Chameleonic reactivity of α-amino nitrile-derived ureas. Synthesis of highly functionalized imidazolidin-2-one and imidazolidine-2,4-dione derivatives

Article abstract of DOI:10.1016/j.tet.2014.03.082

The potential of α-amino nitrile-derived ureas for the synthesis of imidazolidin-2-one derivatives has been studied in the context of a medicinal chemistry project focused on the search of antagonists of the thrombin receptor PAR1. In this study α-amino nitrile-derived ureas have shown chameleonic reactivity. Thus, under neutral, basic or mild acid media they cyclize to 4-iminoimidazolidin-2-one derivatives, which tautomerize to 4-amino-2,3-dihydro- 1H-imidazol-2-ones. This tautomerism triggers epimerization at the C₅ of the imidazolidine ring, as well as its oxidation. However, they give stable highly functionalized hydantoin derivatives under strong acid media, by a no-epimerizing two-step hydrolysis.

Full text of DOI:10.1016/j.tet.2014.03.082

Tetrahedron 70 (2014) 3407e3412
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Chameleonic reactivity of a-amino nitrile-derived ureas. Synthesis
of highly functionalized imidazolidin-2-one and imidazolidine-2,4-
dione derivatives
*
ꢀ
ꢀ
ꢀ
Pilar Ventosa-Andres, Juan A. Gonzalez-Vera, M. Teresa García-Lopez, Rosario Herranz
ꢀ
Instituto de Química Medica (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The potential of
been studied in the context of a medicinal chemistry project focused on the search of antagonists of the
thrombin receptor PAR1. In this study -amino nitrile-derived ureas have shown chameleonic reactivity.
Thus, under neutral, basic or mild acid media they cyclize to 4-iminoimidazolidin-2-one derivatives,
which tautomerize to 4-amino-2,3-dihydro-1H-imidazol-2-ones. This tautomerism triggers epimeriza-
tion at the C5 of the imidazolidine ring, as well as its oxidation. However, they give stable highly func-
tionalized hydantoin derivatives under strong acid media, by a no-epimerizing two-step hydrolysis.
Ó 2014 Elsevier Ltd. All rights reserved.
a-amino nitrile-derived ureas for the synthesis of imidazolidin-2-one derivatives has
Received 27 February 2014
Received in revised form 20 March 2014
Accepted 25 March 2014
Available online 1 April 2014
a
Keywords:
Peptidomimetics
Tautomerism
a
-Amino nitriles
Imidazolidine-2-one derivatives
Hydantoin derivatives
1. Introduction
Diverse analogues of a-amino nitrile-derived ureas have been
described as inhibitors of the cholesteryl ester transfer protein1 and
diverse enzymes, such as dipeptidyl peptidase IV,2e4 prolyl oligo-
peptidases,5 and cysteine cathepsins,6,7 as well as agents for neu-
rological disorders,8 pesticides,9 and fungicides.10 On the other
hand,
thesis of diverse pharmacologically active hydantoin derivatives
from
-amino nitriles.11e13 In view of these precedents and in the
a-amino nitrile-derived ureas are intermediates in the syn-
a
context of a medicinal chemistry project focused on the search of
antagonists of the thrombin receptor PAR1,14,15 by exploring the use
of
a-amino acid-derived amino nitriles as molecular diversity
generators,16 we have recently described a versatile solvent-free
synthesis of basic amino acid-derived N-(cyanomethyl)ureas of
general formula A.17 Now, taking into account that hydantoins
(imidazolidine-2,4-diones) are included among privileged scaffolds
in medicinal chemistry,18,19 natural products,20e26 and organic
synthesis,19,27 we have studied and report herein the cyclization
Scheme 1. Proposed synthesis of imidazolidin-2-one derivatives B.
2. Results and discussion
In general, the synthesis of hydantoins by cyclization of
a
-amino
nitriles involves reaction with isocyanates, followed by in situ acid
hydrolysis of the corresponding intermediate N-(cyanomethyl)
ureas.11,12,28,29 As we were interested in preserving the Boc pro-
tection at the basic side chain of N-(cyanomethyl)ureas A, the cy-
clization in acid media was initially excluded and we decided to try
it first under neutral or basic reaction conditions. The ornithine
derived N-(cyanomethyl)urea (S)-1a (Scheme 2) was chosen for
setting up the methodology. The cyclization was initially attempted
of cyanomethylureas
(Scheme 1).
A to imidazolidin-2-one derivatives B
* Corresponding author. Tel.: þ34 91 2587537; fax: þ34 91 5644853; e-mail
address: Rosario@iqm.csic.es (R. Herranz).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.03.082

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P. Ventosa-Andres et al. / Tetrahedron 70 (2014) 3407e3412
Scheme 2. Cyclization of the N-(cyanomethyl)urea (S)-1a as indicated in Table 1.
by heating (S)-1a in refluxing MeOH. As shown in Table 1 (entry 1),
after 15 min of reaction, the HPLC-MS analysis of the crude reaction
mixture showed the presence of the epimeric mixture of 4-
iminoimidazolidin-2-ones (RS)-2a, as minor products (9%), along
with oxidation products,30,31 the 5-hydroxy-4-iminoimidazolidin-
2-ones (RS)-3a (78%), and the 5-benzylidene-4-iminoimidazolidin-
2-one 4a (13%). To avoid oxidation, the next experiments were
carried out under argon and MeOH was replaced by other solvents.
