The revisited synthesis of tert-butyl pyroglutamate derivatives

Article abstract of DOI:10.1016/j.tet.2013.06.023

The very common protection reactions of scaffolds by introduction of Boc or tert-butyl groups on lactams or acids in the pyroglutamic series have been revisited in a green perspective. Particularly, reaction conditions allowing a quantitative yield in substitution of bromine in tert-butyl bromide were discovered for the first time, allowing the synthesis of tert-butyl pyroglutamate 4. This synthesis of tert-butyl ester by nucleophilic substitution, realized without using concentrated perchloric or sulfuric acid, could be of interest for acid sensitive compounds. On the other hand, we demonstrated that non toxic N-methylimidazole and tert-butanol can pleasantly replace the problematic toxic 4-dimethylaminopyridine (DMAP) and dichloromethane utilized for the N-carbamoylation of lactam 4. This environmentally improved route to compound 4 allowed the development of a multi-gram supply of protected N-aminoethyl and N-hydroxyethyl γ-glutamine 1 and 2.

Full text of DOI:10.1016/j.tet.2013.06.023

Tetrahedron 69 (2013) 6821e6825
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
The revisited synthesis of tert-butyl pyroglutamate derivatives
,
,
b
,
a,
Christelle Claverie a b, Alina Ghinet a , Philippe Gautret b, Chi-Thanh Vuong c,
*
,
b
Benoît Rigo a
a Univ Lille Nord de France, F-59000 Lille, France
b UCLille, EA GRIIOT (4481), Laboratoire de pharmacochimie, HEI, 13 rue de Toul, F-59046 Lille, France
c Rhodia, 52 Rue de la Haie Coq, 93306 Aubervilliers, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The very common protection reactions of scaffolds by introduction of Boc or tert-butyl groups on lactams
or acids in the pyroglutamic series have been revisited in a green perspective. Particularly, reaction
conditions allowing a quantitative yield in substitution of bromine in tert-butyl bromide were discovered
for the first time, allowing the synthesis of tert-butyl pyroglutamate 4. This synthesis of tert-butyl ester
by nucleophilic substitution, realized without using concentrated perchloric or sulfuric acid, could be of
interest for acid sensitive compounds. On the other hand, we demonstrated that non toxic N-methyl-
imidazole and tert-butanol can pleasantly replace the problematic toxic 4-dimethylaminopyridine
(DMAP) and dichloromethane utilized for the N-carbamoylation of lactam 4. This environmentally im-
proved route to compound 4 allowed the development of a multi-gram supply of protected N-aminoethyl
Received 15 March 2013
Received in revised form 2 June 2013
Accepted 7 June 2013
Available online 14 June 2013
Keywords:
Pyroglutamic acid
tert-Butyl pyroglutamate
N-Methylimidazole
Lactam
and N-hydroxyethyl g-glutamine 1 and 2.
Ó 2013 Elsevier Ltd. All rights reserved.
Pyroglutamoylpyroglutamic derivatives
1. Introduction
important step in synthetic methodology,1b and many syntheses of
tert-butyl esters 3 and 4 have already been described. However,
these methods for obtaining 3 and 4 are not really friendly; thus, we
examined more environmentally pleasant and efficient protocols
for the obtention of these compounds. That led us to discover re-
action conditions allowing for the first time the synthesis of tert-
butyl pyroglutamate 4 from tert-butyl bromide in quantitative yield.
In conjunction with an ongoing program, we needed a conve-
nient multi-gram supply of protected N-aminoethyl and N-
hydroxyethyl
g-glutamine 1 and 2 to be used as future building
blocks. A preliminary survey of literature indicated that these am-
ides could be obtained (Scheme 1) by opening the lactam ring of
O
CO2tertBu
CO2tertBu
HX
O
O
N
H
CO2tertBu
CO2tertBu
3
CO2tertBu
O
CO H
N
N
H
N
H
HN
1 X = NH
2 X = O
4
5
Scheme 1. Retrosynthetic pathways for the preparation of amides 1 and 2.
