Hydantoin-free synthesis of peptide ester isocyanates, isothiocyanates, and dipeptidyl ureas: The application of zinc dust in a carbonylation procedure without base

Article abstract of DOI:10.1055/s-0030-1260216

Non-Schotten-Baumann conditions are described for the hydantoin-free synthesis of peptide ester isocyanates using activated zinc dust as a non-basic HCl scavenger. Also, the procedure gives no N-acylated products in the case of the conversion of amino acid and peptide amides into isocyanates. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1260216

PAPER
3247
Hydantoin-Free Synthesis of Peptide Ester Isocyanates, Isothiocyanates, and
Dipeptidyl Ureas: The Application of Zinc Dust in a Carbonylation Procedure
without Base
P
eptide Ester Isocy
.
anates, Isoth
N
iocyanates, and
D
a
ipeptidyl
U
r
reas endra, T. M. Vishwanatha, Vommina V. Sureshbabu*
Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Dr. B. R. Ambedkar Veedhi,
Bangalore University, Bangalore 560001, India
E-mail: sureshbabuvommina@rediffmail.com; E-mail: hariccb@gmail.com
Received 29 April 2011; revised 9 August 2011
phosgene in the presence of pyridine (base is invariably
Abstract: Non-Schotten–Baumann conditions are described for the
required to neutralize the liberated HCl, which otherwise
hydantoin-free synthesis of peptide ester isocyanates using activat-
will lead to inactivation of the amine through protona-
ed zinc dust as a non-basic HCl scavenger. Also, the procedure
tion), in the synthesis of peptide isocyanates.3 A similar
gives no N-acylated products in the case of the conversion of amino
acid and peptide amides into isocyanates.
observation has been reported by Chong and Patello
during the conversion of resin bound Na-Fmoc-protected
peptides into isocyanates by treatment with trichloro(meth-
yl)silane in the presence of triethylamine.4 Consequently,
Nowick et al. used modified Schotten–Baumann condi-
tions (CH2Cl2–aq Na2CO3 biphasic solvent system) with-
out the addition of a tertiary amine base to make
isocyanates.3 Although this method drastically improved
the yields, it could not completely overcome hydantoin
formation, at least in a few sequence specific examples.
Hydantoin formation has also been observed during the
activation (either as isocyanate or activated carbamate) of
the amino terminus of resin-bound peptides and further-
more, the exclusion of base has been shown to avoid this
side reaction.5 An alternative approach that has been pro-
posed as protection against hydantoin formation is protec-
tion of the amide bond with groups such as 2-hydroxy-4-
methoxybenzyl (Hmb), so that the generated isocyanate is
unable to rearrange into hydantoin.6
Key words: zinc dust, peptide ester isocyanates, isothiocyanates,
base-free synthesis, peptidyl ureas, thioureas
Peptide isocyanates as well as amino acid ester isocyan-
ates constitute synthetic building blocks for the assembly
of peptides and a plethora of backbone-modified peptide
mimics such as azapeptides, carbazapeptides, peptidyl
ureas, heterocycles, and b-lactams, and in the construction
of artificial secondary structures.1 Peptide isocyanates are
generally generated by the treatment of peptide esters or
resin-bound peptides with carbonylating agents such as
phosgene or triphosgene and activated carbonates. In ei-
ther case, the formation of isocyanates is frequently asso-
ciated with the co-formation of varying levels of peptide
hydantoins I as side products (Scheme 1). This side reac-
tion is a major contributor to the decrease in yield and ho-
mogeneity of peptide isocyanates. Hydantoin formation
takes place through an intramolecular nucleophilic attack
by the nitrogen of the peptide bond of the N-terminal ami-
no acid of the peptide on the isocyanato group or activated
urethane. This ring-closure process is facilitated by the
application of high temperatures2 or by conditions that can
cause ionization of the weakly nucleophilic amide nitro-
gen, such as the presence of base. The role of the base as
the source of this side reaction has been observed by sev-
eral workers. Nowick et al., obtained appreciable amounts
of hydantoins during the treatment of peptide esters with
In pursuit of a mild, straightforward, and hydantoin-free
synthesis of peptide isocyanates, we envisaged the use of
activated zinc dust as a non-basic HCl scavenger7 and
commercial phosgene in toluene as the carbonylation re-
agent in organic solvent (non-Schotten–Bauman condi-
tions). Zinc dust serves two purposes in the proposed
synthesis viz. trapping of the HCl liberated during the re-
action; and deprotonation, in the initial step, of the peptide
esters when prepared and used as hydrochloride salts. The
use of a tertiary amine for the latter purpose has certain
R1
O
R2
O
O
O
R1
HN
R1
..
O
COOY
R2
O
C N
NH
R2
N
H
N
R1
N
N
N
COOY
H
– MeOH
O
H
..
base
R2
O
O
base
I
II
Scheme 1 Hydantoin formation in the presence of base
SYNTHESIS 2011, No. 20, pp 3247–3254
x
x.
x
x
.
2
0
1
1
Advanced online publication: 07.09.2011
DOI: 10.1055/s-0030-1260216; Art ID: N44611SS
© Georg Thieme Verlag Stuttgart · New York

3248
N. Narendra et al.
PAPER
R1
O
R1
O
Zn dust
CXCl2
H
H
N
N
.
Cl H3N
X C N
CH2Cl2, 0 °C
15 min
O
R2
O
2
R2
R2
1
PhNHEt
CH2Cl2
H2N
X
COOMe
X
R1
O
R2
R1
O
H
H
N
N
N
N
MeOOC
N
N
H
H
H
Ph
O
R2
O
R2
3
4
Scheme 2 Synthesis of peptide ester isocyanates and isothiocyanates, and peptidyl ureas and thioureas
limitations per se.8 Furthermore, since non-Schotten– urea adducts. The yield and purity of isocyanates were
Baumann conditions are employed, the loss in the yield of correlated to the corresponding data of the latter.3 In the
the isocyanates (which inherently do not possess an ac- present study, we adopted a similar approach for the char-
ceptable degree of stability) due to possible hydrolysis by acterization of the peptide isocyanates. Accordingly, iso-
exposure to aqueous solutions (as in Schotten–Baumann cyanate 2a was treated with N-ethylaniline to afford the
condition as reported previously3) can be overcome. Phos- ureido compound 3a.11,12 Using the same procedure,
gene in toluene is a commercially available reagent and OCN-Val-Ala-OMe (2b) and OCN-Val-Cys(Me)-Ala-
unlike gaseous phosgene it can be handled with conve- OMe (2c), which have also been shown to possess a ten-
nience. Its use offers several advantages with respect to dency to form the hydantoin, were prepared. In no case
the present synthesis.9 Accordingly, we herein report an was the expected hydantoin formed. The isocyanates were
efficient and hydantoin-free synthesis of peptide isocyan- also coupled with amino acid methyl esters to obtain
ates through carbonylation under neutral and non- peptide-urea hybrids 4a–d (Table 1).
Schotten–Bauman conditions using zinc as an HCl scav-
The synthesis of peptide isothiocyanates is associated
enger. The procedure has been extended to the preparation
with the formation of peptide thiohydantoins via similar
of peptide ester isothiocyanates and further to the one-pot,
mechanism discussed for the formation of the peptide hy-
two-stage preparation of N,N¢-unsymmetrically substitut-
dantoin.13 The application of the present protocol allowed
us to prepare peptide ester isothiocyanates. Treatment of
ed dipeptidyl ureas and thioureas.
