of carbonyl transfer reagents, we
became interested towards a mild reagent of this class-
carbonyldiimidazole (CDI) which is also known for its abil-
ity to activate carboxyl group [16]. It was envisioned that it
could be a useful reagent for generation of acyl azides from
corresponding acids. CDI possesses several advantages over
the traditional coupling agents such as low cost, high yield
and purity of the products and racemization free coupling.
Fustero et al., carried out total synthesis of tetramic acid us-
ing CDI as carbonyl transfer reagent [17]. Figueiredo group
employed it as hydroxy group activator for the synthesis of
The protocols generally employed to access acyl azides
involve reaction of an azide ion with activated carboxy acids
such as acid chlorides, mixed anhydrides, oxazolidinones
[9]. Subhas Bose et al., reported the synthesis of acyl azides
*Address correspondence to this author at the Department of Studies in
Chemistry, Central College Campus, Bangalore University, Dr. B. R. Am-
bedkar Veedhi, Bangalore -560 001, India Tel: +91-80-2296-1339;
E-mails: sureshbabuvommina@rediffmail.com; hariccb@hotmail.com
0929-8665/11 $58.00+.00
© 2011 Bentham Science Publishers

1094 Protein & Peptide Letters, 2011, Vol. 18, No. 11
Vasantha et al.
substituted azetidines [18]. The protease inhibitor GE 20372
and MAPI containing urea linkage were synthesized by
Zhang and coworkers [19]. It was also employed for the
aqueous phase synthesis of peptides and peptide thioesters
[20]. Recently Dube’s group employed CDI as a promoter
for the Lossen rearrangement of various hydroxamic acids to
isocyanates [21]. Larrivee and others demonstrated CDI me-
diated amidation of acyl imidazoles in presence of diazabi-
cycloundecene (DBU) as catalyst [22]. Despite such wide
spread application, there are no reports on the utility of CDI
for the synthesis of acyl azides. With an aim to demonstrate
the newer application of this reagent, we now, report the
synthesis of acyl azides and then, a one-pot preparation of
ureido derivatives through CDI mediated carboxy activation.
tional amino acid derived acyl azide 3f also. In addition, two
dialkyl amino acid azides Boc-Aib-N3 3i and Boc-Gpn-N3 3j
were also prepared (Table 1).
As a second objective, we undertook an one-pot synthesis
of ureidopeptides. For this, the solution of Fmoc-Ala-N3 pre-
pared as described previously, was subjected to ultrasonica-
tion for 10 min without isolation. The in situ generated iso-
cyanate was treated with leucinyl methyl ester (obtained by
deprotonation of the corresponding hydrochloride salt using
Zn dust) [23] under ultrasonication. The reaction was com-
plete in 15 min to afford the desired urea 4a. This was evi-
dent by TLC analysis and precipitation of insoluble urea
adduct from the reaction mixture. An excess of hexane was
added and the product was collected by filtration. A simple
recrystallization afforded 4a in good yield with excellent
purity as a stable solid (Scheme 2).
RESULTS AND DISCUSSION
In the first part of our work, N-protected amino acyl az-
ides were synthesized from corresponding acids. In a typical
reaction, a chilled solution of Fmoc-Ala-OH 1a in THF was
treated with equimolar quantity of CDI. After 15 min, NaN3
(dissolved using a few drops of DMSO) was added and the
reaction was continued for another 20 min. The resulting
acyl azide 3a was isolated after a simple workup as pure
solid in a yield exceeding 90%. Imidazole byproduct was
removed completely in aqueous workup. Initial characteriza-
tion by IR revealed the presence of a strong peak at 2135 cm-
The sequence of Curtius rearrangement was confirmed
by carrying out a separate experiment without adding amine
component to the reaction mixture. The acyl azide generated
by the reaction of NaN3/DMSO with N-protected amino acid
derived imidazolide, underwent Curtius transformation on
subjecting to ultrasonication to afford the corresponding iso-
cyanate. This was confirmed through IR spectroscopy (2245
cm-1) and complete disappearance of acyl azide peak was
observed after 10 min. The protocol was extended for the
synthesis of few other Fmoc-protected ureas 4a-c, as well as
Boc/Z-protected ureidopeptides 4d-h. All the products were
obtained in excellent yield and purity (Table 2). The case
studies carried out on specimen examples of ureidopeptides
confirmed that the entire protocol is free from racemization
[24].
1
corresponding to the acyl azide. Further analyses through
mass and NMR studies confirmed the product (Scheme 1).
The acyl azide formation is a two-step process involving
first, the activation of carboxy group as acyl imidazole (imi-
dazolide) 2 followed by its azidolysis. The IR analysis of the
isolated imidazolide had a signal at 1650 cm-1, which under-
went rapid azidolysis on addition of NaN3/DMSO. The reac-
tion was monitored by subjecting an aliquot of reaction mix-
ture to IR analysis in frequent intervals of time. Complete
disappearance of imidazolide peak confirmed the completion
of reaction which took only about 20 min.