In this way, the starting urea (S)-1a remained unaltered after 2 days
in toluene or CH3CN at 100 ꢀC. Then, we tried to add a catalytic
amount of base32 (10%, Et3N, K2CO3, and Cs2CO3), which activated
the reaction and decreased the formation of oxidation products.
Thus, both Et3N in toluene and K2CO3, or Cs2CO3 in CH3CN led to
z40% of (RS)-2a (entries 2e4). The increase of base to 100% and the
reaction temperature up to 100 ꢀC, by MW irradiation, in CH3CN
allowed to decrease the reaction time and to increase the yield of
the 4-iminoimidazolidin-2-ones (RS)-2a up to 88% (entry 5). Fi-
nally, the improvement was particularly noteworthy when the re-
action was carried out without solvent (entries 6 and 7), which
yielded quantitatively the desired products (RS)-2a after 5 min of
reaction.
The HPLC-MS analysis of the solvent-free synthesis of (RS)-2a
(Table 1, entries 6 and 7) showed two peaks, at a lower retention
time (3.52 and 3.59 min) that the starting N-(cyanomethyl)urea (S)-
1a (4.59 min), both with identical [Mþ1]þ mass to that of this urea.
The 1H NMR spectrum of (RS)-2a in CDCl3 and in (CD3)2CO showed
the presence of two isomers, as well as the disappearance of the
ureido NH and the appearance of two signals for the 5-H of the
imidazolidin-2-one ring at z0.45 ppm higher field than the proton
in position
a to the CN group of (S)-1a. The imine NH proton could
not be observed, probably due to its fast exchange. No significant
changes were observed in the signals corresponding to the benzyl
amide group, with respect to those of the starting urea (S)-1a. This
fact discarded the alternative cyclization through this group to give
an isomeric 6-imino-piperazine-2-one ring. The duplicity of peaks
in the HPLC-MS and of signals in the NMR spectra indicated that the
cyclization occurred with epimerization at the C5 due to an
equilibrium between the 4-iminoimidazolidin-2-one structure
2a and its tautomer 4-amino-2,3-dihydro-1H-imidazol-2-one
5a (Scheme 3). The racemization of optically active 5-
benzylhydantoins has been explained through a similar tautomer-
ism33 and Bepary et al. have recently reported the tautomerism of
2-iminoimidazolidin-2-ones.34 Interestingly, the HPLC-MS analysis
of the cyclization of (S)-1a in MeOH (Table 1, entry 1) showed only
one peak at 3.67 min. This fact suggested us that the tautomer
equilibrium could be controlled by the solvent and that 5a could be
the main tautomer in MeOH. Then, we attempted to study this
tautomer equilibrium by registering the 1H NMR spectrum of (RS)-
1a in CD3OD at different times. After 3 h, the cyclization was
complete, but, unfortunately, the overlapping of the CD3OD signals
with those of the cyclization products avoided their unequivocal
assignment. We also tried to trap the tautomers by acetylation. For
that purpose, the cyclization of (S)-1a was carried out solvent-free
and under Ar, by MW heating at 100 ꢀC in the presence of 2 equiv of
acetyl chloride and Et3N. The HPLC-MS analysis of the crude re-
action mixture showed the formation of a unique acetylated de-
rivative, to which we assigned the structure of the 4-acetamido-
Table 1
Influence of reaction conditions on the synthesis of the 4-iminoimidazolidin-2-ones
(RS)-2a from (S)-1a
Entry
Base (%)
Solvent
T (ꢀC)
t (min)
Yield (%)a
(RS)-2a
(RS)-3a
4a
1
2
3
4
d
MeOH
Toluene
CH3CN
CH3CN
CH3CN
d
75
100
80
15
30
30
30
15
5
9
44
43
41
88
99
99
78
30
25
29
12
d
13
d
d
d
d
d
d
Et3N (10)
K2CO3 (10)
Cs2CO3 (10)
Et3N (100)
Et3N (100)
K2CO3 (100)
80
5b
6b
7b
100
100
100
d
5
d
a
Determined by HPLC-MS.
MW irradiation.
b
Scheme 3. Synthesis, tautomerism, and acetylation of the 4-iminoimidazolidin-2-ones (RS)-2a.

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P. Ventosa-Andres et al. / Tetrahedron 70 (2014) 3407e3412
3409
2,3-dihydro-1H-imidazol-2-one 6a, based on its 1H NMR spectrum
in CDCl3. Thus, the 5-H proton of (RS)-2a had disappeared and the
5-CH2 protons appeared as an AB system [at 3.72 and 3.79 ppm and
J¼16.5 Hz, z0.5 ppm lower field than the corresponding protons in
(RS)-2a]. However, the acetylated compound 6a resulted highly
unstable and the NMR sample completely decomposed during the
13C NMR registration time (z8 h). This 13C NMR spectrum showed
a complex mixture that could not be assigned. The decomposition
was also evident in the HPLC-MS analysis of the recovered NMR
sample, which showed the almost complete disappearance of the
peak corresponding to 6a and the appearance of multiple peaks of
oxidation products.
