Controlled ring opening of N-sulfinyl- and N-silyl-N-carboxyanhydrides (NCA): One-pot synthesis of dipeptides and unsymmetrical peptidyl ureas from unprotected NCA

Article abstract of DOI:10.1055/s-0028-1087510

We report herein new labile protecting groups of N-carboxyanhydrides (NCA) useful to prevent polymerization during coupling reactions with nitrogen nucleophiles. Thus, N-sulfinyl-NCA 1 and N-silyl-NCA 2 were prepared in situ and involved, without being is

Full text of DOI:10.1055/s-0028-1087510

LETTER
279
Controlled Ring Opening of N-Sulfinyl- and N-Silyl-N-carboxyanhydrides
(NCA): One-Pot Synthesis of Dipeptides and Unsymmetrical Peptidyl Ureas
from Unprotected NCA
S
ynthesis
u
of
D
ipeptide
l
s
andU
i
nsymm
a
etrical
P
eptidyl
U
M
rea
s
ateos-Caro,a Yves Robin,b Vincent Levacher,*a Francis Marsaisa
a
Laboratoire de Chimie Organique Fine et Hétérocyclique, UMR 6014, IRCOF, CNRS, Université et INSA de Rouen,
B.P. 08, 76131 Mont-Saint-Aignan Cédex, France
Fax +33(2)35522475; E-mail: Vincent.levacher@insa-rouen.fr
ISOCHEM, Centre de Recherches du Bouchet, 91710 Vert-le-Petit, France
b
Received 24 September 2008
1 and 2 as new synthons in stepwise peptide synthesis
(Figure 1).
Abstract: We report herein new labile protecting groups of N-car-
boxyanhydrides (NCA) useful to prevent polymerization during
coupling reactions with nitrogen nucleophiles. Thus, N-sulfinyl-
NCA 1 and N-silyl-NCA 2 were prepared in situ and involved, with-
out being isolated, in coupling reactions with various a-amino esters
to furnish dipeptides 3 and unsymmetrical peptidyl ureas 4, respec-
tively, in good yields.
By means of labile protecting groups, our intent was to
accomplish a N-protection–coupling–N-deprotection se-
quence from unprotected NCA in a one-pot procedure.
SOR2
SiMe2R
Key words: N-protected carboxyanhydrides (NCA), peptidyl
ureas, dipeptides
R1
R1
N
N
O
O
O
O
O
O
1a: R1 = i-Pr; R2 = Ph
1b: R1 = i-Pr; R2 = t-Bu
1c: R1 = i-Bu; R2 = t-Bu
2a: R1 = i-Pr; R = Me
2b: R1 = i-Pr; R = t-Bu
2c: R1 = i-Bu; R = Me
So far, N-carboxyanhydrides (NCA), also known as
Leuchs’ anhydrides, have found application mainly as
monomers for the preparation of polypeptides.1 In princi-
ple, these amino acid derivatives are also appealing syn-
thons for stepwise peptide synthesis considering that both
the activation of the carbonyl group and the N-protection
of the amino group are combined within the NCA ring.
Although this coupling process is highly attractive in
terms of atom economy since carbon dioxide is the sole
byproduct of the reaction, this approach has not attracted
much interest in the past. The poor storage stability of
NCA, together with oligomerization reactions accompa-
nying the coupling reaction, seriously limit their develop-
ment in stepwise peptide synthesis.2 To overcome these
problems, various N-protected NCA have been devel-
oped, allowing peptide coupling reactions to take place in
good yields. One can mention urethane-protected NCA
(UNCA),3 N-trityl-NCA4 and N-nitrophenylsulfenyl-NCA5
as the most representative examples. While N-protected
NCA generally gave rise to significant improvement in
terms of yields, many of them still suffered from poor sta-
bility making them difficult to handle and/or from notice-
able loss of the enantiomeric purity during the coupling
step. In this context, there still remains important research
to be done in the development of straightforward and ro-
bust procedures, which inhibit polymerization side reac-
tions, while guaranteeing high yields and enantiomeric
integrity of the coupling product. We turned our interest
to the synthetic potential of N-sulfinyl- and N-silyl NCA
Figure 1 New labile protecting groups of NCA: N-sulfinyl-NCA 1
and N-silyl-NCA 2
We first investigated N-sulfinyl-NCA 1a–c as potential
candidates to develop the three-step sequence. With the
exception of N-sulfenyl derivatives,5 to the best of our
knowledge, sulfur-based protecting group for NCA has
not been reported. The required N-phenylsulfinyl-Val-
NCA 1a was prepared by reaction of the corresponding
Val-NCA6 with phenylsulfinyl choride7 in dry THF at
0 °C in the presence of triethylamine. The reaction was
monitored by in situ infrared spectroscopy indicating that
the reaction was completed within one hour. At this stage,
N-phenylsulfinyl-Val-NCA 1a could be isolated and iden-
tified by 1H NMR revealing the presence of two diastereo-
mers in a 6:4 ratio.8
Addition of phenylalanine ethyl ester hydrochloride af-
forded the dipeptide 3a in 15% yield along with the sym-
metrical urea 3b in 40% yield, the former resulting from a
double addition of phenylalanine ethyl ester at the C-2 po-
sition of 1a. This side reaction could be reduced, but not
eliminated, by conducting the whole reaction sequence in
Et2O at –30 °C. As expected from literature,9 the N -sulfi-
nyl group was easily cleaved under acidic conditions, af-
fording the desired dipeptide H-Val-Phe-OEt (3a) in 55%
from 1a (Scheme 1).