CONCLUSION
In summary, a simple route for the preparation of Nꢀ-
protected amino acyl azides is reported employing CDI as
carboxy activating agent and the protocol is extended for an
one-pot synthesis of ureidopeptides. The reaction is simple,
mild and high yielding.
The importance of the protocol lies in the fact that the
method doesn’t require the addition of an organic base,
which usually is the case in typical coupling reactions during
carboxyl group activation, thus circumventing the base cata-
lyzed side reactions including racemization. The efficacy of
the protocol was demonstrated by preparing some other
Fmoc-protected amino acid azides 3a-d as well. Encouraged
by this result, the protocol was extended to synthesize a few
Z-protected amino acid azides 3e-h including one bifunc-
EXPERIMENTAL PROCEDURE
General
All solvents were distilled prior to use and reagents were
used as received from Sigma-Aldrich. Melting points were
determined on a Buchi model 150 melting point apparatus in
open capillaries and are uncorrected. IR spectra were re-
N
R1
R1
R1
CON3
3a-h
NaN3/DMSO
0 °C, 20 min
CDI, THF
N
PgHN
1a-h
Pg = Fmoc, Z or Boc group
COOH
PgHN
PgHN
0 °C, 15 min
O
2
Ph
COOtBu
2
OBn
R1 =
Scheme (1). Synthesis of urethane protected amino acyl azides.

Carbonyldiimidazole (CDI) Mediated Synthesis of Nꢀ-Protected Amino Acid Azides
Protein & Peptide Letters, 2011, Vol. 18, No. 11 1095
Table 1. List of Urethane Protected Acyl Azides
Entry
Acyl Azide
Yield (%)
Mp (°C)
HRMS [M+Na]+ Obsd./Calcd.
359.1123/359.1120
387.1425/387.1433
473.17/473.18a
3a
3b
3c
3d
3e
3f
Fmoc-Ala-N3
89
87
78
75
88
76
162 (163) [7a]
168 (169) [7a]
169(168-170)[7a]
146
Fmoc-Val-N3
Fmoc-Glu(tBu)-N3
Fmoc-Ser(OBn)-N3
Z-Phe-N3
481.1285/481.1278b
347.1093/347.1120
327.0712/327.0705
145 (146) [11]
Gum
CON3
O
ZN
O
3g
3h
3i
Z-Val-N3
70
74
78
77
Gum
Gum
Gum
Gum
249.13/249.11a
Z-Gpn-N3
Boc-Aib-N3
Boc-Gpn-N3
353.1595/353.1590
251.15/251.11a
3j
335.1489/335.1485b
a ESI-MS; b [M+K]+
R1
R1
O
R2
1) CDI, NaN3, 0 °C
2) H-CH(R2)-OMe
PgHN
COOH
PgHN
N
N
COOMe
H
H
1
4a-h
Pg = Fmoc, Boc or Z group
Scheme (2). One-pot synthesis of ureido peptides.
corded on a Nicolet model impact 400 D FT-IR spectrometer
sonication was continued for another 15 min. Urea product,
which precipitated out from the reaction mixture, was fil-
tered and recrystallized using DMSO-water system. Other-
wise, the product was isolated through simple work up.
1
(KBr pellets, 3 cm-1 resolution). H NMR spectra were re-
corded on a Bruker AMX 400 MHz spectrometer. High-
resolution mass spectra (HR-MS) were recorded on Q- Tof
micromass mass spectrometer. The ultrasound bath (Elma, T
310/H) was German made and operated at 35 kHz.
Spectral Characterization Data
General Procedure for 3a-j: To a solution of N-
protected amino acid (1.0 mmol) in THF (10.0 mL), was
added CDI (162 mg, 1.0 mmol) at 0 °C and the reaction mix-
ture was stirred for 15 min. To this, NaN3 (1.1 mmol, 72 mg)
in DMSO (1-2 drops) was added and the stirring was contin-
ued for another 20 min. The solvent was removed under
vacuum and diluted with CH2Cl2 (20 mL). The organic layer
was washed with 5% Na2CO3 solution (2 x 10 mL), water (2
x 10 mL), brine (10 mL) and dried over anhydrous Na2SO4.
Solvent was evaporated in vacuo to afford the product in 88-
90% yield.
