Application of (S)- and (R)-methyl pyroglutamates as inexpensive, yet highly efficient chiral auxiliaries in the asymmetric Michael addition reactions

Article abstract of DOI:10.1016/j.tetlet.2004.07.096

Methyl N-(E-enoyl)pyroglutamates, derived from inexpensive and readily available in both enantiomeric forms pyroglutamic acid were found to be an efficient Michael acceptors in the addition reactions with nucleophilic glycine equivalent allowing for an ef

Full text of DOI:10.1016/j.tetlet.2004.07.096

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6855–6858
Application of (S)- and (R)-methyl pyroglutamates as
inexpensive, yet highly efficient chiral auxiliaries in the
asymmetric Michael addition reactions
Chaozhong Cai,b Takeshi Yamada,a Rohit Tiwari,a Victor J. Hrubyb and
Vadim A. Soloshonoka,
*
aDepartment of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, USA
bDepartment of Chemistry, University of Arizona, Tucson, AZ 85721, USA
Received 6 July 2004; revised 21 July 2004; accepted 22 July 2004
Abstract—Methyl N-(E-enoyl)pyroglutamates, derived from inexpensive and readily available in both enantiomeric forms pyro-
glutamic acid were found to be an efficient Michael acceptors in the addition reactions with nucleophilic glycine equivalent allowing
for an efficient practical asymmetric synthesis of b-substituted pyroglutamic acids and related compounds.
Ó 2004 Elsevier Ltd. All rights reserved.
Synthesis of sterically constrained amino acids has
attracted a great deal of attention in the past.1 The inter-
est toward these man-made amino acids is
driven mostly by their application as a constrained struc-
tural unit in the de novo peptide design.2 Of particular
interest are b-substituted glutamic/pyroglutamic acids3
as these compounds can be transformed to a family of
the corresponding v-constrained4 five-carbon-atoms
amino acids including glutamines, prolines, orn-
ithines, and arginines.5 The asymmetric synthesis of
b-substituted pyroglutamic acids gains also an addi-
tional impetus considering practical synthetic applica-
tions of the natural pyroglutamic acid for preparing
numerous stereochemically defined and biologically
important compounds.5
oxazolidin-2-ones (1) (Scheme 1) serve as ideal Michael
acceptors in the addition reactions with various chiral
and achiral equivalents of nucleophilic glycine, in partic-
ular the Ni(II)-complex 2,8 introduced by us, to afford
the corresponding addition products 3 in high-to-quan-
titative chemical yields and with virtually complete dia-
stereo- and enantioselectivity.7c,h
However, despite the fact that the Evans-type chiral
auxiliary 5 can be efficiently recovered and reused by
transformation to the starting Michael acceptor 1,9 its
relatively high cost,10 in particular for the large-scale
preparations, poses a sensitive economic issue. There-
fore, we decided to find a simple and economical alter-
native to the chiral auxiliary 5, allowing at the same
time to achieve the same, almost complete, level of ster-
eochemical outcome provided by the Michael acceptors
1. We now wish to report on the application of methyl
pyroglutamate, as one of the most inexpensive, yet very
efficient chiral auxiliaries in controlling the stereochem-
ical outcome of the organic base-catalyzed Michael
addition reactions.
Recently, we have developed organic base-catalyzed,
room-temperature Michael addition reactions between
nucleophilic glycine equivalents and a,b-unsaturated
carboxylic acid derivatives6,7 as an operationally con-
venient and generalized method for preparing b-substi-
tuted glutamic/pyroglutamic acids. In particular, we
have demonstrated that N-(E-enoyl)-4-phenyl-1,3-
Taking into account a close similarity between the struc-
tures of 1,3-oxazolidin-2-ones 5 and pyroglutamic acid
7a (Fig. 1) it is not surprising that many research groups
have been exploring the application of various com-
pounds derived from pyroglutamic acid as Evans-type
chiral auxiliaries for general asymmetric synthesis.11
Keywords: Asymmetric synthesis; Michael addition; Pyroglutamate;
Ni(II)-complex.
