A facile and one-pot synthesis of Nα-Fmoc/Bsmoc/Boc/Z-protected ureidopeptides and peptidyl ureas employing diphenylphosphoryl azide [DPPA]

Article abstract of DOI:10.1016/j.tetlet.2007.12.060

Diphenylphosphoryl azide (DPPA) mediated one-pot synthesis of N^α-Fmoc/Bsmoc/Boc/Z-protected ureidopeptides and peptidyl ureas as well as phenyl/succinimidyl (N^α-urethane protected) methyl carbamates starting from N^α-protec

Full text of DOI:10.1016/j.tetlet.2007.12.060

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1408–1412
A facile and one-pot synthesis of Na-Fmoc/Bsmoc/Boc/Z-protected
ureidopeptides and peptidyl ureas employing diphenylphosphoryl
azide [DPPA]
Vommina V. Sureshbabu *, G. Chennakrishnareddy, N. Narendra
Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Dr. B. R. Ambedkar Veedhi,
Bangalore University, Bangalore 560 001, India
Received 30 September 2007; revised 4 December 2007; accepted 12 December 2007
Available online 11 January 2008
Abstract
Diphenylphosphoryl azide (DPPA) mediated one-pot synthesis of Na-Fmoc/Bsmoc/Boc/Z-protected ureidopeptides and peptidyl
ureas as well as phenyl/succinimidyl (Na-urethane protected) methyl carbamates starting from Na-protected amino acids is reported.
The formation of an azide, its rearrangement and coupling with an amino component is accomplished in a sequence of one-pot oper-
ations. The protocol has incorporated urea linkages in a sterically hindered peptide.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Diphenylphosphoryl azide; Ureidopeptides; Peptidyl ureas; Curtius rearrangement; One-pot synthesis
1. Introduction
obtain new generation molecules like dendrimers and
self-assembling organic nanotubes.16 In this context, the
development of rapid and simplified synthetic procedures
for the insertion of a ureido linkage into peptide sequences
continues to receive attention.17
Peptide backbone modification has developed into a
powerful tool to introduce desired structural motifs and
to enhance biological properties in peptidomimetics.1 The
urea linkage is the most common type of peptide bond
surrogate to be introduced into peptide sequences.2,3 The
metabolic stability and unique bonding properties of the
NH–CO–NH– moiety have resulted in its inclusion in
potent peptidyl conjugates and bioactive oligomers. Some
examples of peptidomimetics containing a urea moiety with
elevated biological properties are the TAR-binding frag-
ment of the Tat protein,4,5 HIV-1 proteases,6 c-secretase,7
aspartic acid protease,8 microbial alkaline proteinase inhib-
itors,9 and aspartic peptidases.10 The ureido analogs of
[Leu5]enkephalin,11 angiotensins,12 gastrin antagonists,
and protease inhibitors13,14 have been prepared. Natural
products containing urea linkages are also known.15 In
addition, urea linkages have been used as scaffolds to
Current strategies to synthesize Na-protected urea-
linked peptides are predominantly based on Curtius and
Hoffmann rearrangements. Sureshbabu et al., reported an
elegant procedure for the synthesis of Fmoc protected
a-ureido peptides,18 oligoureas,19 and a variety of substi-
tuted phenyl-(9-fluorenylmethoxycarbonylamino)methyl
carbamates20 through the classical Curtius rearrangement
employing a series of isocyanates derived from stable Na-
Fmoc amino acid azides.21 Guichard and co-workers,
reported the stepwise synthesis of N,N0-urea-linked oligo-
mers using O-succinimidyl (Na-urethane protected) methyl
carbamates.17 Lipton and co-workers, employed bis[triflu-
oroacetoxy]phenyliodine (PIFA) for synthesizing ureido-
peptides from Na-protected amino and peptide amides via
Hoffmann rearrangement.22 Appella and co-workers used
the same reagent to prepare 2,3-diaminopropionic acid
starting from Boc-Asn.23
*
Corresponding author. Tel.: +91 8022961339.
