One-step synthesis of N-acetylcysteine and glutathione derivatives using the Ugi reaction

Article abstract of DOI:10.1016/j.tet.2009.04.030

Fully protected natural and unnatural N-acetylcysteine, dipeptide Cys-Gly, glutathione, and homoglutathione derivatives were synthesized by the Ugi four-component reaction using various benzylthio aldehydes and ketones as carbonyl building blocks. The scope and limitations of the method were investigated. Formation of imidazoline by-products in the Ugi reaction was discussed. 2,2,2-Trifluoroethanol was shown to be a superior reaction media than methanol in some reactions. Also, the 4-methyl-2,6,7-trioxabicyclo[2.2.2]octyl derivative (OBO-ester) of isocyanoacetic acid was shown to be superior to use than ethyl isocyanoacetate as a peptide synthesis precursor in cases when higher reactivity of an isocyanide is required.

Full text of DOI:10.1016/j.tet.2009.04.030

Tetrahedron 65 (2009) 4692–4702
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
One-step synthesis of N-acetylcysteine and glutathione derivatives
using the Ugi reaction
*
Alexander G. Zhdanko, Anton V. Gulevich, Valentine G. Nenajdenko
Chemistry Department, Moscow State University, Leninskije Gory, 119991 Moscow, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
Fully protected natural and unnatural N-acetylcysteine, dipeptide Cys–Gly, glutathione, and homo-
glutathione derivatives were synthesized by the Ugi four-component reaction using various benzylthio
aldehydes and ketones as carbonyl building blocks. The scope and limitations of the method were
investigated. Formation of imidazoline by-products in the Ugi reaction was discussed. 2,2,2-Tri-
fluoroethanol was shown to be a superior reaction media than methanol in some reactions. Also, the
4-methyl-2,6,7-trioxabicyclo[2.2.2]octyl derivative (OBO-ester) of isocyanoacetic acid was shown to be
superior to use than ethyl isocyanoacetate as a peptide synthesis precursor in cases when higher re-
activity of an isocyanide is required.
Received 21 August 2008
Received in revised form 25 March 2009
Accepted 9 April 2009
Available online 17 April 2009
Keywords:
Ugi reaction
Cysteine
Glutathione
Homoglutathione
Imidazoline
Peptide chemistry
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
L
-
a
-glutamyl-
L-cysteine-b-alanine) can be found in several tissues
and organs of legumes.7
Glutathione (GSH) is present in all living organisms and plays an
Although GSH is a commonly available substance, its unnatural
analogs have been available very scarcely by classic methods of
peptide synthesis.8 It is well known that the replacement of natural
amino acids in biologically relevant peptides may influence their
properties dramatically.9 Therefore, the development of new
methodology for the synthesis of unnatural analogs of GSH is
a modern synthetic problem.
N-Acetylcysteine (NAC) is a precursor of glutathione in an or-
ganism but it also possesses antioxidant properties. It is a phar-
macological agent used mainly as a mucolytic agent and in the
management of paracetamol overdose. We report herein our in-
vestigations toward the direct synthesis of unnatural cysteine and
glutathione analogs by the Ugi reaction. The synthesis of several
NAC derivatives by the Ugi reaction is also described in this article.
important role in life processes.1 This simple tripeptide (
g-Glu-Cys-
Gly) is a powerful antioxidant preventing oxidation of SH groups of
peptides. The ratio of GSSG/GSH is an important marker of oxida-
tive stress. The principle of action as an antioxidant is based on the
fact that it reduces other toxic substances before they can attack
other molecules. Also, it binds free radicals, heavy metals, and toxic
substances. Due to these properties it slows aging processes and
protects cells from damage.2 GSH is one of the strongest anti-cancer
agents manufactured by the body.3 However, most tumor cells
contain GSH in high concentration and this may be an important
factor in resistance to chemotherapy.4 A specific function of GSH in
maintenance of the ascorbate pool in plant cells has been demon-
strated.5 Apparently, GSH is a very important biomolecule and its
depletion in an organism causes diseases and aging. On the other
hand, many diseases (such as cancer, AIDS, and neurodegenerative
diseases) lead to decrease of GSH level, making an organism more
vulnerable.6 Therefore, maintenance of the proper level of GSH is
important for health. Homologs of GSH can be found in different
plant species, where some of the constitutive amino acids differ
from those found in GSH. For instance, homoglutathione (hGSH,
2. Results and discussion
To our knowledge, there is only one example of a GSH derivative
synthesized by an Ugi three-component reaction (U-3CR) using
a cyclic aldimine as a precursor.10 We supposed that GSH de-
rivatives could be prepared in one step by U-4CR between a pro-
tected glutamic acid, an amine component, a carbonyl compound
bearing a protected thiol group and ethyl isocyanoacetate as the
glycine building block (Scheme 1).11 In this strategy, the cysteine
moiety is constructed directly by the Ugi reaction. This method
* Corresponding author. Tel.: þ7 495 939 2276; fax: þ7 495 932 8846.
E-mail address: nen@acylium.chem.msu.ru (V.G. Nenajdenko).
would open access to fully protected
a-substituted cysteine and
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.04.030

A.G. Zhdanko et al. / Tetrahedron 65 (2009) 4692–4702
4693
glutathione derivatives. Also, subsequent modification of the pep-
tide would be possible after partial deprotection.12
R
R
HN
N
S
S
HS
-H2O
O
S
O
CN
CO2Et
NH2
O
(n)
15, R = Alk
SH
H
N
R
(n)
R'NH2
NHPg
O
HO2C
N
H
CO2H
O
O
NR
SPg
O
RNH2
RNH2
R
S
SH
Glutathione (GSH): n=1, R=H
Homoglutathione (hGSH): n=2, R=H
SH
SH
PgO2C
CO2H
B
A
-RNHCOCH3
O
10
BnNH2
O
variation of the carbonyl component leads to
variation of the aminoacid in a peptide
O
O
O
[O]
S
BnNH2
H
N
S
R
Ar
SH
Ar
Ar
R'NH2
RNC
OH
SH
2
11
O
O
-BnNHCOCH3
Ar = 4-C6H4Cl
Scheme 3. Possible mechanisms of the reaction of 10 and 11 with amines.
O
SPg
R
AcOH
NAC derivatives
Scheme 1. Multicomponent approach to GSH and NAC.
We have found that S-protected mercapto carbonyls should be
based on literature procedures (Scheme 4) and first tested in
a model Ugi reaction with benzylisocyanide, benzylamine, and
acetic acid to investigate the scope of the method.
used in the reaction13 and our first attempts were made to employ
an acetyl protecting group because it is removable under mild
conditions in high yield (0.2 M NaOH aq).14 The corresponding
carbonyl compounds bearing an acetylthio group were prepared by
known methods (Scheme 4) and subjected to the Ugi reaction, but
this led to unexpected results. No Ugi products 14 were obtained in
reaction of 10–11 with benzylisocyanide, acetic acid, and benzyl-
amine under classic conditions (Scheme 2). However, it was found
that carbonyl compounds 10–11 react smoothly with aliphatic
amines in MeOH or EtOH, to form unreactive species, and this
process appears to be much more favorable than the Ugi reaction.
Aliphatic ketone 10 forms bicyclic products 15a–c, but aromatic
ketone 11 forms the disulfide 16. These results can be explained by
the high susceptibility of the acetylthio group to nucleophilic attack.
A possible mechanism of these reactions is outlined in Scheme 3.
The results are summarized in Table 1. The reaction was found to
be sensitive to steric effects and the nature of the carbonyl group.
Aromatic ketones 8 and 9 were completely unreactive even on
heating because of reduced carbonyl activity (entry 10). Cyclo-
propyl ketone 4 was also unreactive; w11% of the desired peptide
was isolated together with the minor byproduct with an opened
cyclopropyl ring (entry 6). Bulky tert-butyl ketone 5 did not give
any Ugi product (entry 7). Other ketones 3 and 6 formed the cor-
responding N-acetylcysteine analogs in more than 60% yield, rep-
resenting good results in the Ugi reaction with ketones (entries 5
and 8).
These results were achieved by simple mixing of all four com-
ponents together in a solvent. But surprisingly, application of such
conditions to aldehydes 1 and 2, which were expected to be more
reactive than ketones initially gave poor results (entries 1 and 3).
Both reactions were accompanied by precipitation of a viscous oil.
These results can be explained by side condensation processes,
which become dominant in the case of 1. After a brief examination
of reaction conditions we have found that the influence of the side
processes can be greatly diminished by using specific conditions.
The best results were achieved when trifluoroethanol was used as
a solvent and an aldehyde was slowly added to the mixture of an
amine, an acid, and an isocyanide. Such a technique maintains a low
concentration of the aldehyde to minimize the influence of the
competitive processes. As a result, no oil was formed and the Ugi
products were obtained in good yields (entries 2 and 4). Further, we
have found that precipitation of the oil occurs only with primary
amines. Secondary amines do not give any oil under these
We suppose that both reactions proceed via a-mercapto ketones A
since formation of bicyclic products of type 15 in reaction of A with
amines is a known process.15 Formation of bicyclic products is very
sensitive to steric effects, for example, i-PrNH2 reacts with 10 slowly
but does not give any 15. Formation of disulfide 16 is explained by
the lower reactivity of an aromatic carbonyl group, which caused
oxidation of the thiol group by air to be more favorable than for-
mation of the Schiff base B.
Finally we used the benzyl group as a more inert protecting
group.12 The corresponding carbonyl compounds were prepared
O
Ugi
Bn
N
R
O
NHBn
O
S
BnNC
BnNH2
CH3CO2H
R1
14
O
O
O
1) Br2
R = CH3
N
R = CH3 (10), p-ClC6H4 (11)
R1NH2
S
SAc
2) AcSH/Et3N
R
R
R
R1 = Alk
S
O
MeOH, rt
S
OMe
OMe
O
1) BnSNa/EtOH/KI/reflux
2) 0.5 M H2SO4/60 °C
15a-c
Cl
BnS
R = CH3 (10),
H
Cl
O
1
R = p-ClC6H4
(11)
S
S
Cl
BnNH2
1) NCS/CCl4
BnS
CHO
7
PhCH2SH
O
16
Cl
2) i-PrCHO/CCl4
EtOH, rt
O
O
R
BnSH
H2O, 35 °C
R1
Bn
Compound
15a
Yield,%
90
R = H (2), CH3 (3)
BnS
R
O
R
O
CH2CH2CH2OMe
C2H5
15b
83
1) Br2
2) BnSH/Et3N
R = CH3 (6), t-Bu (5),
MeOC6H4 (8), p-O2NC6H4 (9),
(4),
SBn
R
15c
93
Scheme 2. Use of thioacetic protecting group in the Ugi reaction.
Scheme 4. Synthesis of the carbonyl compounds.

4694
A.G. Zhdanko et al. / Tetrahedron 65 (2009) 4692–4702
Table 1
Table 2
Model Ugi reaction with carbonyl compounds 1–9a
Synthesis of Cys–Gly derivativesa
AcOH
O
AcOH
Bn
N
O
MeOH,
Bn
N
O
O
or CF3CH2OH
MeOH
BnNC
N
H
CO2Et
NHBn
R1
R2
R1
R2
CN
CO2Et
R1 R2
1 mmol scale
R1 R2
1 mmol scale
O
O
1, 2, 3, 6, 7
1 - 9
19a-e
BnNH2
17a-f
BnNH2
N
1
Carbonyl
Product
Yield, %
21
Solvent
N
1
Carbonyl
Product
Yield, %
15
Note
-20 ꢀC
O
O
17a
19a
CF3CH2OH
BnS
BnS
2
3
52
47
rtb
rt
H
H
1
1
2
3
O
13b
43
Methanol
CF3CH2OH
O
19b
17b
17c
17d
4
5
76
64
rtb
rt
BnS
BnS
H
3
2
4
5
16b
40
Methanol
CF3CH2OH
O
O
19c
19d
SBn
BnS
6
3
BnS
CHO
7
O
4
6
90
Methanol
6
11
Reflux
SBn
SBn
7
8
49
72
Methanol
CF3CH2OH
O
19e
O
7
8
d
0
rt
rt
BnS
H
2
t-Bu
5
a
All reactions were run on a 1 mmol scale at rt in 1 mL of the solvent.
Imidazolines were formed as by-products (see text).
O
b
17e
78
SBn
6
BnS
CHO
7
9
17f
80
0
rt
Isocyanoacetate 18 is widely used in the Ugi reaction, but to our
knowledge, formation of side products in the four-component
variant with ketones has never been discussed before. Therefore we
focused on identification of these products and explanation of
possible reasons why trifluoroethanol in this case does cause the
Ugi reaction to run cleanly, albeit still in moderate yield due to the
low reactivity of inputs. After careful chromatography we isolated
mixtures of imidazoline derivatives 20 and 21 as the main by-
products (Scheme 5). Apparently they were formed in a three-
component reaction (3CR) taking place under our conditions
competitively. This reaction itself was recently published as a sep-
arate synthetic method; however, it was not studied on asymmetric
ketones.19 In our conditions (MeOH) imidazoline formation was
accompanied by the transesterification (interestingly, it was not
observed in the corresponding Ugi products 19b–e). Quantitative
composition of the imidazoline mixtures was established by careful
analysis of the NMR spectra after control experiments with benzyl-
amine 18 and ketones 3 and 6 in ethanol in a transesterification-
free 3CR.
O
10
d
Reflux
SBn
8, 9
Ar
All reactions were run on a 1 mmol scale in 1 mL of methanol, except if other-
wise noted.
a
b
In CF3CH2OH.
conditions.16 In contrast to enolisable aldehydes, the non-enolis-
able or sterically hindered aldehydes, e.g., 7, represent the best
substrates for the Ugi reaction. The corresponding product was
obtained in high yield (entry 9) simply by mixing all four compo-
nents together in methanol. As a result, the scope of carbonyl
compounds suitable for use in further studies was limited to ali-
phatic aldehydes and ketones such as 1, 2, 3, 6, and 7.
Having investigated the reactions with benzylisocyanide we
proceeded to synthesize derivatives of the dipeptide Cys–Gly. Ethyl
isocyanoacetate (18) was used as the isocyanide component for the
Ugi reaction, and the other components (benzylamine and acetic
acid) were the same as in previous model reactions. The results are
summarized in Table 2. It is noteworthy that ethyl isocyanoacetate
behaved differently to benzylisocyanide. Due to the presence of an
electron withdrawing group this isocyanide was less reactive; this
especially became apparent in reactions with ketones 3, 6, and al-
dehyde 1. The latter gave a poor yield (Entry 1) even in optimal
conditions apparently because the lesser reaction ability of 18 led to
increased relative rate of side processes. As a result, we could not
avoid formation of the oil observed in the previous experiments.