In view of the epimerization observed in the cyclization of (S)-
1a, the versatility of the MW-promoted and base-catalyzed
solvent-free cyclization was studied using epimeric mixtures of
the N-(cyanomethyl)ureas (RS)-1aee (Scheme 4). In this way, the
corresponding 4-iminoimidazolidin-2-ones (RS)-2aee were ob-
tained in higher than 95% yield. Although the HPLC analysis of the
crude reactions showed a high degree of purity, the NMR spectra of
(RS)-2aee showed low resolution, due to the presence of mixtures
of epimers and to the high tendency of these 4-iminoimidazolidin-
2-ones to oxidation. The assignment of these spectra was based on
2D HSQC and HMBC spectra.
Scheme 5. Acid hydrolysis of the 4-iminoimidazolidin-2-ones (RS)-2a.
In view of the difficulties to obtain hydantoins by hydrolysis of
4-iminoimidazolidin-2-ones, we turned to study their preparation
by direct hydrolysis of the starting N-(cyanomethyl)ureas (S)-1aee.
The setting up of reaction conditions was carried out with (S)-1a. As
shown in Table 2, treatment of this urea with 0.1 N solution of HCl in
EtOAc for 3 days led almost quantitatively to the Boc-protected 4-
iminoimidazolidin-2-ones (RS)-2a (entry 1), while, increasing the
HCl concentration up to 3 N gave a mixture of deprotected imi-
noimidazolidin-2-ones (RS)-7a and the hydantoin (S)-12a (entry 3).
As shown in Scheme 6, this compound was the only reaction
product when the hydrolysis was carried out in 20% TFA solution in
CH2Cl2 at rt (entry 4) or in 12 N aqueous HCl at 100 ꢀC (entry 5). In
this latter case, neither hydrolysis of the benzyl amide group nor
epimerization at C5 was observed. This different behavior respect to
the commented hydrolysis of 4-iminoimidazolidin-2-ones (RS)-2a
suggested that the hydrolysis mechanism was different and that it
should not go through the 4-iminoimidazolidin-2-ones (RS)-7a.
To study the process, the TFA-mediated reaction was monitored
by HPLC-MS at different times. After 5 h, the starting urea
(tR¼5.79 min, [Mþ1]þ¼570.46) was completely transformed into
the acid (S)-11a (tR¼3.25 min, [Mþ1]þ¼488.46), that is, after 24 h,
completely cyclized to the hydantoin (S)-12a (tR¼3.30 min,
Scheme 4. Synthesis of the 4-iminoimidazolidin-2-ones (RS)-2aee.
4-Iminoimidazolidin-2-ones are known to give hydantoins in
acid media.28,33,35 Based on this knowledge, we decided to study
the hydrolysis of (RS)-2aee to the corresponding hydantoin de-
rivatives. We first tried the hydrolysis in acid conditions compatible
with the presence of the Boc protection in the basic side chain, such
as (0.1e1.0 N) HCl in EtOAc, 20% AcOH in MeOH or (1:1:1) AcOH/
MeOH/H2O at rt. In all cases, the starting 4-iminoimidazolidin-2-
ones (RS)-2a were recovered unaltered. Then, we tried the stan-
dard acid conditions for Boc removal, 3 N HCl in EtOAc, and 20% TFA
in CH2Cl2, at rt. After 30 min, the removal of the Boc group was
complete in both cases, but the iminoimidazolidin-2-one ring was
unaltered. After 24 h, the HPLC-MS of the crude reaction mixture
showed 58% of ring oxidation, but no hydrolysis. Finally, we studied
the hydrolysis of (RS)-2a at 100 ꢀC in concentrated aqueous HCl
(12 N). Under these conditions, complete hydrolysis required
overnight heating, which besides the hydrolysis of the iminoimi-
dazolidin-2-one ring, also produced the hydrolysis of the benzyl
amide group at the basic amino acid residue to carboxylic acid and
partial oxidation of the ring (Scheme 5). The mixture of products
(RS)-9a and 10a, although was identified by their [Mþ1]þ in the
HPLC-MS analysis, could not be separated.
Table 2
Influence of the acid media in the hydrolysis of the N-(cyanomethyl)urea (S)-1a
Entry
Acid
T (ꢀC)
t
Yield (%)a
(RS)-2a
(RS)-7a
(S)-12a
1
2
3
4
5
0.1 N HCl/EtOAc
0.3 N HCl/EtOAc
3 N HCl/EtOAc
20% TFA/CH2Cl2
12 N HCl/H2O
rt
rt
rt
rt
3 days
15 min
30 min
24 h
95
62
d
d
d
d
38
55
d
d
d
d
45
95b
85b
100
30 min
a
Determined by HPLC-MS analysis of the crude reaction. Sunfire C18 (4.6ꢁ50 mm,
m).