The peptide esters employed as starting materials were dipeptide ester with thiophosgene (2.1 equiv) in presence
prepared as the hydrochloride salts through catalytic hy- of zinc dust produced isothiocyanates 2d, 2e, and 2i,
drogenolysis of the corresponding Na-Z-protected dipep- which were trapped with N-ethylaniline as well as amino
tide esters in the presence of concentrated hydrochloric acid methyl esters. HPLC as well as 1H NMR analysis of
and acetic acid.10 In a typical reaction, a suspension of H- the thioureas confirmed the absence of thiohydantoin.
Leu-Gly-OMe·HCl (a peptide whose isocyanate has
This procedure was extended to the one-pot, two-stage
preparation of N,N¢-unsymmetrically substituted dipepti-
dyl ureas 6a–f (Table 2) by treating the hydrochloride
shown to be sensitive to hydantoin formation3) and acti-
vated zinc dust in anhydrous dichloromethane was stirred
at room temperature to convert the hydrochloride salt into
salts of amino acid esters with phosgene in toluene in
the free amino peptide ester. The solution was cooled to 0
presence of activated zinc dust followed by coupling of
°C and treated with phosgene in toluene to produce the de-
the isocyanates 5 directly with amino acid methyl esters
sired isocyanate [IR: 2249 cm–1] (Scheme 2). The excess
[obtained by deprotonation of corresponding HCl salts]
zinc, and the zinc chloride formed were filtered off and the
with activated zinc dust (Scheme 3).
unreacted phosgene was removed through evaporation in
Ureas 6g, 6h as well as thioureas 6i and 6j were also pre-
pared by coupling the isocyanates and isothiocyanates
vacuo.
The product was not analyzed further in the isocyanate
(prepared by treating the amino acid esters with thiophos-
form since peptide ester isocyanates, unlike amino acid
gene under similar conditions) with functionalized alkyl-
ester isocyanates (which are distillable liquids), are not
and arylamines including glycosylamine (Table 2). Such
stable to isolation. This has compelled the authors who
compounds are extensively used as catalysts in asymmet-
first described these compounds to analyze them as their
ric synthesis.14 Since the synthesis is devoid of base, the
R1
X
R1
R1
Zn dust
CXCl2
R3-NH2
R3
.
Cl
COOR2
H3N
COOR2
XCN
COOR2
N
N
CH2Cl2, 0 °C
CH2Cl2, r.t.
H
H
5
6
Scheme 3 Synthesis of N,N¢-unsymetrically substituted dipeptidyl ureas
Synthesis 2011, No. 20, 3247–3254 © Thieme Stuttgart · New York

PAPER
Peptide Ester Isocyanates, Isothiocyanates, and Dipeptidyl Ureas
3249
Table 1 Peptide Isocyanates and Isothiocyanates 2 and Peptidyl Ureas and Thioureas 3 and 4 Prepared
Entry
1
Peptide isocyanate or isothiocyanate 2
Peptidyl urea or thiourea
Yield (%) Mp (°C)
i-Bu
H
O
O
O
i-Bu
H
N
2a
2b
3a
3b
91
89
142–144
136–137
N
COOMe
Et
Et
Et
COOMe
N
N
H
OCN
OCN
OCN
Ph
O
O
i-Pr
i-Pr
H
N
H
N
2
3
COOMe
O
COOMe
O
N
N
H
Ph
O
O
i-Pr
i-Pr
H
N
H
N
2c
3c
86
gum
N
H
COOMe
N
N
H
N
H
COOMe
O
Ph
O
SMe
SMe
Ph
Ph
S
H
N
H
N
4
5
6
7
8
2d
2e
2f
3d
3e
4a
4b
4c
91
85
93
91
87
gum
COOMe
Et
COOMe
SCN
N
N
H
O
i-Bu
Ph
O
i-Bu
i-Pr
S
i-Pr
H
N
H
N
131–133
158–160
167–168
149–150
COOMe
Et
COOMe
SCN
OCN
N
N
H
O
Ph
O
i-Pr
O
H
N
H
N
COOMe
Ph
COOMe
Ph
MeOOC
N
N
H
H
O
O
i-Pr
n-Bu
O
O
S
i-Pr
H
N
H
N
2g
2h
COOMe
COOMe
OCN
MeOOC
MeOOC
MeOOC
MeOOC
MeOOC
N
H
N
H
O
O
H
N
H
N
COOMe
COOMe
OCN
N
H
N
H
O
s-Bu
O
O
s-Bu
H
N
2
H
N
COOMe
Ph
COOMe
Ph
SCN
9
2i
4d
88
gum
N
H
N
H
O
known base-catalyzed cyclization into hydantoin II
(Scheme 1) of compounds that contain an ureido linkage
a to the ester bond15 is precluded. Furthermore, in the one-
pot protocol yields are increased.
O
O
Cl
R1
N
OCN
R2
R1
During the preparation of isocyanates of amino acid
amides, acylation of the amide bond by phosgene, espe-
cially in case of unhindered alkyl amides, has been ob-
served. It was envisaged that zinc dust mediated
carbonylation could prevent this undesired acylation since
ionization of the amide nitrogen does not take place. Con-
sequently, isocyanates 8a–c were prepared from amino
acid methyl and ethyl amides 7 and coupled directly to N-
ethylaniline to give the products 9, which were analyzed
(Table 3). In all cases, no N-acylated amide was detected
(Scheme 4).3
Zn dust
COCl2
H
R1
N
H3N
R2
.
H
N
Cl
CH2Cl2, 0 °C
OCN
R2
O
O
R = Me, Et
8
PhNHEt
CH2Cl2
7
O
R1
H
N
N
N
H
R2
Ph
O
9
In conclusion, the use of activated zinc as an HCl scaven-
ger during the synthesis of peptide ester isocyanates and
isothiocyanates ensures neutral condition and avoids the
Scheme 4 Synthesis of isocyanato amino acid amides 8 and urea ad-
ducts 9
Synthesis 2011, No. 20, 3247–3254 © Thieme Stuttgart · New York

3250
N. Narendra et al.
PAPER
Table 3 Urea Adducts 9 Prepared
Table 2 N,N¢-Unsymmetrical Dipeptidyl Ureas 6
Entry Urea derivative 6 Yield (%)Mp (°C)
Entry Isocyanato amide 8
Urea adduct 9
Yield
(%)
i-Bu
O
O
1
2
6a
6b
89
85
109–110
169–171
MeO
OMe
H
N
H
N
N
N
1
2
8a
8b
9a
9b
75
Et
H
H
OCN
Me
N
N
H
Me
O
O
O
Ph
O
Ph
i-Pr
O
Ph
Ph
O
O
EtO
OMe
H
N
H
N
N
N
69
71
Et
Et
H
H
OCN
OCN
Me
Et
N
N
H
Me
Et
O
O
O
O
Ph
O
i-Bu
i-Bu
O
O
OEt
OEt
H
N
H
N
3
6c
91
81–83
3
8c
9c
MeO
N
N
H
N
N
H
H
O
Ph
O
O
O
O
i-Pr
Buchi model 150 melting point apparatus in open capillaries and are
uncorrected. IR spectra were recorded on a Nicolet model impact
400 D FT-IR spectrophotometer. 1H and 13C NMR spectra were re-
corded on 400 MHz and 100 MHz Bruker spectrometers, respec-
tively. HRMS were recorded on Q-Tof micromass mass
spectrometer. Elemental analysis was performed on a Thermo
Finnigan FLASH EA 1112 CHN analyzer. Optical rotations were
measured on Jasco P2000 digital polarimeter.