(S)-(9H-Fluoren-9-yl)methyl 1-azido-1-oxopropan-2-
ylcarbamate {Fmoc-Ala-N3} (3a): IR (KBr): 1698, 2135
cm-1; 1H NMR (400 MHz, CDCl3): white solid; ꢀ (ppm) 1.42
(3H, d, J = 7.2 Hz), 3.88 (1H, m), 4.35 (1H, t, J = 3.8 Hz),
4.48 (2H, d, J = 6.8 Hz), 6.89 (1H, br), 7.3-7.9 (8H, m); 13C
NMR (100 MHz, CDCl3): ꢀ (ppm) 18.6, 47.5, 51.9, 67.5,
120.5, 125.4, 127.6, 128.3, 141.8, 144.1, 150.6, 180.9.
(S)- (9H-Fluoren-9-yl)methyl 1-azido-3-methyl-1-
oxobutan-2-ylcarbamate {Fmoc-Val-N3} (3b): IR (KBr):
1701, 2138 cm-1; 1H NMR (400 MHz, CDCl3): white solid; ꢀ
(ppm) 0.93 (6H, d, J = 6.2 Hz), 2.15 (1H, m), 3.99 (1H, br),
4.12 (1H, t, J = 3.8 Hz), 4.25 (2H, d, J = 6.4 Hz), 5.89 (1H,
br), 7.22-7.75 (8H, m); 13C NMR (100 MHz, CDCl3): ꢀ
(ppm) 17.7, 31.4, 47.7, 61.2, 67.6, 125.4, 125.5, 127.6,
128.23, 141.8, 144.2, 156.8, 180.1.
General procedure for 4a-g: To a chilled solution of N-
protected amino acid (1.0 mmol) in THF (10 mL), CDI (162
mg, 1.0 mmol) was added and the reaction mixture was
stirred for 15 min. NaN3 (72 mg, 1.1 mmol in few drops of
DMSO) was added and the stirring was continued for 20
min. Then the reaction mixture was ultrasonicated for 10
min, amino acid ester (1.1 mmol, obtained by neutralizing its
hydrochloride salt with Zn dust) was added and the ultra-
(S)-tert-Butyl-4(((9H-fluoren-9-yl)methoxy)carbonyl)-
5-azido-5-oxopentanoate {Fmoc-Glu(OtBu)-N3} (3c): IR
(KBr): 1695, 2136 cm-1; 1H NMR (400 MHz, CDCl3): white
solid; ꢀ (ppm) 1.38 (9H, s), 1.79-1.82 (2H, m), 2.10 (1H, br),

1096 Protein & Peptide Letters, 2011, Vol. 18, No. 11
Vasantha et al.
Table 2. List of Urethane Protected Ureidopeptides
Entry
Urea
Yield (%)
Mp (°C)
HRMS [M+Na]+ Found/Calcd.
4a
94
200 (199)[7b]
476.2153/473.2161
O
FmocHN
N
H
N
H
COOMe
BnO
4b
4c
89
88
167- 168
568.2432/568.2424
640.2432/640.2425b
O
FmocHN
N
H
N
H
COOMe
BuOtOC
135
Ph
O
2
FmocHN
N
H
N
H
COOMe
Ph
4d
4e
89
91
168 (169) [15a]
422.1681/422.1692
450.23/420.20a
O
ZHN
N
H
N
COOMe
H
Ph
188
O
ZHN
N
H
N
H
COOMe
4f
92
79
172 (170) [15a]
340.1845/340.1848
398.2052/398.2057b
O
BocHN
N
N
COOMe
H
H
4g
174-175 (175) [14]
O
BocHN
N
H
N
H
COOMe
a ESI-MS; b [M+K]+
2.18-2.25 (2H, m), 3.87 (1H, m), 4.12-4.27 (3H, m), 7.33-
7.89 (8H, m); 13C NMR (100 MHz, CDCl3): ꢀ (ppm) 27.7,
31.3, 38.5, 46.5, 51.5, 65.5, 79.6, 127.2, 127.4, 127.6, 129.0,
140.6, 142.5, 155.8, 168.0, 171.5.
(S)-Benzyl 4-(2-azido-2-oxoethyl)-5-oxooxazolidine-3-
carboxylate {Z-Asp(oxa)-N3} (3f): IR (film): 1712, 2146
1
cm-1; H NMR (400 MHz, CDCl3): gum; ꢀ (ppm) 2.89 (2H,
d, J = 6.4 Hz), 4.01 (1H, t, J = 4.2 Hz), 5.16 (2H, s), 5.65
(2H, s), 7.19-7.21 (5H, m); 13C NMR (100 MHz, CDCl3): ꢀ
(ppm) 21.4, 55.6, 67.7, 79.0, 128.5, 128.9, 129.2, 136.9,
153.3, 172.6, 180.3.
