Silver/ThioClickFerrophos complex as an effective catalyst for asymmetric conjugate addition of glycine imino ester to unsaturated malonates and α-enones

Article abstract of DOI:10.1021/ol4019584

The AgOAc/ThioClickFerrophos complex effectively catalyzed the conjugate addition of glycine imino esters to arylidene and alkylidene malonates, furnishing the corresponding adducts in good yields with high enantioselectivities, in the presence or absence of an external base. The complex also catalyzed conjugate addition to α-enones in the presence of 1,4-diazabicyclo[2.2.2]octane with high enantioselectivity, with formation of a small amount of cycloadducts.

Full text of DOI:10.1021/ol4019584

ORGANIC
LETTERS
2013
Vol. 15, No. 17
4418–4421
Silver/ThioClickFerrophos Complex as
an Effective Catalyst for Asymmetric
Conjugate Addition of Glycine Imino Ester
to Unsaturated Malonates and r‑Enones
Takashi Konno, Sayo Watanabe, Tatsuki Takahashi, Yuichiro Tokoro, and
Shin-ichi Fukuzawa*
Department of Applied Chemistry, Institute of Science and Engineering,
Chuo University, Tokyo, Japan
orgsynth@kc.chuo-u.ac.jp
Received July 12, 2013
ABSTRACT
The AgOAc/ThioClickFerrophos complex effectively catalyzed the conjugate addition of glycine imino esters to arylidene and alkylidene
malonates, furnishing the corresponding adducts in good yields with high enantioselectivities, in the presence or absence of an external base.
The complex also catalyzed conjugate addition to R-enones in the presence of 1,4-diazabicyclo[2.2.2]octane with high enantioselectivity, with
formation of a small amount of cycloadducts.
Glycine imino esters are often used as building blocks in
the synthesis of optically active R-amino acid derivatives.1
For example, the asymmetric and 1,4-conjugate addition
of glycine imino esters to nitroalkenes leads to the forma-
tion of R-imino-γ-nitro esters, which can be transformed
into R,γ-diaminobutyric acid derivatives after consecutive
hydrolysis of the imino group and reduction of the nitro
group.2 On the other hand, 1,4-conjugate addition of
glycine imino esters to R,β-unsaturated carbonyl compounds
provides an efficient route to obtain optically active glu-
tamic acid derivatives, which exhibit extensive biological
activity.3 Kobayashi et al. successfully executed the con-
jugate addition of glycine imino esters to acrylate by
using a chiral calcium isopropoxide/bisoxazoline (BOX)
complex to furnish the conjugate adduct in 98% ee.3c,d
However, the conjugate adduct could not be obtained
in the reaction with crotonate, which instead generated
the cycloadduct as a major product. The use of the more
sterically hindered tert-butyl imino ester enabled exclusive
conjugate addition to the crotonate.3e Arylidene malo-
nates were demonstrated to be effective alternative
Michael acceptors in cases where conjugate addition of
glycine imino esters to cinnamate (β-aryl acrylate) was
not successful. Chiral P,S-(FeSulphos),4 P,N-(FcFOX),5
and N,O-ligand/copper6 complexes have been proposed
as catalysts for diastereo- and enantioselective conjugate
(1) For examples for the reaction with glycine imino ester in reviews,
see: (a) O’Donnel, M. J. Acc. Chem. Res. 2004, 37, 506–517. (b)
Hashimoto, T.; Maruoka, K. Chem. Rev. 2007, 107, 5656–5682. (c)
Adrio, J.; Carreteo, J. C. Chem. Commun. 2011, 47, 6784–6794. (d)
Shirakawa, S.; Maruoka, K. Angew. Chem., Int. Ed. 2013, 52, 4312–
4348.
(2) For recent examples, see: (a) Li, Q.; Ding, C.-H.; Hou, X.-L.; Dai,
L.-X. Org. Lett. 2010, 12, 1080. (b) Kim, H. Y.; Li, J.-Y.; Kim, S.; Oh, K.
J. Am. Chem. Soc. 2011, 133, 20750. (c) Vivanco, S.; Lecea, B.; Arrieta,
A.; Prieto, P.; Morao, I.; Linden, A.; Cossio, F. P. J. Am. Chem. Soc.
2000, 122, 6078.
(3) (a) Ishikawa, T.; Araki, Y.; Kumamoto, T.; Seki, H.; Fukuda, K.;
Isobe, T. Chem. Commun. 2001, 245. (b) Arai, S.; Tsuji, R.; Nishida, A.
Tetrahedron Lett. 2002, 43, 9535. (c) Saito, S.; Tsubogo, T.; Kobayashi,
S. J. Am. Chem. Soc. 2007, 129, 5364. (d) Tsubogo, T.; Saito, S.; Seki, K.;
Yamashita, Y.; Kobayashi, S. J. Am. Chem. Soc. 2008, 130, 13321. (e)
Kobayashi, S.; Tsubogo, T.; Saito, S.; Yamashita, Y. Org. Lett. 2008, 10,
807. (f) Hut’ka, M.; Tsubogo, T.; Kobayashi, S. Adv. Synth. Catal. 2013,
355, 1561–1569.
ꢀ
ꢀ
(4) Hernandez-Toribio, J.; Arrayas, R. G.; Carretero, J. C. Chem.;
Eur. J. 2011, 17, 6334–6337.
(5) Hou, X.; Li, Q.; Jun, Y.; Dai, L. Chin. J. Chem. 2010, 28, 1761–
1764.
r
10.1021/ol4019584
Published on Web 08/27/2013
2013 American Chemical Society