E-mail address: hariccb@rediffmail.com (V. V. Sureshbabu).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.060

V. V. Sureshbabu et al. / Tetrahedron Letters 49 (2008) 1408–1412
1409
The synthesis of ureidopeptides through classical Cur-
tius rearrangement24 involves
multi-step protocol
and isocyanates. In addition, the complete sequence of
functional group transformations can be accomplished in
one-pot.
a
whereby an acid azide is prepared via a mixed anhydride
or acid chloride, its isolation and rearrangement into an
isocyanate followed by coupling with an amine. This proto-
col has considerable limitations such as the isolation of
potentially explosive acid azides, which cause handling
problems, and the inherently unstable isocyanates, espe-
cially those derived from Bsmoc, Boc, and Z-amino acids,
which can undergo partial degeneration even before cou-
pling with the amine. On the other hand, the protocol using
bis[trifluoroacetoxy]phenyliodine is particularly useful in
Boc and Z chemistry. Its utility in Fmoc chemistry is not
satisfactory due to the necessity of higher equivalents of
bases. Therefore, a simple, improved, and scalable protocol
which produces higher yields of the urea and which also
tolerates different urethane protecting groups is desirable.
DPPA is used as an azide transfer reagent in organic
synthesis.25–33 Despite its extensive applications, to the best
of our knowledge, there are no reports on the synthesis of
Na-urethane protected ureidopeptides and peptidyl ureas
using DPPA.17,34,35 Herein, the properties of DPPA as a
carboxy activating and azido group transfer reagent are
exploited in obtaining ureido peptidomimetics. This proto-
col has advantages over previous methods as it circumvents
the pre-activation of the carboxylic group before reaction
with azide donors and isolation of unstable acid azides
2. Results and discussions
In a typical reaction, a solution of Na-Fmoc/Bsmoc/
Boc/Z-amino acid or peptide acid in THF was maintained
at 0 °C. To this, equimolar quantities of diisopropylethyl-
amine (DIEA) and DPPA were added successively. The
reaction mixture was stirred at 0 °C for 20 min followed
by addition of the amino acid ester. The resulting reaction
mixture was subjected to reflux/ultrasonication/microwave
irradiation. The in situ generated isocyanate immediately
reacted with the amino acid ester to afford the required
ureas 1a–4b and 5a–d (Scheme 1, Table 1). IR analysis of
the reaction mixture without addition of the amino/phenol
component revealed a distinct isocyanate peak at around
2300 cmꢀ1. Product isolation in most cases was straight-
forward as they precipitated from the reaction mixture as
solids. However, some of the Boc, Bsmoc, and Z-ureido-
peptides did not precipitate and required a simple work-
up. The Fmoc-ureidopeptides/carbamates were recrystal-
lized as pure crystalline solids using DMSO/water (8:2).
When the reaction was carried out under microwave irradi-
ation, the Na-protected amino acids were dissolved in a
minimum amount of THF and then diluted with toluene
R3
R2
R2
O
R3
DPPA, DIEA
R1
R1
OY
+
OH
X-H2N
CO2Y
N
H
N
H
N
H
N
H
THF
O
O
1a-d; 2a,b; 3a-c; 4a,b; 5a-d
X=HCl or TsOH salt
Scheme 1. Synthesis of Na-protected urea esters.