Also formation of significant amounts of side products (but not the
oil) was observed in reactions of ketones 3 and 6. Accordingly, the
yields of the desired dipeptides 19c,d were unsatisfactory (entries 2
and 4). Formation of these side products (which appeared to be
imidazolines, vide infra) was monitored by TLC and was completely
avoided using trifluoroethanol instead of methanol, but the yields
were still less than 50% (entries 3 and 5).17,18 In contrast to ketones,
aldehydes 2 and 7 react smoothly and give the desired dipeptides in
good yields (entries 6 and 8). We may conclude that the side pro-
cesses for aldehyde 2 are less favorable than that for 1 therefore
they do not influence so dramatically.
Further, our observations suggest that in the case of aldehydes
the Ugi reaction is faster, therefore imidazolines are not formed. But
the Ugi reaction with ketones is slow, therefore both processes
BnNH2
CN
CO2Et
H+
CN
CO2Et
+
BnNH3
18
18a
NHBn
O
NBn
~H+
+
BnNH2
R1
R1
R1
3 and 6
18a
18a
Bn
cyclization,
Bn
NH NC
N
N
CO2R
transesterification
R = Et, Me
R1
R1
CO2Et
20, R1 = CH2CH2SBn,
21, R1 = CH2SBn
Scheme 5. Side processes occurring in the Ugi reaction with 18 and ketones 3 and 6 in
methanol.

A.G. Zhdanko et al. / Tetrahedron 65 (2009) 4692–4702
4695
Table 3
Table 4
Synthesis of glutathione derivatives
Synthesis of homoglutathione derivatives
BnNH2
O
BnNH2
NHBoc
O
NHBoc
O
NHBoc
O
r. t.
Bn
N
Bn
N
R1
1, 3, 6
R2
BnO2C
CO2Et
R1
R2
R3O2C
N
H
R4
NHBoc
BnO2C
N
H
R1 R2
R1 R2
OH
O
1, 2, 3, 6, 7 R3O2C
O
CO2H
25a-c
22a-j
13
12-13
O
CN
O
R4
24
CO2Et
CN
O
O
OBO =
18(R4 = CO2Et), 23(R4 = OBO)
N
R1 (carbonyl)
R2
Product
Yield, %
Solvent
N
R1 (carbonyl)
R2
R3
R4
Product
Yield, %
1
2
3
–CH2SBn 1
–CH2SBn 6
–CH2CH2SBn 3
H
Me
Me
25a
25b
25c
44
45
67
CF3CH2OH
CF3CH2OH
MeOH
1c
–CH2SBn 1
H
H
H
Bn
Me
Me
Me
Me
Bn
Bn
Bn
Bn
Bn
Bn
CO2Et
22a
22b
22c
22d
22e
22f
22g
22h
22i
22
57
37
33
23
67
37
71
76
46
52
2a
3b
4c
–C(CH3)2SBn 7
–CH2CH2SBn 2
–CH2CH2SBn 3
–CH2SBn 6
–CH2CH2SBn 2
–CH2SBn 6
–C(CH3)2SBn 7
–C(CH3)2SBn 7
–CH2SBn 6
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
OBO
Me
Me
H
Me
H
H
Me
Me
5c
6c
the negative influence of the COOEt group can be diminished after
replacement by an OBO group. Indeed, reaction with 23 gave
a better yield (Table 3, entries 9–11), indicating the higher reactivity
of the isocyanide in comparison with 18. Moreover, in contrast to
18, reaction of ketones 3 and 6 with 23 in methanol proceeds in-
deed cleanly so that the use of trifluoroethanol is not necessary.
In all cases, no diastereoselectivity was observed and glutathi-
one derivatives 22a–j were obtained as w1:1 mixtures of in-
separable diastereomers. It should be also noted that the suggested
methodology can be used in the synthesis of selenium-containing
peptide derivatives, which are compounds of biochemical
interest.23
The OBO-protecting group was shown to be removable in high
yield under mild conditions using a two-step one-pot procedure
[(1) TFA–H2O–CH2Cl2, (2) 0.4 M NaOH–H2O–THF, then acidification
with HCl].22
To further confirm our view about the influence of COOEt group
in isocyanide 18, we conducted a few reactions with isocyanide 24
and synthesized homoglutathione derivatives (Table 4). Since 24
has an electron withdrawing group at a greater distance from iso-
cyanide functionality it has normal reactivity. As expected, homo-
7c
8a
9a
10a
11a
OBO
OBO
22j
22k
–CH2CH2SBn 3
a
b
c
C¼0.5 M in methanol.
C¼0.5 M in methanol–THF 10:1.
C¼0.5 M in CF3CH2OH.
occur. We believe that imidazoline formation may take place in
four-component Ugi reactions with any other CH-acidic isocyanides
in MeOH or EtOH media. However it does not proceed in three-
component Ugi reactions with imines as starting materials.20
As we stated above, formation of imidazolines could be signifi-
cantly diminished by changing the solvent to trifluoroethanol. The
most reasonable explanation would be the high acidity of this
solvent (pKaw12.4 in water), which is at least 1000 times higher in
comparison to other alcohols. In this media the equilibrium con-
centration of the isocyanoacetate C-anion 18a, the key intermediate
in the imidazoline formation, should be low enough to prevent this
process. We believe that it is due to the acidity factor, because this
reaction was shown to proceed in wide range of polar protic and
aprotic solvents with different dipole moments and dielectric
constants.19
glutathione derivatives were obtained in
demonstrating the higher reactivity of the isocyanide in compari-
son with 18.
a
better yield
Bearing in mind the peculiarities of the reactions with ethyl
isocyanoacetate 18, we proceeded to synthesize glutathione de-
rivatives. Boc-protected glutamic monoesters 12 and 13 used in this
study were synthesized by a known method.21 The results are
summarized in Table 3. In comparison to previous experiments, we
diluted the reaction mixtures, because of high molecular weight of
the acid and hence, higher viscosity of the reaction media. But
nevertheless, the increase of molecular complexity influenced
negatively on the reaction rate. Ketones react with difficulty under
these conditions if 18 is used as an isocyanide component (entries
4, 5, and 7). Also the reaction with aldehyde 1 suffers from com-
petitive side processes, therefore natural glutathione derivative
was obtained in low yield (entry 1). Reaction with other aldehydes
gives better yields (entries 2, 3, and 6). Obviously the use of 18 has
serious limitations. A more reactive isocyanide is required to ex-
pand the scope of the method. Such isocyanide can be 4-methyl-
2,6,7-trioxabicyclo[2.2.2]octyl (OBO) ester of isocyanoacetic acid
23, just developed in our laboratory. It was synthesized from
commercially available Cbz-glycine (Scheme 6).22 We expected that
3. Conclusion
We have elaborated a new synthesis of various natural and
unnatural substituted totally protected cysteine, glutathione, and
homoglutathione derivatives using the Ugi four-component re-
action. The scope and limitations of the method were discussed. We
have described the formation of imidazoline by-products in the Ugi
four-component reaction with ethyl isocyanoacetate 18 concerned
with its specific CH-acidic properties. 2,2,2-Trifluoroethanol was
shown to be the solvent of choice in the Ugi reaction of 18 with
ketones. Also we have demonstrated that the OBO-ester of iso-
cyanoacetic acid 23 is more convenient in the corresponding
reactions.
4. Experimental
4.1. General information
1H and 13C NMR spectra were recorded on Bruker Avance 400
(on 400 and 100 MHz correspondingly). Chemical shifts are given
O
O
in
d (ppm) scale. IR spectra were recorded on UR-20 spectrometer.
i, ii, iii
iv, v
O
O
O
O
CbzHN
CO2H
CN
H2N
Elemental analysis was performed in the analytical laboratory of
A.N. Nesmeyanov Institute of Organoelement Compounds, Russian
Academy of Sciences. TLC was performed using 25 DC-Alufolien
Kieselgel 60 F254 (Merck). Fluka Silica gel 60 (0.063–0.200 mm) was
used for column chromatography. Commercial reagents and
23
Scheme 6. Synthesis of isocyanide 23: (i) 3-methyl-3-oxetanemethanol, DCC, DMAP,
CH2Cl2, rt, 95%; (ii) BF3$Et2O, CH2Cl2, rt, 98%; (iii) H2–Pd–C, MeOH, rt, 99%; (iv) HCOOEt,
reflux, 80%; (v) POCl3, Et3N, CH2Cl2, ꢁ20 ꢀC, 90%.

4696
A.G. Zhdanko et al. / Tetrahedron 65 (2009) 4692–4702
solvents were generally used as received. Methylene chloride was
distilled over P2O5, ethyl acetate, and triethylamine were stood over
CaH2 and then distilled. Benzylamine was stood over CaH2 and then
distilled in vacuo.
bath and the remaining amount of bromine was added dropwise at
<10 ꢀC. Then water (130 mL) was added to the colorless reaction
solution and stirred for 15 min. After this, reaction mixture was
carefully hydrolyzed by the addition of 8.4 g NaHCO3 and extracted
with methylene chloride (2ꢂ50 mL). The organic phase was dried
over Na2SO4 and concentrated. The residue was purified by vacuum
distillation to afford bromomethyl cyclopropyl ketone (11.9 g, 73%)
as a colorless liquid that can be stored in freezer.27 1H NMR
4.2. Starting materials
4.2.1. Benzyl thiol
To a warm solution of 78 g (1.02 mol) thiourea in 500 mL of
ethanol was added 115 mL (126 g, 1.0 mol) benzyl chloride. The
reaction mixture was heated to reflux for 10 min (TLC control,
CH2Cl2–MeOH 10:1). The resulting colorless transparent solution
was concentrated in vacuo almost to dryness and then a solution of
70 g (1.8 mol) NaOH in 600 mL water was added (a white pre-
cipitate was formed). The reaction mixture was heated to reflux for
an hour and cooled (a precipitate shouldn’t appear; if it does, the
mixture should be heated longer). The reaction mixture was
extracted with methylene chloride (400 mL). The organic phase
was dried over Na2SO4 and concentrated to give benzyl thiol (118 g,
95%) as a colorless liquid. Rf (EA–hexanes 1:5) 0.60. Rf (EA–hexanes
(400 MHz, CDCl3): d 4.04 (2H, s, CH2CO), 2.26–2.20 (1H, m, CHCO),
1.17–1.13 (2H, m), 1.06–1.01 (2H, m).
Bromomethyl cyclopropyl ketone (11.7 g, 0.0718 mol) was dis-
solved in ether (120 mL). The solution was cooled in an ice–NaCl
bath and triethylamine (11.0 mL, 0.0789 mol) was added. Then,
benzyl thiol (8.53 mL, 9.02 g, 0.0726 mol) was added dropwise at
<10 ꢀC (white precipitate is formed immediately). The reaction
mixture was stirred for additional 30 min and was filtered through
short SiO2-column. The filtrate was concentrated in vacuo to afford
4 (14.1 g, 95%) as a colorless liquid. Rf (EA–hexanes 1:2) 0.6. [Found:
C, 69.71; H, 6.83. C12H14OS requires C, 69.86; H, 6.84%.] nmax (neat,
cmꢁ1): 1690 (C]O), 1600, 1390, 713. 1H NMR (400 MHz, CDCl3):
1:2) 0.81. 1H NMR (400 MHz, CDCl3):
d
7.24–7.37 (5H, m, Ph), 3.78
d
7.24–7.37 (5H, m, Ph), 3.70 (2H, s, PhCH2), 3.28 (2H, s, SCH2CO),
(2H, d, CH2, J¼7.6 Hz), 1.79 (1H, t, SH, J¼7.6 Hz).24
2.12–2.80 (1H, m, COCH), 0.91–1.09 (4H, m, CH2CH2). 13C NMR
(100 MHz, CDCl3):
11.6.
d 205.7, 137.4, 129.2, 128.5, 127.2, 40.9, 36.0, 19.3,
4.2.2. 2-(Benzylthio)acetaldehyde (1)25
Sodium (1.13 g, 0.0492 mol) was dissolved in dry ethanol
(25 mL), and benzyl thiol (6.11 g, 5.78 mL, 0.0493 mol), KI (0.25 g),
and dimethyl chloroacetal (6.11 g, 0.0493 mol) were added. The
reaction mixture was heated to reflux for 5–7 h (TLC control:
EtOAc–hexanes 1:5). The precipitate was filtered off, washed with
ethanol, the filtrate was concentrated in vacuo, diluted with water
(30 mL), and extracted with methylene chloride (50 mL). The or-
ganic phase was dried over Na2SO4 and concentrated. The residue
was purified by column chromatography on silica gel (EA–hexanes
1:5, Rf 0.37) to afford 2-(benzylthio)-dimethyl acetal (7.13 g, 68%) as
4.2.6. 1-(Benzylthio)-3,3-dimethylbutanone-2 (5)
Methyl tert-butyl ketone (13 mL, 0.10 mol) was brominated in
50 mL of ether as described for 4. The reaction mixture was care-
fully neutralized by NaHCO3 aq, washed with brine (10 mL), dried
over Na2SO4, and concentrated in vacuo. The residue was purified
by vacuum distillation to yield 1-brom-3,3-dimethylbutanone-2
(12.13 g, 68%) as a colorless liquid, can be stored in freezer. 1H NMR
(400 MHz, CDCl3):
d 4.20 (2H, s, CH2CO), 1.25 (9H, s, CH3).
A
solution of 1-bromo-3,3-dimethylbutanone-2 (12.13 g,
a slightly yellow oil. 1H NMR (400 MHz, CDCl3):
d
7.35–7.25 (5H, m,
0.0677 mol) in acetone (120 mL) was treated as described for 4 to
yield 5 (15.25 g, 96%) as a colorless liquid. Rf (EA–hexanes 1:5) 0.5.
[Found: C, 70.29; H, 8.10. C13H18OS requires C, 70.22; H, 8.16%.] nmax
(neat, cmꢁ1): 1700 (C]O), 1600, 710. 1H NMR (400 MHz, CDCl3):
Ph), 4.43 (1H, t, J¼5.6 Hz, CH), 3.80 (2H, s, PhCH2), 3.36 (6H, s,
OCH3), 2.61 (2H, d, J¼5.6 Hz, SCH2).