acyl carbamate 3 synthesized from tert-butyl ester 4 issued from
2. Results and discussion
renewable synthon -pyroglutamic acid 5, sometimes called ‘the
L
forgotten amino acid’.1a The use of a protective group is an
2.1. Synthesis of tert-butyl pyroglutamate 4
The retrosynthetic pathways described in Scheme 1 start from
pyroglutamic acid 5. SciFinder reports about 8000 references for
this amidoacid, and many of the described synthetic schemes ex-
ploit protected forms of the carboxylic group of 5. One of these
* Corresponding author. Tel.: þ33 (0) 3 28 38 48 58; fax: þ33 (0) 3 28 38 48 04;
e-mail address: alina.ghinet@hei.fr (A. Ghinet).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.06.023

6822
C. Claverie et al. / Tetrahedron 69 (2013) 6821e6825
widely utilized compounds is tert-butyl pyroglutamate 4. Mainly,
two syntheses are employed to obtain this ester: the general
method of reaction of a carboxylic acid with isobutene,2 catalyzed
by great amount of sulfuric acid in dichloromethane or dioxane,
furnished with pyroglutamic acid 5 very variable yields of 4
(14e78%).3 In another method, pyroglutamic acid 5 was reacted
with a large amount of tert-butyl acetate in the presence of
0.7 equiv of 70% perchloric acid; accordingly, ester 4 was described
to be obtained in 31e100% yields.4 The principal problems con-
cerning these syntheses of tert-butyl ester 4 are the nature and the
amount of acidic catalyst and solvent, as well as the seemly irre-
producible yields. In order to envisage a possible reuse of the acidic
catalyst, we attempted to modify this last reaction by stirring
pyroglutamic acid 5 and tert-butyl acetate in the presence of
NafionÒ resin (tert-butanol was utilized as a co-solvent) for a week
at room temperature. However, only low and irreproducible yields
(9e30%) of ester 4 were obtained.
It has been described that carboxylic acids react with Boc2O in
the presence of DMAP to give symmetric anhydrides,5 which then
can react with tert-butanol to obtain tert-butyl esters, and this
method has been utilized with N-protected glutamic or pyroglu-
tamic acids, providing good yields of the corresponding ester 3.2,6
When we applied this method to pyroglutamic acid 5, according
to the different reaction conditions (Scheme 2), esters 3 and 4 were
obtained in low yields, along with dimeric compounds 6, 7, and 8.
Diketopiperazine 8 has already been described.7 On the other side,
compounds analogs to N-pyroglutamoylpyroglutamic derivatives 6
and 7 have been isolated from the reaction of pyroglutamoyl
chloride with amines.8 Products 6 and 7 can be isolated in good
yields (70% and 52%); this needs to be noted as these scaffolds
proved to be interesting in the field of pseudopeptide foldamers.9
Given these results, although ‘with a few exceptions, nucleophilic
substitutions at a tertiary carbon have little or no preparative value,10
’
it was decided to explore the solvolytic displacement of tert-butyl
halide by the carboxylate anion issued from pyroglutamic acid. A
selection of the various reaction conditions employed can be found
in Table 1. The temperatures were chosen in order to limit the
formation of isobutene. The use of t-BuOH is often interesting in
pyroglutamic chemistry because it is one of the rare and good
solvents for this acid. However, triethylamine salt of 5 forms an
insoluble mobile oil in many solvents (2-Me-THF, acetone.), and is
soluble in CH2Cl2 and propylene carbonate. It can be observed that
in standard conditions, whatever the solvent and the amine used,
the reaction rate is very low without additive (Entries 1e4) and that
the bromide is more reactive that the chloride. It was reported in
the literature that bismuth carboxylate in CCl4,11a and zinc car-
boxylate in an excess of carboxylic acid,11b react easily with tertiary
alkyl halide to give very good yields of tert-butyl esters; thus acid 5
was reacted with halide in presence of ZnO,11b or BiCl3 and trie-
thylamine. In that case, the reaction mixture in tert-butanol became
very thick and could not be stirred (Entry 7); with ZnO as additive,
the bromide again gave better yields than chloride (Entries 5 and 6),
and the 38% of tert-butyl pyroglutamate isolated after 36 h (Entry 6)
confirms the interest of the presence of zinc additive.12 However, it
was observed that a large part of tert-BuBr was hydrolyzed to tert-
BuOH, thus ZnO was replaced by ZnCl2 (entry 8). In these
O
O
CO
tertBu
+
O
CO2H DMAP Boc O
CO2tertBu
O
CO2tertBu
CO2tertBu
O
CO tertBu
+
O
+
+
O
+
+
N
2
2
N
H
N
N
N
N
H
N
O
O
O
O
NH
N
CO2tertBu
O
O
5
4
3
6
7
8
RT 12 h
0.04 equiv. 2 equiv. tertBuOH
0.04 equiv. 2 equiv. tertBuOH
9 %
0 %
4 %
11 %
32 %
0 %
70 %
52 %
16 %
0 %
0 %
0 %
0 %
reflux 12 h
RT 24 h
0.10 equiv. 1 equiv.
52 %
2.3 %
MeCN
Et3N 1 equiv.
Scheme 2. Reaction of pyroglutamic acid with Boc2O.