Encouraged by these preliminary results, controlled ring
opening of N-sulfinyl-NCA was then further investigated.
Interestingly, the delicate balance of the ambident reactiv-
ity between C-2 and C-5 positions of N-sulfinyl-NCA
could be finely tuned at C-5 by increasing the steric hin-
SYNLETT 2009, No. 2, pp 0279–0283
Advanced online publication: 15.01.2009
DOI: 10.1055/s-0028-1087510; Art ID: G31308ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
0
9

280
J. Mateos-Caro et al.
LETTER
1) L-PheOEt,
HCl (1 equiv)
Et3N (1 equiv)
O
PhSOCl (1 equiv)
Et3N (1 equiv)
–30 °C, 1 h
H
N
Ph
O
S
N
2) HCl (4 M in dioxane)
O
O
O
O
O
Val-NCA
1a
Ph
Ph
O
H
EtOOC
Ph
N
+
NH2
EtOOC
N
N
COOEt
H
H
O
3b
3a
(THF, 0 °C) 40%
(Et2O, –30 °C) 5%
15%
55%
Scheme 1 Ambident reactivity of N-phenylsulfinyl-Val-NCA 1a with phenylalanine ester
drance of the sulfinyl moiety (Table 1). Thus, with the We then focused on the preparation of N-silylated NCA
more sterically hindered N-tert-butylsulfinyl-Val-NCA 2a–c. Both Val- and Leu-NCA were reacted with chloro-
1b, phenylalanine ethyl ester reacted exclusively at C-5, trialkylsilanes at –30 °C in THF in the presence of triethyl-
affording H-Val-Phe-OEt (3a) in 80% overall yield (en- amine. The corresponding N-silylated-NCA 2a–c were
try 1). In practice, the formation of N-tert-butylsulfinyl- stable enough to be isolated in 92–99% yields and fully
1
Val-NCA 1b from Val-NCA and tert-butylsulfinyl characterized.12 The H NMR, 13C NMR, and infrared
chloride10 was monitored by in situ infrared spectroscopy spectra of the isolated products showed that, in both
and then engaged in the next step without being isolated. CDCl3 and solid state, N-carboxyanhydrides 2b,c co-exist
Following this one-pot procedure11 from Leu-NCA, H- with isocyanates 2¢b,c, while only N-carboxyanhydride
Leu-Phe-OEt (3b) was obtained in 76% overall yield (en- 2a could be dectected.12 These data strongly suggest that,
try 2). The usefulness of the procedure was then illustrated under the reaction conditions (THF, –30 °C), an equilibri-
with various amino esters affording the corresponding um may occur between N-carboxyanhydrides 2 and isocy-
dipeptides 3c–f in 40% to 91% yields (entries 3–6). We anates 2¢, leading, respectively, by addition of an nitrogen
were pleased to notice that neither byproducts resulting nucleophile, to either the formation of a dipeptide or an
from the ring opening at C-2 nor polymerization products urea. In attempting to anticipate the outcome of the reac-
were detected in the crude mixture. Although the conver- tion sequence, the course of the silylation was monitored
sion proved to be excellent in all cases, entries 5 and 6 ex- by means of in situ infrared spectroscopy. Initial pre-
hibit rather modest yields owing to the difficulty in cooled solutions of NCA in THF (–30 °C) showed two
isolating dipeptides 3e and 3f .
characteristic absorption bands in the region of 1790 cm–1
and 1830 cm–1. Although no significant absorbance
Table 1 One-Pot Synthesis of Dipeptides 3a–f11 from Val-NCA and Leu-NCA
COOEt
NH
O
R4
O
t--Bu
O
t-BuSOCl
Et3N (1 equiv)
THF, 0 °C
H
S
R1
O
R1
O
THF
0 °C to 20 °C
N
N
O
R1
O
O
H2N
3a–f
1b: R1 = i-Pr
1c: R1 = i-Bu
Val-NCA: R1 = i-Pr
Leu-NCA: R1 = i-Bu
Entry
NCA
Amino estera
Productc
Yield (%)b
1
2
3
4
5
6
Val-NCA
Leu-NCA
Val-NCA
Val-NCA
Val-NCA
Val-NCA
L-Phe-OEt
L-Phe-OEt
L-Thr-OEt
L-Pro-OEt
L-Met-OMe
L-Ala-OEt
H-Val-Phe-OEt (3a)
H-Leu-Phe-OEt (3b)
H-Val-Thr-OEt (3c)
H-Val-Pro-OEt (3d)
H-Val-Met-OEt (3e)
H-Val-Ala-OEt (3f)
80
76
91
70
50
40
a Amino ester used as their hydrochloride salt.
b Overall yield from Val-NCA and Leu-NCA.
c Dipeptides 3a–f were determined to be diastereomerically pure by 1H NMR spectroscopy.