4
5
6
7
6d
6e
6f
82
88
85
84
92–94
gum
MeO
Ph
OEt
N
H
N
H
O
O
O
Ph
Ph
OMe
N
N
H
H
O
Ph
Activation of Zinc Dust
gum
OMe
N
H
N
H
Commercial zinc must be washed from surface oxides to make it
pure sufficiently to carry out reactions; this is called activation of
zinc powder. Typically, commercial Zn (400 g) is stirred in 10%
HCl (150 mL) for 2 min, filtered, washed with H2O (300 mL) and
acetone (100 mL), and then dried under vacuum at r.t. for 10 min.
O
AcO
AcO
O
H
N
H
6g
171–172
O
N
AcO
OMe
Ph
OAc
CF3
O
Methyl (S)-2{(S)-2-[3-Ethyl-3-phenylureido]-3-methylbutan-
amido}propanoate (3b); Typical Procedure
[Caution: Phosgene is toxic and should be handled with utmost
care: use a fume hood.] To a soln of Val-Ala-OMe·HCl (1a, 1.190
g, 5.0 mmol) in anhyd CH2Cl2 (50.0 mL), was added activated Zn
dust (0.812 g, 25.0 mmol) and stirred for 10 min at r.t. and then
cooled to 0 °C. To this, 1.93 M phosgene in toluene (5.2 mL, 20.0
mmol; Sigma-Aldrich) was transferred through a syringe and the
mixture was stirred at this temperature for another 10–15 min till
completion of the reaction (TLC and IR analysis). The solid residue
was filtered off and the filtrate was subjected to evaporation in vac-
uo. The crude isocyanate (1.106 g, 93%) was then dissolved in an-
hyd CH2Cl2 (20.0 mL) and N-ethylaniline (1.21 mL, 9.6 mmol) was
added in a single portion at r.t. The mixture was stirred overnight,
the solvent was removed under reduced pressure, and the residue
was recrystallized (n-hexane) to afford the urea 3b (2.07 g, 89%) as
a white solid. The crude product was analyzed by HPLC and NMR
analysis, which found no hydantoin formation.
O
8
9
6h
6i
82
75
121–123
106–108
OMe
F3C
N
H
N
H
O
O
AcO
H
H
O
AcO
AcO
N
N
OMe
OAc
S
s-Bu
CF3
S
i-Bu
O
10
6j
92
gum
OMe
F3C
N
N
H
H
formation of hydantoin side products. The procedure fur-
nishes quantitative yields and is free from racemization
(see experimental part). The protocol can be extended to
the preparation of dipeptidyl ureas. Furthermore, isocyan-
ates from amino acid amides can be prepared without acy-
lation of the amide nitrogen. We anticipate that the
procedure would be advantageous for preparation of ho-
mogenous samples of bioactive compounds from peptide
and amino acid isocyanates.
All thiourea compounds were prepared following a similar proce-
dure outlined in the typical procedure by using thiophosgene (2.1
equiv) as the thiocarbonylating agent.
Methyl (S)-2-[2-(3-Ethyl-3-phenylureido)-4-methylpentano-
amido]acetate (3a)
White solid; yield: 91%; mp 142–144 °C; Rf = 0.42 (CHCl3–MeOH,
7:3).
IR (KBr): 3384, 1752, 1677, 1638 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.88 (d, J = 6.1 Hz, 3 H), 0.98 (d,
J = 5.6 Hz, 3 H), 1.05 (t, J = 5.4 Hz, 3 H), 1.49 (dd, J = 4.8, 6.9 Hz,
2 H), 1.69–1.73 (m, 1 H), 2.98–3.04 (m, 2 H), 3.52 (s, 3 H), 4.09 (s,
All solvents were distilled prior to use and reagents were used as re-
ceived from Sigma-Aldrich. Melting points were determined on a
Synthesis 2011, No. 20, 3247–3254 © Thieme Stuttgart · New York

PAPER
Peptide Ester Isocyanates, Isothiocyanates, and Dipeptidyl Ureas
3251
2 H), 4.29–4.33 (m, 1 H), 5.98 (br s, 1 H), 6.03 (br s, 1 H), 6.98 (d,
HRMS: m/z [M + Na]+ calcd for C25H33N3NaO3S : 478.2140; found:
J = 4.8 Hz, 1 H), 7.11–7.45 (m, 4 H).
478.2125.
13C NMR (100 MHz, CDCl3): d = 11.9, 19.6, 21.1, 21.3, 31.5, 39.8,
40.1, 50.5, 52.6, 120.4, 120.5, 124.6, 128.8, 128.9, 138.4, 154.9,
168.5, 171.0.
Anal. Calcd for C25H33N3O3S: C, 65.90; H, 7.30; N, 9.22; O, 10.53;
S, 7.04. Found: C, 65.80; H, 7.16; N, 9.31; O, 10.28; S, 6.98.
Methyl (S)-2-[(S)-2-(3-Ethyl-3-phenylthioureido)-3-methylbu-
tanamido]propanoate (3e)
Yellow solid; yield: 85%; mp 131–133 °C; Rf = 0.48 (CHCl3–
MeOH, 8:2).
IR (KBr): 3291, 1735, 1648, 1550 cm–1.
HRMS: m/z [M + Na]+ calcd for C18H27N3NaO4: 372.1899; found:
372.1879.
Anal. Calcd for C18H27N3O4: C, 61.87; H, 7.79; N, 12.03; O, 18.32.
Found: C, 61.70; H, 7.81; N, 12.16; O, 18.22.
Methyl (S)-2[(S)-2-(3-Ethyl-3-phenylureido)-3-methylbutan-
amido]propanoate (3b)
White solid; yield: 89%; mp 136–137 °C; Rf = 0.51 (CHCl3–MeOH,
7:3).
1H NMR (400 MHz, CDCl3): d = 0.78 (d, J = 5.8 Hz, 3 H), 0.81 (d,
J = 4.9 Hz, 3 H), 1.08 (t, J = 6.0 Hz, 3 H), 1.36 (d, J = 3.1 Hz, 3 H),
2.18–2.22 (m, 1 H), 3.39–3.40 (m, 2 H), 3.41 (d, J = 4.8 Hz, 1 H),
3.51 (s, 3 H), 4.55–4.58 (m, 1 H), 5.89 (br s, 1 H), 6.29 (br s, 1 H),
6.49 (d, J = 5.2 Hz, 1 H), 6.48–7.04 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 11.8, 16.9, 17.1, 17.3, 29.8, 47.1,
49.6, 50.8, 65.5, 123.3, 125.8, 126.3, 128.5, 128.7, 139.8, 170.9,
171.0, 183.0.