Table 1
Reaction of pyroglutamic acid with tert-butyl halides
additive
base
X
O
N
CO H
CO tertBu
+
+
+
O
N
H
H
5
4
Entry
tBuX (equiv)
Base (equiv)
Additive (equiv)
Temperature ꢀC
Solvent (mL/mol)
THF (200)
THF (200) CHCl3 (50)
MeCN (400)
Time
Yielda
%
1
2
3
4
X¼Cl (1.25)
X¼Cl (1.20)
X¼Br (3.00)
X¼Br (3.00)
X¼Cl (1.50)
X¼Br (1.50)
X¼Br (1.25)
X¼Br (1.50)
X¼Br (2.00)
X¼Br (2.00)
X¼Br (3.00)
X¼Br (3.00)
X¼Br (3.00)
Et3N (1.25)
DIPA (1.25)
Et3N (3.00)
Py (3.00)
d
d
70
70
30
40
55
45
40
40
40
40
40
40
40
7 d
8 d
5 d
9
18
d
d
35 (isolated)
10
4
38 (isolated)
5
22
43 (isolated)
53 (isolated)
91 (isolated)
25
d
CH2Cl2 (600)
24 h
24 h
36 h
7 d
48 h
20 h
20 h
14 h
48 h
15 h
5
ZnO (0.50)
ZnO (1.00)
BiCl3 (0.25)
ZnCl2 (0.50)
ZnBr2 (0.50)
ZnBr2 (1.00)
ZnBr2 (2.50)
ZnBr2 (2.50)
ZnBr2 (2.50)
Dioxane (2000)
Dioxane (2000)
tert-BuOH(1500)
CHCl3 (2500)
tert-BuOH(1600)
CH2Cl2 (1000)
CH2Cl2 (1250)
MeTHF (1250)
PCe (1250)
6
d
7b
8
Et3N (1.00)
Et3N (1.00)
Et3N (2.00)
Et3N (2.00)
Et3N (3.60)
Et3N (3.60)
Et3N (3.60)
9c
10d
11
12
13
82 (isolated)
a
Determined by 1H NMR of the reaction mixture.
Very thick mixture.
b
c
Formation of a crystallized mass.
d
e
ꢀ
4 A MS (100 g/mol) was added.
Propylene carbonate.

C. Claverie et al. / Tetrahedron 69 (2013) 6821e6825
6823
conditions, two secondary reactions occurred: (a) an important
amount of tert-butyl bromide was transformed in less reactive
chloride, and (b) the amount of ester decreased after 48 h of re-
action. This indicates that the quantity of base was too low, and that
after consumption of all the triethylamine, the zinc halide decom-
posed the tert-butyl ester13 to give isobutene and pyroglutamic
acid. Thus, the amounts of Et3N and of alkyl bromide were in-
creased to 2 equiv and, in tert-butanol as solvent (Entry 9),
a promising 43% yield of ester 4 was obtained in 20 h. On the other
hand, the salts issued from the reaction lead to the formation of an
important crystallized mass, prohibiting stirring. Thus, in the next
experiments using more base and reagents, dichloromethane was
utilized as a better solvent for the salts. Drying the reaction medium
room temperature, furnishing 94% of carbamate 3 after work up,
without the need of chromatographic purification (Scheme 4)
NMe2
N
NMe2
tertBuO
O
O
-
tertBuO
CO2
O
+
+
+
+
N
tertBuO
O
tertBuO
9
10
Scheme 3. Reaction of DMAP with Boc2O.
tert-BuOH
ꢀ
+
CO2tertBu
Boc2O
CO2tertBu
O
O
with 4 A MS did not prove to be determinant (Entry 10), but with
N
N
N-Methylimidazole
20°C, 2.5 h
H
3 equiv of halide, 3.6 equiv of triethylamine and 2.5 equiv of zinc
dibromide, a quantitative reaction was observed by 1H NMR after
14 h at 40 ꢀC, leading to the isolation of 91% of tert-butyl pyroglu-
tamate 4 (Entry 11). The amount of base and additive being opti-
mized, search for a greener solvent was undertaken; disappointing
results were obtained with 2-methyl-tetrahydrofuran (Entry 12):
this solvent led to the formation of two non-miscible phases, and
24 h were needed to obtain a 25% NMR conversion, which did not
increase after 48 h heating at 40 ꢀC. Thus, a more polar green sol-
vent was chosen; gratefully, propylene carbonate14 furnished a to-
tal conversion by 1H NMR to tert-butyl pyroglutamate 4; ethyl
acetate/water partition, followed by distillation of the solvent
allowed the isolation of 82% of ester 4 and the recovery of 64% of
propylene carbonate.
CO2tertBu
3 94%
4
Scheme 4. Synthesis of carbamate 3.