Table 1
Na-Fmoc/Bsmoc/Boc/Z-protected ureidopeptides and peptidyl ureas
Entry
R1
R2
R3
Y
Mp (°C)
Yield (%)
Method
Mass
A
B
C
1a
1b
1c
1d
2ac
2b
3a
3b
3c
4a
4b
5a
5b
5c
5d
a
Fmoc
Fmoc
Fmoc
Fmoc
Bsmoc
Bsmoc
Boc
Boc
Boc
Z
Z
CH2OCH2C6H5
CH2CH2COOtBu
(CH2)4NHBoc
CH2SCH2NHCOCH3
CH2SCH2C6H5
CH2C6H5
CH2OCH2C6H5
CH2COOCH2C6H5
CH3
CH2C6H5
CH(CH3)2
CH3
CH2C6H5
CH3
CH3
Bn
CH3
Bn
CH3
Et
CH3
Et
CH3
CH3
Bn
CH3
Bn
184
147
180
175
148
182
123
140
170
169
197
147
173
175
192
94
89
92
72
78
70
78
80
90
86
92
90
91
75
80
95
85
95
78
83
75
77
75
80
80
89
85
92
78
85
79
71
80
70
75
74
72
70
75
70
82
—
—
—
—
518.2a
616.2a
597.3a
577.2a
534.1a
530.2a
382.2a
438.2a
318.2a
400.2a
504.2a
624.3b
764.3b
556.3b
592.3b
CH2C6H5
CH(CH3)2
H
CH3
CH(CH3)2
H
CH3
CH(CH3)2
CH3
CH2C6H5
CH2C6H5
CH3
CH(CH3)C2H5
CH(CH3)2
Fmoc-Leu
Fmoc-Ser(OBn)
Boc-Pro
Z-Val
CH(CH3)2
CH(CH3)CH2CH3
Bn
Bn
ESI MS [M+H].
MALDI TOF [M+Na].
HRMS: found, 556.1185 (M+Na); calcd, 556.1188 (M+Na).
b
c

1410
V. V. Sureshbabu et al. / Tetrahedron Letters 49 (2008) 1408–1412
due to its better compatibility in microwave synthesis.
Also, replacing THF with other solvents such as CH2Cl2,
CHCl3, and DMF gave no significant changes in the prod-
uct yields. A number of Na-Fmoc/Boc/Z-protected ureid-
odipeptide esters were synthesized in 71–94% yields.
Ureidopeptides, 2a,b, containing the highly base-sensitive
Bsmoc group were also prepared in good yields. Urea-
linked dipeptides with at least one side-chain functionalized
amino acid were synthesized in about 75% yields via the
described procedure. Moreover, NMR analysis of the
products revealed the entire protocol to be free from
epimerization.36 Though all the three described methods
worked well for the synthesis of ureidopeptides, better
results were obtained when the reaction was carried out
under thermal and ultrasonication in terms of purity and
yield.
N-protected amino acids were subjected to similar reaction
conditions with the addition of phenol/N-hydroxy-
succinimide, carbamates 6a–e were obtained in yields of
78–95% (Scheme 2, Table 2). It is noteworthy that our
attempts to prepare these carbamates in a one-pot reaction
using PIFA resulted in lower yields.
Finally, the versatility of the reported protocol for the
insertion of a urea linkage in large peptides was demon-
strated by the incorporation of the –NH–CO–NH– moiety
between the 4th and 5th positions of the b-sheet octapep-
tide Boc-Leu-Aib-Val-b-Ala-c-Abu-Leu-Aib-Val-OMe.37
The octapeptide length was maintained constant by replac-
ing c-Abu with b-Ala. The synthesis of 9 (Scheme 3) was
accomplished by coupling of Boc-Leu-Aib-Val-b-Ala-OH
7 with b-Ala-Leu-Aib-Val-OMe 8 in the presence of an
equimolar quantity of DPPA and DIEA under ultrasonica-
tion. After simple work-up and recrystallization, 9 was
The protocol was also useful to synthesize Na-urethane
protected amino methyl carbamates, which are known to
be stable precursors for insertion of a urea moiety. When
1
obtained in 84% yield and characterized using H NMR
and MALDI-mass spectrometry.
R
O
R
DPPA, DIEA
Y
OH
+
HO-Y
PG HN
N
H
O
PG HN
THF
O
6a-e
Y=C6F5, C6H2Cl3,
C4H4NO2, C6Cl5
p-C6H4NO2
Scheme 2. Synthesis of Na-protected active methyl carbamates.
Table 2
Active phenyl/succinimidyl Na-Fmoc/Boc/Z-protected methyl carbamates
Entry
PG
R
Y
Mp (°C)
Yield (%)
Method
Massa [M+H]
A
B
6a
6b
6c
6d
6e
a
Fmoc
Fmoc
Fmoc
Boc
CH2C6H5
C6F5
C6H2Cl3
p-C6H4NO2
C4H4NO2
163
116
136
107
162
92
95
87
79
85
90
91
89
78
83
569.16
547.10
548.25
344.16
526.95
b
CH(CH3)C2H5
CH2COOtBu
CH2CH(CH3)2
CH(CH3)CH2CH3
c
Z
C6Cl5
ESI MS.
b
c
2,4,5-Trichlorophenyl.