*
Corresponding author. Tel.: +1-4053258279; fax: +1-4053256111;
e-mail: vadim@ou.edu
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.096

6856
C. Cai et al. / Tetrahedron Letters 45 (2004) 6855–6858
O
O
O
Ph
R
N
1. MeOH/HCl
2. NH4OH
3. Dowex
N
N
CO2H
O
N
H
N
N
O
N
O
H
Ph
N
N
O
N
O
(S)-1
H
Ni
+
(2S,3R)-4
Ni
R
O
O
O
+
DBU (15 mol )%, DMF, r.t.
O
H
O
O
O
Me
Me
O
Me
HN
N
Ph
6
Ph
(S)-5
O
2
(2S,3S)-3 R = Alkyl
(2S,3R)-3 R = Aryl
ref. 8
ref. 9
2
(S)-1
Scheme 1.
(amino)acetophenone derived complex 2 as it was shown
to provide the highest reaction rate and diastereo-
selectivity in the Michael addition reactions using
N-(E-enoyl)-oxazolidinones 1. All reactions were con-
ducted at room temperature in a commercial-grade
DMF using 15-mol% of DBU as a catalyst.
O
O
O
O
HN
HN
N
R'
COOR
R
COOR
5
7a-c
8b,c
Figure 1. Reagents: (a) R = H; (b) Me; (c) Et.
First we tried the reaction between crotonyl derived
Michael acceptor (S)-9a and Ni(II)-complex 2. To our
delight the addition occurred at high reaction rate giving
rise to a sole reaction product 10a (Table 1, entry 1).
Sterically bulkier ethyl (S)-9b and n-butyl (S)-9c con-
taining derivatives reacted with complex 2 with a slightly
slower rate however with the same complete diastereo-
selectivity as only one reaction product was detected
However, most of the reported examples involve multi-
step modification of the pyroglutamic acid skeleton and
therefore they lose the appeal of very inexpensive, read-
ily available source of chirality. To the best of our
knowledge, there are only three reports in the literature
on application of methyl 7b and ethyl 7c pyroglutamates
derived butadienes 8 in the Diels–Alder reactions.12
1
by H NMR of the crude reaction mixture (entries 2
and 3). Unfortunately, in the reaction of i-propyl con-
taining Michael acceptor (S)-9d with Ni(II)-complex 2
no products were observed after 2h of the reaction time
(entry 4). Nevertheless, this outcome came without any
surprise, as the corresponding i-propyl containing oxa-
zol-idinone derived Michael acceptor also did not react
with complex 2.7c,h Application of (R)-configured
Michael acceptor 9a mirrored the result obtained with
(S)-9a (entry 5).
To explore an effectiveness of pyroglutamates as chiral
auxiliaries in our Michael addition reactions, we pre-
pared, according to the recently published procedure,
a series of Michael acceptors 9 (Scheme 2) bearing var-
ious alkyl as well as aryl groups with electron-withdraw-
ing and electron-releasing substituents. Our choice of
the methyl ester 7b was based on an expected simplicity
of the NMR spectra over the corresponding products
obtained form the ethyl ester 7c. As an equivalent of
nucleophilic glycine we chose the picolonic acid/o-
In the aromatic series we first conducted the addition
between cinnamoyl containing Michael acceptor (S)-9e
O
R
R
N
1. MeOH/HCl
2. NH4OH
3. Dowex
N
N
O
CO2Me
O
CO2H
N
H
N
N
O
N
O
H
N
N
O
N
O
(S)-9a-h
Ni
Ni
H
+
R
O
O
(2R,3R)-11a
(2R,3S)-11e
O
DBU (15 mol %), DMF, r.t.