IR (KBr): 3298, 1724, 1691, 1611 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.77 (d, J = 6.4 Hz, 3 H), 0.89 (d,
J = 6.6 Hz, 3 H), 1.08 (t, J = 5.8 Hz, 3 H), 1.32 (d, J = 7.1 Hz, 3 H),
2.53–2.58 (m, 1 H), 3.01–3.08 (m, 2 H), 3.58 (s, 3 H), 4.43 (d,
J = 3.8 Hz, 1 H), 4.59–4.62 (m, 1 H), 5.96 (br s, 1 H), 6.03 (br s, 1
H), 6.97 (d, J = 2.8 Hz, 1 H), 7.08–7.22 (m, 4 H).
HRMS: m/z [M + Na]+ calcd for C18H27N3NaO3S : 365.1773; found:
365.1759.
13C NMR (100 MHz, CDCl3): d = 11.3, 16.1, 16.5, 17.0, 29.5, 45.0,
47.8, 50.6, 60.1, 119.8, 120.0, 123.6, 128.9, 129.0, 138.6, 154.5,
170.0, 170.3.
Anal. Calcd for C18H27N3O3S: C, 59.15; H, 7.45; N, 11.50; O,
13.13; S, 8.77. Found: C, 59.05; H, 7.36; N, 11.50; O, 13.22; S,
8.69.
HRMS: m/z [M + Na]+ calcd for C18H27N3NaO4: 372.1899; found:
372.1855.
Methyl (R)-2-{3-[(S)-1-[(S)-1-Methoxy-1-oxo-3-phenylpropan-
2-ylamino]-1-oxopropan-2-yl]ureido}-3-methylbutanoate (4a)
White solid; yield: 93%; mp 158–160 °C; Rf = 0.31 (CHCl3–MeOH,
7:3).
Anal. Calcd for C18H27N3O4: C, 61.87; H, 7.79; N, 12.03; O, 18.32.
Found: C, 61.88; H, 7.59; N, 12.08; O, 18.30.
IR (KBr): 3208, 1751, 1742, 1670 cm–1.
Methyl (S)-2-{(R)-2-[(S)-2-(3-Ethyl-3-phenylureido)-3-meth-
ylbutanamido]-3-(methylthio)propanamido}propanoate (3c)
Gum; yield: 86%; Rf = 0.19 (CHCl3–MeOH, 7:3).
IR (neat): 3291, 1738, 1647 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.78 (d, J = 5.6 Hz, 3 H), 0.81 (d,
J = 5.9 Hz, 3 H), 1.08 (t, J = 6.0 Hz, 3 H), 1.32 (d, J = 4.9 Hz, 3 H),
1.98 (s, 3 H), 2.55–2.58 (m, 1 H), 2.61–2.68 (m, 2 H), 3.11–3.15 (m,
2 H), 3.58 (s, 3 H), 4.31 (d, J = 2.9 Hz, 1 H), 4.49–4.52 (m, 1 H),
4.77–4.80 (m, 1 H), 5.65 (br s, 1 H), 5.77 (br s, 1 H), 6.19 (br s, 1
H), 6.99 (d, J = 3.2 Hz, 1 H), 7.08–7.16 (m, 4 H).
1H NMR (400 MHz, CDCl3): d = 0.78 (d, J = 4.2 Hz, 3 H), 0.82 (d,
J = 5.2 Hz, 3 H), 1.44 (d, J = 7.1 Hz, 3 H), 2.65–2.72 (m, 2 H),
2.98–3.02 (m, 1 H), 3.55 (s, 3 H), 3.59 (s, 3 H), 4.38 (d, J = 2.6 Hz,
1 H), 4.51–4.68 (m, 1 H), 4.71–4.78 (m, 1 H), 5.85 (br s, 1 H), 6.11
(br s, 1 H), 6.18 (br s, 1 H), 7.02–7.19 (m, 5 H).
13C NMR (100 MHz, CDCl3): d = 16.8, 17.0, 17.2, 29.1, 36.8, 50.5,
50.6, 51.3, 52.5, 56.8, 120.3, 125.8, 127.3, 128.0, 128.2, 138.1,
155.8, 170.8, 171.0, 171.5.
HRMS: m/z [M + Na]+ calcd for C20H29N3NaO6: 430.1954; found:
430.1948.
13C NMR (100 MHz, CDCl3): d = 11.3, 15.8, 16.0, 16.9, 17.0, 29.8,
35.4, 44.6, 48.0, 50.8, 51.1, 59.5, 119.7, 120.0, 123.6, 128.5, 128.8,
138.7, 154.6, 171.0, 171.2, 171.5.
Anal. Calcd for C20H29N3O6: C, 58.95; H, 7.17; N, 10.31; O, 23.56.
Found: C, 58.81; H, 7.12; N, 10.19; O, 23.50.
HRMS: m/z [M + Na]+ calcd for C22H34N4NaO5S: 489.2148; found:
489.2123.
Methyl (R)-2-{3-[(S)-1-(2-Methoxy-2-oxoethylamino)-3-meth-
yl-1-oxobutan-2-yl]ureido}hexanoate (4b)
White solid; yield: 91%; mp 167–168 °C; Rf = 0.36 (CHCl3–MeOH,
6:4).
Anal. Calcd for C22H34N4O5S: C, 56.63; H, 7.34; N, 12.01; O,
17.14; S, 6.87. Found: C, 56.68; H, 7.22; N, 12.00; O, 17.31; S,
6.55.
IR (KBr): 3301, 2918, 1734, 1759, 1660 cm–1.
Methyl (S)-2-[(S)-2-(3-Ethyl-3-phenylthioureido)-3-phenylpro-
panamido]-4-methylpentanoate (3d)
Gum; yield: 91%; Rf = 0.51 (CHCl3–MeOH, 9:1).
IR (KBr): 3301, 1750, 1698, 1451 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.86 (d, J = 5.8 Hz, 3 H), 0.92 (d,
J = 5.5 Hz, 3 H), 1.10 (t, J = 6.1 Hz, 3 H), 1.77–1.79 (m, 1 H), 1.85
(dd, J = 3.6, 6.2 Hz, 1 H), 2.89–2.96 (m, 2 H), 3.36–3.41 (m, 2 H),
3.56 (s, 3 H), 3.83–3.91 (m, 1 H), 4.21 (t, J = 6.8 Hz, 1 H), 5.96 (br
s, 1 H), 6.55 (br s, 1 H), 6.61 (d, J = 2.9 Hz, 1 H), 7.01 (br s, 1 H),
6.78–7.31 (m, 9 H).
13C NMR (100 MHz, CDCl3): d = 11.6, 21.3, 21.5, 22.0, 36.8, 39.1,
48.1, 49.4, 50.6, 59.9, 123.9, 125.5, 126.0, 126.1, 127.7, 127.9,
128.5, 128.9, 129.1, 129.4, 138.8, 139.5, 170.8, 171.2, 182.3.
1H NMR (400 MHz, CDCl3): d = 0.75 (t, J = 7.2 Hz, 3 H), 0.83 (d,
J = 5.6 Hz, 3 H), 0.88 (d, J = 5.1 Hz, 3 H), 1.01 (d, J = 3.1 Hz, 3 H),
1.12–1.16 (m, 2 H), 2.56–2.60 (m, 1 H), 2.86–2.90 (m, 1 H), 3.48
(s, 3 H), 3.54 (s, 3 H), 4.03 (s, 2 H), 4.35 (d, J = 4.8 Hz, 1 H), 4.40
(d, J = 6.1 Hz, 1 H), 5.85 (br s, 1 H), 6.01 (br s, 1 H), 6.15 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 10.8, 13.6, 15.7, 15.8, 23.8, 29.5,
34.4, 39.6, 50.8, 51.0, 55.1, 59.8, 156.6, 168.9, 170.8, 171.1.