Synlett 2009, No. 2, 279–283 © Thieme Stuttgart · New York

LETTER
Synthesis of Dipeptides and Unsymmetrical Peptidyl Ureas
281
Table 2 One-Pot Synthesis of Unsymmetrical Peptidyl Ureas 4a–j16
changes were detected after addition of triethylamine, the
appearance of two new absorption bands at 2280 cm–1 and
1730 cm–1 upon addition of the silylating agent was asso-
ciated with the formation of the isocyanates 2¢a–c. In ad-
dition, a quantitative 13C NMR study performed in THF-
d8 at –30 °C confirmed the presence of the isocyanates
2¢a–c as the major product (Scheme 2).
from Val-NCA and Leu-NCAa
OH
OH
OH
O
O
O
R1
O
R1
O
R1
O
H
R1
O
HN
HN
HN
HN
HN
HN
Ph
N
O
O
R4
NH
2280 cm–1
O
OR3
Val-NCA: R1 = i-Pr
Leu-NCA: R1 = i-Bu
H
SiMe2R
R1
O
4c
O
R1
O
R1
O
C
4a,b
R4
–
4d–j
Yield (%)b
4a 90
N
N
N
(a)
O
O
Entry NCA
R3
–
92–99%
O
O
OSiMe3
1830 cm–1
1
2
3
4
5
6
7
Val-NCA
Leu-NCA
Val-NCA
Val-NCA
Val-NCA
Val-NCA
Val-NCA
1730 cm–1
1790 cm–1
2a: R1 = i-Pr ; R = Me
2b: R1 = i-Pr ; R = t-Bu
2c: R1 = i-Bu ; R = Me
2'a
2'b
2'c
Val-NCA: R1 = i-Pr
Leu-NCA: R1 = i-Bu
–
–
4b 75
–
–
4c 55
Scheme 2 Silylation of Val-NCA and Leu-NCA. Equilibrium bet-
ween N-silyl-NCA 2a–c and isocyanates 2¢a–c. Reagents and condi-
tions: (a) RMe2SiCl (1.5 equiv), Et3N (1 equiv), THF, –30 °C, 5 h.
Bn
Me
Me
Et
i-Bu
4d 67
CH2CH2COOMe
s-Bu
4e 47
4f 72
As a result of the presence of the isocyanate form, addi-
tion of amino esters is therefore expected, in contrast to
N-sulfinyl NCA, to give rise to unsymmetrical peptidyl
ureas resulting from a formal addition at C-2 of the NCA
ring.13 Unsymmetrical peptidyl ureas have recently
gained interest in the design of peptidomimetics.14 Al-
though a survey of the literature makes it apparent that
there are numerous ways of preparing unsymmetrical pep-
tidyl ureas,15 it also reveals that existing methods general-
ly require several steps, long reaction times, and excessive
use of reagents.15e–15k In addition to these disadvantages,
symmetrical ureas are formed as byproducts in many
CH2CH2SMe
4g 70
4h 90
8
Val-NCA
Et
Bn
4h 52c
9
Val-NCA
Leu-NCA
Et
Et
4i 65
4j 80
N
H
10
Bn
a TMSCl, Et3N, –30 °C, THF, 4.5 h, then cyclohexylamine or phenyl
hydrazine or amino esters were added at 0 °C.
cases.15a–15d We thus explored the reactivity of silylated
NCA with various amino esters with intent to develop an
efficient one-pot access to unsymmetrical peptidyl ureas
from unprotected NCA.
b Overall yield from Val- and Leu NCA; ureas 4a–j were determined
to be diastereomerically pure by 1H NMR.
c Reaction carried out in CHCl3.
After silyl protection of NCA by means of TMSCl in THF
at –30 °C, the resulting silylated NCA were subsequently
subjected to reaction with different amines at 0 °C. As one
would have predicted, all amines reacted regioselectively
at the C-2 position, providing the corresponding unsym-
metrical ureas in 55–90% overall yields (Table 2). In ad-
dition to various amino esters (entries 4–10) and
cyclohexyl amine (entries 1 and 2), phenylhydrazine
could smoothly react with silylated Val-NCA to give 4c in
55% yield (entry 3). As previously mentioned, although
NMR analyses revealed that N-silylated Val-NCA 2a is
the major form present in chloroform, attempts to switch
the regioselectivity of the ring opening of silylated NCA
at C-5 by performing the reaction in that solvent failed, af-
fording urea 4h as the sole product (entry 8). This one-pot
procedure provides a straightforward access to unsym-
metrical peptidyl ureas from unprotected NCA, with the
additional advantage over existing methods of leading to
the carboxylic acid at one end of the ureas.