O
H
O
Me
Me
O
ref. 9
Me
N
2
CO2Me
6
2
(2R,3R,5'S)-10a-c (2R,3S, 5'S)-10e-h
Scheme 2. Reagents: (a) R =Me; (b) Et; (c) n-Bu; (d) i-propyl; (e) Ph; (f) 4-OMe–C6H4; (g) 4-OMe–C6H4; (h) C6H5.

C. Cai et al. / Tetrahedron Letters 45 (2004) 6855–6858
Table 1. Reactions between Michael acceptors 9a–h and Ni(II)-complex 2a
6857
Entry
R
9a–h
t (min)
Yield, %b
% de of 10a–hd
1
2
3
4
5
6
7
8
9
Me
Et
(S)-a
(S)-b
(S)-c
(S)-d
(R)-a
(S)-e
(S)-f
(S)-g
(S)-h
25
30
30
120
25
30
60
5
96
98
98
>96c
>96c
>96c
n-Butyl
i-Propyl
Me
No reaction
95
96
91
95
92
>96c
>90
>88
>94
>96c
Ph
4-OMe–C6H4
4-CF3–C6H4
C6F5
2
a All reactions were run in dry DMF in the presence of 15mol% of DBU at room temperature. Molar ratio (S)- or (R)-2/9a–h: 1.0/1.1.
b Isolated yield of pure product.
c Only one product was observed in the reaction mixture.
d Determined by 1H NMR of the crude reaction mixture.
and complex 2. The reaction occurred at high rate, com-
parable with that of the aliphatic series (entry 6). On the
other hand, the stereochemical outcome was found to be
Acknowledgements
The work was supported by the start-up fund provided
by the Department of Chemistry and Biochemistry,
University of Oklahoma (to V.A.S.), and by the grants
from US Public Health Service Grant and the National
Institute of Drug Abuse (DA 06284, DA 04248,
and DK 17420 to V.J.H.).
1
a bit less perfect, as in the crude H NMR of the reac-
tion mixture one could find some signals (<5%) possibly
belonging to other than (S)-10e diastereomer. Michael
acceptor (S)-9f, containing electron-releasing p-methoxy
group, reacted with complex 2 at noticeably slower reac-
tion rate and with slightly lower diastereoselectivity
(entry 7). By contrast, the addition between the trifluoro-
methyl containing (S)-9g and complex 2 occurred at
very fast rate and with improved stereochemical out-
come (entry 8). Of particular interest was the reaction
of pentafluorophenyl derivative (S)-9h. Due to high elec-
trophilicity of the C, C double bond in compound (S)-9h
its reaction with Ni(II)-complex 2 occurred almost in-
stantly giving rise to the product 10h in high chemical
yield (entry 9). Notably, the stereochemical outcome
of this reaction was the highest in the aromatic series
as sole product 10h was detected in the crude reaction
References and notes
1. For recent collection of leading papers, see: ÔAsymmetric
Synthesis of Novel Sterically Constrained Amino AcidsÕ,
Tetrahedron Symposia-in-Print; #88; Guest Editors:
Hruby, V. J.; Soloshonok, V. A. Tetrahedron 2001, 57, 30.
2. (a) Hruby, V. J. Life Sci. 1982, 31, 189; (b) Hruby, V. J.;
Al-Obeidi, F.; Kazmierski, W. M. Biochem. J. 1990, 268,
249; (c) Hruby, V. J. Biopolymers 1993, 33, 1073; (d)
Hruby, V. J.; Li, G.; Haskell-Luevano, C.; Shenderovich,
M. D. Biopolymers 1997, 43, 219; (e) Cai, M.; Cai, C.;
Mayorov, A. V.; Xiong, C.; Cabello, C. M.; Soloshonok,
V. A.; Swift, J. R.; Trivedi, D.; Hruby, V. J. J. Pept. Res.
2004, 63, 116.
3. For a review on asymmetric synthesis of b-substituted
glutamic/pyroglutamic acids, see: Soloshonok, V. A. Curr.