2-(Benzylthio)-dimethyl acetal (7.13 g) was heated at w60 ꢀC
with 0.5 M H2SO4 (30 mL) for 2–3 h (TLC control, toluene–metha-
nol 20:1). Then the reaction mixture was neutralized with NaHCO3
and extracted three times with 20 mL portions of methylene
chloride. The organic phase was dried over Na2SO4 and concen-
trated to afford 1 (5.58 g, 100%) as a slightly yellow liquid, nd 1.5692
d
7.22–7.36 (5H, m, Ph), 3.78 (2H, s, PhCH2), 3.28 (2H, s, COCH2), 1.18
(9H, s, CH3). 13C NMR (100 MHz, CDCl3):
127.2, 43.3, 35.8, 34.6, 26.8.
d 210.4, 137.5, 129.2, 128.5,
4.2.7.
It was prepared as described for 5, yield 44%. 1H NMR (400 MHz,
CDCl3): 7.24–7.37 (5H, m, Ph), 3.70 (2H, s, PhCH2), 3.13 (2H, s,
a
-(Benzylthio)acetone (6)28
(lit.25 1.5699). 1H NMR (400 MHz, CDCl3):
CHO), 7.25–7.38 (5H, m, Ph), 3.65 (2H, s, PhCH2), 3.11 (2H, d, CH2).
d
9.44 (1H, t, J¼3.4 Hz,
d
COCH2), 2.25 (3H, s, CH3).
4.2.3. 3-(Benzylthio)-propanal (2)26
A mixture of benzyl thiol (3.73 g, 3.52 mL, 0.030 mol), water
(30 mL), and acrolein (2.1 mL, w0.033 mol) was stirred at 30–35 ꢀC
for 15 min (TLC control: EtOAc–hexanes 1:5), and was extracted
with methylene chloride (2ꢂ20 mL). The organic phase was dried
over Na2SO4 and concentrated in vacuo to afford 2 (5.15 g, 95%) as
a colorless liquid. Rf (EA–hexanes 1:5) 0.29. 1H NMR (400 MHz,
4.2.8. 2-(Benzylthio)-2-methylpropanal (7)29
NCS (6.69 g, 0.050 mol) was dissolved in CCl4 (20 mL) and
benzyl thiol (6.2 g, 5.8 mL, 0.050 mol) was added. The reaction is
slightly exothermic. The reaction mixture was stirred for 2 h. The
precipitate was filtered off, isobutyric aldehyde (3.6 g, 0.050 mol)
was added to the yellow solution, and the reaction mixture was left
to stand overnight. The resulting colorless solution was washed
with water, dried over Na2SO4, and concentrated in vacuo. The
residue was purified by column chromatography on silica gel (EA–
hexanes 1:6) to yield 7 (4.07 g, 42%) as a colorless liquid (w2 g of
crystalline benzyl disulfide was obtained as byproduct because of
incomplete chlorination). nd 1.546 (lit. 1.545). 1H NMR (400 MHz,
CDCl3):
d 9.73 (1H, s, CHO), 7.25–7.37 (5H, m, Ph), 3.76 (2H, s,
PhCH2), 2.65–2.75 (4H, m, CH2CH2).
4.2.4. 4-(Benzylthio)-butanone-2 (3)26
Obtained by the same procedure as 2 in 90% yield. 1H NMR
(400 MHz, CDCl3): d 7.23–7.35 (5H, m, Ph), 3.74 (2H, s, PhCH2), 2.66
(4H, s, CH2CH2), 2.13 (3H, s, CH3).
CDCl3): d 9.16 (1H, s, CHO), 7.23–7.34 (5H, m, Ph), 3.54 (2H, s, CH2),
1.41 (6H, s, CH3).
4.2.5. 2-(Benzylthio)-1-cyclopropylethanone (4)
Methyl cyclopropyl ketone (8.41 g, 0.10 mol) was dissolved in
methanol (60 mL) and a few drops of bromine solution (16.0 g
(5.15 mL, 0.1 mol) in 10 mL of methanol) were added. When the
solution became colorless, the reaction flask was placed into a cold
4.2.9. 4-Methoxy-a-(benzylthio)acetophenone (8)
4-Methoxyacetophenone (15.1 g, 0.101 mol) was brominated in
a mixture of ether (30 mL) and methylene chloride (60 mL) as de-
scribed for 5. The reaction mixture was evaporated to dryness and

A.G. Zhdanko et al. / Tetrahedron 65 (2009) 4692–4702
4697
the residue was recrystallized from ethanol to yield 4-methoxy-
bromoacetophenone (18.8 g, 82%) as a colorless solid.
a
-
(1H, br s, NH), 4.38 (1H, br s, CH), 3.77 (3H, s, OCH3), 2.39–2.55 (2H,
m, CH2CO), 2.14–2.27 (1H, m), 1.89–2.03 (1H, m), 1.46 (9H, s, CH3).
A solution of 4-methoxy-
a
-bromoacetophenone (18.8 g) in ac-
13C NMR (100 MHz, DMSO-d6):
d 175.0 (minor), 174.1, 173.2, 171.7
etone (200 mL) was treated as described for 4. The reaction mixture
was filtered, the filtrate was evaporated to dryness, and the residue
was recrystallized from a little amount of ethanol to yield 8 (20.7 g,
92%) as a colorless solid. Rf (EA–hexanes 1:1) 0.6. [Found: C, 70.69;
H, 9.04; S,11.70. C16H16O2S requires C, 70.56; H, 5.92; S,11.77%.] nmax
(KBr, cmꢁ1): 1660 (C]O), 1595, 1240, 1040, 700. 1H NMR (400 MHz,
(m), 155.9, 78.7, 72.9 (m), 54.4 (m), 53.1, 52.1, 43.2 (m), 30.4 (m),
28.6, 28.3 (m), 26.4.
4.2.15. N-(Boc)-L-glutamic acid a-benzyl ester (13)
It was prepared using literature procedure.21 NaHSO4 was used
instead of citric acid at the end. Rf (EtOAc) 0.6. Yield 10.41 g (38%) as
25
CDCl3):
d, Ph, J¼8.9 Hz), 3.88 (3H, s, CH3), 3.78 (2H, s, CH2), 3.65 (2H, s,
PhCH2). 13C NMR (100 MHz, CDCl3):
193.2, 163.7, 137.5, 131.1 (2C),
129.3 (2C),128.5 (2C),128.4 (Cquat),127.2,113.9 (2C), 55.5, 36.2, 35.8.
d
7.92 (2H, d, Ph, J¼8.9 Hz), 7.25–7.38 (5H, m, Ph), 6.94 (2H,
a white solid. [
d
a
]
D
ꢁ27.3 (c 0.1, MeOH). 1H NMR (400 MHz, CDCl3):
7.37 (5H, m, Ph), 5.19 (2H, s), 5.19 (1H, br s), 4.41 (1H, m), 2.37–
d
2.52 (2H, m), 2.16–2.27 (1H, m), 1.91–2.05 (1H, m), 1.45 (9H, s). 13C
NMR (100 MHz, CDCl3): 177.9, 172.1, 155.5, 135.2, 128.7, 128.5,
d
128.3, 80.3, 67.3, 52.9, 30.0, 28.3, 27.6.
4.2.10. 4-Nitro-a-(benzylthio)acetophenone (9)
It was prepared as described for 8, yield 68%. Rf (EA–hexanes
1:2) 0.5. [Found: C, 62.75; H, 4.52; S, 11.26. C15H13NO3S requires C,
62.70; H, 4.56; S, 11.16%.] nmax (Nujol, cmꢁ1): 1680 (C]O), 1600,
4.3. Reaction of acetylthio ketones 10 and 11 with aliphatic
amines (synthesis of 15a–c and 16)
1525, 1355, 720. 1H NMR (400 MHz, CDCl3):
d
8.31 (2H, d, Ph,
J¼8.9 Hz), 8.08 (2H, d, Ph, J¼8.9 Hz), 7.25–7.38 (5H, m, Ph), 3.75 (2H,
s, CH2), 3.70 (2H, s, PhCH2). 13C NMR (100 MHz, CDCl3):
192.5,
150.3, 139.9, 136.8, 129.8, 129.3, 128.6, 127.5, 123.8, 36.13, 36.06.
4.3.1. 7-Benzyl-1,4-dimethyl-2,5-dithia-7-azabicyclo[2.2.1]-
heptane (15a)
d
A solution of 10 (0.132 g, 1 mmol) and benzylamine (0.107 g,
1 mmol) in 0.5 mL of ethanol was kept 2 h at rt. Precipitate was
filtered, washed with ethanol, and dried to give 0.104 g of white
solid. Rf (EA–hexanes 1:2) 0.73. [Found: C, 61.84; H, 6.93. C13H17NS2
requires C, 62.11; H, 6.82%.] nmax (KBr, cmꢁ1): 1600, 1490, 1450,
4.2.11.
a
-Acetylthioacetone (10)30
Acetone (100 mL) was brominated by 3 mL (9.3 g, 58.2 mmol) of
bromine. A mixture of triethylamine (8.1 g, 80 mmol), acetone
(20 mL), and thioacetic acid (4.53 g, 59.5 mmol) (prepared sepa-
rately on cooling) was dropwise added (at <10 ꢀC) to the cooled
reaction mixture. The reaction mixture was left to stand overnight
and filtered, filtrate was evaporated to dryness, the residue chro-
matographed on silica gel (gradient elution EA–hexanes 1:3/EA)
1430, 1230, 1135, 780, 720. 1H NMR (400 MHz, CDCl3):
d 7.44 (2H, d,
Ph), 7.34 (2H, t, Ph), 7.25 (1H, t, Ph), 3.75 (1H, d, J¼16.0 Hz, CH2N),
3.61 (1H, d, J¼16.0 Hz, CH2N), 3.43 (2H, d, J¼9.0 Hz, CH2S), 3.28 (2H,
d, J¼9.0 Hz, CH2S), 1.63 (6H, s, CH3). 13C NMR (100 MHz, CDCl3):
d
139.9, 128.3, 127.6, 126.7, 82.5 (2C), 50.2 (2C), 47.2, 21.3 (2C).
to yield
a
-acetylthioacetone (5.07 g, 66%) as a liquid. Rf (EA–hex-
4.3.2. 7-(3-Methoxypropyl)-1,4-dimethyl-2,5-dithia-7-
azabicyclo[2.2.1]heptane (15b)
anes 1:2) 0.42. 1H NMR (400 MHz, CDCl3):
(3H, s), 2.27 (3H, s).
d
3.75 (2H, s, CH2), 2.39
A solution of 10 (0.264 g, 2 mmol) and 3-methoxypropylamine-
1 (0.267 g, 3 mmol) in 1 mL of methanol was kept for 40 min at rt.
Then it was evaporated, the residue was chromatographed to afford
15b (83%) as a white oil. Rf (EA–hexanes 1:2) 0.47. [Found: C, 51.63;
H, 8.33; S, 27.25. C10H19NOS2 requires C, 51.46; H, 8.21; S, 27.48%.]
nmax (KBr, cmꢁ1): 1480, 1410, 1220, 1100. 1H NMR (400 MHz, CDCl3):
4.2.12. N-(Boc)-
L-glutamic acid
L-Glutamic acid (29.4 g, 0.20 mol) was dissolved in 350 mL of
aqueous solution of NaOH (25 g, 0.63 mol). The solution (pHw11)
was cooled and a solution of Boc2O (52.4 g, 0.24 mol) in THF
(160 ml) was added at <10 ꢀC (slightly exothermic reaction). Then
the reaction mixture was stirred at rt for 20 h. TLC control: MeOH–
CH2Cl2–AcOH 10:10:1. The organic phase was separated off, the
water phase was extracted with hexanes (2ꢂ40 mL), acidified by
dilute HCl to pHw2, and extracted with ethyl acetate (2ꢂ200).
Combined organic phases was dried over Na2SO4, evaporated in
vacuo, diluted with methylene chloride, and evaporated again. The
product is obtained as a sticky oil, which could be crystallized by
triturating with hexanes after prior standing for 2–3 days to yield
d
3.46 (2H, m, OCH2), 3.35 (2H, d, J¼9.0 Hz, CH2S), 3.17 (2H, d,
J¼9.0 Hz, CH2S), 3.34 (3H, s, OCH3), 2.50 (2H, m, CH2N), 1.77 (2H, m,
CH2), 1.73 (6H, s, CH3). 13C NMR (100 MHz, CDCl3):
58.5, 50.0 (2C), 39.8, 30.9, 20.9 (2C).
d 82.4 (2C), 70.2,
4.3.3. 7-Ethyl-1,4-dimethyl-2,5-dithia-7-azabicyclo-
[2.2.1]heptane (15c)
Compound 15c was prepared from 10 as described for 15b. Yield
93%. White oil. Rf (EA–hexanes 1:2) 0.58. [Found: C, 50.92; H, 7.91;
S, 33.70. C8H15NS2 requires C, 50.75; H, 7.99; S, 33.87%.] nmax (KBr,
N-(Boc)-
L-glutamic acid (43.5 g, 89%) as a colorless solid. Mp 113–
114 ꢀC (lit.21 110–112 ꢀC). 1H NMR (400 MHz, CDCl3):
d
mixture of
cmꢁ1): 1480, 1420, 1230. 1H NMR (400 MHz, CDCl3):
d 3.37 (2H, d,
rotamers 2:1 (signals of the minor rotamer are given in parenthe-
ses) 10.1 (2H, br s, COOH), 5.39 (6.63) (1H, d, NH), 4.40 m (4.23 br s)
(1H, NCH), 2.52 (2H, t, CH2CO), 2.19–2.27 (1H, m), 2.05–2.11 (1H, m),
1.46 (9H, s, CH3).
J¼9.0 Hz, CH2S), 3.19 (2H, d, J¼9.0 Hz, CH2S), 2.47 (2H, m, CH2N),
1.76 (6H, s, CH3), 1.19 (3H, t, CH3). 13C NMR (100 MHz, CDCl3):
(2C), 50.0 (2C), 37.6, 21.0 (2C), 16.5.
d 82.4
4.3.4. 2,20-Dithiobis[1-(4-chlorophenyl)ethanone] (16)31
4.2.13. N-(Boc)-
L
-glutamic anhydride
Compound 16 was prepared from 11 as described for 15a. Rf
(EA–hexanes 1:1) 0.5. White solid. Mp 123–124 ꢀC (lit. 123–124 ꢀC).