In summary, N-sulfinyl and N-silyl protecting groups of
NCA have been successfully used to prevent polymeriza-
tion during coupling reactions with amino esters. One-pot
procedures have been developed from unprotected NCA,
avoiding the necessity of isolating N-protected NCA in-
termediates and making them more useful as building
blocks for the synthesis of dipeptides and unsymmetrical
peptidyl ureas. Whereas N-tert-butylsulfinyl-NCA react-
ed regioselectively at C-2 to give dipeptides 3a–f in 40–
91% overall yields, the reactivity of NCA could be com-
pletely inverted at C-5 by means of N-silyl-NCA furnish-
ing unsymmetrical peptidyl ureas 4a–j in 47–90% overall
yields.
References and Notes
(1) For an excellent review on the main applications of NCA,
see: Kricheldorf, H. R. Angew. Chem. Int. Ed. 2006, 45,
5752.
Synlett 2009, No. 2, 279–283 © Thieme Stuttgart · New York

282
J. Mateos-Caro et al.
LETTER
(2) (a) Barlett, P. D.; Jones, R. H. J. Am. Chem. Soc. 1957, 79,
37. (b) Grant, N. H.; Alburn, H. E. J. Am. Chem. Soc. 1964,
86, 3870. (c) Brenner, M.; Hofer, W. Helv. Chim. Acta 1961,
44, 1798.
(3) Fuller, W. D.; Cohen, M. P.; Shabankareh, M.; Blair, R. K.
J. Am. Chem. Soc. 1990, 112, 7414.
(4) Sim, T. B.; Papoport, H. J. Org. Chem. 1999, 64, 2532.
(5) Katakai, R. J. Org. Chem. 1975, 40, 2697.
(6) Val-NCA and Leu-NCA were generously gifted by
1 H, J = 5.5 Hz), 3.79 (m, 1 H), 3.50 (m, 1 H), 2.23–2.11 (m,
2 H), 1.89 (m, 3 H), 1.17 (t, 3 H, J = 7.0 Hz), 0.99 (dd, 6 H,
J = 6.8, J = 6.6 Hz). 13C NMR (75 MHz, DMSO): d = 14.3,
17.6, 18.5, 25.1, 29.0, 29.8, 47.6, 55.8, 59.2, 61.0, 167.4,
171.6. IR (KBr): 1739, 1652 cm–1. HRMS: m/z calcd for
C12H22N203 [MH+]: 243.1705; found: 243.1708. [a]D20 –47.7
(c 1.01, EtOH).
H-Val-Met-OEt (3e): 1H NMR (300 MHz, CDCl3): d = 7.89
(d, 1 H, J = 7.7 Hz), 4.68 (m, 1 H), 4.20 (q, 2 H, J = 7.2 Hz),
3.28 (d, 1 H, J = 4.0 Hz), 2.49 (m, 2 H), 2.30–1.95 (m, 6 H),
1.28 (t, 3 H, J = 7.2 Hz), 0.99 (d, 3 H, J = 7.0 Hz), 0.84 (d,
3 H, J = 7.0 Hz). 13C NMR (75 MHz, CDCl3): d = 14.6, 15.9,
16.6, 20.0, 30.4, 31.2, 32.4, 51.6, 60.5, 61.9, 172.4, 174.6. IR
(KBr): 1720, 1650 cm–1. HRMS: m/z calcd for C12H24N203S
[MH+]: 277.1508; found: 277.1510.
ISOCHEM company.
(7) Youn, J.; Herrmann, R. Tetrahedron Lett. 1986, 27, 1493.
(8) After elimination of the triethylamine hydrochloride salt by
filtration and evaporation of THF, the major diastereomer
could be isolated by precipitation in Et2O. Selected data of
the major diastereomer: 1H NMR (300 MHz, CDCl3): d =
7.69 (m, 5 H), 3.77 (d, 1 H, J = 3.4 Hz), 2.45 (m, 1 H), 1.02
(d, 3 H, J = 6.8 Hz), 0.95 (d, 3 H, J = 7.1 Hz). 13C NMR (75
MHz, CDCl3): d = 16.0, 17.9, 31.7, 65.8, 125.3, 130.5,
133.6, 139.7, 150.8, 165.2. IR (KBr): 1853, 1787 cm–1.
(9) Tang, T. P.; Volkman, S. K.; Ellman, J. A. J. Org. Chem.
2001, 66, 8772.
H-Val-Ala-OEt (3f): 1H NMR (300 MHz, CDCl3): d = 7.75
(d, 1 H, J = 6.0 Hz), 4.55 (m, 1 H), 4.15 (q, 2 H, J = 7.2 Hz),
3.23 (d, 1 H, J = 4.0 Hz), 2.25 (m, 1 H), 1.39 (d, 3 H, J = 7.2
Hz), 1.26 (t, 3 H, J = 7.0 Hz), 0.97 (d, 3 H, J = 7.0 Hz), 0.81
(d, 3 H, J = 7.0 Hz). 13C NMR (75 MHz, CDCl3): d = 14.5,
16.4, 18.5, 20.0, 31.3, 48.1, 60.4, 61.7, 173.5, 174.5. IR
(KBr): 1745, 1636 cm–1. HRMS: m/z calcd for C10H20N203
[MH+]: 217.1556; found: 217.1552.