Org. Chem. 2002, 6, 341–364.
4. For recent reviews on v-constrained amino acids, see:
Gibson, S. E.; Guillo, N.; Tozer, M. J. Tetrahedron 1999,
55, 585.
1
mixture by H NMR.
Methyl and phenyl containing products 10a,e were
hydrolyzed under the standard conditions7h,13 to furnish
the corresponding b-substituted pyroglutamic acids
11a,e as well as ligand, which was reused for preparation
of starting complex 2.8 On the basis of spectroscopic
data and optical rotations of compounds 11a,e their
absolute configuration was assigned as (2R,3R) for 11a
and (2R,3S) for 11b.14 These stereochemical results are
in full agreement with the data obtained in the previous
works using N-(E-enoyl)-oxazolidinones 1 as chiral
Michael acceptors.7
5. For recent review on various synthetic transformations of
pyroglutamic acid and its derivatives, see: Najera, C.; Yus,
M. Tetrahedron: Asymmetry 1999, 10, 2245.
6. For Michael addition reactions between chiral nucleophi-
lic glycine equivalents and a,b-unsaturated carboxylic acid
esters, see: (a) Soloshonok, V. A.; Avilov, D. V.; KukharÕ,
V. P.; Meervelt, L. V.; Mischenko, N. Tetrahedron Lett.
1997, 38, 4903; (b) Soloshonok, V. A.; Cai, C.; Hruby, V.
J.; Meervelt, L. V.; Mischenko, N. Tetrahedron 1999, 55,
12031; (c) Soloshonok, V. A.; Cai, C.; Hruby, V. J.;
Meervelt, L. V. Tetrahedron 1999, 55, 12045.
7. For Michael addition reactions between chiral/achiral
nucleophilic glycine equivalents and chiral/achiral N-(E-
enoyl)-1,3-oxazolidin-2-ones, see: (a) Soloshonok, V. A.;
Cai, C.; Hruby, V. J. Tetrahedron: Asymmetry 1999, 10,
4265; (b) Soloshonok, V. A.; Cai, C.; Hruby, V. J.
Tetrahedron Lett. 2000, 41, 135–139; (c) Soloshonok, V.
A.; Cai, C.; Hruby, V. J. Org. Lett. 2000, 2, 747; (d)
Soloshonok, V. A.; Cai, C.; Hruby, V. J. Angew. Chem.,
In summary, we have demonstrated that inexpensive
and readily available in both enantiomeric forms methyl
pyroglutamate 7b can be used as a chiral auxiliary in the
place of expensive Evans-type 4-phenyloxazolidin-2-one
5. Taking into account almost 100-fold difference in the
price between these chiral auxiliaries, successful applica-
tion of methyl pyroglutamate derived Michael acceptors
render our organic base-catalyzed, room-temperature
Michael addition reactions even more practical and
appealing for large-scale preparations of enantiomeri-
cally pure b-substituted glutamic/pyroglutamic acids
and related compounds.

6858
C. Cai et al. / Tetrahedron Letters 45 (2004) 6855–6858
In. Ed. 2000, 39, 2172; (e) Soloshonok, V. A.; Cai, C.;
13. General procedure for the reactions of glycine complexes
with (5S)-N-(E-enoyl)-5-methoxycarbonyl-2-pyrrolidin-
ones. To a suspension of Ni(II)-complex (1.0mmol) in
DMF (3.0mL), (5S)-N-(E-enoyl)-5-methoxycarbonyl-2-
pyrrolidinones (1.1mmol) was added with stirring. The
mixture was stirred at rt for 10–15min to get a homoge-
neous solution, and then DBU (22mg, 0.15mmol) was
added. The course of reaction was monitored by TLC
(SiO2). Upon disappearance of the starting compounds,
the reaction mixture was poured into icy 5% aqueous
acetic acid (100mL) and stirred with a glass bar to initiate
crystallization of the product. The crystalline product was
filtered off, thoroughly washed with water, and dried in
vacuo to give addition products. For standard procedure
for hydrolysis of Ni(ii)-complexes and isolation of target
amino acids, see Refs. 6 and 7. (2R,3S)-3-Phenylpyro-
Hruby, V. J.; Meervelt, L. V.; Yamazaki, T. J. Org. Chem.