N-Hydroxysuccinimidyl.
O
O
O
H
N
H
N
H
N
OMe
O
OH
+
TFA.H2N
N
H
N
BocHN
N
H
H
O
8
O
O
O
7
O
O
O
O
H
H
N
H
N
DPPA, DIEA
THF
OMe
N
BocHN
N
N
N
H
N
N
H
H
H
H
O
O
O
O
9
Scheme 3. Synthesis of urea linkage-containing octapeptide 9.

V. V. Sureshbabu et al. / Tetrahedron Letters 49 (2008) 1408–1412
1411
3. Conclusion
5. Selected spectral data
In conclusion, we have developed a useful one-pot pro-
tocol for the incorporation of a urea moiety in Na-urethane
protected peptides employing DPPA. Fmoc/Bsmoc/Boc/Z-
protected ureidopeptide esters and various active carb-
amates have been prepared in good yields without
epimerization.
5.1. Na-Boc-Ser (OBn)-w(NH–CO–NH)-Gly-OMe ð3aÞ
1H NMR (300 MHz, DMSO-d6): d 1.35 (s, 9H), 3.60 (s,
3H), 3.52–3.75 (m, 4H), 4.48 (s, 2H), 5.32 (m, 1H), 6.23 (m,
2H), 6.82 (t, J = 10.4 Hz, 1H), 7.30–7.42 (m, 5H): 13C
NMR (100 MHz, DMSO-d6): 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 382.2 [M+H]+. Anal. Calcd for
C18H27N3O6: C, 56.68; H, 7.15; N, 11.02. Found: C,
56.38; H, 7.20; N, 11.10.
4. General experimental procedure for the preparation of
ureido peptides, methyl carbamates, and peptidyl ureas
4.1. Method A: thermal
5.2. Na-Z-Phe-w(NH–CO–NH)-Ala-OMe ð4aÞ
To a solution of Na-protected amino acid/peptide acid
(1.0 mmol) in THF, DPPA (1.0 mmol) and DIEA
(1.0 mmol) were added successively at 0 °C and the reac-
tion stirred for 20 min. To this, amino acid ester salt
(1.0 mmol) neutralized with N-methylmorpholine (NMM)
(1.0 mmol) in THF was added and the reaction mixture
refluxed for about 30 min until completion (as monitored
by TLC). The precipitated crude ureido peptides were iso-
lated by simple filtration and recrystallized using DMSO/
water (8:2). In the case of several Boc/Z/Bsmoc-protected
products, simple workup was required. The solvent was
removed in vacuo and the reaction mixture was taken into
ethyl acetate. The organic layer was washed with 10% citric
acid solution, NaHCO3 (10%) solution, brine, and dried
over anhydrous Na2SO4. The solvent was removed under
reduced pressure to afford the product, which was recrys-
tallized from DMSO/ water (8:2).