Isolated yield.
3.5
m
b

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P. Ventosa-Andres et al. / Tetrahedron 70 (2014) 3407e3412
Scheme 6. Synthesis of the hydantoin derivatives (S)-12aee by acid hydrolysis of the N-(cyanomethyl)ureas (S)-1aee.
[Mþ1]þ¼471.99). This two-step hydrolysis was also monitored by
1H NMR in CDCl3, which confirmed the mechanism. In view of the
good results of this methodology, it was applied to the synthesis of
the series (S)-12aee (Scheme 6). These hydantoins derivatives were
isolated from the reaction mixtures as TFA salts in higher than 95%
yield and were screened as antagonists of the thrombin receptor
PAR1 in an assay of human platelet aggregation inhibition.14 None
of them displayed significant activity at 0.1 mg/mL concentration.
crude reaction was dissolved in EtOAc (10 mL), washed with H2O
(3ꢁ3 mL), and brine (3 mL), dried over Na2SO4, and concentrated
under vacuum. The residue was purified by flash chromatography,
using 0e15% MeOH in CH2Cl2 gradient as eluent, to afford the title
compounds (RS)-2aee as foams that decomposed on standing.
4. 2.1. tert-Butyl [(4S)-4-(5-benzyl-4-imino-2-oxo-3-
phenylimidazolidin-1-yl)-5-(benzylamino)-5-oxopentyl]carbamate
(RS)-2a. Yield 97%; foam; HPLC-MS (15e95% gradient of A in B for
3. Conclusions
5 min) tR 3.55 and 3.61 min; 1H NMR [(CD3)2CO, 300 MHz]
d 1.26 (s,
9H, Boc), 1.43 (m, 2H),1.96 (m, 2H), 2.91e3.35 (m, 4H), 4.15e4.42
(2m, 3H), 4.50 (t, J¼5 Hz, 0.5H), 4.68 (t, J¼5 Hz, 0.5H), 5.96 (br s,1H),
6.79e7.43 (m, 15H), 7.87 and 7.91 (2t, J¼6 Hz, 1H); 13C NMR
In conclusion, the results herein described show that N-(cya-
nomethyl)ureas display a chameleonic reactivity that can act as
a double-edged sword. Adequately controlled, this reactivity may
have high synthetic potentiality. Thus, under neutral, basic or mild
acid media they cyclize to 4-iminoimidazolidin-2-one derivatives,
which tautomerize to 4-amino-2,3-dihydro-1H-imidazol-2-ones.
This tautomerism triggers epimerization at the C5 of the imidazo-
lidine ring, as well as its oxidation. However, under strong acid
media, N-(cyanomethyl)ureas in a no-epimerizing two-step hy-
drolysis, through the corresponding carboxylic acids, give stable
highly functionalized hydantoin derivatives.
[(CD3)2CO, 100 MHz]
d 27.2, 27.8, 28.0, 28.4 (CH2), 28.7 (CH3), 38.3,
38.8, 40.4, 40.5, 43.5, 43.7 (CH2), 57.7, 59.4, 60.0, 61.9 (CH), 78.5 (C),
127.7, 127.8, 127.8, 128.3, 128.5, 129.0, 129.1, 129.2, 129.4, 131.0, 131.1
(CH), 136.6, 140.0, 140.1, 141.2 (C), 156.8, 157.8, 170.8, 171.0 (CO). ES-
MS m/z [Mþ1]þ calcd for C33H39N5O4 570.3, found, 570.4.
4.2.2. tert-Butyl [(4S)-5-(benzylamino)-4-(3,5-dibenzyl-4-imino-2-
oxoimidazolidin-1-yl)-5-oxopentyl]carbamate (RS)-2b. Yield 95%;
foam; HPLC-MS (15e95% gradient of A in B for 5 min) tR 3.67 and
3.77 min; 1H NMR [(CD3)2CO, 400 MHz]
d 1.25 (s, 9H, Boc), 1.38 (m,
4. Experimental section
4.1. General methods
2H),1.93 (m, 2H), 2.83e3.25 (m, 4H), 4.12e4.60 (m, 6H), 5.92 (br s,
1H), 6.93e7.22 (m, 15H), 7.74 and 7.86 (2t, J¼6 Hz, 1H); 13C NMR
[(CD3)2CO, 100 MHz]
d 27.0, 27.8, 27.9, 28.4 (CH2), 28.6 (CH3), 37.8,
38.1, 40.3, 40.5, 42.6, 43.5, 43.7, 44.4 (CH2), 57.8, 59.1, 59.7, 62.0
(CH), 78.5 (C), 127.6, 127.7, 127.8, 128.2, 128.2, 128.4, 129.0, 129.0,
129.1, 129.2, 130.8, 130.9 (CH), 136.4, 140.0, 140.0 (C), 156.8, 158.9,
159.1, 171.0 (CO). ES-MS m/z [Mþ1]þ calcd for C34H41N5O4 584.3,
found, 584.4.