2000, 65, 6688; (f) Soloshonok, V. A.; Cai, C.; Hruby, V. J.
Tetrahedron Lett. 2000, 41, 9645; (g) Cai, C.; Soloshonok,
V. A.; Hruby, V. J. J. Org. Chem. 2001, 66, 1339; (h)
Soloshonok, V. A.; Ueki, H.; Tiwari, R.; Cai, C.; Hruby,
V. J. J. Org. Chem. 2004, 69, 98.
8. For recent, improved procedure for Ni(II)-complex 2
preparation, see: Ueki, H.; Ellis, T. K.; Martin, C. H.;
Soloshonok, V. A. Eur. J. Org. Chem. 2003, 1954.
9. For a convenient, room-temperature organic base-cata-
lyzed protocol for preparing chiral N-(enoyl)-1,3-oxazol-
idine-2-ones, see: Soloshonok, V. A.; Ueki, H.; Jiang, C.;
Cai, C.; Hruby, V. J. Helv. Chim. Acta 2002, 85, 3616.
10. According to the Aldrich catalog: 5g of (S)-4-phenyl-1,3-
oxazolidin-2-one 7 costs $ 179.30; (S)-pyroglutamic acid is
more than 100 times cheaper, priced at $ 148.80 for 500g.
11. For some recent applications of chiral auxiliaries derived
from pyroglutamic acid, see: Itoh, T.; Miyazaki, M.;
Ikeda, S.; Nagata, K.; Yokoya, M.; Matsuya, Y.;
Enomoto, Y.; Ohsawa, A. Tetrahedron 2003, 59, 3527;
Kawanami, Y.; Murao, S.; Ohga, T.; Kobayashi, N.
Tetrahedron 2003, 59, 8411; Mantecon, S.; Vaquero, J. J.;
Alvarez-Builla, J.; Luz de la Puente, M.; Espinosa, J. F.;
Ezquerra, J. Org. Lett. 2003, 5, 3791; Adam, W.; Zhang,
A. Eur. J. Org. Chem. 2004, 1, 147.
25
glutamic acid: yield: 82%; mp 138.0–139.0°C; ½aꢀD ꢁ81.0 (c
1
1.3, CH3OH); H NMR (CDCl3) d 2.31 (1H, dd, J = 6.0,
17.1Hz), 2.73 (1H, dd, J = 9.3, 17.1Hz), 3.45–3.61 (1H,
m), 4.21 (1H, d, J = 5.1Hz), 7.12–7.26 (5H, m); 13C NMR
(CDCl3) d 39.3, 45.6, 64.6, 127.9, 128.4, 129.9, 143.9,
174.9, 179.6; HRMS(FAB) [M+H]+ calcd for C11H12NO3
206.0817, found 206.0813.
14. The (2R,3S) relative stereochemistry for the aromatic
(R = Ph) derivatives is a consequence of the Cahn–Ingold–
Prelog priority (see Ref. 15) and is stereochemically
equivalent to the (2R,3R) configuration in the aliphatic
(R = Me) series of compounds.
12. (a) Menezes, R. F.; Zecca, C. A.; Sheu, J.; Smith, M. B.
Tetrahedron Lett. 1989, 30, 3295; (b) Defoin, A.; Pires, J.;
Streith, J. Synlett 1991, 417; (c) Defoin, A.; Pires, J.;
Streith, J. Synlett 1990, 111.
15. Cahn, R. S.; Ingold, C.; Prelog, V. Angew. Chem., Int. Ed.
Engl. 1966, 5, 385.