[Found: C, 51.93; H, 3.16; S, 17.21. C16H12Cl2S2O2 requires C, 51.76; H,
It was prepared in 33.7 g (98%) yield using the literature pro-
cedure.21 Rf (EA–hexanes 1:2) 0.32. Mp 118–119 ꢀC (lit.15 115–
116 ꢀC). 1H NMR (400 MHz, CDCl3):
d
5.37 (1H, br s, NH), 4.43 (1H, br
3.26; S, 17.27%.] 1H NMR (400 MHz, CDCl3):
d
7.89 (4H, d, J¼8.3 Hz,
s, CH), 3.02–3.08 (1H, m), 2.86–2.92 (1H, m), 2.45 (1H, br s), 1.96
(1H, m), 1.48 (9H, s, CH3).
Ph), 7.46 (4H, d, J¼8.3 Hz, Ph), 4.16 (4H, s, CH2). 13C NMR (100 MHz,
CDCl3):
d 193.0 (CO), 140.3, 133.7, 130.2, 129.2, 45.1 (CH2).
4.2.14. N-(Boc)-
L
-glutamic acid
a
-methyl ester (12)
4.4. Synthesis of NAC derivatives 17a–f
It was prepared using literature procedure.21 NaHSO4 was used
instead of citric acid at the end. Rf (EtOAc) 0.6. Yield 0.241 g (36%) as
Method A. A solution of carbonyl compound 3, 6 or 7 (1 mmol),
benzylamine (1 mmol), acetic acid (1 mmol), and benzylisocyanide
an amorphous solid. Rf (EA) 0.6. 1H NMR (400 MHz, CDCl3):
d
5.18

4698
A.G. Zhdanko et al. / Tetrahedron 65 (2009) 4692–4702
(1 mmol) in 1 mL of methanol was kept at rt for 1 h for aldehyde 7
and 2–3 days for ketones 3 and 6. Then the mixture was evaporated,
the residue was chromatographed (gradient elution EA–hexanes
1:1/EA). The product appears as an oil that could be crystallized.
Method B. An aldehyde 1 or 2 (1 mmol) was slowly (in 20 min)
added dropwise to a mixture of benzylamine (1 mmol), acetic acid
(1 mmol), and ethyl isocyanoacetate (1 mmol) in 1 mL of tri-
fluoroethanol. The reaction mixture was stirred at rt for additional
40 min and was evaporated, the residue was chromatographed
(gradient elution EA–hexanes 1:1/EA). The product appears as an
oil that could be crystallized.
4.4.5. N2-Acetyl-N1,N2-dibenzyl-2-methyl-S-(1-methyl-1-
phenylethyl)cysteinamide (17f)
Method A. Yield 0.369 g, 80%. White solid. Mp 127–128 ꢀC. Rf
(EA–hexanes 1:2) 0.32. [Found: C, 73.13; H, 6.95. C28H32N2O2S re-
quires C, 73.01; H, 7.00%.] nmax (Nujol, cmꢁ1): 3270 (NH), 1680
(amide), 1635 (amide). 1H NMR (400 MHz, CDCl3):
d 7.38–7.05 (16H,
m, PhþNH), 5.62 (1H, s, CH), 5.40 (1H, d, J¼17.4 Hz, PhCH2N), 4.68
(1H, d, J¼17.4 Hz, PhCH2N), 4.36 (1H, dd, J¼6.1, 14.7 Hz, PhCH2NH),
4.14 (1H, dd, J¼5.3, 14.7 Hz, PhCH2NH), 3.88 (1H, d, J¼12.0 Hz,
PhCH2S), 3.83 (1H, d, J¼12.0 Hz, PhCH2S), 1.87 (3H, s, CH3CO), 1.60
(3H, s), 1.52 (3H, s). 13C NMR (100 MHz, CDCl3):
d 173.9, 168.3, 138.5,
138.1, 137.0, 129.3, 128.6, 128.5, 128.2, 127.4, 127.0, 126.8, 125.6, 60.5
(NCHCO), 50.5 (SCquat), 50.2 (PhCH2N), 43.4 (PhCH2NH), 33.7
(PhCH2S), 26.6, 26.5, 22.7 (CH3CO).
4.4.1. N2-Acetyl-N1,N2,S-tribenzylcysteinamide (17a)
Method B. Yield 0.207 g, 52%. Orange solid. Mp 93–95 ꢀC. Rf (EA–
hexanes 1:1) 0.36. [Found: C, 72.34; H, 6.61. C26H28N2O2S requires
C, 72.19; H, 6.52%.] nmax (Nujol, cmꢁ1): 3310 (NH), 1670 (amide),
4.5. Synthesis of Cys–Gly dipeptide derivatives 19a–f
1630 (amide). 1H NMR (400 MHz, CDCl3):
d 7.40–7.08 (15H, m, Ph),
6.89 (1H, br t, NH), 5.06 (1H, t, NCHCO), 4.58 (2H, s, PhCH2N), 4.45
(1H, dd, J¼6.0, 14.9 Hz, PhCH2NH), 4.28 (1H, dd, J¼5.3, 14.9 Hz,
PhCH2NH), 3.71 (2H, s, PhCH2S), 2.97 (1H, dd, J¼8.6, 13.6 Hz,
CH2SBn), 2.66 (1H, dd, J¼6.6,13.6 Hz, CH2SBn), 2.09 (3H, s). 13C NMR
Method C. A solution of carbonyl compound (1 mmol), benzyl-
amine (1 mmol), acetic acid (1 mmol), and ethyl isocyanoacetate
(1 mmol) in methanol (1 mL) for aldehyde 7 or trifluoroethanol
(1 mL) for ketones 3 and 6 was kept at rt for 1 h for aldehyde 7 and
2–3 days for ketones. Then the mixture was evaporated, the residue
was chromatographed (gradient elution EA–hexanes 1:1/EA). The
product appears as an oil that could be crystallized in some cases.
Method D. Similar to method B (use 18 or 23 instead of
benzylisocyanide).
(100 MHz, CDCl3):
d 172.8, 169.4, 138.01, 137.96, 137.1, 129.0, 128.8,
128.65, 128.60, 127.7, 127.44, 127.41, 127.2, 126.1, 57.0 (NCHCO), 49.5
(PhCH2N), 43.5 (PhCH2NH), 36.4 (PhCH2S), 30.0 (BnSCH2), 22.2
(CH3CO).
4.4.2. N2-Acetyl-N1,N2,S-tribenzylhomocysteinamide (17b)
Method B. Yield 0.341 g, 76%. White solid. Mp 67–69 ꢀC. Rf (EA–
hexanes 1:1) 0.42. [Found: C, 72.50; H, 6.88. C27H30N2O2S requires
C, 72.61; H, 6.77%.] nmax (Nujol, cmꢁ1): 3300 (NH), 1680 (amide),
4.5.1. Ethyl N-acetyl-N,S-dibenzylcysteinylglycinate (19a)
Method D. Yield 0.090 g, 21%. Sticky oil. Rf (EA) 0.53. [Found: C,
64.56; H, 6.83. C23H28N2O4S requires C, 64.46; H, 6.59%.] nmax
(Nujol, cmꢁ1): 3250 (NH), 1750 (COO), 1680 (amide), 1625 (amide).
1630 (amide). 1H NMR (400 MHz, CDCl3):
d 7.38–7.11 (15H, m, Ph),
6.82 (1H, t, J¼5.0 Hz, NH), 5.07 (1H, dd, CH), 4.57 (2H, s, PhCH2N),
4.41 (1H, dd, J¼5.8, 15.0 Hz, PhCH2NH), 4.30 (1H, dd, J¼5.8, 15 Hz,
PhCH2NH), 3.64 (2H, s, PhCH2S), 2.45–2.22 (3H, m), 2.07 (3H, s,
1H NMR (400 MHz, CDCl3):
d 7.33–7.13 (10H, m, Ph), 7.01 (1H, br t),
5.14 (1H, t), 4.60 (1H, d, J¼17.8 Hz, PhCH2N), 4.52 (1H, d, J¼17.8 Hz,
PhCH2N), 4.21 (2H, q, J¼7.1 Hz, OCH2CH3), 4.00 (1H, dd, J¼6.1,
18.2 Hz, NHCH2COO), 3.85 (1H, dd, J¼5.1, 18.2 Hz, NHCH2COO), 3.70
(2H, s, PhCH2S), 2.94 (1H, dd, J¼8.6, 13.6 Hz, CH2SBn), 2.60 (1H, dd,
J¼6.6, 13.6 Hz, CH2SBn), 2.15 (3H, s), 1.29 (3H, t, J¼7.1 Hz, OCH2CH3).
CH3CO), 1.82 (1H, m). 13C NMR (100 MHz, CDCl3):
d 172.9, 170.1,
138.3, 138.2, 137.3, 128.9, 128.7, 128.5, 127.7, 127.5, 127.4, 127.0, 126.1,
56.8 (NCHCO), 49.6 (PhCH2N), 43.4 (PhCH2NH), 36.1 (PhCH2S), 28.2,
28.0, 22.3 (CH3CO).
13C NMR (100 MHz, CDCl3):
d 173.2, 169.9, 169.5, 137.8, 136.8, 129.0
(2C), 128.8 (2C), 128.6 (2C), 127.5, 127.1, 126.2 (2C), 61.4 (OCH2CH3),
56.8 (NCHCO), 49.7 (PhCH2N), 41.2 (NCH2CO), 36.3 (PhCH2S), 29.3
(BnSCH2), 22.2 (CH3CO), 14.2 (OCH2CH3).
4.4.3. N2-Acetyl-N1,N2-dibenzyl-4-(benzylthio)isovalinamide (17c)
Method A. Yield 0.295 g, 64%. White solid. Mp 115–116 ꢀC. Rf
(EA–hexanes 1:1) 0.3. [Found: C, 72.93; H, 7.02. C28H32N2O2S re-
quires C, 73.01; H, 7.00%.] nmax (Nujol, cmꢁ1): 3355 (NH), 1660
4.5.2. Ethyl N-acetyl-N-benzyl-4-(benzylthio)isovalylglycinate (19b)
Method C. Yield 0.197 g, 43%. Sticky oil. Rf (EA) 0.42. [Found: C,
65.49; H, 6.84. C25H32N2O4S requires C, 65.76; H, 7.06%.] nmax (Nujol,
cmꢁ1): 3280 (NH), 1750 (COO), 1680 (amide), 1635 (amide). 1H NMR
(amide), 1640 (amide). 1H NMR (400 MHz, CDCl3):
d 7.43–7.24 (15H,
m, Ph), 5.89 (1H, t, NH, J¼5.0 Hz), 4.55 (1H, d, PhCH2N, J¼18.0 Hz),
4.47 (1H, d, PhCH2N, J¼18.0 Hz), 4.44 (2H, d, PhCH2NH, J¼5.0 Hz),
3.65 (2H, s, PhCH2S), 2.48–2.32 (2H, m), 2.28 (1H, dt, J¼5.0, 11.0 Hz),
2.09 (3H, s), 1.99 (1H, dt, J¼5.0, 11.0 Hz), 1.39 (3H, s, CH3). 13C NMR
(400 MHz, CDCl3):
d
7.48–7.20 (10H, m), 6.26 (1H, t, J¼4.6 Hz), 4.55
(1H, d, J¼18.2 Hz, PhCH2N), 4.49 (1H, d, J¼18.2 Hz, PhCH2N), 4.23
(2H, q, J¼7.2 Hz, OCH2CH3), 4.00 (2H, d, J¼4.6 Hz, NHCH2COO), 3.67
(1H, d, J¼14.1 Hz, PhCH2S), 3.64 (1H, d, J¼14.1 Hz, PhCH2S), 2.37 (2H,
m), 2.30 (1H, dt, J¼3.0, 9.7 Hz), 2.10 (3H, s, CH3CO), 2.02 (1H, t), 1.38
(3H, s), 1.30 (3H, t, J¼7.2 Hz, OCH2CH3). 13C NMR (100 MHz, CDCl3):
(100 MHz, CDCl3):
d 173.8, 172.1, 138.5, 138.4, 138.2, 129.1, 129.0,
128.7, 128.6, 127.9, 127.5, 127.1, 126.2, 64.9 (NCquatCO), 49.1
(PhCH2N), 43.9 (PhCH2NH), 36.0 (PhCH2SCH2CH2), 25.8 (SCH2CH2),
23.3 (CH3), 21.9 (CH3CO).
d
173.8,172.2,170.2,138.3,138.1,129.2,129.0,128.5,127.5,127.0,126.1,
4.4.4. N2-Acetyl-N1,N2,S-tribenzyl-2-methylcysteinamide (17e)
Method A. Yield 0.349 g, 78%. White solid. [Found: C, 72.41; H,
6.83. C27H30N2O2S requires C, 72.61; H, 6.77%.] nmax (Nujol, cmꢁ1):
3290 (NH), 1685 (amide), 1640 (amide). 1H NMR (400 MHz, CDCl3):
64.8 (NCquatCO), 61.5 (OCH2CH3), 49.14 (PhCH2N), 41.8 (NCH2CO),
35.93, 35.85, 25.5 (SCH2CH2), 23.3, 21.6 (CH3CO), 14.2 (OCH2CH3).