addition, furnishing β-aryl-γ-imino 1,3-esters in good to
excellent enantiomeric excess; the β-aryl-γ-imino ester can
beused asa precursor for β-substituted glutamic acids such
as 3-p-chlorophenylglutamic acid (chlorpheg), a selective
L-homocysteic acid (HCA) uptake inhibitor. To the best of
our knowledge, the only distinctively effective catalysts for
the reaction are the FeSulphos/copper complex and other
two complexes, which are limited in terms of the diastereo-
and enantioselectivity. The development of a new catalyst
for the asymmetric conjugate reaction of glycine imino
esters to arylidene malonate remains a challenge.
external base; this is markedly different from the previous
reaction with nitroalkenes.7d Thus, the AgOAc/TCF complex
proved to be a bifunctional (Lewis acid and base) catalyst
for the reaction; this is the first bifunctional catalysis in
conjugate addition.8
Scheme 1. Reaction of Glycine Imino Ester 1 with Benzylidene
Malonate
Our previous studies have demonstrated that the silver/
ThioClickFerrophos complex is an efficient catalyst for
enantioselective [3 þ 2] cycloaddition, the Mannich reac-
tion, and conjugate addition reactions of glycine imino
esters with activated alkenes, imines, and nitroalkenes,
respectively.7 In the reaction of glycine imino esters with
nitroalkenes, the conjugate adducts can be obtained as
major products by adding triethyl amine to the reaction,
whereas cycloadducts are generated as major products
when triethylamine is eliminated from the reaction.7d
Thus, the product selectivity can be controlled by the
presence or absence of an amine. Our ongoing evalua-
tion of the potential catalytic activity of the silver/
ThioClickFerrophos complex has revealed that the chiral
silver complex works as an efficient bifunctional catalyst
for the asymmetric conjugate addition of glycine imino
esterstoarylidene malonates togiveasyn-adductwithhigh
enantioselectivity in the absence of an external amine. The
scope of this catalyst has been expanded to the asymmetric
conjugate addition of imino esters to R-enones, the results
of which are disclosed herein.
Initially, the ThioClickFerrophos (TCF) ligands were
optimized in the reaction of diphenylene glycine imino
methyl ester with diethyl benzylidene malonate (Scheme 1).
The reaction was carried out in tetrahydrofuran (THF),
at room temperature, for 24 h, using 5 mol % AgOAc
and 5 mol % TCF. tert-Butyl-TCF (L1) was the most
effective ligand, affording the syn adduct (3-phenyl-4-imino
glutarate) as a major diastereomer (syn/anti = 97/3)
in 76% yield with 99% ee; 93% ee (42% yield, syn/anti =
91/9) and 90% ee (69% yield, syn/anti = 93/7) were
respectively obtained with ethyl-TCF (L2) and phenyl-
TCF (L3). Here, the stereochemistry of the conjugate
adduct was assigned as syn according to Carretero’s
definition.4 The reaction proceeded without addition of
an external base such as triethyl amine, whereas addition
of Cs2CO3 (20 mol %) accelerated the reaction to reach
completion within 2 h with improved yield (with 98% ee).
The conjugate adduct was the sole product, with no
cycloadduct being produced in spite of the absence of an
The scopes of arylidene and alkylidene malonates were
examined under generally base-free conditions, but occa-
sionally, Cs2CO3 was used as an external base when the
yield of the product was not satisfactory. Table 1 sum-
marizes the results obtained with substituted benzylidene
malonates bearing electron withdrawing and donating
substituents. Regardless of the electronic nature of the
substituent, the corresponding syn adducts were obtained
as the major diastereomer in good yields with high en-
antioselectivities (entries 3ꢀ9). Interestingly, heteroaryl
substituents such as 2-pyridylidene and 2-thienylidene
malonates were tolerated in the reaction to give the
corresponding syn adducts in good yields with high en-
antioselectivities (entries 10ꢀ11). Carretero et al. high-
lighted that coordinating groups, such as the pyridyl
group, tend to bind to the catalyst.4 The relative and
absolute configuration of the conjugate adduct was con-
firmed via X-ray analysis of the 2-thienyl glutarate (3j); the
configuration was revealed to be syn-(2S,3S) (see Support-
ing Information (SI)). With the use of ferrocenyl substi-
tuents, the addition of Cs2CO3 improved the reaction
performance to give syn adducts in 82% yield with 97%
ee, whereas, in the absence of external base, the reaction
yield was low (entries 12ꢀ13). The addition of Cs2CO3 was
criticaltoobtaina productfrom alkylidene malonatessuch
as cyclohexylidene malonate; nevertheless, the yield of the
product was moderate (entries 14ꢀ15).
Inspired by the success of the conjugate addition of the
glycine imino esters to a variety of arylidene malonates, we
then explored the potential of the silver catalyst in con-
jugate addition to R-enones. To the best of our knowledge,
only one report of a successful chiral metal complex
(6) (a) Wang, M.; Shi, Y.-H.; Luo, J.-F.; Du, W.; Shi, X.-X.; Fossey,
J. S.; Deng, W.-P. Cat. Sci. Technol. 2011, 1, 100–103. (b) Shi, Y.-H.;
Wang, Z.; Hu, B.; Wang, M.; Fossey, J. S.; Deng, W.-P. Org. Lett. 2011,
13, 6010–6013.
(7) (a) Oura, I.; Shimizu, K.; Ogata, K.; Fukuzawa, S.-i. Org. Lett.
2010, 12, 1752. (b) Shimizu, K.; Ogata, K.; Fukuzawa, S.-i. Tetrahedron
Lett. 2010, 51, 5068. (c) Imae, K.; Shimizu, K.; Ogata, K.; Fukuzawa,
S.-i. J. Org. Chem. 2011, 76, 3604. (d) Imae, K.; Konno, T.; Ogata, K.;
Fukuzawa, S.-i. Org. Lett. 2012, 14, 4410–4413.
(8) For
a review of AgOAc bifunctional catalysis (base-free
conditions), see: Chen, Q.-A.; Wang, D.-S.; Zhou, Y.-G. Chem. Com-
mun. 2010, 46, 4043–3051.
Org. Lett., Vol. 15, No. 17, 2013
4419