(S)-(9H-Fluoren-9-yl)methyl 1-azido-3-(benzyloxy)-1-
oxopropan-2-ylcarbamate {Fmoc-Ser(OBn)-N3} (3d): IR
(KBr): 1697, 2142 cm-1; 1H NMR (400 MHz, CDCl3): white
solid; ꢀ (ppm) 3.28 (2H, s), 3.65 (2H, d, J = 4.6 Hz), 4.15
(1H, t, J = 3.8 Hz), 4.27 (2H, d, J = 6.4 Hz), 4.65 (1H, m),
6.95 (1H, br), 7.22-7.81 (13H, m); 13C NMR (100 MHz,
CDCl3): ꢀ (ppm) 28.5, 47.6, 52.5, 68.5, 69.8, 127.0, 127.6,
128.1, 128.4, 128.7, 128.9, 129.2, 137.5, 141.1, 143.8, 156.1,
171.9.
(S)-Benzyl
1-azido-3-methyl-1-oxobutan-2-ylcarba-
mate {Z-Val-N3} (3g): IR (film): 1702, 2142 cm-1; 1H NMR
(400 MHz, CDCl3): gum; ꢀ (ppm) 0.92 (6H, d, J = 6.4 Hz),
2.18 (1H, m), 3.95 (1H, br), 5.36 (2H, s), 6.23 (1H, br), 7.22-
7.70 (5H, m); 13C NMR (100 MHz, CDCl3): ꢀ (ppm) 17.5,
30.4, 53.5, 67.8, 127.2, 127.8, 128.9, 139.9, 155.8, 179.5.
(S)-Benzyl 1-azido-1-oxo-3-phenylpropan-2-ylcarba-
mate {Z-Phe-N3} (3e): IR (KBr): 1695, 2132 cm-1; 1H NMR
(400 MHz, CDCl3): white solid; ꢀ (ppm) 2.51 (2H, d, J = 5.6
Hz), 3.67 (1H, m), 5.09 (2H, s), 6.98 (1H, br), 7.13-7.35
(10H, m); 13C NMR (100 MHz, CDCl3): ꢀ (ppm) 38.1, 57.2.
67.6, 128.1, 128.6, 128.9, 129.1, 129.3, 129.7, 135.9, 136.7,
156.4, 179.8.
Benzyl 1-(azidocarbonyl)cyclohexylcarbamate {Z-
Gpn-N3} (3h): IR (film): 1699, 2141 cm-1.
1H NMR (400 MHz, CDCl3): gum; ꢀ (ppm) 1.18-1.25
(10H, m), 2.35 (2H, s), 2.89 (2H, br), 5.25 (2H, s), 6.99 (1H,
br), 7.19-7.21 (5H, m); 13C NMR (100 MHz, CDCl3): ꢀ
(ppm) 21.8, 24.7, 28.8, 37.5, 39.3, 41.8, 65.6, 126.9, 127.5,
128.9, 139.8, 155.6, 171.3.

Carbonyldiimidazole (CDI) Mediated Synthesis of Nꢀ-Protected Amino Acid Azides
Protein & Peptide Letters, 2011, Vol. 18, No. 11 1097
tert-Butyl 1-azido-2-methyl-1-oxopropan-2-ylcarba-
Hz ), 3.56 (3H, s), 4.51-4.82 (2H, m), 5.25 (2H, s), 5.69 (1H,
br), 6.96 (2H, m), 7.19-7.21 (10H, m); 13C NMR (100 MHz,
DMSO-d6): ꢀ (ppm) 17.8, 25.6, 36.8, 41.2, 48.5, 52.5, 65.9,
125.6, 126.9, 127.1, 127.9, 128.2, 128.8, 139.1, 141.6, 155.6,
156.9, 169.9.
1
mate {Boc-Aib-N3} (3i): IR (film): 1694, 2138 cm-1; H
NMR (400 MHz, CDCl3,): gum; ꢀ (ppm) 1.39 (9H, s), 1.47
(6H, s), 5.02 (1H, br); 13C NMR (100 MHz, CDCl3): ꢀ (ppm)
24.5, 28.9, 52.3, 79.3, 155.6, 180.1.
tert-Butyl
1-(azidocarbonyl)cyclohexylcarbamate
(S)-Methyl
2-(3-((S)-1-(tert-butoxycarbonyl)ethyl)
1
{Boc-Gpn-N3} (3j): IR (film): 1702, 2138 cm-1; H NMR
(400 MHz, CDCl3): gum; ꢀ (ppm) 1.36 (9H, s), 1.19-1.43
(10H, m), 2.33 (2H, s), 2.92 (2H, br), 6.95 (1H, br); 13C
NMR (100MHz, CDCl3,): ꢀ (ppm) 21.5, 24.3, 27.5, 28.3,
36.4, 39.2, 42.5, 78.6, 156.5, 171.9.
uriedo)-3-methylbutanoate {Boc-Ala- ꢁ[NHCONH]-Val-
OMe} (4f): IR (KBr): 1649, 1705 1739 cm-1; H NMR (400
1
MHz, DMSO-d6): white solid; ꢀ (ppm) 0.84 (6H, d, J = 6.0
Hz), 1.25 (3H, d, J = 7.2 Hz), 1.36 (9H, s), 2.12 (1H, m),
3.64 (3H, s), 4.25-4.37 (2H, m), 4.76 (1H, br), 6.22–6.58
(2H, br); 13C NMR (100 MHz, DMSO-d6): ꢀ (ppm) 17.6,
17.7, 27.6, 31.9, 47.5, 51.2, 62.5, 75.4, 154.6, 156.2, 173.6.