4.5.3. Ethyl N-acetyl-N,S-dibenzyl-2-methylcysteinylglycinate (19c)
Method C. Yield 0.177 g, 40%. White solid. Mp 85–87 ꢀC. [Found: C,
65.02; H, 6.96. C24H30N2O4S requires C, 65.13; H, 6.83%.] nmax (Nujol,
cmꢁ1): 3345 (NH),1750 (COO),1675 (amide),1640 (amide), 745, 705.
d
7.44–7.22 (15H, m, Ph), 6.14 (1H, t, NH, J¼5.0 Hz), 4.74 (1H, d,
PhCH2N, J¼18.2 Hz), 4.68 (1H, d, PhCH2N, J¼18.2 Hz), 4.46 (1H, dd,
PhCH2NH, J¼5.0, 12.0 Hz), 4.42 (1H, dd, PhCH2NH, J¼5.0, 12.0 Hz),
3.72 (1H, d, J¼13.1 Hz, PhCH2S), 3.67 (1H, d, J¼13.1 Hz, PhCH2S),
3.55 (1H, d, J¼12.6 Hz), 3.01 (1H, d, J¼12.6 Hz), 2.13 (3H, s, CH3CO),
1H NMR (400 MHz, CDCl3):
d
7.5–7.23 (10H, m), 6.47 (1H, t, J¼5.4 Hz),
4.73 (2H, s, PhCH2N), 4.23 (2H, q, J¼7.2 Hz, OCH2CH3), 4.10 (1H, dd,
J¼4.0,18.5 Hz, NHCH2COO), 3.95 (1H, dd, J¼4.0,18.5 Hz, NHCH2COO),
3.75 (1H, d, J¼13.4 Hz, PhCH2S), 3.70 (1H, d, J¼13.4 Hz, PhCH2S), 3.60
(1H, d, J¼12.7 Hz), 3.02 (1H, d, J¼12.7 Hz), 2.14 (3H, s, CH3CO), 1.41
(3H, s), 1.30 (3H, t, J¼7.2 Hz, OCH2CH3). 13C NMR (100 MHz, CDCl3):
1.44 (3H, s, CCH3). 13C NMR (100 MHz, CDCl3):
d 173.57, 172.3, 138.6,
138.2, 137.9, 129.11, 128.9, 128.7, 128.6, 127.9, 127.4, 127.3, 126.1, 65.1
(NCquatCO), 50.0 (PhCH2N), 44.0 (PhCH2NH), 37.9 (PhCH2SCH2C),
23.3, 23.0 (CH3CO).

A.G. Zhdanko et al. / Tetrahedron 65 (2009) 4692–4702
4699
d
173.8, 172.4, 170.1, 138.5, 138.02, 129.2, 128.9, 128.6, 127.5, 127.3,
127.1, 75.3 (CHCOO), 66.8 (Cquat), 60.9 (OCH2CH3), 46.0 (PhCH2N),
38.9 (SCH2CH2), 36.3 (PhCH2S), 25.2 (SCH2CH2), 19.9 (CCH3), 14.3
126.1, 64.9 (NCquatCO), 61.5 (OCH2CH3), 50.2 (PhCH2N), 41.9
(NCH2CO), 37.9, 37.67, 23.2, 22.9 (CH3CO), 14.2 (OCH2CH3).
(OCH2CH3). Minor: 1H NMR (400 MHz, CDCl3):
d 7.34–7.20 (10H, m,
Ph), 6.84 (1H, s, CH), 4.46 (1H, s, CH), 4.29–4.16 (2H, m, OCH2CH3),
4.06 (1H, d, J¼15.2 Hz, PhCH2N), 3.98 (1H, d, J¼15.2 Hz, PhCH2N),
3.70 (1H, d, J¼13.6 Hz, PhCH2S), 3.65 (1H, d, J¼13.6 Hz, PhCH2S),
2.49 (1H, m), 2.21 (1H, m), 1.94–1.74 (2H, m), 1.34 (3H, s), 1.30 (3H, t,
4.5.4. Ethyl N-acetyl-N-benzyl-3-(benzylthio)valylglycinate (19d)
Method C. Yield 0.411 g, 90%. White solid. Mp 107–109 ꢀC. Rf
(EA–hexanes 1:1) 0.5. [Found: C, 65.42; H, 6.96. C25H32N2O4S re-
quires C, 65.76; H, 7.06%.] nmax (Nujol, cmꢁ1): 3280 (NH), 1740
(COO), 1685 (amide), 1630 (amide). 1H NMR (400 MHz, CDCl3):
J¼7.2 Hz, OCH2CH3). 13C NMR (100 MHz, CDCl3):
d 170.7, 156.6
(C]N), 138.2, 137.5, 128.8, 128.5, 127.8, 127.7, 127.0, 77.8 (CHCOO),
67.6 (Cquat), 61.1 (OCH2CH3), 46.0 (PhCH2N), 36.3 (PhCH2S), 35.2
(SCH2CH2), 26.7 (CCH3), 25.9 (SCH2CH2), 14.3 (OCH2CH3).
d
7.59 (1H, t, J¼5.5 Hz, NH), 7.39–7.04 (10H, m, Ph), 5.71 (1H, s,
NCHCO), 5.30 (1H, d, PhCH2N, J¼17.0 Hz), 4.73 (1H, d, PhCH2N,
J¼17.0 Hz), 4.17 (2H, q, J¼7.2 Hz, OCH2CH3), 3.95 (1H, d, PhCH2S,
J¼11.2 Hz), 3.86 (1H, d, PhCH2S, J¼11.2 Hz), 3.89 (1H, dd, J¼5.5,
18.0 Hz, NHCH2COO), 3.72 (1H, dd, J¼5.5, 18.0 Hz, NHCH2COO), 2.02
(3H, s, CH3CO), 1.59 (3H, s), 1.55 (3H, s), 1.26 (3H, t, J¼7.2 Hz,
4.6.2. Ethyl 1-benzyl-5-[(benzylthio)methyl]-5-methyl-4,5-
dihydro-1H-imidazole-4-carboxylate (21)
The product was prepared as described for 20 in 0.12 g (31%)
unoptimized yield as an oily 2:1 mixture of two separable di-
astereomers. [Found: C, 69.23; H, 6.94. C22H26N2O2S requires C,
69.08; H, 6.85%.] nmax (neat, cmꢁ1): 1750 (COO),1600 (C]N); Major:
OCH2CH3). 13C NMR (100 MHz, CDCl3):
d 174.1, 169.5, 168.9, 138.4,
138.0, 129.4, 128.6, 127.0, 126.8, 125.7, 61.3 (OCH2CH3), 60.5
(NCHCO), 50.7 (SCquat), 50.1 (PhCH2N), 41.0 (NCH2CO), 33.7
(PhCH2S), 26.8, 26.2, 22.8 (CH3CO), 14.2 (OCH2CH3).
1H NMR (400 MHz, CDCl3):
d 7.38–7.20 (10H, m, Ph), 6.83 (1H, s,
CH), 4.81 (1H, s, CH), 4.27–4.16 (2H, m, OCH2CH3), 4.07 (1H, d,
J¼15.2 Hz, PhCH2N), 4.05 (1H, d, J¼15.2 Hz, PhCH2N), 3.74 (2H, s,
PhCH2S), 2.83 (1H, d, J¼12.8 Hz, CH2SBn), 2.70 (1H, d, J¼12.8 Hz,
CH2SBn), 1.29 (3H, t, J¼7.1 Hz, OCH2CH3), 1.14 (3H, s). 13C NMR
4.5.5. Ethyl N-acetyl-N,S-dibenzylhomocysteylglycinate (19e)
Method D. Yield 0.317 g, 72%. White solid. Mp 97–98 ꢀC. Rf (EA–
hexanes 1:1) 0.4. [Found: C, 65.42; H, 6.69. C24H30N2O4S requires C,
65.13; H, 6.83%.] nmax (Nujol, cmꢁ1): 3235 (NH), 1750 (COO), 1685
(100 MHz, CDCl3):
d 170.8, 156.4 (C]N), 138.1, 137.2, 128.9, 128.8,
(amide), 1625 (amide). 1H NMR (400 MHz, CDCl3):
d
7.37–7.14 (10H,
128.6,128.1,127.9,127.2, 75.4 (CHCOO), 67.2 (Cquat), 60.9 (OCH2CH3),
46.3 (PhCH2N), 40.6 (BnSCH2), 37.4 (PhCH2S), 19.2 (CCH3), 14.3
m), 7.03 (1H, t, J¼5.4 Hz), 5.13 (1H, dd, J¼6.1, 8.8 Hz), 4.60 (1H, d,
J¼17.8 Hz, PhCH2N), 4.50 (1H, d, J¼17.8 Hz, PhCH2N), 4.19 (2H, q,
J¼7.2 Hz, OCH2CH3), 3.96 (1H, dd, J¼5.4, 18.0 Hz, NHCH2COO), 3.84
(1H, dd, J¼5.4, 18.0 Hz, NHCH2COO), 3.64 (2H, s, PhCH2S), 2.46–2.17
(3H, m), 2.12 (3H, s, CH3CO), 1.82–1.73 (1H, m), 1.28 (3H, t, J¼7.2 Hz,
(OCH2CH3). Minor: 1H NMR (400 MHz, CDCl3):
d 7.38–7.20 (10H, m,
Ph), 6.87 (1H, s, CH), 4.45 (1H, s, CH), 4.28–4.17 (2H, m, OCH2CH3),
4.08 (1H, d, J¼15.2 Hz, PhCH2N), 4.08 (1H, d, J¼15.2 Hz, PhCH2N),
3.65 (1H, d, J¼13.6 Hz, PhCH2S), 3.59 (1H, d, J¼13.6 Hz, PhCH2S),
2.78 (1H, d, J¼12.6 Hz, CH2SBn), 2.66 (1H, d, J¼12.6 Hz, CH2SBn),
1.38 (3H, s), 1.30 (3H, t, J¼7.2 Hz, OCH2CH3). 13C NMR (100 MHz,
OCH2CH3). 13C NMR (100 MHz, CDCl3):
d 173.3, 170.7, 169.5, 138.3,
137.2, 128.9, 128.5, 127.5, 127.0, 126.1, 61.37 (OCH2CH3), 56.5
(NCHCO), 49.7 (PhCH2N), 41.2 (NCH2CO), 36.0 (PhCH2S), 27.9, 27.8,
22.4 (CH3CO), 14.19 (OCH2CH3).
CDCl3):
d 170.8, 156.4 (C]N), 138.0, 137.2, 128.7, 128.5, 127.8, 127.7,
127.2, 78.2 (CHCOO), 61.5 (Cquat), 61.1 (OCH2CH3), 46.6 (PhCH2N),
37.8 (PhCH2S), 36.3 (BnSCH2), 26.0 (CCH3), 14.1 (OCH2CH3).
4.5.6. N2-Acetyl-N2,S-dibenzyl-N1-[(4-methyl-2,6,7-trioxabicyclo-
[2.2.2]oct-1-yl)methyl]cysteinamide (19f)
4.7. General procedure for synthesis of glutathione
derivatives 22a–k
Method D. Yield 0.181 g, 39%. White solid. Mp 152–154 ꢀC. Rf (EA)
0.49. [Found: C, 64.52; H, 6.60. C26H32N2O5S requires C, 64.44; H,
6.66%.] nmax (Nujol, cmꢁ1): 3310 (NH), 1680 (amide), 1630 (amide).
Method E. A solution of carbonyl compound (1 mmol), benzyl-
amine (1 mmol), acid 12 or 13 (1 mmol), and ethyl isocyanoacetate
(1 mmol) in methanol (2 mL) for aldehyde 7 or trifluoroethanol
(2 mL) for ketones 3 and 6 was kept at rt for 2 h for aldehyde 7 and
2–3 days for ketones. Then the mixture was evaporated and the
residue was chromatographed (gradient elution EA–hexanes 1:2 or
1:1/3:2 or 1:0). In the case of 23 all reactions were run in
methanol. In all cases the products were obtained as 1:1 mixtures
of diastereomers.
1H NMR (400 MHz, CDCl3):
d 7.30–7.13 (10H, m, Ph), 6.50 (1H, br t),
5.22 (1H, t), 4.58 (1H, d, J¼18 Hz, PhCH2N), 4.52 (1H, d, J¼18 Hz,
PhCH2N), 3.92 (6H, s), 3.71 (2H, s, PhCH2S), 3.41 (2H, m), 2.91 (1H,
dd, J¼8.0, 13.9 Hz, CH2SBn), 2.66 (1H, dd, J¼7.1, 13.9 Hz, CH2SBn),
2.09 (3H, s), 0.83 (3H, s). 13C NMR (100 MHz, CDCl3):
d 172.9, 169.4,
138.0, 137.2, 129.0 (2C), 128.8 (2C), 128.5 (2C), 127.3, 127.1, 126.1
(2C), 107.0, 72.7, 56.6 (NCHCO), 49.3 (PhCH2N), 43.8 (NCHOBO), 36.3
(PhCH2S), 30.6 (Cquat), 29.8 (BnSCH2), 22.2 (CH3CO), 14.4.
Method F. Similar to method B (use 18 or 23 instead of benzyl-
isocyanide and 12 or 13 instead of acetic acid). Use gradient elution
EA–hexanes 1:2 or 1:1/3:2 or 1:0.
4.6. Imidazolines 20 and 21
4.6.1. Ethyl 1-benzyl-5-[2-(benzylthio)ethyl]-5-methyl-4,5-
dihydro-1H-imidazole-4-carboxylate (20)
4.7.1. Ethyl N,S-dibenzyl-N-{(4S)-4-(benzyloxycarbonyl)-4-[(tert-
butoxycarbonyl)amino]butanoyl}-cysteinylglycinate (22a)
A
mixture of carbonyl compound (1 mmol), benzylamine
(1 mmol), and ethyl isocyanoacetate (1 mmol) and Na2SO4 (0.1 g) in
ethanol (1 mL) was kept at rt for 2 days. Then the mixture was
evaporated, the residue was chromatographed (gradient elution
CH2Cl2–EtOH–NH3aq 100:5:0.5). The product was obtained in
0.201 g (51%) unoptimized yield as an oily 2:1 mixture of two in-
separable diastereomers. [Found: C, 69.89; H, 7.03. C23H28N2O2S
requires C, 69.66; H, 7.12%.] nmax (neat, cmꢁ1): 1750 (COO), 1600
Method F. Mixture of diastereomers, some NMR signals were
assigned to an accompanying diastereomer and are given in pa-
rentheses. Yield 0.153 g, 22%. Sticky oil. [Found: C, 65.41; H, 7.02.