HRMS: m/z [M + Na]+ calcd for C16H29N3NaO6: 382.1954; found:
382.1939.
Anal. Calcd for C16H29N3O6: C, 53.47; H, 8.13; N, 11.69; O, 26.71.
Found: C, 53.40; H, 8.03; N, 11.88; O, 26.69.
Synthesis 2011, No. 20, 3247–3254 © Thieme Stuttgart · New York

3252
N. Narendra et al.
PAPER
Dimethyl (R)-2-{3-[(S)-1-(2S,3S)-1-Methoxy-3-methyl-1-oxo-
pentan-2-ylamino]-1-oxopropan-2-yl]ureido}succinate (4c)
White solid; yield: 87%; mp 149–150 °C; Rf = 0.49 (CHCl3–MeOH,
6:4).
1 H), 4.38–4.41 (m, 1 H), 5.18 (br s, 1 H), 5.72 (br s, 1 H), 6.98–
7.15 (m, 5 H).
13C NMR (100 MHz, CDCl3): d = 13.8, 16.9, 17.0, 29.5, 35.1, 50.4,
54.1, 57.6, 60.9, 124.5, 125.8, 126.7, 127.2, 127.8, 138.4, 156.6,
170.2, 171.0.
IR (KBr): 3298, 1717, 1735, 1756, 1679, 1547 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.78 (t, J = 6.8 Hz, 3 H), 1.03 (d,
J = 4.2 Hz, 3 H), 1.18–1.21 (m, 2 H), 1.39 (d, J = 5.0 Hz, 3 H),
2.55–2.65 (m, 2 H), 2.86–2.88 (m, 1 H), 3.51 (s, 3 H), 3.53 (s, 3 H),
3.55 (s, 3 H), 4.38 (d, J = 3.6 Hz, 1 H), 4.55–4.59 (m, 1 H), 4.96–
5.02 (m, 1 H), 5.68 (br s, 1 H), 5.91 (br s, 1 H), 6.25 (br s, 1 H).
HRMS: m/z [M + Na]+ calcd for C18H26N2NaO5: 373.1739; found:
373.1711.
Anal. Calcd for C18H26N2O5: C, 61.70; H, 7.48; N, 7.99; O, 22.83.
Found: C, 61.59; H, 7.36; N, 7.82; O, 22.88.
13C NMR (100 MHz, CDCl3): d = 10.6, 14.8, 16.6, 24.9, 35.5, 35.9,
49.8, 50.5, 50.8, 51.0, 51.2, 52.4, 156.6, 170.8, 171.1, 171.3, 172.6.
Diethyl (S)-2-{3-[(S)-1-Methoxy-1-oxopropan-2-yl]ureido}suc-
cinate (6c)
White solid; yield: 91%; mp 81–83 °C; Rf = 0.45 (n-hexane–EtOAc,
7:3).
[a]D24 –21.1 (c 0.8, MeOH).
IR (KBr): 3291, 1760, 1771, 1669 cm–1.
HRMS: m/z [M + Na]+ calcd for C17H29N3NaO8: 426.11852; found:
426.1860.
Anal. Calcd for C17H29N3O8: C, 50.61; H, 7.25; N, 10.42; O, 31.73.
Found: C, 50.49; H, 7.33; N, 10.30; O, 31.48.
1H NMR (400 MHz, CDCl3): d = 1.26 (t, J = 4.8 Hz, 3 H), 1.28 (t,
J = 5.2 Hz, 3 H), 1.44 (d, J = 6.1 Hz, 3 H), 2.55–2.61 (m, 2 H), 3.58
(s, 3 H), 4.04–4.11 (m, 4 H), 4.33–4.38 (m, 1 H), 4.96–4.98 (m, 1
H), 5.15 (br s, 1 H), 5.28 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 13.6, 13.9, 16.0, 35.8, 49.1, 49.9,
50.6, 50.4, 60.8, 155.7, 170.2, 170.9, 172.1.
Dimethyl (R)-2-{(S)-3-[(S)-1-methoxy-1-oxo-3-phenylpropan-2-
ylamino]-1-oxopropan-2-yl]thioureido}pentanedioate (4d)
Gum; yield: 88%; Rf = 0.45 (CHCl3–MeOH, 8:2).
IR (KBr): 3284, 2958, 1724, 1759, 1762, 1669, 1550, 1451 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.16 (d, J = 4.8 Hz, 3 H), 2.18 (dd,
J = 3.9 Hz, 2 H), 2.23–2.26 (m, 2 H), 2.96–3.01 (m, 2 H), 3.36 (t,
J = 7.0 Hz, 1 H), 3.50 (s, 3 H), 3.52 (s, 3 H), 3.58 (s, 3 H), 3.61–3.63
(m, 1 H), 4.71–4.74 (m, 1 H), 6.01 (br s, 1 H), 6.81–7.19 (m, 5 H),
7.25 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 17.3, 25.4, 27.1, 36.6, 50.8, 51.3,
51.4, 52.0, 55.1, 58.8, 125.4, 126.1, 126.9, 127.3, 128.1, 138.9,
170.8, 171.3, 172.0, 180.6.
HRMS: m/z [M + Na]+ calcd for C13H22N2NaO7: 341.1325; found:
341.1309.
Anal. Calcd for C13H22N2O7: C, 49.05; H, 6.97; N, 8.80; O, 35.18.
Found: C, 48.98; H, 6.89; N, 8.82; O, 35.10.
Ethyl (S)-2-[3-(2-Methoxy-2-oxoethyl)ureido]-3-methylbu-
tanoate (6d)
White solid; yield: 82%; mp 92–94 °C; Rf = 0.40 (n-hexane–EtOAc,
HRMS: m/z [M + Na]+ calcd for C21H29N3NaO7S: 467.1726; found:
467.1708.
6:4).
Anal. Calcd for C21H29N3O7S: C, 53.95; H, 6.25; N, 8.99; O, 23.95;
S, 6.86. Found: C, 53.79; H, 6.20; N, 8.80; O, 23.70; S, 6.60.
[a]D24 –52.2 (c 0.6, MeOH).
IR (KBr): 3285, 1745, 1669, 1516 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.78 (d, J = 5.1 Hz, 3 H), 0.82 (d,
J = 4.9 Hz, 3 H), 2.96–3.01 (m, 1 H), 3.58 (s, 3 H), 3.60 (s, 3 H),
3.91 (s, 2 H), 4.28 (d, J = 6.1 Hz, 1 H), 5.09 (br s, 1 H), 5.18 (br s,
1 H).
13C NMR (100 MHz, CDCl3): d = 16.5, 16.8, 29.1, 41.2, 50.5, 50.9,
56.8, 156.6, 168.9, 170.4.