2.3. Synthesis of amides 1 and 2
Then, syntheses of amides 1 and 2 were undertaken. As planned
in the retrosynthetic approach (Scheme 1) these compounds could
be obtained from ring opening of carbamate 3. Selective cleavage of
Boc-acylamides has been described.24 In the case of N-Boc pyroglu-
tamic esters,16 the nucleophiles utilized were organometals (giving
ketones),20a,25 hydride ions (furnishing alcohols),4e,19,26 sodium hy-
droxide (yielding acids).4c As for alcohols and amines, they provide
esters,27 and amides,20b,28 respectively; these last reactions can be
catalyzed by trimethylaluminium29 or by cyanide ion,30 which forms
a more reactive intermediate acylnitrile. Thus, to obtain our targets,
ethylenediamine was reacted with N-acyl carbamate 3; no cyanide
catalysis was needed, however when reaction mixture was heated at
reflux, only 27% of amide 1 were isolated, and 22% of dimer 11 were
also obtained. Performing the reaction at room temperature allowed
the exclusive formation of aminoamide 1 in 95% yields. The same
reaction conditions applied to ethanolamine furnished 66% of ami-
doalcohol 2 (Scheme 5).
2.2. Synthesis of carbamate 3
With ester 4 in hands, synthesis of carbamate 3 can appear
trivial. Indeed, the general introduction of a Boc group on amines by
using Boc2O and catalyst (I2,
b
-cyclodextrine, Zn(ClO4)2),15 was
adapted to lactams16 then to pyroglutamic esters17 by employing
dimethylaminopyridine (DMAP) as an activating agent. In the case
of tert-butyl pyroglutamate 4, this reaction was realized in THF4a or
in MeCN,4b,e,6b,18 eventually in the presence also of Et3N19 with
O
O
O
CO2tertBu
CO2tertBu
CO2tertBu
CO2tertBu
tertBuO2C
tertBuO2C
HX
N
H
N
H
N
H
HX
+
CO2tertBu
CO2tertBu
3
+
O
N
NH2
HN
HN
NH
1 X = NH
2 X = O
11
Scheme 5. Synthesis of amides 1 and 2.
yields ranging from 72 to 100%. In the case of different pyrogluta-
mic esters, other solvents (CH2Cl2,20 DMF/DIPA.9.) were also uti-
lized. Dichloromethane or acetonitrile are not very friendly, and
DMAP is very toxic. Thus, we though to use greener conditions to
obtain ester 3.
Literature described that in these reactions the tert-Boc-dime-
thylaminopyridinium cation 9 acts as an acylating reagent,21 and
that the highly basic tert-butoxide anion 10 is involved in the
proton abstraction from the lactam ring (Scheme 3).22 It is known
that the greener N-methylimidazole can efficiently catalyze some
acylation reactions,23 and we postulated that it could activate the
Boc2O acylation reagent in the same way as DMAP (Scheme 3). Thus
this catalyst was chosen, and the carbamoylation of pyroglutamic
ester 4 was carried out in the friendly tert-butanol solvent. Grate-
fully, a full NMR conversion was observed after 2.5 h of stirring at
3. Conclusion
Protection of scaffolds by introduction of Boc or tert-butyl
groups on lactams or acids is very common for synthetic organist
chemists. In the case of pyroglutamic acid derivatives, we have
revisited these reactions in a green perspective, and obtained very
good yields of tert-butyl pyroglutamate 4 and the corresponding N-
Boc derivative 3. We thought that these results can be extended to
many other scaffolds. Particularly the method of synthesis of tert-
butyl ester by using tert-butyl bromide, realized without using
sulfuric or perchloric acid, could be of interest for acid sensitive
compounds. On the other hand, we demonstrated that non toxic N-
methylimidazole and tert-butanol can pleasantly replace the
problematic toxic DMAP and dichloromethane utilized for the N-
carbamoylation of this lactam.

6824
C. Claverie et al. / Tetrahedron 69 (2013) 6821e6825
4. Experimental section
(0.700 g, 3.78 mmol) in tert-BuOH (15 mL) at 30 ꢀC. The solution was
stirred 10 min at this temperature, and then at room temperature for
3 h. Solvents were removed under vacuum, the residue was dissolved
in ethyl acetate (30 mL), the solution was washed with water
(2ꢂ10 mL) and the aqueous phases were extracted with ethyl acetate
(2ꢂ20 mL). The combined organic phases were dried (MgSO4), and
the solvent wasremoved undervacuum. The residuewasdissolved in
absolute EtOH, and the solution was cooled at 0 ꢀC to give of pure
compound 3 (1.013 g, 94%) with the same properties as described in
4.1. General
Starting materials are commercially available and were used
without further purification. Melting points were measured on
a MPA 100 OptiMeltÒ apparatus and are uncorrected. NMR spectra
were acquired at 400 MHz for 1H NMR and 100 MHz for 13C NMR on
a Varian 400 MHz Premium ShieldedÒ spectrometer. Chemical
shifts (
d
) are given in parts per million relative to CDCl3 (7.26 ppm;
literature.6b 1H NMR (400 MHz, CDCl3)
d 1.49 (s, 9H, (CH3)3C), 1.51 (s,
77.1 ppm). Splitting patterns are designed as: s, singlet; d, doublet;
dd, doublet of doublets; t, triplet; m, multiplet, and sym m, sym-
metric multiplet. Coupling constants J are reported in hertz (Hz).