C39H49N3O8S requires C, 65.07; H, 6.86%.] nmax (Nujol, cmꢁ1): 3320
(NH), 1750 (COO), 1720 (carbamate), 1670 (amide), 1630 (amide). 1H
NMR (400 MHz, CDCl3):
d
7.38–7.11 (16H, m, PhþNH), 5.43–5.30
(2H, m, NHþNCHCO), 5.18–5.12 (2H, m, PhCH2O), 4.65–4.38 (3H, m,
PhCH2NþCHNBoc), 4.20 (2H, m, OCH2CH3), 4.13–3.81 (2H, m,
CH2NH), 3.72 (3.68) (2H, s, PhCH2S), 3.14–2.98 (1H, m, BnSCHH),
2.67 (2.51) (1H, m, BnSCHH), 2.41–2.2 (3H, m), 2.03–1.8 (1H, m),
1.42 (9H, s, C(CH3)3), 1.28 (3H, t, OCH2CH3, J¼7.1 Hz). 13C NMR
(C]N); Major: 1H NMR (400 MHz, CDCl3):
d 7.34–7.20 (10H, m, Ph),
6.85 (1H, s, CH), 4.46 (1H, s, CH), 4.29–4.16 (2H, m, OCH2CH3), 4.07
(2H, s, PhCH2N), 3.69 (2H, s, PhCH2S), 2.39 (2H, m), 1.94–1.74 (2H,
m), 1.30 (3H, t, J¼7.2 Hz, OCH2CH3), 1.10 (3H, s). 13C NMR (100 MHz,
CDCl3):
d
170.7, 156.7 (C]N), 138.1, 137.2, 128.8, 128.6, 127.9, 127.7,
(100 MHz, CDCl3): d [174.2, 172.5 (172.4), 170.0 (169.9),169.7 (169.6)

4700
A.G. Zhdanko et al. / Tetrahedron 65 (2009) 4692–4702
(C]O)], 155.8 (155.6), 137.9 (137.8), 136.9 (136.7), 135.4 (135.3),
129.00 (128.99), 128.9 (128.8), 128.60, 128.55, 128.4, 128.3, 127.6,
127.5, 127.1, 127.0, 126.4, 126.2, 79.9 (OC(CH3)3), 67.20 (67.16)
(PhCH2O), 61.4 (61.3) (OCH2CH3), 57.6 (57.1) (NCHCO), 53.0 (52.89)
(CHNBoc), 49.6 (49.3) (PhCH2N), 41.4 (41.2) (NCH2CO), 36.4 (36.3)
(PhCH2S), 29.7 (29.6) (CH2CH2CON), 29.5 (29.4) (BnSCH2), 28.3
(C(CH3)3), 27.7 (CH2CH2CON), 14.19 (14.18) (OCH2CH3).
61.31 (61.27) (OCH2CH3), 52.8, 52.34 (52.29), 48.3 (48.1) (PhCH2N),
41.6 (NCH2CO), [36.9, 36.0, 35.93, 35.89 (2C) (PhCH2SCH2CH2)], 30.5
(30.4) (CH2CH2CON), 28.3 (C(CH3)3), 28.0 (27.7) (CH2CH2CON), 25.9
(25.8) (SCH2CH2), 22.0 (21.1) (CCH3), 14.2 (OCH2CH3).
4.7.5. Ethyl N-{(4S)-4-(methyloxycarbonyl)-4-[(tert-butoxycarbon-
yl)amino]butanoyl}-N,S-dibenzyl-2-methylcysteinylglycinate (22e)
Method E. Mixture of diastereomers, some NMR signals were
assigned to an accompanying diastereomer and are given in
parentheses. Yield 0.074 g (on 0.5 mmol scale), 23%. Sticky oil. [Found:
C, 61.22; H, 7.11. C33H45N3O8S requires C, 61.57; H, 7.05%.] nmax (Nujol,
cmꢁ1): 3290 (NH), 1750 (COO), 1715 (carbamate), 1670 (amide), 1640
4.7.2. Ethyl N-{(4S)-4-(methyloxycarbonyl)-4-[(tert-butoxy-
carbonyl)amino]butanoyl}-N-benzyl-3-(benzylthio)-
valylglycinate (22b)
Method E. Mixture of diastereomers, some NMR signals were
assigned to an accompanying diastereomer and are given in pa-
rentheses. Yield 0.375 g, 57%. White solid. Mp 55–60 ꢀC. [Found: C,
61.90; H, 7.04. C34H47N3O8S requires C, 62.08; H, 7.20%.] nmax (Nujol,
cmꢁ1): 3300 (NH), 1750 (COO), 1715 (carbamate), 1680 (amide),
(amide). 1H NMR (400 MHz, CDCl3):
d 7.46–7.21 (10H, m, Ph), 6.62
(6.51) (1H, t, NH), 5.37 (5.16) (1H, d, J¼7.3 Hz NH), 4.74 and 4.66 (2d)
(4.70, s) (2H, PhCH2N), 4.23 (1H, m, CHNHBoc), 4.22 (4.21) (2H, q,
J¼7.1 Hz, OCH2CH3), 4.08 (1H, m, CH2NH), 3.95 (1H, m, CH2NH), 3.71
(3.68) (3H, s, OCH3), 3.65 (2H, s, PhCH2S), 3.64–3.01 (2H, 4d, SCH2C,
J¼13.0 Hz), 2.41 (2H, m, CH2), 2.20 (1H, m, CHH),1.91 (1H, m, CHH),1.42
(9H, s, C(CH3)3),1.40 (3H, s, CH3),1.29 (1.28) (3H, t, OCH2CH3, J¼7.1 Hz).
1640 (amide). 1H NMR (400 MHz, CDCl3):
d 7.4–7.12 (10H, m, Ph),
6.74 (6.67) (1H, br d, NH), 5.62 (5.58) (1H, s, NCHCO), 5.20–4.70 (3H,
m, PhCH2NþNH), 4.25–4.17 (3H, q, OCH2CH3þCHNHBoc), 3.95–3.83
(4H, m, CH2NHþPhCH2S), 3.66 (3H, s, OCH3), 2.40–2.04 (3H, m),
1.95–1.78 (1H, m), 1.58 (3H, s, CH3), 1.53 (1.52) (3H, s, CH3), 1.43 (9H,
s, C(CH3)3), 1.29 (3H, t, OCH2CH3). 13C NMR (100 MHz, CDCl3):
13C NMR (100 MHz, CDCl3):
d [173.8, 173.71, 173.67, 173.5 (2C) (C]O)],
173.0 (172.9), 170.2, 155.8 (155.5), 138.4, 138.2 (138.1), 129.2 (2C), 128.9
(2C), 128.6 (2C), 127.5, 127.22 (127.19), 126.1 (126.0) (2C), 79.9
(OC(CH3)3), 65.4 (65.2) (NCquatCO), 61.4 (61.3) (OCH2CH3), [52.96
(52.87), 52.30 (52.26), (OCH3þCHNBoc)], 49.5 (49.2) (PhCH2N), 41.8
(41.7) (NCH2CO), [37.98, 37.86, 37.7 (2C) (PhCH2SCH2C)], 30.6 (30.5)
(CH2CH2CON), 28.33 (28.26) (C(CH3)3), 27.7 (27.5) (CH2CH2CON), 23.0
(22.8) (CCH3), 14.2 (OCH2CH3).
d
[175.5, 173.0 (172.9), 169.6 (169.5), 168.8 (C]O)], 155.6 (155.4),
138.3 (138.1), 138.1 (138.0), 129.3, 128.7, 128.5, 126.9, 125.8, 125.7,
79.7 (OC(CH3)3), 61.41 (61.37) (OCH2CH3), 60.77 (NCHCO), [53.2
(52.9), 52.3 (OCH3þCHNBoc)], 50.3 (SCquat), 50.1 (PhCH2N), 41.1
(40.9) (NCH2CO), 33.7 (PhCH2S), 30.5 (30.2) (CH2CH2CON), 28.3
(C(CH3)3), 28.0 (27.9) (CH2CH2CON), 26.8 (26.6) (CCH3), 26.3 (26.2)
(CCH3), 14.2 (OCH2CH3).
4.7.6. Ethyl N,S-dibenzyl-N-{(4S)-4-(benzyloxycarbonyl)-4-[(tert-
butoxycarbonyl)amino]butanoyl}-homocysteylglycinate (22f)
Method F. Mixture of diastereomers, some NMR signals were
assigned to an accompanying diastereomer and are given in pa-
rentheses. Yield 0.48 g, 67%. Sticky oil. [Found: C, 65.33; H, 6.98.
C39H49N3O8S requires C, 65.07; H, 6.86%.] nmax (Nujol, cmꢁ1): 3300
(NH), 1750 (COO), 1715 (carbamate), 1680 (amide), 1640 (amide). 1H
4.7.3. Ethyl N-{(4S)-4-(methyloxycarbonyl)-4-[(tert-butoxycarb-
onyl)amino]butanoyl}-N,S-dibenzylhomocysteylglycinate (22c)
Method F. Mixture of diastereomers, some NMR signals were
assigned to an accompanying diastereomer and are given in paren-
theses. Yield 0.235 g, 37%. Sticky oil. [Found: C, 61.22; H, 7.14.
C33H45N3O8S requires C, 61.57; H, 7.05%.] nmax (Nujol, cmꢁ1): 3310
(NH), 1750 (COO), 1720 (carbamate), 1680 (amide), 1630 (amide). 1H
NMR (400 MHz, CDCl3):
d
7.38–7.12 (16H, m, PhþNH), 5.35–5.29
(2H, m, NHþNCHCO), 5.14 (2H, m, PhCH2O), 4.62–4.35 (3H, m,
PhCH2NþCHNBoc), 4.19 (2H, q, OCH2CH3), 4.08–3.80 (2H, m,
CH2NH), 3.64 (3.63) (2H, s, PhCH2S), 2.52–2.2 (6H, m), 1.83–1.69
(2H, m), 1.41 (9H, s, C(CH3)3), 1.27 (3H, t, OCH2CH3, J¼7.1 Hz). 13C
NMR (400 MHz, CDCl3): d 7.36–7.14 (10H, m, Ph), 6.98, 5.37, 5.27, 4.98,
4.67–4.91 (2H, PhCH2N), 4.34 (1H, m, CHNHBoc), 4.20 (2H, q,
OCH2CH3, J¼7.1 Hz), 4.11–3.81 (2H, m, CH2NH), 3.73–3.50 d, d, s (5H,
COOCH3, PhCH2S), 2.55–1.75 (8H, m, 4CH2),1.43 (9H, s, C(CH3)3), 1.29
NMR (100 MHz, CDCl3):
d [174.1, 172.5 (172.4), 170.8 (170.6), 169.9
(3H, t, OCH2CH3, J¼7.1 Hz). 13C NMR (100 MHz, CDCl3):
d
[174.2, 173.2
(169.7) (C]O)], 155.8 (155.7), 138.3, 137.3 (137.1), 135.5 (135.4),
128.9, 128.6, 128, 128.3, 128.2, 127.50 (127.46), 126.9, 126.4, 126.1,
79.9 (OC(CH3)3), 67.0 (PhCH2O), 61.23 (61.18) (OCH2CH3), 57.2 (56.8)
(NCHCO), 53.0 (52.9) (CHNBoc), 49.5 (49.2) (PhCH2N), 41.3 (41.1)
(NCH2CO), 35.9 (PhCH2S), 29.7 (29.6) (CH2CH2CON), 28.3 (C(CH3)3),
28.1, 27.6 (CH2CH2CONþSCH2CH2), 14.2 (OCH2CH3).
(172.9), 170.8 (170.7),169.8 (169.7) (C]O)],155.8 (155.6),138.3,138.1
(138.0),129.2,128.97 (128.92) (2C),128.4 (2C),127.5,127.0,126.0 (2C),
79.9 (OC(CH3)3), 61.3 (OCH2CH3), 57.3 (56.9) (NCHCO), 52.8 (52.6),
52.44 (52.37), 49.6 (49.3) (PhCH2N), 41.3 (41.1) (NCH2CO), 35.9
(PhCH2S), 29.7 (29.5) (CH2CH2CON), [28.5, 28.1, 28.3, 28.0, 27.0
(C(CH3)3þCH2CH2CONþSCH2CH2)], 14.2 (OCH2CH3).
4.7.7. Ethyl N-{(4S)-4-(benzyloxycarbonyl)-4-[(tert-butoxycarbon-
yl)amino]butanoyl}-N,S-dibenzyl-2-methylcysteinylglycinate (22g)
Method E. Mixture of diastereomers, some NMR signals were
assigned to an accompanying diastereomer and are given in pa-
rentheses. Yield 37%. Sticky oil. Rf (EA–hexanes 1:1) 0.46. [Found: C,
64.83; H, 6.95. C39H49N3O8S C, 65.07; H, 6.86%.] nmax (Nujol, cmꢁ1):
3320 (NH), 1750 (COO), 1720 (carbamate), 1680 (amide), 1645
4.7.4. Ethyl N-{(4S)-4-(methyloxycarbonyl)-4-[(tert-butoxycarbon-
yl)amino]butanoyl}-N-benzyl-4-(benzylthio)isovalylglycinate (22d)
Method E. Mixture of diastereomers, some NMR signals were
assigned to an accompanying diastereomer and are given in pa-
rentheses. Yield 0.111 g (on 0.5 mmol scale), 33%. Sticky oil. [Found:
C, 62.43; H, 7.52. C34H47N3O8S requires C, 62.08; H, 7.20%.] nmax
(Nujol, cmꢁ1): 3240 (NH), 1750 (COO), 1715 (carbamate), 1670
(amide). 1H NMR (400 MHz, CDCl3):
d 7.42–7.23 (15H, m, Ph), 6.60
(amide), 1630 (amide). 1H NMR (400 MHz, CDCl3):
d
7.46–7.21 (10H,
(6.50) (1H, br t, NH), 5.42 (5.25) (1H, br d, NH), 5.11 (5.09) (2H, s,
PhCH2O), 4.7, 4.63 (2d) (4.66, s) (2H, PhCH2N), 4.28 br s (1H,
CHNBoc), 4.28 (4.19) (2H, q, OCH2CH3), 4.11 (dd, J¼5.1, 18.4 Hz) and
3.92 (dd, J¼3.79, 18.4 Hz) (4.02, br s) (2H, NCH2COO), 3.72 (1H, d,
J¼13.9 Hz, PhCH2S), 3.68 (1H, d, J¼13.9 Hz, PhCH2S), 3.61–3.49 (1H,
2d, J¼12.6 Hz), 3.09–3.00 (1H, 2d, J¼12.6 Hz) (2H, SCH2C), 2.41 (2H,
m), 2.20 (1H, m), 1.94 (1H, m), 1.42 (9H, s, C(CH3)3), 1.39 (3H, s, CH3),
m, Ph), 6.53 (6.43) (1H, t, NH), 5.29 (5.25) (1H, d, NH), 4.60 and 4.49
(2d) (4.52, s) (2H, PhCH2N), 4.23 (1H, m, CHNHBoc), 4.22 (4.21) (2H,
q, OCH2CH3, J¼7.1 Hz), 4.10 (1H, m, CH2NH), 3.90 (1H, m, CH2NH),
3.75–3.59 m (5H, COOCH3, PhCH2S), 2.53–2.18 (6H, m, 3CH2), 2.05
(1H, m),1.82 (1H, m),1.43 (9H, s, C(CH3)3),1.39 (3H, s, CH3),1.29 (3H,
t, OCH2CH3, J¼7.1 Hz). 13C NMR (100 MHz, CDCl3):
d [173.8, 173.5,
173.4, 173.2 (2C) (C]O)], 172.9 (C]O), 170.3 (C]O), 155.5, 138.2,
138.1 (138.0), 129.2 (129.1) (2C), 128.97 (128.92) (2C), 128.4 (2C),
127.5, 127.0, 126.0 (2C), 79.9 (OC(CH3)3), 65.3 (65.2) (NCquatCO),
1.28 (1.26) (3H, t, OCH2CH3). 13C NMR (100 MHz, CDCl3):
d [173.8,
173.7, 173.5, 172.4, 172.3, 170.2, (C]O)], 155.8 (155.6) (NCOO),
[138.4, 138.2 (138.1), 135.4, 129.2, 128.9, 128.6, 128.3, 128.2, 127.5,

A.G. Zhdanko et al. / Tetrahedron 65 (2009) 4692–4702
4701
127.2, 126.1, 126.0 (Ph)], 79.8 (OC(CH3)3), 67.04 (66.96) (PhCH2O),
65.4 (65.2) (Cquat.), 61.4 (61.3) (OCH2CH3), 53.2 (53.1) (CHNBoc),
49.5 (49.2) (PhCH2N), 41.8 (41.7) (NCH2COO), 37.9 (37.8), 37.8 (37.7),
30.6 (30.5) (CH2CH2CON), 28.32 (28.27) (C(CH3)3), 27.5 (27.2)
(CH2CH2CON), 23.0 (22.8) (CCH3), 14.1 (OCH2CH3).