All reagents were of commercial quality. Solvents were dried
and purified by standard methods. Analytical TLC was performed
on aluminum sheets coated with a 0.2 mm layer of silica gel 60 F254
.
Silica gel 60 (230e400 mesh) was used for flash chromatography.
Analytical RP-HPLC was performed on a Sunfire C18 (4.6ꢁ150 mm,
3.5
mm) column, with a flow rate of 1 mL/min, using a tunable UV
4 . 2 . 3 . t e r t - B u t y l [ ( 4 S ) - 4 - ( 5 - b e n z y l - 4 - i m i n o - 3 - ( 4 -
methoxyphenethyl)-2-oxoimidazolidin-1-yl)-5-(benzylamino)-5-
oxopentyl]carbamate carbamate (RS)-2c. Yield 95%; foam; HPLC-MS
(15e95% gradient of A in B for 5 min) tR 3.61 min; 1H NMR
detector set at 214 and 254 nm and gradient of CH3CN (solvent A)
and 0.05% TFA in H2O (solvent B) as mobile phase. HPLC-MS was
performed on a Sunfire C18 (4.6ꢁ50 mm, 3.5
m
m) column at 30 ꢀC,
with a flow rate of 1 mL/min and gradient of 0.1% of formic acid in
CH3CN (solvent A) in 0.1% of formic acid in H2O (solvent B) was used
as mobile phase. Electrospray in positive mode was used for ioni-
zation. NMR spectra were recorded using Varian Inova 300, Varian
Inova or Mercury 400, and Varian Unity 500 spectrometers. The
NMR spectra assignments were based on COSY, HSQC, and HMBC
spectra. MW experiments were carried out in sealed vessels in an
MW EmrysÔ Synthesizer (Biotage AB), with transversal IR sensor
for reaction temperature monitoring.
[(CD3)2CO, 300 MHz] d 1.25 (s, 9H, Boc), 1.33 (m, 2H),1.95 (m, 2H),
2.45, 2.70, 2.98, 3.24, 3.41 (5m, 8H), 3.61 and 3.62 (2s, 3H),
4.05e4.48 (m, 6H), 5.92 (br s, 1H), 6.70 (d, J¼9 Hz, 2H), 6.93 (dd,
J¼9, 3 Hz, 2H), 7.00e9.19 (m, 12H), 7.68 and 7.82 (2t, J¼6 Hz, 1H);
13C NMR [(CD3)2CO, 75 MHz]
d 26.5, 27.0, 28.0, 28.7 (CH2), 28.9
(CH3), 33.1, 33.3, 38.6, 38.9, 40.7, 40.9, 43.8, 44.0, 44.1, 44.2 (CH2),
55.7 (CH3), 56.9, 57.9, 60.0, 62.2 (CH), 78.8 (C), 114.9, 127.7, 127.9,
127.9, 128.5, 128.6, 128.9, 129.2, 129.3, 129.3, 129.5, 130.7, 130.7,
130.8, 130.9, 131.7 (CH), 136.8, 137.0, 140.3 (C), 157.0, 158.7, 159.5,
159.5, 171.2, 171.3 (CO). ES-MS m/z [Mþ1]þ calcd for C36H45N5O5
628.3, found, 628.5.
4.2. General procedure for the solvent-free synthesis of the 4-
iminoimidazolidin-2-ones (RS)-2aee
4.2.4. tert-Butyl [(4S)-4-(5-benzyl-3-(4-fluorophenethyl)-4-imino-2-
oxoimidazolidin-1-yl)-5-(benzylamino)-5-oxopentyl]carbamate
(RS)-2d. Yield 96%; foam; HPLC-MS (15e95% gradient of A in B for
Et3N (28 mL, 0.2 mmol) was added under argon to a solution of
the corresponding N-(cyanomethyl)urea (RS)-1aee (0.2 mmol) in
CH2Cl2 (0.50 mL). After 5 min of stirring at rt, the solvent was
evaporated under argon stream. The homogeneous mixture was
heated at 100 ꢀC by MW irradiation for 5 min. After cooling to rt, the
5 min) tR 3.67 and 3.72 min; 1H NMR [(CD3)2CO, 500 MHz]
d 1.26 (s,
9H, Boc), 1.36 (m, 2H),1.92 (m, 2H), 2.35e3.58 (m, 8H), 4.09 (t,
J¼7 Hz, 0.5H), 4.24 and 4.34 (2m, 2.5H), 4.48 (br s, 0.5H), 4.61 (br s,

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P. Ventosa-Andres et al. / Tetrahedron 70 (2014) 3407e3412
3411
0.5H), 5.91 (br s, 1H), 6.87 (dd, J¼9, 3 Hz, 1H), 6.89 (dd, J¼9, 3 Hz,
1H), 6.97e7.27 (m, 10H), 7.76 and 7.82 (2t, J¼6 Hz, 1H); 13C NMR
6.72e7.41 (m,15H), 8.26 and 8.45 (2t, J¼6 Hz,1H); 13C NMR [CD3OD,
125 MHz]
d 24.2, 26.8, 36.1, 38.7, 38.7, 42.9, 43.0 (CH2), 57.9, 58.0,
[(CD3)2CO, 125 MHz]
d
25.8, 26.4, 26.5, 26.8 (CH2), 27.2 (CH3), 31.4,
59.2, 60.9, 61.6 (CH), 126.2, 127.0, 127.0, 127.3, 128.1, 128.1, 128.2,
128.2, 128.5, 128.6, 129.3, 131.3 (CH), 134.7, 137.0, 138.1 (C), 156.3,
169.7, 169.7, 171.4, 172.3 (CO). ES-MS m/z [Mþ1]þ calcd
31.7, 36.4, 36.9, 38.9, 39.1, 39.2, 39.4, 42.2, 42.4 (CH2), 56.7, 58.1,
58.3, 60.4 (CH), 77.1, 77.5 (C), 114.3, 114.5, 126.4, 126.5, 126.5, 126.8,
126.9, 126.9, 127.1, 127.4, 127.5, 127.7, 127.8, 127.8, 127.8, 127.8, 127.8,
127.9, 129.5, 129.6, 130.1, 130.1, 130.2 (CH), 133.8, 134.9, 138.5, 138.7
(C), 155.5, 156.4, 160.1, 162.0, 162.1, 169.3, 169.5 (CO). ES-MS m/z
[Mþ1]þ calcd for C35H42FN5O4 616.3, found, 616.5.