(10) Evans, J. W.; Fierman, M. B.; Miller, S. J.; Ellman, J. A.
J. Am. Chem. Soc. 2004, 126, 8134.
(11) General Procedure for the One-Pot Synthesis of
Dipeptides 3a–f
(12) General Procedure for the Preparation of N-Silylated-
NCA 2a–c
To a solution of Val-NCA or Leu-NCA (7 mmol) in dry THF
(20 mL) at 0 °C was added dropwise Et3N (1 mL, 7 mmol)
followed by tert-butylsulfinyl chloride (0.98g, 7 mmol). The
resultant solution was stirred at this temperature for 5 h
before adding the amino ester hydrochloride (7 mmol) and
Et3N (7 mmol). After stirring for 5 h at r.t., the solvent was
evaporated under reduced pressure. Ethanol (20 mL) and dry
HCl (4 M) in dioxane (3.5 mL) were added at 0 °C. The
solution was stirred for 2 h at 0 °C and then concentrated
under vacuum. Dipeptides 3a–f were obtained as white
solids after precipitation from EtOH with Et2O.
To a solution of Val-NCA or Leu-NCA (7 mmol) in dry THF
(20 mL) at –30 °C, were added dropwise Et3N (7 mmol) and
then Me3SiCl or TBSCl (10.5 mmol). The resulting solution
was stirred at this temperature for 5 h. The reaction mixture
was filtered under a nitrogen atmosphere and evaporated in
vacuo at r.t. to give N-trialkylsilyl-NCA 2a–c in 95–99%
yields as white solids without further purification.
Selected Data for N-TMS-Val-NCA 2a
1H NMR (300 MHz, CDCl3): d = 4.07 (d, 1 H, J = 3.4 Hz),
2.08 (m, 1 H), 1.19 (d, 3 H, J = 7.1 Hz), 0.94 (d, 3 H, J = 7.1
Hz), 0.39 (s, 9 H). 13C NMR (75 MHz, CDCl3): d = 15.0,
16.5, 18.2, 32.4, 66.1, 154.2, 169.7. IR (KBr): 1840, 1785
cm–1.
H-Val-Phe-OEt (3a): 1H NMR (300 MHz, CDCl3): d = 8.23
(d, 1 H, J = 7.1 Hz), 7.92 (s, 2 H), 6.92 (m, 5 H), 4.38 (m,
1 H), 3.78 (q, 2 H, J = 7.1 Hz), 3.43 (d, 1 H, J = 5.3 Hz), 2.73
(m, 2 H), 1.85 (m, 1 H), 0.86 (t, 3 H, J = 7.1 Hz), 0.66 (m, 6
H). 13C NMR (75 MHz, CDCl3): d = 14.2, 17.7, 18.6, 30.4,
37.5, 54.1, 58.2, 61.3, 126.9, 128.6, 129.5, 136.8, 168.7,
171.2. IR (KBr) 1721, 1692 cm–1. HRMS: m/z calcd for
C16H25N2O3 [MH+]: 293.1865; found: 293.1864.
[a]D20 +21.1 (c 0.75, EtOH).
Selected Data for N-TBS-Val-NCA 2b
1H NMR (300 MHz, CDCl3): d = 3.87 (d, 1 H, J = 3.4 Hz),
2.19 (m, 1 H), 0.99 (d, 3 H, J = 6.8 Hz), 0.90 (s, 9 H), 0.84
(d, 3 H, J = 6.8 Hz), 0.27 (s, 3 H), 0.26 (s, 3 H). 13C NMR
(75 MHz, CDCl3): d = 3.4, 3.5, 17.9, 18.2, 19.2, 21.5, 26.9,
27.2, 32.4, 33.2, 64.7, 65.8, 128.9, 154.3, 171.3, 172.7. IR
(KBr): 2258, 1857, 1786, 1733 cm–1.
H-Leu-Phe-OEt (3b): 1H NMR (300 MHz, CDCl3): d = 8.38
(d, 1 H, J = 7.5 Hz), 7.89 (s, 2 H), 6.77 (m, 5 H), 4.17 (m,
1 H), 3.61 (q, 2 H, J = 7.0 Hz), 3.40 (m, 1 H), 2.60 (m, 3.5
H), 1.19 (m, 3 H), 0.89 (t, 1.5 H, J = 7.4 Hz), 0.70 (t, 3 H,
J = 7.0 Hz), 0.45 (m, 6 H). 13C NMR (75 MHz, CDCl3): d =
8.7, 14.1, 22.2, 22.8, 24.0, 37.3, 45.9, 51.6, 54.2, 61.1, 126.8,
128.4, 129.4, 136.8, 169.4, 171.0. IR (KBr): 1732, 1667
cm–1.