(S)-Methyl
2-(3-((S)-1-(((9H-fluoren-9-yl)methoxy)
carbonyl)ethyl)uriedo)-4-methylpentanoate {Fmoc-Ala-
ꢁ[NHCONH]-Leu-OMe} (4a): IR (film): 1649, 1698, 1739
cm-1; 1H NMR (400 MHz, DMSO-d6): white solid; ꢀ (ppm)
0.92 (6H, d, J = 6.4 Hz), 1.17 (3H, d, J = 6.4 Hz), 1.32 (2H,
m), 1.52 (1H, m), 3.61 (3H, s), 3.67-3.82 (2H, m), 4.12 (2H,
d, J = 7.2 Hz), 4.21 (1H, t, J = 4.4 Hz), 5.01 (1H, d, J = 7.2
Hz), 5.35 (1H, br), 6.98 (1H, br), 7.25-7.81 (8H, m); 13C
NMR (100 MHz, DMSO-d6): ꢀ (ppm) 17.2, 22.3, 23.2, 40.1,
47.2, 48.8, 50.4, 61.6, 66.5, 120.1, 124.6, 127.2, 127.6,
141.5, 143.8, 155.5, 156.6, 171.5.
(S)-Methyl 2-(3-((S)-1-(tert-butoxycarbonyl)-3-methyl-
butyl)ureido)-3-methylbutanoate
{Boc-Leu-ꢁ[NHCONH]-Val-OMe} (4g): IR (KBr):
1645, 1702 1738 cm-1; 1H NMR (400 MHz, DMSO-d6): whi-
te solid; ꢀ (ppm) 0.93 (12H, m), 1.21 (2H, m), 1.38 (9H, s),
1.72 (1H, m), 2.12 (1H, m), 3.63 (3H, s), 4.21 (1H, m), 4.32
(1H, m), 5.03 (1H, br), 6.41-6.53 (2H, m); 13C NMR (100
MHz, DMSO-d6): ꢀ (ppm) 17.8, 18.5, 23.7, 31.0, 46.9, 52.9,
55.1, 58.3, 63.1, 76.3, 155.8, 156.3, 172.6.
(S)-Methyl
carbonyl)-2-(benzyloxy)ethyl)uriedo)-3-methylbutanoate
{Fmoc-Ser(OBn)-ꢁ[NHCONH]-Val-OMe} (4b): IR
2-(3-((S)-1-(((9H-fluoren-9-yl)methoxy)
ACKNOWLEDGEMENT
(KBr): 1648, 1701, 1738 cm-1; 1H NMR (400 MHz, DMSO-
d6): white solid; ꢀ (ppm) 0.94 (6H, d, J = 6.4 Hz), 2.18 (1H,
m), 3.28 (2H, s), 3.62 (2H, d, J = 4.6 Hz), 3.68 (3H, s), 3.98-
4.02 (2H, m), 4.12 (2H, d, J = 7.4 Hz), 4.27 (1H, t, J = 4.2
Hz), 5.82 (1H, br), 6.51-6.72 (2H, m), 7.33-7.75 (13H, m);
13C NMR (100 MHz, DMSO-d6): ꢀ (ppm) 17.5, 31.4, 47.3,
50.5, 52.5, 61.9, 65.9, 68.3, 69.8, 120.5, 125.6, 127.1, 127.4,
127.9, 128.8, 129.1, 136.9, 141.5, 144.7, 155.5, 156.9, 171.1.
We thank University Grant Commission (UGC) [Grant
No. 37-79/2009 (SR)], New Delhi, India for financial sup-
port.
REFERENCES
[1]
(a) Curtius, T. Hydrazide und azide organischer s uren I. abhand-
lung. J. Prakt. Chem., 1894, 50(2), 275-294; (b) Klausner, Y. S.;
Bodanszky, M. The azide method in peptide synthesis: Its scope
and limitations. Synthesis, 1974, (8), 549-559.
[2]
[3]
[4]
Meienhofer, J. In: The azide method in peptide synthesis; Gross,
E.; J. Meienhofer, Eds.; Academic press: New York, 1979; Vol. 1,
pp. 198 and references cited therein.