1H NMR (300 MHz, DMSO-d6): d 1.50 (d, J = 6.2 Hz,
3H), 2.92 (d, J = 6.7 Hz, 2H), 3.52 (s, 3H), 4.12 (m, 1H),
4.80 (s, 2H), 5.21 (br m, 1H), 6.45 (d, J = 7.2 Hz, 1H),
6.57 (d, J = 7.4 Hz, 1H), 7.10–7.40 (m, 10H), 7.79 (d,
J = 6.9 Hz, 1H). 13C NMR (100 MHz, DMSO-d6): d
17.0, 41.2, 50.2, 51.1, 63.5, 65.3, 126.0, 127.4, 127.6,
128.0, 128.6, 129.0, 129.8, 138.6, 141.2, 156.1, 158.5,
171.9. ESI MS: m/z 400.2 [M+H]+.
5.3. Fmoc-Leu-Ala-w(NH–CO–NH)-Phe-OMe ð5aÞ
1H NMR (300 MHz, DMSO-d6) d 0.85–0.90 (m, 6H),
1.17 (d, J = 6.3 Hz, 3H), 1.35 (m, 2H), 1.40–1.60 (m,
1H), 2.95 (d, J = 6.7 Hz, 2H), 3.15 (m, 2H), 3.60 (s, 3H),
3.95 (m, 1H), 4.20–4.45 (m, 3H), 5.36 (br, 1H), 6.50 (m,
2H), 7.15–7.50 (m, 9H), 7.75 (d, J = 7.1 Hz, 2H), 7.90 (d,
J = 7.1 Hz, 2H), 8.15 (m, 1H). 13C NMR (100 MHz,
DMSO-d6): d 17.5, 22.0, 23.7, 25.0, 37.9, 41.5, 47.6, 49.5,
52.3, 54.0, 65.3, 67.3, 120.1, 125.3, 126.7, 127.3, 127.9,
128.5, 129.3, 137.8, 141.5, 144.0, 156.7, 169.1, 172.1,
173.6. MALDI-TOF MS: m/z observed 623.3 [M+Na].
4.2. Method B: ultrasonication at ambient temperature
To a solution of Na-protected amino acid/peptide acid
(1.0 mmol) in THF, DPPA (1.0 mmol) and DIEA
(1.0 mmol) were added at 0 °C and the reaction stirred
for 20 min. To this, amino acid ester (1.0 mmol) neutral-
ized with NMM (1.0 mmol) in THF was added and the
reaction mixture was subjected to ultrasonic irradiation
(35 kHz, ELMA, TRANSSONIC 310/H) at ambient tem-
perature for 20 min, until the reaction was complete. The
resulting products were isolated using the procedure
described in method A.
5.4. Bsmoc-Phe-w(NH–CO–NH)-Val-OEt ð2bÞ
1H NMR (300 MHz, DMSO-d6) d 0.95 (d, J = 7.8 Hz,
6H), 1.13 (t, J = 8.1 Hz, 3H), 1.81 (m, 1H), 2.98 (m, 2H),
4.28 (s, 2H), 4.48 (m, 2H), 4.51 (m, 1H), 6.12 (d,
J = 6.5 Hz, 1H), 6.30 (m, 1H), 6.9–7.7 (m, 10H), 9.0 (m,
2H) 13C NMR (100 MHz, DMSO-d6): d 15.12, 18.24,
38.23, 41.35, 58.91, 60.12, 69.22, 70.15, 112.53, 118.75,
125.29, 126.21, 127.21, 128.12, 129.82, 132.82, 133.53,
135.58, 139.23, 141.20, 155.45, 160.52, 175.18. HRMS:
found, 529.1881 [M+Na]; calcd, 529.1883 [M+Na].
4.3. Method C: microwave irradiation
To a solution of Na-protected amino acid/peptide
acid (1.0 mmol) in THF/toluene mixture, DPPA (1.0 mmol)
and DIEA (1.0 mmol) were added at 0 °C and the reaction
stirred for 20 min. To this, amino acid ester (1.0 mmol)
neutralized with NMM (1.0 mmol) in THF was added
and then the reaction mixture was exposed to microwave
irradiation (Samsung M1739N oven with a frequency of
2450 MHz, at 60% of the total power output, i.e., 720 W)
until the reaction was complete. The reaction was worked
up as described in method A.
5.5. p-Nitrophenyl-{1-(9-fluorenylmethoxycarbonylamino)-
2-[tert-butoxycarbonyl]methyl}carbamate ð6cÞ
1H NMR (300 MHz, DMSO-d6): d 1.45 (s, 9H), 2.45 (m,
2H), 4.20–4.35 (m, 4H), 6.65 (d, J = 7.4 Hz, 1H), 7.20–8.14
(m, 13H). 13C NMR (100 MHz, DMSO-d6): d 28.0, 37.9,
47.3, 49.1, 66.7, 81.6, 120.1, 121.8, 125.1, 127.0, 127.7,
141.4, 143.8, 144.6, 153.7, 155.6, 156.8, 171.3. MS

1412
V. V. Sureshbabu et al. / Tetrahedron Letters 49 (2008) 1408–1412
(MALDI-TOF) m/z observed: 570.0 [M+Na]+, 586.2
[M+K]+. Anal. Calcd for C29H29N3O8: C, 63.61; H, 5.34;
N, 7.67. Found: C, 63.52; H, 5.22; N, 7.56.