Selected Data for N-TMS-Leu-NCA 2c
1H NMR (300 MHz, CDCl3): d = 4.19 (dd, 0.5 H, J = 3.8, 9.8
Hz), 3.96 (dd, 0.5 H, J = 6.8, 7.9 Hz), 1.99 (m, 0.5 H), 1.85–
1.61 (m, 3.5 H), 0.96 (m, 6 H), 0.39 (s, 4.5 H), 0.32 (s, 0.5
H). 13C NMR (75 MHz, CDCl3): d = 0.01, 0.39, 21.5, 21.8,
23.3, 24.2, 25.5, 42.4, 42.9, 57.4, 59.4, 68.4, 127.0, 154.8,
171.5, 172.5. IR (KBr): 2255, 1845, 1780, 1720 cm–1.
(13) The formation of ureas from the reaction of unprotected
NCA with silylated amines has been reported previously and
was explained by the formation of an isocyanate as
intermediate: Kricheldorf, H. R.; Greber, G. Chem. Ber.
1971, 104, 3168.
H-Val-Thr-OEt (3c): 1H NMR (300 MHz, DMSO): d =
11.12 (s, 1 H), 9.12 (d, 1 H, J = 6.6 Hz), 8.33 (s, 3 H), 7.61
(d, 1 H, J = 7.7 Hz), 7.47 (d, 1 H, J = 7.9 Hz), 7.19 (s, 1 H),
7.13 (m, 2 H), 4.65 (dd, 1 H, J = 6.6, 7.7 Hz), 4.51 (s, 1 H),
4.12 (q,
(14) (a) Myers, A. C.; Kowalski, J. A.; Lipton, M. A. Bioorg.
Med. Chem. Lett. 2004, 14, 5219. (b) Dales, N. A.;
Bohacek, R. S.; Satyshur, K. A.; Rich, D. H. Org. Lett. 2001,
3, 2313. (c) Moriuchi, T.; Tamura, T.; Hirao, T. J. Am.
Chem. Soc. 2002, 124, 9357. (d) He, J. X.; Cody, W. L.;
Doherty, A. M. J. Org. Chem. 1995, 60, 8262. (e) Zhang,
X.; Rodrigues, J.; Evans, L.; Hinkle, B.; Ballantyne, L.;
Pena, M. J. Org. Chem. 1997, 62, 6420. (f) Konda, Y.;
Takahashi, Y.; Arima, S.; Sato, N.; Takeda, K.; Dobashi, K.;
Baba, M.; Harigaya, Y. Tetrahedron 2001, 57, 4211.
2 H, J = 7.2 Hz), 3.81 (s, 1 H), 3.27–3.15 (m, 2 H), 2.26 (m,
1 H), 1.18–1.06 (m, 6 H). 13C NMR (75 MHz, DMSO): d =
14.2, 17.9, 18.6, 27.2, 30.2, 39.0, 40.4, 53.8, 56.4, 57.3, 61.0,
109.2, 111.8, 118.2, 121.3, 124.5, 127.3, 136.4, 168.5,
171.6. IR (KBr): 1728, 1672 cm–1. Anal. Calcd for
C18H26ClN3O3: H, 7.48; N, 10.75. Found: H, 7.46; N, 10.72.
Mp 152 °C. [a]D20 –125.1 (c 0.51, EtOH).
H-Val-Pro-OEt (3d): 1H NMR (300 MHz, DMSO): d = 8.34
(s, 1 H), 4.35 (m, 1 H), 4.08 (q, 2 H, J = 7.0 Hz), 3.99 (d,
Synlett 2009, No. 2, 279–283 © Thieme Stuttgart · New York

LETTER
Synthesis of Dipeptides and Unsymmetrical Peptidyl Ureas
283
(15) (a) Goldschmidt, S.; Wick, M. Z. Naturforsch. B: Chem.
Biochem. Biophys. Biol. 1950, 5, 170. (b) Goldschmidt, S.;
Wick, M. Justus Liebigs Ann. Chem. 1952, 575, 217.
(c) Nowick, J. S.; Holmes, D. L.; Noronha, G.; Smith, E. M.;
Ngugen, T. M.; Huang, S. J. Org. Chem. 1996, 61, 3929.
(d) Weiberth, F. J. Tetrahedron Lett. 1999, 40, 2895.
(e) Kruijtzer, J. A. W.; Lefeber, D. J.; Liskamp, R. M. J.
Tetrahedron Lett. 1997, 38, 5335. (f) Hutchins, S. M.;
Chapman, K. T. Tetrahedron Lett. 1995, 36, 2583.
(g) Anbazhagan, M.; Deshmukh, A. R. A. S.; Rajappa, S.
Tetrahedron Lett. 1998, 39, 3609. (h) Azad, S.; Kumamoto,
K.; Uegaki, K.; Ichikawa, Y.; Kotsuki, H. Tetrahedron Lett.
2006, 47, 587. (i) Matsumura, Y.; Satoh, Y.; Onomura, O.;
Maki, T. J. Org. Chem. 2000, 65, 1549. (j) Leung, M.; Lai,
J.; Lau, K.; Yu, H.; Hsiao, H. J. Org. Chem. 1996, 61, 4175.
(k) Gallou, I.; Eriksson, M.; Zeng, X.; Senanayake, C.;
Farina, V. J. Org. Chem. 2005, 70, 6960. (l) Patil, B. S.;
Vasanthakumar, G.; Babu, V. V. S. J. Org. Chem. 2003, 121,
1597.