Yajima, H.; Fujii, N. Studies on peptides. 103. Chemical synthesis
of a crystalline protein with the full enzymic activity of ribonucle-
ase A. J. Am. Chem. Soc., 1981, 103(19), 5867- 5871.
(S)-tert-Butyl-4(((9H-fluoren-9-yl)methoxy)carbonyl)-
4-(3-((S)-1-methoxy-1-oxo-3-phenylpropan-2-
yl)ureido)butanoate
{Fmoc-Glu(OtBu)-ꢁ[NHCONH]-
Phe-OMe} (4c): IR (KBr): 1644, 1692, 1731 cm-1; 1H NMR
(400 MHz, DMSO-d6): white solid; ꢀ (ppm) 1.42 (9H, s ),
2.1 (2H, t, J = 7.2 Hz), 2.52 (2H, m), 2.87 (2H, d, J = 6.8
Hz), 3.65 (3H, s), 4.15 (1H, t, J = 4.4 Hz), 4.29 (2H, d, J =
7.2 Hz), 4.40-4.47 (2H, m), 5.65 (1H, d, J = 6.0 Hz), 6.75-
6.91 (2H, m), 7.54-7.85 (13H, m); 13C NMR (100 MHz,
DMSO-d6): ꢀ (ppm) 27.8, 35.3, 37.7, 46.5, 51.8, 54.3, 61.5,
62.4, 66.6, 73.5, 119.8, 124.6, 126.1, 126.8, 127.2, 128.6,
129.2, 137.6, 141.1, 143.6, 155.3, 156.6, 170.8, 171.4.
(a) Fletcher, M. D.; Campbell, M. M. Partially modified retro-
inverso peptides: development, synthesis, and conformational be-
havior. Chem. Rev., 1998, 98(2), 763-796; (b) Sibi, M. P.;
Deshpande, P. K. A new methodology for the synthesis of ꢀ-amino
acids. J. Chem. Soc. Perkin Trans. 1, 2000, (8), 1461-1466; (c)
Guichard, G.; Semetey, V.; Didierjean, C.; Aubry, A.; Briand, J.-P.;
Rodriguez, M. Effective preparation of O- succinimidyl-2-(tert-
butoxycarbonylamino)ethylcarbamate derivatives from ꢀ-amino a-
cids. Application to the synthesis of urea-containing pseudopep-
tides and oligoureas. J. Org. Chem., 1999, 64(23), 8702-8705; (d)
Sureshbabu, V. V.; Kantharaju.; Sudarshan, N. S. Synthesis of
Fmoc-protected ꢀ-amino alcohols and peptidyl alcohols from
Fmoc-amino acid/peptide acid azides. Indian J. Chem., 2006,
45B(8), 1880-1886.
(a) Brase, S.; Gil, C.; Knepper, K.; Zimmermann, V. Organic azi-
des: an exploding diversity of a unique class of compounds. Angew.
Chem. Int. Ed. Eng., 2005, 44(33), 5188-5240; (b) Kangani, C. O.;
Day, B. W.; Kelley, D. E. Controlled conversion of phenylacetic
acids to phenylacetonitriles or benzonitriles using bis(2-
methoxyethyl)aminosulfur trifluoride. Tetrahedron Lett., 2008,
49(5), 914-918.
(S)-Methyl 2-(3-((S)-1-(benzyloxycarbonyl)-2-phenyl-
ethyl)ureido)propanoate {Z-Phe- ꢁ[NHCONH]-Ala-
OMe} (4d): IR (KBr): 1647, 1699, 1734 cm-1; 1H NMR (400
MHz, DMSO-d6): white solid; ꢀ (ppm) 1.42 (3H, d, J = 7.2
Hz), 2.72 (2H, d, J = 5.2 Hz), 3.56 (3H, s), 3.89 (2H, m),
5.25 (2H, s), 6.76-6.98 (3H, m), 7.12-7.19 (10H, m); 13C
NMR (100 MHz, DMSO-d6): ꢀ (ppm) 17.9, 36.5, 42.8, 45.7,
52.5, 62.3, 125.6, 126.3, 127.1, 127.8, 128.3, 128.9, 138.5,
139.9, 155.5, 156.5, 171.1.
[5]
(S)-Methyl 2-(3-((S)-1-(benzyloxycarbonyl)-2-methyl-
[6]
[7]
(a) Saunders, J. H.; Slocombe, R. J. The chemistry of the organic
isocyanates. Chem. Rev., 1948, 43(2), 203-218; (b) Ozaki, S. Re-
cent advances in isocyanate chemistry. Chem. Rev., 1972, 72(5),
457-496.