Methyl (S)-2-{3-[(S)-1-Methoxy-1-oxopropan-2-yl]ureido}-4-
methylpentanoate (6a)
White solid; yield: 89%; mp 109–110 °C; Rf = 0.36 (n-hexane–
EtOAc, 7:3).
[a]D24 –25.6 (c 0.1, MeOH).
IR (KBr): 3301, 1744, 1755, 1671 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.78 (d, J = 5.4 Hz, 3 H), 0.82 (d,
J = 6.2 Hz, 3 H), 1.36 (d, J = 2.9 Hz, 3 H), 1.78–1.82 (m, 3 H), 3.56
(s, 3 H), 3.59 (s, 3 H), 4.08 (t, J = 3.1 Hz, 1 H), 4.43–4.48 (m, 1 H),
5.22 (br s, 1 H), 5.56 (br s, 1 H).
HRMS: m/z [M + Na]+ calcd for C11H20N2NaO5: 283.1270; found:
283.1244.
Anal. Calcd for C11H20N2O5: C, 50.76; H, 7.74; N, 10.76; O, 30.73.
Found: C, 50.59; H, 7.79; N, 10.65; O, 30.70.
13C NMR (100 MHz, CDCl3): d = 15.9, 20.6, 20.9, 21.4, 38.8, 49.9,
Methyl (S)-2-Phenyl-2-{3-[(R)-1-phenylethyl]ureido}acetate
(6e)
Gum; yield: 88%; Rf = 0.55 (n-hexane–EtOAc, 7:3).
50.6, 50.9, 51.2, 156.6, 171.0, 171.2.
HRMS: m/z [M + Na]+ calcd for C21H29N3NaO7S: 297.1426; found:
297.1411.
[a]D24 –10.2 (c 1.0, MeOH).
IR (neat): 3288, 1733, 1666 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.41 (d, J = 4.1 Hz, 3 H), 3.59 (s,
3 H), 4.91–4.94 (m, 1 H), 5.13 (br s, 1 H), 5.43 (s, 1 H), 5.56 (br s,
1 H), 7.05–7.23 (m, 10 H).
Anal. Calcd for C12H22N2O5: C, 52.54; H, 8.08; N, 10.21; O, 29.16.
Found: C, 52.41; H, 8.00; N, 10.09; O, 29.11.
Ethyl (S)-2-{3-[(S)-1-Methoxy-1-oxo-3-phenylpropan-
2-yl]ureido}-3-methylbutanoate (6b)
13C NMR (100 MHz, CDCl3): d = 20.4, 50.8, 51.5, 56.7, 124.4,
124.5, 125.6, 125.8, 126.9, 127.0, 127.4, 128.4, 128.6, 128.9, 134.6,
142.8.
HRMS: m/z [M + Na]+ calcd for C18H20N2NaO3: 335.1372; found:
335.1366.
White solid; yield: 85%; mp 169–171 °C; Rf = 0.45 (n-hexane–
EtOAc, 7:3).
[a]D24 –22.0 (c 0.35, MeOH).
IR (KBr): 3291, 1744, 1735, 1669, 1451 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.77 (d, J = 5.2 Hz, 3 H), 0.86 (d,
J = 6.0 Hz, 3 H), 1.22 (t, J = 7.0 Hz, 3 H), 2.91–2.96 (m, 1 H), 3.03–
3.13 (m, 2 H), 3.56 (s, 3 H), 4.04–4.09 (m, 2 H), 4.12 (d, J = 4.2 Hz,
Anal. Calcd for C18H20N2O3: C, 69.21; H, 6.45; N, 8.97; O, 15.37.
Found: C, 69.18; H, 6.36; N, 8.98; O, 15.29.
Synthesis 2011, No. 20, 3247–3254 © Thieme Stuttgart · New York

PAPER
Peptide Ester Isocyanates, Isothiocyanates, and Dipeptidyl Ureas
3253
Methyl (S)-2-Phenyl-2-{3-[(S)-1-phenylethyl]ureido}acetate
IR (KBr): 3211, 1739, 1734, 1698 cm–1.
(6f)
1H NMR (400 MHz, CDCl3): d = 0.89 (t, J = 7.1 Hz, 3 H), 1.02 (d,
J = 8.2 Hz, 3 H), 1.13–1.18 (m, 2 H), 2.00 (s, 3 H), 2.04 (s, 3 H),
2.14 (s, 3 H), 2.19 (s, 3 H), 2.41–2.49 (m, 1 H), 3.25 (d, J = 3.2 Hz,
1 H), 3.59 (s, 3 H), 4.11–4.23 (m, 2 H), 4.31 (dd, J = 3.6, 11.4 Hz,
1 H), 4.38–4.44 (m, 1 H), 4.61–4.77 (dd, J = 2.8, 7.9 Hz, 1 H), 5.11
(dd, J = 2.9, 9.6 Hz, 1 H), 5.43 (t, J = 5.8 Hz, 1 H), 6.01 (br s, 1 H),
7.11 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 11.0, 15.1, 20.1, 20.5, 20.9, 21.2,
24.8, 35.8, 50.9, 58.6, 59.3, 67.8, 69.1, 72.1, 75.4, 86.1, 169.6,
170.4, 171.1, 171.5, 171.8, 181.0.
Gum; yield: 85%; Rf = 0.55 (n-hexane–EtOAc, 7:3).
[a]D24 +22.2 (c 1.0, MeOH).
IR (neat): 3300, 1735, 1665 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.45 (d, J = 5.8 Hz, 3 H), 3.50 (s,
3 H), 4.01–4.13 (m, 1 H), 5.18 (br s, 1 H), 5.55 (br s, 1 H), 5.61 (s,
1 H), 7.11–7.28 (m, 10 H).
13C NMR (100 MHz, CDCl3): d = 20.8, 50.1, 51.9, 55.5, 124.1,
124.5, 125.5, 125.9, 127.3, 127.6, 128.1, 128.4, 128.5, 129.0, 134.1,
141.2.
HRMS: m/z [M + Na]+ calcd for C22H34N2NaO11S: 557.1781;
found: 557.1745.
HRMS: m/z [M + Na]+ calcd for C18H20N2NaO3: 335.1372; found:
335.1359.
Anal. Calcd for C22H34N2O11S: C, 49.43; H, 6.41; N, 5.24; O, 32.95;
S, 6.00. Found: C, 49.40; H, 6.21; N, 5.25; O, 32.54; S, 5.98.
Anal. Calcd for C18H20N2O3: C, 69.21; H, 6.45; N, 8.97; O, 15.37.
Found: C, 69.11; H, 6.51; N, 8.68; O, 15.30.
Methyl (S)-2-{3-[3,5-Bis(trifluoromethyl)phenyl]thioureido}-4-
methylpentanoate (6j)
Gum; yield: 92%; Rf = 0.55 (n-hexane–EtOAc, 8:2).
[a]D24 –15.8 (c 1.0, CHCl3).
IR (neat): 3129, 1703, 1638 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.89 (t, J = 5.8 Hz, 3 H), 1.01 (d,
J = 7.1 Hz, 3 H), 1.22–1.25 (m, 2 H), 2.40–2.44 (m, 1 H), 3.28 (d,
J = 6.2 Hz, 1 H), 3.55 (s, 3 H), 4.98 (br s, 1 H), 5.15 (br s, 1 H), 6.96
(s, 2 H), 7.09 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 10.8, 14.6, 24.4, 35.8, 50.5, 59.4,
118.7, 123.6, 123.7, 124.5, 124.6, 129.8, 130.5, 136.8, 170.4, 175.8.