Urea 4d: 1H NMR (300 MHz, CDCl3): d = 7.28 (m, 5 H),
5.11 (m, 2 H), 4.37 (m, 1 H), 4.25 (m, 1 H), 2.15 (m, 1 H),
1.54 (m, 3 H), 0.85 (m, 12 H). 13C NMR (75 MHz, CDCl3):
d = 16.4, 17.8, 20.8, 21.6, 23.7, 30.0, 40.5, 51.1, 57.4, 66.5,
127.2, 127.5, 127.6, 134.0, 157.5, 173.7, 175.2. IR (KBr):
1715, 1644, 1566 cm–1. HRMS: m/z calcd for C19H28N205
[MH+]: 365.1998; found: 365.2006. [a]D20 –14.5 (c 1.0,
EtOH).
Urea 4e: 1H NMR (300 MHz, CDCl3): d = 7.09 (m, 2 H),
4.47 (m, 1 H), 4.35 (m, 1 H), 3.77 (s, 3 H), 3.70 (s, 3 H), 2.47
(m, 2 H), 2.20 (m, 2 H), 2.06 (m, 1 H), 0.98 (m, 6 H). 13
C
NMR (75 MHz, CDCl3): d = 17.8, 19.1, 27.8, 30.4, 31.4,
52.7, 53.2, 53.3, 58.8, 158.8, 173.9, 175.1, 176.7. IR (KBr):
1720, 1655, 1561 cm–1. HRMS: m/z calcd for C13H22N207
[MH+]: 318.1427; found: 318.1430. [a]D20 +4.3 (c 0.58,
EtOH).
Urea 4f: 1H NMR (300 MHz, CDCl3): d = 4.33 (m, 2 H), 3.77
(s, 3 H), 2.21 (m, 2 H), 1.87 (m, 1 H), 1.41 (m,1 H), 1.18 (m,
1 H), 0.95 (m, 12 H). 13C NMR (75 MHz, CDCl3): d = 11.8,
15.7, 18.0, 19.2, 25.4, 31.5, 38.5, 52.9, 58.8, 68.3, 158.8,
174.7, 175.6. IR (KBr): 1721, 1640, 1566 cm–1. HRMS: m/z
calcd for C13H24N205 [MH+]: 289.1762; found: 289.1763.
[a]D20 +10.1 (c 0.89, EtOH).
(16) General Procedure for the One-Pot Preparation of
Unsymmetrical Peptidyl Ureas 4a–j
To a solution of Val-NCA or Leu-NCA (7 mmol) in dry THF
(20 mL) maintained at –30 °C were dropwise added Et3N
(1 mL, 7 mmol) and TMSCl (1.33 mL, 10.5 mmol). The
resultant solution was stirred at this temperature for 4.5 h
before adding the amine nucleophile (7 mmol) and Et3N
(2 mL, 14 mmol). After stirring for 2 h at 0 °C, the solution
was acidified to pH 4.0 with HCl (4 M) in dioxane. The
precipitate was then filtered and dried to afford peptidyl
ureas 4d,h,i. Ureas 4a–c,e,f,g,j were isolated as followed.
After acidification of the solution to pH 4 with HCl (4 M in
dioxane), solvents were evaporated and the resulting residue
was dissolved in CH2Cl2. The CH2Cl2 layer was washed with
brine and evaporated in vacuo to provide pure ureas 4a–c,
e,f,g,j.
Urea 4g: 1H NMR (300 MHz, CDCl3): d = 5.98 (m, 2 H),
4.54 (m, 1 H), 4.33 (m, 1 H), 4.19 (q, 2 H, J = 7.1 Hz), 2.50
(m, 2 H), 2.16–1.91 (m, 6 H), 1.26 (t, 3 H, J = 7.1 Hz), 0.94
(d, 3 H, J = 6.8 Hz), 0.88 (d, 3 H, J = 6.8 Hz). 13C NMR (75
MHz, CDCl3): d = 14.5, 15.7, 18.1, 19.4, 30.3, 31.5, 32.7,
52.8, 58.6, 62.2, 158.5, 174.1, 176.3. IR (KBr): 1740, 1704,
1634 cm–1. Mp 118 °C. Anal. Calcd for C13H24N2O5S: C,
48.73; H, 7.55; N, 8.74. Found: C, 48.79; H, 7.58; N, 8.65.
[a]D20 +7.6 (c 0.8, EtOH).