catalyzed asymmetric conjugate addition to an R-enone
has been published,9 although some successful organoca-
talysts (phase transfer catalysts) have been reported.10
According to the literature, the conjugate adduct 5 be-
comes a good precursor for substituted proline esters
after sequential hydrolysis and intramolecular cyclization
followed by hydrogenation.
obtained in up to 88% yield, contaminated with a
slight amount (4%) of the cycloadduct (see SI). Thus,
the substrate scope of R-enones was evaluated under the
optimized conditions. The results of the reaction with
1-aryl-2-propene-1-one are summarized in Table 2. Elec-
tron donating substituents such as p-methylphenyl and
p-methoxyphenyl produced similarly good yields and
high enantioselectivities as in the case of electron neutral
substrates (entries 2 and 4). The presence of a sterically
crowded substituent, i.e., a mesityl (2,6-dimethylphenyl)
group, hardly affected the reaction (entry 3). The halogen
substituted phenyl groups afforded good yields of the
corresponding conjugate adduct with excellent enantio-
selection (entries 5ꢀ7). In the reaction with ferrocenyl
substituents, the yield of the conjugate adducts was good
(entry 8). The reaction with aliphatic R-enones, such as
methyl vinyl ketone, also gave the corresponding conju-
gate adduct in a good yield with high enantioselectivity
(entry 9).
Table 1. Substrate Scope of Arylidene and Alkylidene Malonatesa
yield
(%)b
ee (%)d
syn
Table 2. Substrate Scope of R-Enonesa
entry
R
product
syn/antic
1
C6H5
C6H5
3a
3a
3b
3c
3d
3e
3f
76
97
86
87
83
95
83
99
74
70
92
36
82
NR
60
97/3
97/3
97/3
96/4
97/3
97/3
97/3
97/3
96/4
93/7
94/6
94/6
89/11
ꢀ
99
98
95
93
98
98
98
99
97
97
98
90
94
ꢀ
2e
3
o-MeC6H4
p-MeC6H4
p-MeOC6H4
p-FC6H4
p-ClC6H4
p-BrC6H4
2-C10H7
4
5
6
7
8
3g
3h
3i
yield
(%)b
ee
(%)c
9
entry
R
product
config.
10
11
12
13e
14
15e
2-pyridyl
2-thienyl
(C5H5)2Fe
(C5H5)2Fe
c-C6H11
1
2
3
4
5
6
7
8
9
C6H5
5a
5b
5c
5d
5e
5f
89
82
90
83
87
93
92
84
92
99
99
98
98
99
99
97
90
96
(ꢀ)
(ꢀ)
(ꢀ)
(ꢀ)
(ꢀ)
(ꢀ)
(ꢀ)
(ꢀ)
(ꢀ)
3j
p-MeC6H4
2,6-Me2C6H3
p-MeOC6H4
p-FC6H4
3k
3k
ꢀ
c-C6H11
3l
80/20
97
p-ClC6H4
p-BrC6H4
(C5H5)2Fe
Me
a 1 (0.20 mmol), 2 (0.24 mmol), AgOAc (0.01 mmol, 5 mol %), L1
(0.011 mmol, 5.5 mol %), THF (2.0 mL); rt, 24 h. b Combined isolated
yield of syn and anti isomers. c Determined by 1H NMR. d Determined by
HPLC. e Cs2CO3 (0.05 mmol) was added; reaction time was 2 h.
5g
5h
5i
a 1 (0.20 mmol), 4 (0.24 mmol), AgOAc (0.01 mmol, 5 mol %), L1