(a) Sureshbabu, V. V.; Ananda, K.; Vasanthakumar, G.-R. (Flou-
ren-9-ylmethoxy)carbonyl (Fmoc) amino acid azides: Synthesis,
propyl)ureido)-3-phenylpropanoate
{Z-Val-
ꢁ[NHCONH]-Phe-OMe} (4e): IR (KBr): 1652, 1701, 1738
1
cm-1; H NMR (400 MHz, DMSO-d6): white solid; ꢀ (ppm)
0.78 (6H, d, J = 5.6 Hz), 1.75 (1H, m), 2.89 (2H, d, J = 7.4

1098 Protein & Peptide Letters, 2011, Vol. 18, No. 11
Vasantha et al.
isolation, characterization, stability and application to synthesis of
peptides. J. Chem. Soc. Perkin Trans. 1, 2000, (24), 4328-4331; (b)
Patil B, S.; Vasanthakumar, G. R.; Sureshbabu, V. V. Isocyanates
from carboxylic acids: application of peptide coupling agents EDC
and HBTU. Org. Biomol. Chem., 2010, 8, 835-840.
[16]
a) Sharma, R. K. 1,1'-Carbonyldiimidazole (CDI). Synlett, 2007,
(19), 3073-3074 and references cited therein. b) Woodman, E. K.;
Chaffey, J. G. K.; Hopes, P. A.; Hose, D. R. J.; Gilday, J. P. N, N-
Carbonyldiimidazole-mediated amide coupling: Significant rate
enhancement achieved by acid catalysis with imidazole.HCl. Org.
Proc. Res. Dev., 2009, 13, 106-113. c) Weisenburger, G. A.; An-
derson, D. K.; Clark, J. D.; Edney, A. D.; Karbin, P. S.; Gallgher,
D. J.; Knable, C. M.; Pietz, M. A. Pilot-plant preparation of an ꢀvꢂ3
integrin antagonist: process development of a carbonyldiimidazole
peptide coupling. Org. Proc. Res. Dev., 2009, 13, 60-63.
Fustero, S.; Torre, M. G.; Sanz-Cervera, J. F.; Arellano, C. R.;
Piera, J.; Simn, A. A concise, asymmetric synthesis of tetramic acid
derivatives. Org. Lett., 2002, 4(21), 3651- 3654.
of Nꢀ-[(9-Fluorenylmethyl)oxy]
carbonyl amino Acids: Synthe-
sis, isolation, characterization, and application to the efficient syn-
thesis of urea peptidomimetics. J. Org. Chem., 2003, 68(19), 7274-
7280; (c) Sudarshan, N. S.; Narendra, N.; Hemantha, H. P.;
Sureshbabu, V. V. An efficient conversion of the carboxylic group
of N-Fmoc ꢀ-amino acids/peptide acids into N-formamides em-
ploying isocyanates as key intermediates. J. Org. Chem., 2007,
72(25), 9804-9807.
(a) Lam, P. Y.; Jadhav, P. K.; Eyermann, C. J.; Hodge, C. N.; Ru,
Y.; Bacheler, L. T.; Meek, J. L.; Otto, M. J.; Rayner, M. M.; Wong,
Y. N.; Chang, C. H.; Weber, P. C.; Jackson, D. A.; Sharpe, T. R.;
Erickson-Viitanen, S. Rational design of potent, bioavailable, non-
peptide cyclic ureas as HIV protease inhibitors. Science, 1994,
263(5145), 380-384; (b) Bakshi, P.; Wolfe, M. S. Stereochemical
analysis of (hydroxyethyl)urea peptidomimetic inhibitors of ꢁ-
secretase. J. Med. Chem., 2004, 47(26), 6485-6489.
[8]
[17]
[18]
Figueiredo, R. M.; Fröhlich, R.; Christmann, M. N,N‘-
Carbonyldiimidazole-mediated cyclization of amino alcohols to
substituted azetidines and other N-heterocycles. J. Org. Chem.,
2006, 71(11), 4147-4154.
[9]
(a) Padwa, A.; Crawford, K. R.; Rashatasakhon, P.; Rose, M. Sev-
eral convenient methods for the synthesis of 2-amido substituted
furans. J. Org. Chem., 2003, 68(7), 2609-2617; (b) Wilder, R.;
Mobashery, S. J. The use of triphosgene in preparation of N-
carboxy alpha amino acid anhydrides. J. Org. Chem., 1992, 57(9),
2755-2756; (c) Kuramochi, K.; Watanabe, H.; Kitahara, T. Syn-
thetic study on oximidines: A concise synthesis of (Z)- enamides.
Synlett, 2000, (3), 397-399.
Subhas Bose, D.; Narasimha Reddy, A. V. Iodine(V) reagents in
organic synthesis. Dess-Martin periodinane mediated efficient one-
pot oxidation of aldehydes to acyl azides. Tetrahedron Lett., 2003,
44(17), 3543-3545.