Thin layer chromatographies were realized on Macherey Nagel
silica gel plates with a fluorescent indicator and were visualized
with UV-lamp at 254 nm and 366 nm. Column chromatographies
were performed using a CombiFlash Rf Companion (Teledyne-Isco
System) and RediSep packed columns. IR spectra were recorded on
a Varian 640-IR FT-IR Spectrometer. Elemental analyses (C, H, N) of
9H, (CH3)3C), 1.95e2.05 (m, 1H, CH2CH2CH), 2.24e2.35 (m, 1H,
CH2CH2CH), 2.43e2.53 (m, 1H, CH2CH2CH), 2.55e2.66 (m, 1H,
CH2CH2CH), 4.48 (dd, J¼9.4, 2.7 Hz, 1H, CH2CH2CH).
4.1.4. tert-Butyl pyroglutamate (4). Triethylamine (14.5 g, 0.143 mol)
was added to a stirred suspension of -pyroglutamic acid 5 (5.2 g,
L
0.040 mol) in propylene carbonate (40 mL). Upon solubilization, zinc
bromide (22.5 g, 0.100 mol) was slowly (30 min) added to the stirred
solution to give a cloudy suspension (exothermic solubilization;
cooling bath), then tert-butyl bromide (16.4 g, 0.120 mol) was added
all atonce. Themixturewasheated for15 hbyusinganoilbath(40ꢀC).
The solvent was evaporated in part, and then water (150 mL) was
added leading precipitation of a crystallized precipitate, which was
washed with water (20 mL). The solid was dissolved in ethyl acetate,
and the combined aqueous phases were extracted with ethyl acetate
(3ꢂ40 mL), and then the organic phases were combined, washed with
water (3ꢂ30 mL), dried (MgSO4) then evaporated under reduced
pressure (100 mmHg). Propylene carbonate was distilled under vac-
uum (0.3 mmHg) Bp¼45 ꢀC. Upon cooling, the residue crystallized to
give pure product 4 (6.2 g, 82%) with the same properties as described
^
ꢁ
new compounds were determined by ‘Pole Chimie Moleculaire’,
ꢁ
ꢁ
Faculte de Sciences Mirande, Universite de Bourgogne, Dijon,
France.
4.1.1. tert-Butyl N5-(2-aminoethyl)-N2-(tert-butoxycarbonyl)-
a-gluta-
minate (1). To a stirred solution of carbamate 3 (50.0 g, 0.175 mol) in
1,2-dichloroethane (300 mL) was added via syringe 1,2-ethylene
diamine (29.5 mL, 0.438 mol). The resulting solution was stirred at
room temperature overnight. Volatiles were removed under re-
duced pressure. The crude reaction mixture was dissolved in CH2Cl2
(300 mL) and washed with water (100 mL). MeOH was added to the
organic phase (50 mL) and it was dried (Na2SO4) and concentrated
under reduced pressure to give the pure product (57.42 g, 86%) as
a white solid; mp (CH2Cl2/MeOH): 135e136 ꢀC; Rf (CH2Cl2/MeOH: 9/
in literature.4d 1H NMR (400 MHz, CDCl3)
d 1.48 (s, 9H, (CH3)3C),
2.13e2.23 (m, 1H, CH2CH2CH), 2.29e2.49 (m, 3H, CH2CH2CH), 4.14 (q,
J¼8.2, 5.5 Hz, 1H, CH2CH2CH), 6.23 (broad s, 1H, NH).
1) 0.13; IR
(400 MHz, DMSO-d6)
n
cmꢁ1: 3385, 2961, 2887, 1719, 1685, 1654, 1152; 1H NMR
(ppm) 1.39 (s, 9H, (CH3)3C), 1.40 (s, 9H,
d
4.1.5. tert-Butyl 1-(tert-butoxycarbonyl)-pyroglutamoylpyroglutamate
(6). A stirred mixture of pyroglutamic acid 5 (5.0 g, 38.7 mmol), Boc
anhydride (16.9 g, 77.4 mmol), and DMAP (0.2 g, 1.6 mmol) in tert-
BuOH (20 mL) was refluxed for 12 h under nitrogen atmosphere.