14. Guerlavais, V.; Boegglin, D.; Mousseaux, D.; Oiry, C.; Heitz, A.;
Deghengi, R.; Locatelli, V.; Torsello, A.; Ghe, C.; Catapano, F.;
Muccioli, G.; Galleyrand, J.-C.; Fehrentz, J.-A.; Martinez, J. J. Med.
Chem. 2003, 46, 1191–1203.
15. Teng, H.; He, Y.; Wu, L.; Su, J.; Feng, X.; Qiu, G.; Liang, S.; Hu, X.
Synlett 2006, 877–880.
5.6. Compound 9
16. Semetey, V.; Didierjean, C.; Briand, J.-P.; Aubry, A.; Guichard, G.
Angew. Chem., Int. Ed. 2002, 41, 1895–1898.
17. Fischer, L.; Semetey, V.; Lozano, J.-M.; Schaffner, A. P.; Briand,
J.-P.; Didierjean, C.; Guichard, G. Eur. J. Org. Chem. 2007, 15, 2511–
2525.
18. Patil, B. S.; Vasanthakumar, G. R.; Sureshbabu, V. V. J. Org. Chem.
2003, 68, 7274–7280.
19. Sureshbabu, V. V.; Patil, B. S.; Venkatramanarao, R. J. Org. Chem.
2006, 71, 7697–7705.
1H NMR (400 MHz, DMSO-d6) d 0.75–0.95 (m, 24H),
1.39 (s, 9H), 1.52 (m, 6H), 1.62 (m, 2H), 1.69–1.85 (m,
12H), 1.97 (m, 1H), 2.28 (m, 2H), 2.98 (m, 2H), 3.15–
3.21 (m, 3H), 3.85–3.97 (m, 2H), 4.03–4.15 (m, 3H), 4.59
(m, 1H), 6.87–6.96 (m, 2H), 7.01–7.22 (m, 3H), 7.59–7.85
(m, 3H), 8.15 (s, 1H), 8.21 (s, 1H). MALDI-TOF MS:
m/z observed 906.5 [M+Na], 922.5 [M+K]. HRMS: found,
906.5653 [M+Na]; calcd, 906.5640 [M+Na].
20. Patil, B. S.; Sureshbabu, V. V. Lett. Pept. Sci. 2003, 10, 93–97.
21. Sureshbabu, V. V.; Ananda, K.; Vasanthakumar, G. R. J. Chem.
Soc., Perkin Trans. 1 2000, 4328–4331.
22. Myers, A. C.; Kowalski, J. A.; Lipton, M. A. Bioorg. Med. Chem.
Lett. 2004, 14, 5219–5222.
Acknowledgments
23. Englund, E. A.; Gopi, H. N.; Appella, D. H. Org. Lett. 2004, 6, 213–
215.
24. Smith, P. A. S. Org. React. 1946, 3, 337–449.
25. Jacobi, P. A.; Zheng, W. Tetrahedron Lett. 1993, 34, 2581–2584.
26. Shao, H.; Colucci, M.; Tong, S.; Zhang, H.; Castelhano, A. L.
Tetrahedron Lett. 1998, 39, 7235–7238.
We thank the Department of Science and Technology,
New Delhi, for financial assistance. We also thank Pro-
fessor Fred Naider, CUNY, New York, for useful
discussions.
27. Wu, Y.; Esser, L.; De Brabander, J. K. Angew. Chem., Int. Ed. 2000,
39, 4308–4310.
References and notes
28. Kedrowski, B. L. J. Org. Chem. 2003, 68, 5403–5406.
29. Yamada, S.; Ikota, N.; Shioiri, T.; Tachibana, S. J. Am. Chem. Soc.
1975, 97, 7174–7175.
1. Nowick, J. S.; Smith, E. M.; Pairish, M. Chem. Soc. Rev. 1996, 25,
401–415.