Katritzky, A. R.; Widyan, K.; Kirichenko, K. Preparation of poly-
functional acyl azides. J. Org. Chem., 2007, 72(15), 5802-5804.
Sureshbabu, V. V.; Patil, B. S.; Venkataramanarao, R. Preparation,
isolation, and characterization of Nꢀ-Fmoc-peptide isocyanates:
Solution synthesis of oligo-ꢀ-peptidyl ureas. J. Org. Chem., 2006,
71(20), 7697-7705.
(a) Nowick, J. S.; Holmer, D. L.; Noronha, G.; Smith, E. M.;
Nguyen, J. M.; Huang, S. L. Synthesis of peptide isocyanates and
isothiocyanates. J. Org. Chem., 1996, 61(11), 3929- 3934; (b)
Boeijen, A.; Ameijde, J. V.; Liskamp, R. M. J. Solid-phase synthe-
sis of oligourea peptidomimetics employing the Fmoc protection
strategy. J. Org. Chem., 2001, 66(25), 8454-8462.
[19]
Zhang, X.; Rodrigues, J.; Evans, L.; Hinkle, B.; Ballantyne, L.;
Pena, M. Formation of urea dipeptides from carbonyldiimidazole:
Application towards the protease inhibitors GE 20372 and MAPI.
J. Org. Chem., 1997, 62(18), 6420-6423.
Dawson, P. E.; Muir, T. W.; Clark-Lewis, I.; Kent, S. B. H. Syn-
thesis of proteins by native chemical ligation. Science, 1994,
266(5186), 776-779.
Dubé, P.; Fine Nathel, N. F.; Vetelino, M.; Couturier, M.; Abous-
safy, C. L.; Pichette, S.; Jorgensen, M. L.; Hardink, M. Carbonyldi-
imidazole-mediated Lossen rearrangement. Org. Lett., 2009,
11(24), 5622-5625.
Larrivee-Aboussafy, C.; Jones, B. P.; Price, K. E.; Hardink, M. A.;
McLaughlin, R. W.; Lillie, B. M.; Hawkins, J. M.; Vaidyanathan,
R. DBU catalysis of N,Nꢃ-Carbonyldiimidazole-mediated amida-
tions. Org. Lett., 2010, 12(2), 324-327.
(a) Sureshbabu, V. V.; Ananda, K. Deprotonation of hydrochloride
salts of amino acid esters and peptide esters using commercial zinc
dust. J. Pept. Res., 2001, 57(3), 223-226; (b) Gopi, H. N.; Suresh-
babu, V. V. Synthesis of peptides employing Fmoc-amino acid
chlorides and commercial zinc dust. Tetrahedron Lett., 1998,
39(52), 9769-9772.
To check the possibility of racemization both during the prepara-
tion of acyl azide and ureidopeptides, two diasteriomeric urei-
dopeptides were prepared by treating Z-Val-CON3 with R or S-1-
phenylethylamine and its racemate. The Methyl resonances of the
phenylethylamine residue in Z-Val-ꢁ(NHCONH)-R-(+)-1-phenyl-
ethylamine and Z-Val-ꢁ(NHCONH)-S-(-)-1-phenylethylamine
were observed as distinct doublets at ꢄ 1.30, 1.32 and ꢄ 1.29, 1.31,
respectively. For Z-Val-ꢁ(NHCONH)-R,S-(±)-1-phenylethylamine,
the corresponding methyl resonances were observed as two
doublets at ꢄ 1.33, 1.31 and 1,32, 1.30. This clearly showed that
there was no formation of an epimeric mixture (absence of two –
CH3 doublets when optically pure phenylethylamines were cou-
pled) during the reaction.
[20]
[21]
[10]
[22]
[23]
[11]
[12]
[13]
[14]
[24]
(a) SureshBabu, V. V.; Chennakrishnareddy, G.; Narendra, N. A
facile and one-pot synthesis of Nꢀ-Fmoc/Bsmoc/Boc/Z-protected
ureidopeptides and peptidyl ureas employing diphenylphosphoryl
azide [DPPA]. Tetrahedron Lett., 2008, 49(8), 1408-1412; (b) He-
mantha, H. P.; Chennakrishnareddy, G.; Vishwanatha, T. M.;
Sureshbabu, V. V. One-pot synthesis of ureido peptides and urea-
tethered glycosylated amino acids employing Deoxo-fluor/TMSN3.
Synlett, 2009, (3), 407-410.
[15]
Sureshbabu, V. V.; Lalithamba, H. S.; Narendra, N.; Hemantha, H.
P. New and simple synthesis of acid azides, ureas and carbamates
Received: October 21, 2010
Revised: May 5, 2011
Accepted: May 6, 2011