Upon cooling at room temperature, solvent was removed under
vacuum, and the residue was purified by flash chromatography
(SiO2, gradient n-heptane/ethyl acetate, 100/0 to 0/100), to give
firstly compound 6 as an oil crystallizing in absolute EtOH to provide
(CH3)3C), 1.67e1.77 (m, 1H, CH2CH), 1.85e1.94 (m, 1H, CH2CH), 2.15
(t, J¼7.5 Hz, 2H, CH2C]O), 2.66 (t, J¼6.3 Hz, 2H, CH2NH2), 3.10e3.15
(m, 2H, CH2NH), 3.74e3.80 (m, 1H, CH), 4.46 (broad s, 2H, NH2), 7.12
(d, J¼7.8 Hz, 1H, NHBoc), 7.92 (t, J¼5.4 Hz, 1H, NHCH2); 13C NMR
(100 MHz, DMSO-d6)
d 26.6 (CH2), 27.9 (3CH3), 28.4 (3CH3), 31.8
(CH2), 37.3 (CH2), 39.1 (CH2), 54.2 (CH), 78.3 (C), 80.5 (C), 155.7 (C),
171.8 (C), 172.2 (C). Anal. Calcd for C16H31N3O5, 2H2O: C, 50.38; H,
9.25; N, 11.02. Found: C, 50.16; H, 9.09; N, 10.94.
pure compound 6 (5.3 g, 70%) as a white solid; mp: 128e131 ꢀC; IR
cmꢁ1: 1794, 1746, 1708, 1225, 1147. 1H NMR (400 MHz, CDCl3)
1.46
n
d
4.1.2. tert-Butyl N2-(tert-butoxycarbonyl)-N5-(2-hydroxyethyl)-
a-glu-
(s, 9H, (CH3)3C), 1.48 (s, 9H, (CH3)3C), 2.05e2.15 (m, 2H, 2CH2CH2),
2.34e2.76 (m, 6H, 2CH2CH2), 4.71 (dd, J¼9.8, 2.7 Hz, 1H,
CH2CH2CHCOt2Bu), 5.74 (dd, J¼9.4, 2.4 Hz, 1H, CH2CH2CHCON); 13C
taminate (2). To a stirred solution of carbamate 3 (50.0 g, 0.175 mol)
in 1,2-dichloroethane (300 mL) was added via syringe ethanolamine
(17.0 mL, 0.283 mol). The resulting solution was stirred at room
temperature overnight. Volatiles were removed under reduced
pressure. The crude reaction mixture was purified by flash chro-
matography (SiO2, gradient CH2Cl2/MeOH from 100/0 to 95/5) to
isolate amidoalcohol 2 as a thick yellow oil (65.5 g, 66%), Rf (CH2Cl2/
NMR (100 MHz, CDCl3)
d 20.9 (CH2), 21.7 (CH2), 27.9 (3CH3), 28.0
(3CH3), 31.0 (CH2), 31.6 (CH2), 58.3 (CH), 59.6 (CH), 82.9 (C), 83.3 (C),
149.9 (C), 169.8 (C), 171.5 (C), 173.4 (C), 174.8 (C). Anal. Calcd for
C19H28N2O7: C, 57.56; H, 7.12; N, 7.07. Found: C, 57.48; H, 7.51; N, 6.95.
tert-Butyl pyroglutamate 4 (0.6 g, 9%) 4d then Boc ester 3 (1.2 g, 11%)
with the same properties as described in literature,6b were also
isolated after purification by flash chromatography.
MeOH: 9/1) 0.62; IR
NMR (400 MHz, DMSO-d6)
n
cmꢁ1: 3303, 2977, 2933, 1694, 1647, 1149; 1H
(ppm) 1.37 (s, 9H, (CH3)3C), 1.38 (s, 9H,
d
(CH3)3C),1.65e1.74 (m,1H, CH2CH),1.82e1.90 (m,1H, CH2CH), 2.12 (t,
J¼7.6 Hz, 2H, CH2C]O), 3.08 (dd, J¼11.9, 5.8 Hz, 2H, CH2NH), 3.36 (d,
J¼6.1 Hz, 2H, CH2OH), 3.72e3.78 (m, 1H, CH), 4.61 (t, J¼5.5 Hz, 1H,
4.1.6. tert-Butyl 5-oxoprolyl-5-oxoprolinate (7) and dihydro-1H,5H-
dipyrrolo[1,2-a:10,20-d]pyrazine-3,5,8,10(2H,5aH,10aH)-tetrone
(8). Triethylamine (4.1 g, 40.6 mmol) was added to a stirred mix-
ture of pyroglutamic acid 5 (5.0 g, 38.7 mmol) and Boc anhydride
(8.9 g, 40.6 mmol) in MeCN (30 mL). A yellow solution was ob-
tained, and after stirring the reaction mixture 27 h at room tem-
perature, the solid formed was filtered to recover 0.6 g (12%) of
starting pyroglutamic acid 5. Volatiles were removed under re-
duced pressure and the residue was dissolved in absolute EtOH. The
solid obtained upon cooling at 0 ꢀC for 3 days gave dimer 8 (0.1 g,
2.3%) with the same physico-chemical properties as described in
OH), 7.10 (d, J¼7.9 Hz, 1H, NHBoc), 7.77 (t, J¼5.2 Hz, 1H, NHCH2); 13
C
NMR (100 MHz, DMSO-d6) d 27.1 (CH2), 28.1 (3CH3), 28.6 (3CH3), 31.6
(CH2), 41.9 (CH2), 54.4 (CH), 60.3 (CH2), 78.4 (C), 80.7 (C), 155.9 (C),
171.9 (C),172.0 (C). Anal. Calcd for C16H30N2O6, H2O: C, 52.73; H, 8.85;
N, 7.69. Found: C, 52.51; H, 9.22; N, 7.32.