for
C28H30N4O3 471.2, found, 471.4; Anal. Calcd for
C28H30N4O3$C2HF3O: C, 61.64; H, 5.35; N, 9.58. Found: C, 61.38; H,
5.46; N, 9.37.
4.4.2. (2S)-5-Amino-N-benzyl-2-[(S)-3,5-dibenzyl-2,4-
dioxoimidazolidin-1-yl]pentanamide trifluoroacetate (S)-12b. With
z25% of the epimer (R)-12b, yield 95%; foam; HPLC-MS (15e95%
gradient of A in B for 5 min) tR 3.22 min; 1H NMR [CD3OD, 500 MHz]
4.2.5. tert-Butyl [(5S)-6-(benzylamino)-5-(4-imino-2-oxo-5-
phenethyl-3-phenylimidazolidin-1-yl)-6-oxohexyl]carbamate (RS)-
2e. Yield 95%; foam; HPLC-MS (15e95% gradient of A in B for
d
1.54 and 1.71 (2m, 2H), 1.90, 2.03, 2.14 (3m, 2H), 2.82 (t, J¼7 Hz,
2H), 3.14 (m, 2H), 4.09 (t, J¼8 Hz, 0.75H), 4.17e4.50 (m, 5.25H),
6.83e7.35 (m, 15H); 13C NMR [CD3OD, 125 MHz]
25.6, 28.2, 36.6,
5 min) tR 3.57 min; 1H NMR [(CD3)2CO, 300 MHz]
d 1.25 (s, 9H, Boc),
1.29, 1,38 (2m, 4H), 1.79e2.27 (m, 4H), 2.37e3.01 (m, 6H), 4.34 (m,
4H), 5.84 (br s, 1H), 7.01e7.49 (m, 15H), 7.70 and 7.98 (2t, J¼6 Hz,
d
40.1, 43.2, 44.3 (CH2), 59.3, 63.2 (CH), 128.3, 128.4, 128.4, 128.7,
128.7, 129.0, 129.4, 129.5, 129.6, 129.6, 129.6, 129.9, 130.2, 130.7,
131.1 (CH), 136.0, 137.0, 139.3 (C), 158.7, 159.9, 170.9, 171.2, 173.7,
174.3 (CO). ES-MS m/z [Mþ1]þ calcd for C29H32N4O3 485.3, found,
485.5; Anal. Calcd for C29H32N4O3$C2HF3O: C, 62.20; H, 5.56; N,
9.36. Found: C, 62.03; H, 5.49; N, 9.06.
1H); 13C NMR [(CD3)2CO, 75 MHz]
d 23.2, 27.2 (CH2), 27.4 (CH3),
29.6, 33.0, 33.5, 34.4, 34.6, 39.6, 42.4, 42.6 (CH2), 56.3, 57.2, 58.9,
59.6 (CH), 77.1 (C), 125.3, 125.4, 126.4, 127.0, 127.1, 127.8, 127.8, 127.8,
127.9, 127.9, 128.0, 128.1 (CH), 138.8, 138.9, 139.9, 140.1, 141.0, 141.1
(C), 155.3, 155.7, 156.5, 169.5, 169.7 (CO). ES-MS m/z [Mþ1]þ calcd
for C35H43N5O4 598.3, found, 598.3.