[129.20, 129.17, 128.9, 128.6, 128.4, 128.3, 128.2, 127.4, 127.3, 127.1,
126.13, 126.08], 107.2 (Cquat), 79.8 (OC(CH3)3), 72.6 (3CH2), 67.03
(66.95) (PhCH2O), 65.38 (65.35) (NCquatCO), 53.42 (53.43)
(CHNBoc), 49.4 (49.3) (PhCH2N), 44.2 (44.1) (NCH2OBO), 37.9, 37.8
(PhCH2SþSCH2C), 30.7, 30.6 (CH2CH2CONþCquat), 28.32 (28.26)
(C(CH3)3), 27.5 (27.2) (CH2CH2CON), 23.0 (CCH3), 14.3 (CCH3).
4.7.8. Ethyl N-{(4S)-4-(benzyloxycarbonyl)-4-[(tert-butoxycarbo-
nyl)amino]butanoyl}-N-benzyl-3-(benzylthio)valylglycinate (22h)
Method E. Mixture of diastereomers, some NMR signals were
assigned to an accompanying diastereomer and are given in pa-
rentheses. Yield 0.52 g (71%). White solid. Rf (EA–hexanes 1:1) 0.5.
[Found: C, 65.73; H, 6.91. C40H51N3O8S require C, 65.46; H, 7.00%.]
nmax (Nujol, cmꢁ1): 3290 (NH), 1750 (COO), 1715 (carbamate), 1680
4.7.11. Benzyl (2S)-5-{benzyl[3-(benzylthio)-1-methyl-1-{[(4-methyl-
2,6,7-trioxabicyclo[2.2.2]oct-1-yl)methyl]carbamoyl}propyl]amino}-2-
[(tert-butoxycarbonyl)amino]-5-oxopentanoate (22k)
Method E. Mixture of diastereomers, some NMR signals were
assigned to an accompanying diastereomer and are given in pa-
rentheses. Yield 0.41 g, 52%. White solid. Mp 78–80 ꢀC. Rf (EA–
hexanes 1:1) 0.2, (EA) 0.6. [Found: C, 65.85; H, 7.29. C43H55N3O9S
requires C, 65.38; H, 7.02%.] nmax (Nujol, cmꢁ1): 3280 (NH), 1750
(COO), 1720 (carbamate), 1660 (amide), 1635 (amide). 1H NMR
(amide), 1640 (amide). 1H NMR (400 MHz, CDCl3):
d 7.4–7.12 (10H,
m, Ph), 6.67 (6.62) (1H, br d, NH), 5.60 (5.57) (1H, s, NCHCO), 5.28–
5.06 (4H, m, PhCH2OþNH PhCH2N), 4.65 (4.61) (1H, d, PhCH2N),
4.22 (3H, m, OCH2CH3þCHNHBoc), 3.95–3.84 (4H, m,
CH2NHþPhCH2S), 2.37–2.07 (3H, m), 1.94 (1H, m), 1.57 (3H, s, CH3),
1.52 (1.51) (3H, s, CH3), 1.42 (9H, s, C(CH3)3), 1.29 (3H, t, OCH2CH3).
(400 MHz, CDCl3):
d 7.39–7.22 (15H, m, Ph), 6.08 (5.96) (1H, br t,
NH), 5.27 (1H, d, NH), 5.16–5.09 (2d) (5.11, s) (2H, PhCH2O), 4.56–
4.41 (2H, m, PhCH2N), 4.23 (1H, br s, CHNBoc), 3.86 (6H, s, 3CH2),
3.65 (2H, s, PhCH2S), 3.59–3.40 (2H, m, NCH2OBO), 2.51–2.14 (6H,
m), 1.98 (2H, m), 1.42 (9H, s, C(CH3)3), 1.37 (s) (1.36, s) (3H, CH3),
13C NMR (100 MHz, CDCl3):
d [175.55 (175.51), 172.5 (172.3), 169.8
(169.7), 168.9 (C]O)], 155.7 (155.5), 138.5 (138.4), 138.01 (137.97),
135.5,129.3,128.7,128.61,128.58,128.48,128.39,128.3,128.2,126.9,
126.8, 125.8, 125.6, 79.63 (79.55) (OC(CH3)3), 66.92 (66.87)
(PhCH2O), 61.3 (OCH2CH3), 60.0 (NCHCO), 53.5 (53.2) (CHNBoc),
50.4 (50.3) (SCquat), 49.9 (PhCH2N), 41.0 (40.9) (NCH2CO), 33.6
(PhCH2S), 30.7 (30.5) (CH2CH2CON), 28.4 (C(CH3)3), 27.9 (27.6)
(CH2CH2CON), 26.9 (CCH3), 26.1 (CCH3), 14.2 (OCH2CH3).
0.79 (3H, s, CH3). 13C NMR (100 MHz, CDCl3):
d [173.3, 173.1, 172.3,
170.9 (C]O)], 155.6 (NCOO), 138.4, 138.30, 138.28, 135.5, [129.07,
129.05, 128.91, 128.88, 128.55, 128.47, 128.3, 127.26, 127.38, 127.0,
126.1], 107.28 (107.25) (Cquat), 79.8 (OC(CH3)3), 72.6 (3CH2), 66.99
(66.96) (PhCH2O), 65.3 (NCquatCO), 53.3 (CHNBoc), 48.1 (PhCH2N),
44.0 (43.9) (NCH2OBO), 36.11, 36.09 (PhCH2SCH2C), 30.63, 30.56
(CH2CH2CONþCquat), 28.3 (C(CH3)3), 27.6 (27.5) (CH2CH2CON),
26.00 (25.97) (SCH2CH2), 21.7 (21.6) (CCH3), 14.3 (CCH3).
4.7.9. Benzyl (2S)-5-{benzyl[2-(benzylthio)-2-methyl-1-{[(4-methyl-
2,6,7-trioxabicyclo[2.2.2]oct-1-yl)methyl]carbamoyl}propyl]amino}-
2-[(tert-butoxycarbonyl)amino]-5-oxopentanoate (22i)
4.8. Homoglutathione derivatives 25a–c
Method E. Mixture of diastereomers, some NMR signals were
assigned to an accompanying diastereomer and are given in paren-
theses. Yield 0.596 g, 76%. White solid. Rf (EA–hexanes 1:1) 0.38, (EA)
0.58. [Found:C, 65.14; S, 4.34; H, 7.05. C43H55N3O9S require C, 65.38; S,
4.06; H, 7.02%.] nmax (Nujol, cmꢁ1): 3340 (NH), 1750 (COO), 1715
(carbamate),1680 (amide), 1640 (amide). 1H NMR (400 MHz, CDCl3):
4.8.1. Ethyl N,S-dibenzyl-N-{(4S)-4-(benzyloxycarbonyl)-4-[(tert-
butoxycarbonyl)amino]butanoyl}-cysteinyl-b-alaninate (25a)
Aldehyde 1 (1 mmol) was slowly (in 20 min) added dropwise to
a mixture of benzylamine (1 mmol), acid 13 (1 mmol), and 24
(1 mmol) in 1 mL of trifluoroethanol. The reaction mixture was
stirred at rt for additional 2 h and was evaporated, the residue was
chromatographed (gradient elution EA–hexanes 1:2/2:3) to af-
ford the title compound (0.314 g, 44%) as an 1:1 oily mixture of
diastereomers, some NMR signals were assigned to an accompa-
nying diastereomer and are given in parentheses. [Found: C, 65.41;
H, 6.97. C39H49N3O8S requires C, 65.07; H, 6.86%.] nmax (Nujol,
cmꢁ1): 3300 (NH), 1750 (COO), 1720 (carbamate), 1670 (amide),
d
7.39–7.11 (15H, m, Ph), 6.32 (1H, br s, NH), 5.51 (1H, s, NCH), 5.30–
5.06 and 4.62–4.54 (5H, m, PhCH2NþNHþPhCH2O), 4.20 (1H, br s,
CHNBoc), 3.93 (3.92) (6H, s, 3CH2), 3.47–3.28 (2H, m, NCH2OBO), 2.33
(m), 2.14, 2.00,1.80,1.57 (1.55) (3H, s, CH3),1.50 (1.49) (3H, s, CH3),1.42
(9H, s, C(CH3)3), 0.84 (0.83) (3H, s, CH3). 13C NMR (100 MHz, CDCl3):
d
175.4 (175.2), 172.3, 168.30 (168.27), 155.5 (155.4) (NCOO), 138.5
(138.3), 137.9 (137.8), 135.5, [129.3, 128.7, 128.6, 128.5, 128.4, 128.3,
126.9, 125.9, 125.8], 107.0 (Cquat), 79.7 (OC(CH3)3), 72.7 (3CH2), 67.0
(66.9) (PhCH2O), w61 (NCHCO), 53.5 (53.1) (CHNBoc), 50.1–49.9
(PhCH2NþSCquat), 43.8 (43.7) (NCH2OBO), 33.7 (PhCH2S), 30.6, 30.4
(CH2CH2CONþCquat), 28.3 (C(CH3)3), 27.8 (27.4) (CH2CH2CON), 26.5
(C(CH3)2), 14.4 (CCH3).
1640 (amide). 1H NMR (400 MHz, CDCl3):
d 7.38–7.11 (15H, m, Ph),
6.87 (6.80) (1H, br t, NH), 5.34 (5.30) (1H, d, J¼8.1 Hz, NH), 5.19–5.12
(2.5H, m, PhCH2Oþ1/2NCHCO), 4.80 (0.5H, m, 1/2NCHCO), 4.56–
4.35 (3H, m, PhCH2NþCHNBoc), 4.15 (2H, m, OCH2CH3), 3.70 (3.68)
(2H, s, PhCH2S), 3.44 (2H, m, NCH2CH2), 3.06–2.97 (1H, m, BnSCHH),
2.71 (2.58) (1H, m, BnSCHH), 2.49 (2.47) (2H, t, J¼7.1, NCH2CH2),
2.41–2.2 (3H, m), 2.03–1.8 (1H, m), 1.43 (9H, s, C(CH3)3), 1.26 (3H, t,
4.7.10. Benzyl (2S)-5-[benzyl(1-[(benzylthio)methyl]-1-methyl-2-{[(4-
methyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)methyl]amino}-2-oxoethyl)-
amino]-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoate (22j)
Method E. Mixture of diastereomers, some NMR signals were
assigned to an accompanying diastereomer and are given in pa-
rentheses. Yield 0.356 g, 46%. White solid. Rf (EA–hexanes 1:1) 0.2,
(EA) 0.67. [Found: C, 65.39; H, 7.00. C42H53N3O9S requires C, 65.01;
H, 6.88%.] nmax (Nujol, cmꢁ1): 3270 (NH), 1750 (COO), 1710 (carba-
mate), 1670 (amide), 1635 (amide). 1H NMR (400 MHz, CDCl3):
OCH2CH3, J¼7.1 Hz). 13C NMR (100 MHz, CDCl3):
d [174.0 (173.76),
172.4, 172.0 (171.9), 169.3 (C]O)], 155.7, 138.0, 136.9 (136.7), 135.4,
129.00 (128.97), 128.85 (128.83), 128.58, 128.55, 128.4, 128.3, 127.6,
127.5, 127.1, 126.5, 126.2, 79.8 (OC(CH3)3), 67.1 (PhCH2O), 60.6
(OCH2CH3), 57.8 (57.2) (NCHCO), 53.1 (53.0) (CHNBoc), 49.6 (49.0)
(PhCH2N), 36.4 (PhCH2S), 35.2 (35.1), 34.0 (33.9), 30.0 (29.9)
(CH2CH2CON), 29.7 (29.6) (BnSCH2), 28.3 (C(CH3)3), 28.0 (27.6)
(CH2CH2CON), 14.2 (OCH2CH3).
d
7.39–7.25 (15H, m, Ph), 6.11 (1H, m, NH), 5.37 (5.22) (1H, d, NH),
5.11 (5.10) (2H, s, PhCH2O), 4.65 (2H, br s, PhCH2N), 4.24 (1H, br s,
CHNBoc), 3.85 (6H, s, 3CH2), 3.70 (2H, m, PhCH2S), 3.63–2.98 (4H,
m, NCH2OBO, CH2SBn), 2.38 (2H, m), 2.19 (1H, m), 2.04–1.94 (1H,
m), 1.42 (3H, s, CH3), 1.39 (9H, s, C(CH3)3), 0.79 (0.78) (3H, s, CH3).