4.1.3. tert-Butyl 1-(tert-butoxycarbonyl)-pyroglutamate (3). N-Meth-
ylimidazole (0.031 g, 0.378 mmol) and Boc anhydride (0.907 g,
4.16 mmol) were added to a mixture of tert-butyl pyroglutamate 4

C. Claverie et al. / Tetrahedron 69 (2013) 6821e6825
6825
the literature.7c The solvents were evaporated under vacuum, and
the residue obtained upon evaporation was purified by automatic
7. (a) King, J. A.; McMillan, F. H. J. Am. Chem. Soc. 1952, 74, 2859; (b) Righetti, B.;
Tamba, M. Spectrochim. Acta 1982, 38A, 57; (c) Parrish, D. A.; Mathias, L. J. J. Org.
Chem. 2002, 67, 1820.
8. (a) Zicane, D.; Petrova, M.; Tetere, Z.; Kreishman, G.; Brooks, E.; Karlson, J.;
Kalejs, U. Int. J. Pept. Protein Res. 1996, 48, 56; (b) Rigo, B.; El Ghammarti, S.;
Gautret, P.; Couturier, D. Synth. Commun. 1994, 24, 2597.
9. Bernardi, F.; Garavelli, M.; Scatizzi, M.; Tomasini, C.; Trigari, V.; Crisma, M.;
Formaggio, F.; Peggion, C.; Toniolo, C. Chem.dEur. J. 2002, 8, 2516.
10. Smith, M. B.; March, J. March’s Advanced Organic Chemistry; Wiley: New York,
NY481.
11. (a) Keramane, E.-M.; Boyer, B.; Roque, J.-P. Tetrahedron Lett. 2001, 42, 855; (b)
Gurudutt, K. N.; Ravindranath, B.; Srinivas, P. Tetrahedron 1982, 38, 1843.
12. To answer a question from Referees concerning the mechanism of this reaction,
hexadecyl bromide and 1-adamantyl bromide were reacted with the mixture of
pyroglutamic acid, ZnBr2, and Et3N. No reaction occurred in the same condi-
tions that above; on the other side, with tBuBr in the absence of the nucleo-
philic pyroglutamoyl anion, only a very few amount of isobutene was formed.
These results suggest that this is not an SN2 process and that, as described for
bismuth carboxylate11a or zinc carboxylate ‘the reaction may be proceeding
through associated ion pairs’.11b
13. (a) Wu, Y.-Q.; Limburg, D. C.; Wilkinson, D. E.; Vaal, M. J.; Hamilton, G. S. Tet-
rahedron Lett. 2000, 41, 2847; (b) Kaul, R.; Brouillette, Y.; Sajjadi, Z.; Hansford,
K. A.; Lubell, W. D. J. Org. Chem. 2004, 69, 6131.
14. The interest of propylene carbonate as a green solvent is strongly emphasized
in the following publication and in references cited therein: Lenden, P.; Ylioja,
P. M.; Gonzalez-Rodriguez, C.; Entwistle, D. A.; Willis, M. C. Green Chem. 2011,
13, 1980.
flash chromatography, with a gradient n-heptane/EtOAc from 100/
4d
0 to 80/20 to isolate firstly tert-butyl pyroglutamate 4
(0.28 g,
4%), then Boc ester 6 (1.23 g, 16%) with the same properties as al-
ready described, and then acid 7 (3.42 g, 52%) as a white solid; mp
(EtOAc/n-heptane): 135e137 ꢀC; 1H NMR (400 MHz, CDCl3)
d (ppm)
1.48 (s, 9H, C(CH3)3), 2.33e2.77 (m, 7H, 2CH2CH2CH), 3.07e3.15 (m,
1H, CH2CH2CH), 4.67 (dd, J¼9.8, 3.1 Hz, 1H, CH2CH2CH), 5.15 (sym
m, 1H, CH2CH2CH), 6.40 (broad s, 1H, NH). Anal. Calcd for
C14H20N2O5: C, 56.75; H, 6.80; N, 9.45. Found: C, 57.01; H, 6.92; N,
9.67.