4 . 4 . 3 . ( 2 S ) - 5 - A m i n o - N - b e n zyl- 2 -[ ( S) - 5 -b en zyl- 3 -( 4 -
4.3. Cyclizationeacetylation of the N-(cyanomethyl)urea (S)-
1a. Synthesis of (S)-tert-butyl (4-(4-acetamido-5-benzyl-2-
oxo-3-phenyl-2,3-dihydro-1H-imidazol-1-yl)-5-(benzyla-
mino)-5-oxopentyl)carbamate 6a
methoxyphenethyl)-2,4-dioxoimidazolidin-1-yl]pentanamide
tri-
fluoroacetate (S)-12c. With z30% of the epimer (R)-12c, yield 97%;
foam; HPLC-MS (15e95% gradient of A in B for 5 min) tR 3.23 min;
1H NMR [CD3OD, 500 MHz]
d 1.52 and 1.68 (2m, 2H), 1.87, 1.96, 2.06
(3m, 2H), 2.40 (t, J¼8 Hz, 0.6H), 2.49 (m, 1.4H), 2.81 (t, J¼7.5 Hz,
1.4H), 2.94e2.09 (m, 2H), 3.12 (m, 0.6H), 3.31e3.51 (m, 2H), 3.63
and 3.64 (2s, 3H), 3.99 (m, 1.4H), 4.16e4.32 (m, 2.6H), 6.70 (m, 2H),
6.91 (m, 2H), 7.02 (m, 2H), 7.09 (m, 2H), 7.14e7.21 (m, 4H), 7.34 (m,
Et3N (8.4
mL, 0.06 mmol) and acetyl chloride (4.3 mL,
0.06 mmol) were added under argon to a solution of the N-(cya-
nomethyl)urea (S)-1a (17.2 mg, 0.03 mmol) in CH2Cl2 (0.50 mL).
After 5 min of stirring at rt, the solvent was evaporated under
argon stream. The homogeneous mixture was heated at 100 ꢀC by
MW irradiation for 25 min. After cooling to rt, the crude reaction
mixture was purified by flash chromatography, using 0e5% MeOH
in CH2Cl2 gradient as eluent, to afford the title compounds 6a
(11 mg, 60%) as a foam that decomposed on standing. HPLC-MS: tR
2H); 13C NMR [CD3OD, 125 MHz]
d 25.6, 28.2, 33.7, 37.2, 40.1, 41.1,
44.3 (CH2), 55.7 (CH3), 59.2, 63.2 (CH), 115.0, 115.0, 128.3, 128.4,
128.7, 129.4, 129.6, 129.6, 129.9, 130.2, 130.7, 130.8, 130.8, 131.0 (CH),
136.4, 139.5, 159.9 (C), 158.5, 171.3, 173.7 (CO). ES-MS m/z [Mþ1]þ
calcd for C31H36N4O4 529.3, found, 529.4; Anal. Calcd for
5.61 min. 1H NMR (CD3Cl, 300 MHz)
d 1.06 (m, 2H), 1.34 (s, 9H),
C31H36N4O4$C2HF3O: C, 61.67; H, 5.80; N, 8.72. Found: C, 61.47; H,
5.89; N, 8.45.
1.80 (s, 3H), 2.00 (m, 2H), 2.80 (m, 2H), 3.70 and 3.82 (2d,
J¼16.5 Hz, 2H), 4.43e4.15 (m, 4H), 6.51 (s, 1H), 7.45e7.05 (m, 15H),
7.99 (s, 1H). The instability of this compound did not allow
obtaining its 13C NMR spectrum. ES-MS m/z [Mþ1]þ calcd for
4 . 4 . 4 . ( 2 S ) - 5 - A m i n o - N - b e n zyl- 2 -[ ( S) - 5 -b en zyl- 3 -( 4 -
fluorophenethyl)-2,4-dioxoimidazolidin-1-yl]pentanamide
tri-
fluoroacetate (S)-12d. With z25% of the epimer (R)-12d, yield 97%;
foam; HPLC-MS (15e95% gradient of A in B for 5 min) tR 3.31 min;
C
35H41N5O5 612.31, found, 612.31.
1H NMR [CD3OD, 500 MHz]
d 1.53 and 1.70 (2m, 2H),1.87, 1.98, 2.08
4.4. Acid hydrolysis of the N-(cyanomethyl)ureas (S)-1aee.
Synthesis of the hydantoin derivatives (S)-12aee
(3m, 2H), 2.44e2.59, 2.49 (m, 2H), 2.82 (t, J¼7.5 Hz,1.5H), 2.96e3.10
(m, 2H), 3.13 (m, 0.5H), 3.35e3.53 (m, 2H), 4.02 (m, 1.4H), 4.17e4.34
(m, 2.6H), 6.87 (m, 2H), 7.01 (m, 3H), 7.10 (m, 2H), 7.19 (m, 5H), 7.34
The corresponding N-(cyanomethyl)urea (S)-1aee [0.125 mmol,
impurified with 0e30% of the respective epimer (R)-1aee, due to
the difficulty of resolution of the epimeric mixtures (RS)-1aee] was
dissolved in 20% solution of TFA in CH2Cl2 (5 mL). After 24 h of
stirring at rt, the reaction mixture was evaporated to dryness. The
residue was coevaporated with CH2Cl2 (3ꢁ2 mL) and triturated
with cold ethyl ether. The residue was dissolved in H2O (3 mL) and
the solution was lyophilized. In this way, the trifluoroacetates of the
hydantoin derivatives (S)-12aee were obtained as amorphous
solids retaining the epimer ratio of the starting urea 1a-e [70e100%
of the (S)-epimer].