4.8.2. Ethyl N-{(4S)-4-(benzyloxycarbonyl)-4-[(tert-butoxycarbonyl)-
amino]butanoyl}-N,S-dibenzyl-2-methylcysteinyl-b-alaninate (25b)
A solution of 6 (1 mmol), benzylamine (1 mmol), acid 13
(1 mmol), and isocyanide 24 (1 mmol) in trifluoroethanol (2 mL)
was kept at rt for 3 days. Then the mixture was evaporated, the
residue was chromatographed (gradient elution EA–hexanes 1:2 to
13C NMR (100 MHz, CDCl3):
d
[173.6, 173.5, 173.4, 172.3 (C]O)],
155.64 (155.56) (NCOO), 138.7, 138.23 (138.21), 135.43 (135.39),

4702
A.G. Zhdanko et al. / Tetrahedron 65 (2009) 4692–4702
B. M.; Malone, M. Ann. Pharmacother 1995, 29, 1263–1273; (d) Lands, L. C.; Grey,
V. L.; Smountas, A. A. J. Appl. Physiol. 1999, 87, 1381–1385.
2. (a) Meister, A. Cancer Res. 1994, 54, 1969S–1975S; (b) Ortolani, O.; Conti, A.; De
Gaudio, A. R.; Moraldi, E.; Novelli, G. P. Recent. Prog. Med. 2002, 93, 125–129; (c)
Amer, M. A. Ann. Nutr. Metab. 2002, 46, 165–168.
3. (a) Bounous, G.; Batist, G.; Gold, P. Cancer Lett. 1991, 57, 91–94; (b) Papen-
burg, R.; Bounous, G.; Fleiszera, D.; Goldb, P. Tumor. Biol. 1990, 11, 129–136;
(c) Bounous, G. Anticancer Res. 2000, 20, 4785–4792; (d) Bounous, G.; Pa-
penburg, R.; Kongshavn, P. A. L.; Gold, P.; Fleiszer, D. Clin. Inv. Med. 1988, 11,
213–217.
4. Kennedy, R. S.; Konok, G. P.; Bounous, G.; Baruchel, S.; Lee, T. D. G. Anticancer
Res. 1995, 15, 2643–2650.
5. (a) Foyer, C. H.; Halliwell, B. Planta 1976, 133, 21–25; (b) Winkler, B. S. Biochim.
Biophys. Acta 1992, 117, 287–290.
6. Baruchel, S.; Viau, G.; Olivier, R.; Bounous, G.; Wainberg, M. A. In Oxidative
Stress in Cancer, AIDS, and Neurodegenerative Diseases; Montagnier, L., Oliver, R.,
Pasquier, C., Eds.; Marcel Dekker: New York, NY, 1998; pp 447–461.
7. (a) Klapheck, S. Physiol. Plant. 1988, 74, 727–732; (b) Frendo, P.; Gallesi, D.;
2:3). Yield 0.33 g, 45%. Sticky oil. [Found: C, 65.35; H, 6.91.
C40H51N3O8S requires C, 65.46; H, 7.00%.] nmax (Nujol, cmꢁ1): 3270
(NH), 1750 (COO), 1720 (carbamate), 1680 (amide), 1630 (amide). 1H
NMR (400 MHz, CDCl3): d 7.41–7.23 (15H, m, Ph), 6.54 (1H, br t, NH),
5.37 (5.26) (1H, d, J¼7.6 Hz, NH), 5.12 (5.10) (2H, s, PhCH2O), 4.69–
4.59 (2H, m, PhCH2N), 4.25 (1H, br s, CHNBoc), 4.17–4.07 (2H, m,
OCH2CH3), 3.72–3.74 (2H, m, PhCH2S), 3.59–3.37 (3H, m,
BnSCHHþNCH2CH2), 3.00 (2.96) (1H, d, J¼12.6 Hz, BnSCHH), 2.62–
2.31 (6H, m), 2.17 (1H, m), 2.01–1.84 (1H, m), 1.42 (1.39) (9H, s,
C(CH3)3), 1.37 (1.36) (3H, s, CH3), 1.24 (1.23) (3H, t, OCH2CH3,
J¼7.1 Hz). 13C NMR (100 MHz, CDCl3):
d [173.8 (173.6), 173.5 (173.3),
173.1 (173.0), 172.30 (172.27) (C]O)], 155.6 (NCOO), [138.4, 138.14
(138.11), 135.4, 129.18 (129.15), 128.91, 128.58, 128.55, 128.4, 128.3,
128.27, 128.21, 127.46, 127.43, 127.16, 126.09, 126.04 (Ph)], 79.8
(OC(CH3)3), 67.05 (66.99) (PhCH2O), 65.37 (65.23) (Cquat.), 60.54
(60.51) (OCH2CH3), 53.2 (CHNBoc), 49.3 (49.2) (PhCH2N), 37.94,
37.84, 37.81 (PhCH2SCH2C), 35.27 (35.21), 33.45, 30.6 (CH2CH2CON),
28.31 (28.26) (C(CH3)3), 27.6 (27.3) (CH2CH2CON), 22.8 (22.7)
(CCH3), 14.2 (OCH2CH3).
´
Turnbull, R.; Van de Sype, G.; Herouart, D.; Puppo, A. Plant J. 1999, 17, 215–219;
(c) Matamoros, M. A.; Moran, J. F.; Iturbe-Ormaetxe, I.; Rubio, M. C.; Becana, M.
Plant Physiol. 1999, 121, 879–888; (d) Frendo, P.; Harrison, J.; Norman, C.; Her-
nandez Jimenez, M. J.; Van de Sype, G.; Gilabert, A. Puppo A. Mol. Plant-Microbe
Interact. 2005, 18, 254–259.
8. (a) Morera, E.; Nalli, M.; Pinnen, F.; Rossi, D.; Lucente, G. Bioorg. Med. Chem. Lett.
2000, 10, 1585–1588; (b) King, F. E.; Clark-Lewis, J. W.; Swindin, W. A. J. Chem.
Soc. 1959, 2259–2263.
9. (a) Willims, M.; Kowaluk, E. A.; Arneric, S. P. J. Med. Chem. 1999, 42, 1481–1500;
(b) Dutta, A. S. Drugs Future 1988, 13, 43–44; (c) Dutta, A. S. Drugs Future 1988,
13, 761–762; (d) Patane, M. A.; DiPardo, R. M.; Price, R. A. P.; Chang, R. S. L.;
Ransom, R. W.; O’Malley, S. S.; Di Salvo, J.; Block, M. G. Bioorg. Med. Chem. Lett.
1998, 8, 2495–2500; (e) Freidinger, R. M. J. Med. Chem. 2003, 46, 5553–5566; (f)
Huruby, V. J. Acc. Chem. Res. 2001, 34, 389–397; (g) Roy, R. S.; Balarm, P. J. Pept.
Res. 2004, 63, 279–289.
10. Groeger, H.; Hatam, M.; Kintscher, J.; Martens, J. Synth. Commun. 1996, 3383–
3394.
11. For a general review on the Ugi and other MCR reactions see: (a) Do¨mling, A.;
Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–3210; (b) Do¨mling, A. Chem. Rev.
4.8.3. Ethyl N-{(4S)-4-(methyloxycarbonyl)-4-[(tert-butoxycarbonyl)-
amino]butanoyl}-N-benzyl-4-(benzylthio)isovalyl-b-alaninate (25c)
A solution of 3 (1 mmol), benzylamine (1 mmol), acid 13
(1 mmol), and isocyanide 24 (1 mmol) in methanol (2 mL) was kept
at rt for 3 days. Then the mixture was evaporated, the residue was
chromatographed (gradient elution EA–hexanes 1:2 to 2:3) to af-
ford the title compound (0.50 g, 67%) as an 1:1 oily mixture of di-
astereomers, some NMR signals were assigned to an accompanying
diastereomer and are given in parentheses. [Found: C, 66.12; H,
7.07. C41H53N3O8S requires C, 65.84; H, 7.14%.] nmax (Nujol, cmꢁ1):
3320 (NH), 1750 (COO), 1720 (carbamate), 1665 (amide), 1640
´
2006, 106, 17–89; (c) Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44,
1602–1634.
12. Removal of benzyl group from protected glutathione derivatives was achieved
by Na–NH3 reduction: (a) Lyttle, M. H.; Satyam, A.; Hocker, M. D.; Bauer, K. E.;
Caldwell, C. G.; Hui, H. C.; Morgan, A. S.; Mergia, A.; Kauvar, L. M. J. Med. Chem.
1994, 37, 1501–1507; (b) Du Vigneaud, V.; Miller, G. L. J. Biol. Chem. 1936, 116,
469–476; Simultaneous removal of p-methoxybenzyl, CO2Bn, Boc groups from
a protected peptide was achieved by HF–PhSMe–m-cresol system: (c) Matsu-
moto, Y.; Okada, Y.; Min, K. S.; Onosaka, S.; Tanaka, K. Chem. Pharm. Bull. 1990,
38, 2364–2368; Hydrolysis of the ester group in the presence of SBn and Cbz
groups in fully protected glutathione was also reported: (d) Goldschmidt; Jutz.
Chem. Ber. 1953, 86, 1116–1120.
13. Non-protected carbonyls do not give any Ugi products because of formation of
bicyclic products of type 15.
14. Zervas, L.; Photaki, I.; Ghelis, N. J. Am. Chem. Soc. 1963, 85, 1337–1341.
15. Asinger, F.; Thiel, M.; Hauthal, H. G. Annalen 1959, 622, 83–93; Asinger, F.; Saus,
A.; Ba¨hr-Wirtz, M. Annalen 1979, 708–726.
(amide). 1H NMR (400 MHz, CDCl3):
d 7.40–7.20 (15H, m, Ph), 6.49
(6.42) (1H, br t, NH), 5.30 (1H, br t, NH), 5.17–5.09 (2H, 2dþs,
PhCH2O), 4.53 (d, J¼18.2 Hz) and 4.44 (d, J¼18.2 Hz) (4.45, s) (2H,
PhCH2N), 4.23 (1H, br s, CHNBoc), 4.13 (2H, q, OCH2CH3, J¼7.1 Hz),
3.63 (2H, s, PhCH2S), 3.47 (2H, m, NCH2CH2), 2.53 (2H, t, J¼5.8 Hz,
NCH2CH2), 2.47–2.11 (6H, m), 2.04–1.84 (2H, m), 1.42 (9H, s,
C(CH3)3), 1.33 (1.32) (3H, s, CH3), 1.25 (3H, t, OCH2CH3, J¼7.1 Hz). 13
C
NMR (100 MHz, CDCl3):
d [173.7 (173.6), 173.2, 173.1, 172.3 (C]O)],
155.6 (NCOO), 138.19 (138.15), 138.1, 135.4, [129.12, 128.93 (128.89),
128.6, 128.5, 128.3, 128.2, 127.5, 127.0, 126.0], 79.8 (OC(CH3)3),
67.02 (66.99) (PhCH2O), 65.20 (65.16) (NCquatCO), 53.26 (53.21)
(CHNBoc), 48.11 (48.05) (PhCH2N), [36.6 (36.1), 35.95, (35.91)
(PhCH2SCH2C)], 35.24 (35.22), 33.43, 30.6 (CH2CH2CON), 28.3
(C(CH3)3), 27.5 (CH2CH2CON), 25.78 (SCH2CH2), 21.6 (21.2) (CCH3),
14.2 (OCH2CH3).
16. Montano, R. G.; Zhu, J. Chem. Commun. 2002, 2448–2449.
17. These by-products are not clearly detectable on a TLC in EtOAc–hexanes due to
very low Rf, but become easily revealable in a more polar eluent such as DCM–
MeOH 10:1.
18. Several times 2,2,2-trifluoroethanol was used in the Ugi reaction: Marcaccini,
S.; Torroba, T. Nature Protocols 2007, 2, 632–639.
19. Elders, N.; Schmitz, R. F.; de Kanter, F. J. J.; Ruijter, E.; Groen, M. B.; Orru, R. V. A.
J. Org. Chem. 2007, 72, 6135–6142.
Acknowledgements
20. (a) Gulevich, A. V.; Shevchenko, N. E.; Balenkova, E. S.; Ro¨schenthaler, G.-V.;
Nenajdenko, V. G. Tetrahedron 2008, 64, 11706–11712; (b) Gulevich, A. V.;
Shevchenko, N. E.; Balenkova, E. S.; Ro¨schenthaler, G.-V.; Nenajdenko, V. G.
Synlett 2009, 403–406.
The authors would like to thank Dr. V. Muzalevskiy for NMR
analysis.
21. Schro¨der, E.; Klieger, E. Annalen 1964, 673, 196–207.
22. Zhdanko, A. G.; Nenajdenko, V. G. J. Org. Chem. 2009, 74, 884–887.
23. Mugesh, G.; du Mont, W.-W.; Sies, H. Chem. Rev. 2001, 101, 2125–2180; Abbas,
M.; Bethke, J.; Wessjohann, L. Chem. Commun. 2006, 541–543.
24. Iimura, S.; Manabe, K.; Kobayashi, S. Org. Lett. 2003, 5, 101–103.
25. Gawron, O.; Glaid, A. J. J. Am. Chem. Soc. 1949, 71, 3232–3233.
26. Khatik, G. L.; Kumar, R.; Chakraborti, A. K. Org. Lett. 2006, 8, 2433–2436.
27. Calverley, M. J. Tetrahedron 1987, 43, 4609–4619.
28. Babu, S. D.; Hrytsak, M. D.; Durst, T. Can. J. Chem. 1989, 67, 1071–1076.
29. Mach, R. H.; Kung, H. F.; Jungwiwattanaporn, P.; Guo, Y.-Z. Tetrahedron Lett.
1989, 30, 4069–4072.
Supplementary data
Copies of 1H and 13C NMR spectra for all new compounds.
Supplementary data associated with this article can be found in the
online version at doi:10.1016/j.tet.2009.04.030.
References and notes
30. Burilov, A. R.; Nikolaeva, I. L.; Pudovik, M. A. Russ. J. General Chem. 1994, 64,
542–545.
31. Nguyen, V. H.; Nishino, H.; Kajikawa, S.; Kurosawa, K. Tetrahedron 1998, 54,
11445–11460.
1. (a) Bray, T. M.; Taylor, C. G. Biochem. Pharmacol. 1994, 47, 2113–2123; (b)
Kerksick, C.; Willoughby, D. J. Int. Soc. Sport. Nutr. 2005, 2, 38–44; (c) Lomaestro,