4.1.7. N1,N2-Di[1-tert-Butyl N-(tert-butoxycarbonyl)glutamoyl]ethyl-
enediamine (11). To a stirred solution of carbamate 3 (1.0 g,
3.50 mmol) in 1,2-dichloroethane (2.0 mL) was added via syringe
1,2-ethylene diamine (0.58 mL, 8.76 mmol). The resulting solution
was stirred under reflux overnight. After cooling to room temper-
ature the reaction mixture was concentrated under reduced pres-
sure and purified by automatic flash chromatography with
a gradient CH2Cl2/MeOH from 100/0 to 90/10 to isolate dimer 11,
(244 mg, 22%), light beige solid; mp (CH2Cl2/MeOH): 100e103 ꢀC; Rf
15. (a) Varala, R.; Nuvula, S.; Adapa, S. R. J. Org. Chem. 2006, 71, 8283; (b) Einhorn,
J.; Einhorn, C.; Luche, J.-L. Synlett 1991, 37; (c) Somi Reddy, M.; Narender, M.;
Nageswar, Y. V. D.; Rama Rao, K. Synlett 2006, 1110; (d) Bartoli, G.; Bosco, M.;
Locatelli, M.; Marcantoni, E.; Massaccesi, M.; Melchiorre, P.; Sambri, L. Synlett
2004, 1794.
(CH2Cl2/MeOH: 9/1) 0.67; IR
n
cmꢁ1: 3373, 3319, 1691, 1525, 1158;
(ppm) 1.38 (s, 18H, 2(CH3)3C), 1.39
1H NMR (400 MHz, DMSO-d6)
d
(s, 18H, 2(CH3)3C), 1.66e1.76 (m, 2H, CH2CH), 1.84e1.92 (m, 2H,
CH2CH), 2.12 (t, J¼7.6 Hz, 4H, 2CH2C]O), 3.06 (s, 4H, 2CH2NH),
3.74e3.79 (m, 2H, 2CH), 7.10 (d, J¼7.9 Hz, 2H, 2NHBoc), 7.81 (broad
16. Flynn, D. L.; Zelle, R. E.; Grieco, P. A. J. Org. Chem. 1983, 48, 2424.
17. Jain, R. Org. Prep. Proced. Int. 2001, 33, 405.
ꢂ
ꢂ
ꢂ ꢂ
ꢂ
18. (a) Malavasic, C.; Brulc, B.; Cebasek, P.; Dahmann, G.; Heine, N.; Bevk, D.;
ꢂ
Groselj, U.; Meden, A.; Stanovnik, B.; Svete, J. J. Comb. Chem. 2007, 9, 219; (b)
s, 2H, 2NHCH2); 13C NMR (100 MHz, DMSO-d6)
d 27.0 (2CH2), 28.1
Harris, P. W. R.; Brimble, M. A.; Gluckmann, P. D. Org. Lett. 2003, 5, 1847.
19. Katoh, T.; Nagata, Y.; Kobayashi, Y.; Arai, K.; Minami, J.; Terashima, S. Tetrahe-
dron 1994, 50, 6221.
(6CH3), 28.6 (6CH3), 32.1 (2CH2), 38.8 (2CH2), 54.4 (2CH), 78.4 (2C),
80.7 (2C), 155.9 (2C), 171.9 (2C), 172.0 (2C). Anal. Calcd for
C30H54N4O10, MeOH: C, 56.80; H, 8.73; N, 8.88. Found: C, 56.61; H,
9.58; N, 8.60. Aminoamide 1, (106 mg, 27%) was also isolated, with
the same properties as already described.
ꢁ
20. (a) Van Betsbrugge, J.; Van den Nest, W.; Verheyden, P.; Tourwe, D. Tetrahedron
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Chem. 2007, 15, 3474; (c) Gloanec, P.; Herve, Y.; Bremand, N.; Lecouve, J.-P.;
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Breard, F.; De Nanteuil, G. Tetrahedron Lett. 2002, 43, 3499.
21. (a) Hoefle, G.; Steglich, W.; Vorbrueggen, H. Angew. Chem., Int. Ed. Engl. 1978,
17, 569; (b) Scriven, E. F. V. Chem. Soc. Rev. 1983, 12, 129; (c) Grehn, L.;
Gunnarson, K.; Ragnarsson, U. Acta Chem. Scand., Ser. B 1986, 40, 745.
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€
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