Urea 4h: 1H NMR (300 MHz, CDCl3): d = 7.13 (m, 3 H),
7.00 (m, 2 H), 5.87 (d, 1 H, J = 8.7 Hz), 5.73 (d, 1 H, J = 7.9
Hz), 4.70 (m, 1 H), 4.30 (m, 1 H), 3.98 (m, 2 H), 3.02 (m,
2 H), 2.07 (m, 1 H), 1.09 (t, 3 H, J = 7.1 Hz), 0.87 (d, 3 H,
J = 6.8 Hz), 0.79 (d, 3 H, J = 6.8 Hz). 13C NMR (75 MHz,
CDCl3): d = 14.2, 17.9, 19.2, 31.1, 54.6, 58.5, 81.8, 127.1,
128.6, 129.6, 136.2, 158.0, 176.1. IR (KBr): 1733, 1637,
1562 cm–1. Anal. Calcd for C17H24N2O5: C, 60.7; H, 7.1; N,
Urea 4a: 1H NMR (300 MHz, CDCl3): d = 6.58 (s, 1 H), 3.84
(m, 2 H), 2.22–2.05 (m, 3 H), 1.80 (d, 2 H, J = 12.8 Hz), 1.62
(d, 3 H), 1.35–1.16 (m, 3 H), 1.01 (d, 3 H, J = 6.9 Hz), 0.86
(d, 3 H, J = 6.8 Hz). 13C NMR (75 MHz, CDCl3): d = 16.0,
19.1, 25.4, 26.1, 26.2, 29.5, 29.8, 30.7, 51.7, 61.9, 158.9,
174.1. IR (KBr): 1641, 1565 cm–1. Anal. Calcd for
C18H26N2O5: C, 59.48; H, 9.15; N, 11.56. Found: C, 59.64;
H, 9.32; N, 11.58. Mp 94 °C. [a]D20 –75.9 (c 0.7, EtOH).
Urea 4b: 1H NMR (300 MHz, CDCl3): d = 4.45 (m, 1 H),
3.57 (m, 1 H), 1.92–1.55 (m, 5 H), 1.52–1.30 (m, 3 H), 1.35–
1.16 (m, 5 H), 1.01 (m, 6 H). 13C NMR (75 MHz, CDCl3):
d = 20.1, 21.9, 22.3, 22.5, 22.9, 28.0, 33.3, 33.4, 39.8, 49.5,
54.3, 157.6, 174.8. IR (KBr): 1638, 1565 cm–1. Anal. Calcd
for C13H24N2O3: C, 60.91; H, 9.44; N, 10.93. Found: C,
60.96; H, 9.48; N, 10.94. [a]D20 –80.0 (c 0.7, EtOH).
Urea 4c: 1H NMR (300 MHz, CDCl3): d = 7.99 (s, 1 H), 7.66
(s, 1 H), 7.15 (t, 2 H, J = 7.9 Hz), 6.72 (d, 3 H, J = 8.7 Hz),
6.25 (d, 1 H, J = 9.0 Hz), 4.07 (dd, 1 H, J = 4.9, 9.0 Hz), 2.03
(m, 1 H), 0.84 (d, 3 H, J = 6.8 Hz), 0.77 (d, 3 H, J = 6.8 Hz).
13C NMR (75 MHz, CDCl3): d = 17.9, 19.5, 30.8, 57.5,
112.7, 129.1, 158.9, 174.0. IR (KBr): 1703, 1621, 1563
cm–1. Anal. Calcd for C12H17N3O3: C, 57.36; H, 6.82; N,
16.72. Found: C, 57.46; H, 6.90; N, 16.94. [a]D20 +24.0 (c
0.58, EtOH).
20
8.3. Found: C, 60.31; H, 7.2; N, 8.3. Mp 102.6 °C. [a]D
+34.5 (c 0.70, EtOH).
Urea 4i: 1H NMR (300 MHz, CDCl3): d = 7.28 (m, 5 H), 5.11
(m, 2 H), 4.37 (m, 1 H), 4.25 (m, 1 H), 2.15 (m, 1 H), 1.54
(m, 3 H), 0.85 (m, 12 H). 13C NMR (75 MHz, CDCl3): d =
16.4, 17.8, 20.8, 21.6, 23.7, 30.0, 40.5, 51.1, 57.4, 66.5,
127.2, 127.5, 127.6, 134.0, 157.5, 173.7, 175.2. IR (KBr):
1715, 1644, 1566 cm–1. HRMS: m/z calcd for C19H25N305
[MH+]: 375.1794; found: 375.1799. [a]D20 +34.0 (c 0.15,
EtOH).
Urea 4j: 1H NMR (300 MHz, CDCl3): d = 7.11 (m, 3 H), 7.01
(m, 2 H), 5.77 (s, 1 H), 5.66 (d, 1 H, J = 7.5 Hz), 4.69 (m,
1 H), 4.31 (m, 1 H), 3.96 (m, 2 H), 2.98 (m, 2 H), 1.57 (m,
2 H), 1.37 (m, 1 H), 1.08 (t, 3 H, J = 7.1 Hz), 0.81 (d, 6 H,
J = 5.7 Hz). 13C NMR (75 MHz, CDCl3): d = 14.4, 22.3,
23.3, 25.1, 39.8, 42.1, 52.7, 54.6, 61.8, 127.2, 136.5, 160.5,
173.3. IR (KBr): 1740, 1644, 1557 cm–1. Anal. Calcd for
C18H26N2O5: C, 61.7; H, 7.48; N, 7.99. Found: C, 61.66; H,
7.46; N, 8.04. [a]D20 +1.2 (c 0.4, EtOH).
Synlett 2009, No. 2, 279–283 © Thieme Stuttgart · New York

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