Methyl (S)-2-[3-(2,3,4,6-Tetra-O-acetyl-b-D-glycopyrano-
syl)ureido]propanoate (6g)
White solid; yield: 84%; mp 171–172 °C; Rf = 0.49 (n-hexane–
EtOAc, 6:4).
[a]D24 +41.6 (c 1.0, MeOH).
IR (KBr): 3300, 1741, 1735, 1665 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.32 (d, J = 6.9 Hz, 3 H), 2.01 (s,
3 H), 2.06 (s, 3 H), 2.12 (s, 3 H), 2.19 (s, 3 H), 3.55 (s, 3 H), 3.90 (t,
J = 8.6 Hz, 1 H), 4.10 (d, J = 6.4 Hz, 2 H), 4.29 (d, J = 10.2 Hz, 1
H), 4.44–4.51 (m, 1 H), 5.01 (dd, J = 3.3, 10.5 Hz, 1 H), 5.52 (t,
J = 9.6 Hz, 1 H), 6.01 (dd, J = 0.82, 3.6 Hz, 1 H), 6.78 (br s, 1 H),
6.91 (br s, 1 H).
HRMS: m/z [M + Na]+ calcd for C16H18F6N2NaO2S: 439.0891;
found: 439.0875.
13C NMR (100 MHz, CDCl3): d = 16.5, 20.0, 20.3, 20.9, 21.0, 50.8,
51.7, 61.6, 67.2, 69.5, 69.9, 70.5, 78.2, 155.5, 169.2, 170.1, 171.0,
171.0.
Anal. Calcd for C16H18F6N2O2S: C, 46.15; H, 4.36; F, 27.38; N,
6.73; O, 7.68; S, 7.70. Found: C, 46.11; H, 4.22; F, 27.20; N, 6.59;
O, 7.44; S, 7.61.
HRMS: m/z [M + Na]+ calcd for C19H28N2NaO12: 499.1540; found:
499.1512.
(S)-1-Ethyl-3-[1-(methylamino)-1-oxopropan-2-yl]-1-phenyl-
urea (9k)
White solid; yield: 75%; mp 122–124 °C; Rf = 0.55 (CHCl3–MeOH,
Anal. Calcd for C19H28N2O12: C, 47.90; H, 5.92; N, 5.88; O, 40.30.
Found: C, 47.78; H, 5.75; N, 5.35; O, 40.12.
6:4).
Methyl (S)-2-{3-[3,5-Bis(trifluoromethyl)phenyl]ureido}-3-
phenylpropanoate (6h)
White solid; yield: 82%; mp 121–123 °C; Rf = 0.45 (n-hexane–
EtOAc, 8:2).
[a]D24 –15.8 (c 1.0, CHCl3).
IR (KBr): 3288, 1733, 1666, 1498 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.98–3.16 (m, 2 H), 3.55 (s, 3 H),
4.77 (dd, J = 2.6, 4.8 Hz, 1 H), 5.85 (br s, 1 H), 6.09 (br s, 1 H), 7.02
(d, J = 5.4 Hz, 1 H), 7.11 (d, J = 3.9 Hz, 1 H), 7.18–7.23 (m, 2 H),
7.42 (s, 1 H), 7.87 (s, 2 H).
[a]D25 +35.9 (c 1.0, CHCl3).
IR (KBr): 3200, 1708, 1649 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.05 (t, J = 7.0 Hz, 3 H), 1.32 (d,
J = 4.6 Hz, 3 H), 2.55 (s, 3 H), 3.11–3.15 (m, 2 H), 4.51–4.54 (m, 1
H), 5.91 (br s, 1 H), 6.98 (d, J = 3.8 Hz, 1 H), 7.11–7.29 (m, 4 H),
7.75 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 11.8, 16.1, 25.8, 45.0, 50.6,
120.5, 120.6, 124.2, 128.4, 128.8, 138.8, 154.6, 171.6.
HRMS: m/z [M + Na]+ calcd for C13H19N3NaO2: 272.1375; found:
272.1349.
13C NMR (100 MHz, CDCl3): d = 50.8, 55.0, 117.6, 119.7, 119.9,
123.6, 123.7, 125.5, 127.7, 127.8, 128.5, 128.8, 130.5, 130.9, 135.8,
138.9, 155.2, 170.6.
Anal. Calcd for C13H19N3O2: C, 62.63; H, 7.68; N, 16.85; O, 12.84.
Found: C, 62.41; H, 7.32; N, 16.39; O, 12.41.
HRMS: m/z [M + Na]+ calcd for C19H16F6N2NaO3: 457.0963;
found: 457.0911.
(S)-1-Ethyl-3-[1-(methylamino)-1-oxo-3-phenylpropan-2-yl]-1-
phenylurea (9l)
White solid; yield: 69%; mp 114–116 °C Rf = 0.58 (CHCl3–MeOH,
6:4).
Anal. Calcd for C19H16F6N2O3: C, 52.54; H, 3.71; F, 26.24; N, 6.45;
O, 11.05. Found: C, 52.50; H, 3.19; F, 25.88; N, 6.59; O, 11.00.
[a]D25 +29.5 (c 1.0, CHCl3).
IR (KBr): 3211, 1751, 1654 cm–1.
Methyl (S)-3-Methyl-2-[3-(2,3,4,6-Tetra-O-acetyl-b-D-glycopy-
ranosyl)thioureido}pentanoate (6i)
White solid; yield: 75%; mp 106–108 °C; Rf = 0.40 (n-hexane–
EtOAc, 7:3).
[a]D25 –3.8 (c 1.0, CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.03 (t, J = 7.2 Hz, 3 H), 2.51 (s,
3 H), 2.88–3.05 (m, 2 H), 3.11–3.14 (m, 2 H), 4.76–4.79 (m, 1 H),
5.91 (br s, 1 H), 6.96–7.23 (m, 10 H), 7.55 (br s, 1 H).
Synthesis 2011, No. 20, 3247–3254 © Thieme Stuttgart · New York

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N. Narendra et al.
PAPER
13C NMR (100 MHz, CDCl3): d = 11.6, 25.4, 36.1, 44.8, 55.0,
120.6, 120.9, 123.4, 125.8, 127.6, 128.8, 129.0, 129.1, 129.3, 138.5,
138.8, 154.4, 171.2.
HRMS: m/z [M + Na]+ calcd for C19H23N3O2: 348.1688; found:
348.1657.
(3) Nowick, J. S.; Holems, D. L.; Noronha, G.; Smith, E. M.;
Nguyen, T. M.; Huang, S.-L. J. Org. Chem. 1996, 61, 3929.
(4) Chong, P. Y.; Petillo, P. A. Tetrahedron Lett. 1999, 40,
4501; the base-catalyzed cyclization has constituted a main
synthetic route for making peptide hydantoins.
(5) (a) Quibell, M.; Turnell, W. G.; Johnson, T. J. Chem. Soc.,
Perkin Trans. 1 1993, 2843. (b) Limal, D.; Semetey, V.;
Dalbon, P.; Jolivet, M.; Briand, J.-P. Tetrahedron Lett. 1999,
40, 2749.