(m, 2H); 13C NMR [CD3OD, 125 MHz]
d 24.1, 26.8, 32.3, 35.7, 38.7,
39.5, 42.9 (CH2), 57.8, 61.7 (CH), 114.6, 114.8, 126.9, 127.0, 127.3,
127.9, 128.1, 128.2, 128.5, 128.7, 129.3, 129.5, 130.1, 130.1 (CH), 133.7,
134.9, 135.3, 138.0, 162.6 (C), 157.1, 169.8, 172.2 (CO). ES-MS m/z
[Mþ1]þ calcd for C30H33FN4O3 517.3, found, 517.4; Anal. Calcd for
C30H33FN4O3$C2HF3O: C, 60.95; H, 5.43; N, 8.88. Found: C, 60.65; H,
5.27; N, 8.69.
4.4.5. (S)-6-Amino-N-benzyl-2-[(S)-2,4-dioxo-5-phenethyl-3-
phenylimidazolidin-1-yl]hexanamide trifluoroacetate (S)-12e. Yield
97%; foam; HPLC-MS (15e95% gradient of A in B for 5 min) tR
3.26 min; 1H NMR [CD3OD, 500 MHz]
d 1.38 (m, 2H), 1.60 (m, 2H),
4.4.1. (2S)-5-Amino-N-benzyl-2-[(S)-5-benzyl-2,4-dioxo-3-
phenylimidazolidin-1-yl]pentanamide trifluoroacetate (S)-12a. With
z28% of the epimer (R)-12a, yield 96%; foam; HPLC-MS (15e95%
gradient of A in B for 5 min) tR 3.08 min; 1H NMR [CD3OD, 500 MHz]
2.00 (q, J¼8 Hz, 2H), 2.12 and 2.21 (2m, 2H), 2.51 and 2.72 (2m, 2H),
2.79 (t, J¼7 Hz, 2H), 4.26e4.36 (m, 4H)), 7.07e7.38 (m, 15H; 13C
NMR [CD3OD, 125 MHz]
d 24.5, 28.2, 30.7, 31.2, 33.3, 40.4, 44.3
(CH2), 59.3, 61.8 (CH), 127.3, 127.8, 127.8, 128.4, 128.7, 129.3, 129.4,
129.4, 129.5, 129.6, 129.6, 129.6, 129.6, 130.0 (CH), 133.1, 139.7, 141.8
(C), 157.7, 171.4, 173.4 (CO). ES-MS m/z [Mþ1]þ calcd for C30H34N4O3
d
1.60 (m, 2H), 2.05 (m, 2H), 2.86 (m, 2H), 3.18 (dd, J¼5, 15.5 Hz, 1H),
3.25 (dd, J¼5, 15.5 Hz, 1H), 4.16 (t, J¼8 Hz, 1H), 4.27 and 4.35 (AB
system, J¼15 Hz, 2H), 4.45 (t, J¼8 Hz, 0.28H), 4.55 (t, J¼5H, 0.78H),

ꢀ
P. Ventosa-Andres et al. / Tetrahedron 70 (2014) 3407e3412
3412
Aparicio, A.; Saunders, J.; Goodfellow, V. S. Bioorg. Med. Chem. Lett. 2007, 17,
2171e2178.
12. Jung, M. E.; Ouk, S.; Yoo, D.; Sawyers, C. L.; Chen, C.; Tran, C.; Wongvipat, J. J.
499.3, found, 499.3; Anal. Calcd for C30H34N4O3$C2HF3O: C, 62.74;
H, 5.76; N, 9.15. Found: C, 62.85; H, 5.83; N, 8.89.
Med. Chem. 2010, 53, 2779e2796.
Acknowledgements
13. Sacchetti, A.; Silvani, A.; Gatti, F. G.; Lesma, G.; Pilati, T.; Trucchi, B. Org. Biomol.
Chem. 2011, 9, 5515e5522.
ꢀ
ꢀ
ꢀ
14. Ventosa-Andres, P.; Valdivielso, A. M.; Pappos, I.; García-Lopez, M. T.; Tsopa-
This work was supported by the Spanish Ministerio de Ciencia e
noglou, N. E.; Herranz, R. Eur. J. Med. Chem. 2012, 58, 98e111.
ꢀ
ꢀ
ꢀ
Innovacion grants SAF2009-09323 and SAF2012-32209. P.V.-A.
ꢀ
ꢀ
~
15. Valdivielso, A. M.; Ventosa-Andres, P.; Tato, F.; Fernandez-Ibanez, M. A.; Pappos,
ꢀ
ꢀ
ꢀ
I.; Tsopanoglou, N. E.; García-Lopez, M. T.; Gutierrez-Rodríguez, M.; Herranz, R.
held an FPI fellowship from the Ministerio de Educacion y Cien-
cia. J.A.G.-V. held a JAEdoc research contract from the CSIC.
Eur. J. Med. Chem. 2013, 70, 199e224.
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