2. 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. Science 1994, 263, 380–384.
3. Burgess, K.; Shin, H.; Linthicum, D. S. Angew. Chem., Int. Ed. Engl.
1995, 34, 907–909.
30. Ninomiya, K.; Shioiri, T.; Yamada, S. Tetrahedron 1974, 30, 2151–
2157.
31. Lal, B.; Pramanik, B. N.; Manhas, M. S.; Bose, A. K. Tetrahedron
Lett. 1977, 18, 1977–1980.
32. Richter, L. S.; Andersen, S. Tetrahedron Lett. 1998, 39, 8747–8750.
33. Daisuke, S. D.; Sasayama, S.; Takahashi, H.; Ikegami, S. Tetrahedron
Lett. 2006, 47, 7219–7223.
4. Wang, X.; Huq, I.; Rana, T. M. J. Am. Chem. Soc. 1997, 119, 6444–
6445.
34. Houben-Weyl: Synthesis of Peptides & Peptidomimetics; Goodman,
M., Felix, A., Moroder, L., Toniolo, C., Eds.; Georg Thieme:
Stuttgart, New York, 2003; Vol. E22c; and references cited therein.
35. Scriven, E. F. V.; Turnbull, K. Chem. Rev. 1988, 88, 297–368.
36. The racemization study was carried out through 1H NMR analysis of
the ureas prepared by coupling Fmoc-Ser(Bn)OH with optically pure
R or S-1-phenylethylamine and its racemate. The methyl resonances
of the phenylethylamine residue in Fmoc-Ser(Bn)-w(NH–CO–NH)-R-
(+)-1-phenylethylamine and Fmoc-Ser(Bn)-w(NH–CO–NH)-S-(ꢀ)-1-
phenylethylamine were observed as distinct doublets at d 1.30, 1.32
and d 1.29, 1.31, respectively, with separation of 0.02 ppm in DMSO-
d6 solution. For Fmoc-Ser(Bn)-w(NH–CO–NH)-R,S-( )-1-phenyl-
ethylamine, the corresponding methyl resonances were observed as
two doublets at d 1.32, 1.30 and d 1.31, 1.29. This clearly showed that
there was no formation of an epimeric mixture (absence of two –CH3
doublets when optically pure phenylethylamines were coupled) during
the reaction. Instead, the reaction resulted in optically pure product.
37. Karle, I. L.; Pramanik, A.; Banerjee, A.; Bhattacharjya, S.; Balaram,
P. J. Am. Chem. Soc. 1997, 119, 9087–9095.
5. Cho, C. Y.; Moran, E. J.; Cherry, S. R.; Stephans, J. C.; Fodor, S. P.;
Adams, C. L.; Sundaram, A.; Jacobs, J. W.; Schultz, P. G. Science
1993, 261, 1303–1305.
6. Navia, M. A.; Fitzgerald, P. M. D.; McKeever, B. M.; Leu, C.-T.;
Heimbach, J. C.; Herber, W. K.; Sigal, I. S.; Darke, P. L.; Springer,
J. P. Nature 1989, 337, 615–620.
7. Bakshi, P.; Wolfe, M. S. J. Med. Chem. 2004, 47, 6485–6489.
8. Kick, E. K.; Ellman, J. A. J. Med. Chem. 1995, 38, 1427–1430.
9. Broadbridge, R. J.; Sharma, R. P.; Akhtar, M. Chem. Commun. 1998,
1449–1450.
10. Dales, N. A.; Bohacek, R. S.; Satyshur, K. A.; Rich, D. H. Org. Lett.
2001, 3, 2313–2316.
11. Kawasaki, K.; Maeda, M.; Watanabe, J.; Kaneto, H. Chem. Pharm.
Bull. 1988, 36, 1766–1771.
12. Vegner, R. E.; Chipens, G. I. J. Gen. Chem. USSR (Engl. Transl.)
1975, 45, 431–434.
13. Rodriguez, M.; Dubreuil, P.; Bali, J. P.; Martinez, J. J. Med. Chem.
1987, 30, 758–763.