(6) Liley, M.; Johnson, T. Tetrahedron Lett. 2000, 41, 3983.
(7) For application of zinc as non-basic HCl scavenger for
racemization free peptide coupling with Fmoc-amino acid
chlorides, and for isolation of free amino acid methyl esters,
see: (a) Sureshbabu, V. V.; Gopi, H. N. Tetrahedron Lett.
1998, 39, 9769. (b) Ananda, K.; Sureshbabu, V. V.
J. Peptide Res. 2001, 57, 223.
(8) Due to difficulty in the addition of a stoichiometric quantity
of the tertiary amine, excess base can be transferred.
Presence of excess base can also promote several other side
reactions which are intrinsic to peptides as substrates.
Bednarek, M. A.; Bodanszky, M. Int. J. Pept. Protein Res.
1995, 45, 64; and references cited therein.
(9) Phosgene in toluene can be used in stoichiometric amounts,
forms no byproducts and the unreacted portion, if any, can
be completely removed simply through evaporation. On the
other hand, other carbonylating agents including triphosgene
and the byproducts they form have to be separated from
isocyanates either through extraction with aqueous solvents
or column chromatography, conditions that tend to reduce
the yields of peptide ester isocyanate. Also, in case of
phosgene the co-product of acylation, HCl, can be
neutralized using non-basic reagent zinc without raising the
pH of the medium. Consequently, we chose this reagent in
spite of its known safety concerns.
(10) (a) Bodansky, M. Principles of Peptide Synthesis, 2nd ed.;
Springer: New York, 1993. (b) Bodansky, M.; Bodansky, A.
The Practice of Peptide Synthesis, 2nd ed.; Springer: New
York, 1994.
(11) HPLC was carried out on Agilent 1100 using an Agilent
EcilpseXDB-C18 G1311A column (4.6 × 150 mm, 5 mm)
and a gradient of 0.1% TFA in H2O–MeCN 30–90% in 30
min with spectrometric monitoring at l = 215 nm. HPLC
profile of the crude 3a showed a sharp single peak at
tR = 20.045 min with a purity of 95%.
Anal. Calcd for C19H23N3O2: C, 70.13; H, 7.12; N, 12.91; O, 9.83.
Found: C, 70.05; H, 7.10; N, 12.88; O, 9.36.
(S)-1-Ethyl-3-[1-(ethylamino)-4-methyl-1-oxopentan-2-yl]-1-
phenylurea (9m)
White solid; yield: 71%; mp 151–153 °C; Rf = 0.36 (CHCl3–MeOH,
6:4).
[a]D25 –1.9 (c 1.0, CDCl3).
IR (KBr): 3196, 1745, 1600 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.78 (d, J = 7.2 Hz, 3 H), 0.88 (d,
J = 5.1 Hz, 3 H), 1.05 (t, J = 7.2 Hz, 3 H), 1.16 (t, J = 6.9 Hz, 3 H),
1.65–1.69 (m, 2 H), 1.77–1.82 (m, 1 H), 3.11–3.14 (m, 2 H), 3.19–
3.22 (m, 2 H), 4.41 (t, J = 3.1 Hz, 1 H), 5.85 (br s, 1 H), 7.02–7.71
(m, 5 H), 7.78 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 11.2, 14.3, 20.4, 21.5, 21.7, 33.8,
39.5, 45.6, 52.5, 119.8, 120.2, 122.7, 128.8, 128.9, 138.6, 155.0,
170.7.
HRMS: m/z [M + Na]+ calcd for C17H27N3NaO2: 328.2001; found:
328.1992.
Anal. Calcd for C17H27N3O2: C, 66.85; H, 8.91; N, 13.76; O, 10.48.
Found: C, 66.49; H, 8.87; N, 13.59; O, 10.20.
Racemization Studies
The NMR spectra of the crude samples of epimeric ureas 6e and 6f
were prepared via the present protocol by coupling the crude isocy-
anate derived from 5e with (R)-phenylethylamine and (S)-phenyl-
ethylamine, respectively, showed signals as follows. A single
doublet at d = 1.41 ppm for 6e and a single doublet at d = 1.45 ppm
for 6f corresponding to the methyl group. The 1:1 mixture of these
compounds prepared by coupling racemic (R/S)-phenylethylamine
contained two methyl group doublets at d = 1.40 and 1.43 ppm. This
showed that the samples of 6e and 6f analyzed contained a single
enantiomerically pure compound. Consequently, it was concluded
that the present protocol did not destroy the integrity of the chiral
centers of the components.
(12) (a) An authentic sample of hydantoin was prepared from
isocyanate 2a. To confirm the present protocol is free from
hydantoin formation (see Supporting Information).
(b) Nefzi, A.; Ostresh, J. M.; Giultanotti, M.; Houghten, R.
A. Tetrahedron Lett. 1998, 39, 8199.
(13) Bohme, H.; Martin, F.; Strahl, J. Arch. Pharm. 1980, 313,
10.
(14) (a) Xu, D.-Q.; Yue, H.-D.; Luo, S.-P.; Xia, A.-B.; Zhang, S.;
Supporting Information for this article is available online at
http//www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
The authors thank CSIR, New Delhi for financial support [grant no.
01(2323)/09/EMR-II]. Narendra gratefully acknowledges CSIR,
New Delhi for the award of a senior research fellowship.
Xu, Z.-Y. Org. Biomol. Chem. 2008, 6, 2054.
(b) Yoshihiro, S.; Tanatani, A.; Hashimoto, Y.; Nagasawa,
K. Chem. Pharm. Bull. 2004, 52, 477.
(15) (a) Boeijen, A.; Liskamp, R. M. J. Eur. J. Org. Chem. 1999,
2127. (b) Colacino, E.; Lamaty, F.; Martinez, J.; Parrot, I.
Tetrahedron Lett. 2007, 48, 5317. (c) Boeijen, A.;
Kruijttzer, J. A. W.; Liskamp, R. M. J. Bioorg. Med. Chem.
Lett. 1998, 8, 2375. (d) Fischer, L.; Semetey, V.; Lozano, J.-
M.; Schaffner, A.-P.; Briand, J.-P.; Didierjean, C.; Guichard,
G. Eur. J. Org. Chem. 2007, 2511. (e) Boeijen, A.;
van Ameijde, J.; Liskamp, R. M. J. J. Org. Chem. 2001, 66,
8454.
References
(1) (a) Nowick, J. S.; Powell, N. A.; Nguyen, T. M.; Noronha,
G. J. Org. Chem. 1992, 57, 7364; and references cited
therein. (b) Nowick, J. S.; Holmes, D. L.; Mackin, G.;
Noronha, G.; Shaka, A. J.; Smith, E. M. J. Am. Chem. Soc.
1996, 118, 2764.
(2) Goldschmidt and Wick, who first attempted to synthesize
these compounds by using gaseous phosgene at a
temperature of 110 °C, found that the formed isocyanate
cyclized to hydantoin: (a) Goldschmidt, S.; Wick, M. Justus
Liebigs Ann. Chem. 1952, 575, 217. (b) Goldschmidt, S.;
Wick, M. Z. Naturforsch., B: Chem. Sci. 1950, 5, 170.
Synthesis 2011, No. 20, 3247–3254 © Thieme Stuttgart · New York