(0.011 mmol, 5.5 mol %), THF (2.0 mL); ꢀ40 °C, 2 h. b Isolated yield of
5. c Determined by HPLC.
The reaction of the glycine imino ester with 1-phenyl-
prop-3-enone proceeded (4a) atꢀ40 °CinTHFfor2hunder
external-base-free conditions to give a mixture of the con-
jugate adduct (5a) and cycloadduct (5a0) in 77% and 21%
yields, respectively; the enantiomeric excess of the conjugate
adduct was 97%. The reaction conditions were optimized in
order to suppress the production of the unwanted cycload-
duct, and it was found that 1,4-diazabicyclo[2.2.2]octane
(DABCO) was the most effective additive for promoting
conjugate adduct selectivity; the conjugate adduct was
The absolute configuration of 5a was determined by
converting it into the corresponding dihydropyrrole 6a via
treatment with acid and comparing the optical rotation of
6a with that of the reported compound; the stereochem-
istry was determined to be the S configuration (Scheme 2);
the stereochemistrywas consistent with that of the reaction
with 2-thienylidene malonate.11
In conclusion, the AgOAc/TCF complex is an effective
bifunctional catalyst for the conjugate addition of glycine
imino esters to arylidene and alkylidene malonates to
give the corresponding adducts in good yields with high
enantioselectivities without requiring the addition of an
(9) Strohmeier, M.; Leach, K.; Zajac, M. A. Angew. Chem., Int. Ed.
2011, 50, 12335–12338.
(10) (a) Akiyama, T.;Hara, M.;Fuchibe, K.;Sakamoto, S.;Yamaguchi,
K. Chem. Commun. 2003, 39, 1734–1735. (b) Lygo, B.; Beynon, C.; Lumley,
C.; McLeod, M. C.; Wada, C. E. Tetrahedron Lett. 2009, 50, 3363–3365.
(c) Ma, T.; Fu, X.; Kee, C. W.; Zong, L.; Pan, Y.; Huang, K.-W.; Tan,
C.-H. J. Am. Chem. Soc. 2011, 133, 2828–2831. (d) Sheshenev, A. E.;
Boltukhina, E. V.; White, A. J. P.; Hii, K. K. Angew. Chem., Int. Ed. 2013,
52, 6988–6991.
(11) van Esseveldt, B. C. J.; Vervoort, P. W. H.; van Delft, F. L.;
Rutjes, F. P. J. T. J. Org. Chem. 2005, 70, 1791–1795.
4420
Org. Lett., Vol. 15, No. 17, 2013

conjugate adducts could be improved by the addition of an
external amine such as DABCO.
Scheme 2. Conversion of 5a to 6a
Acknowledgment. This study was financially supported
by a Grant-in-Aid, No. 25410053, for Scientific Research
from the Japan Society for the Promotion of Science
(JSPS).
Supporting Information Available. Full experimental
procedures, characterization data, 1H and 13C NMR
spectra (PDF) for new compounds, and crystallographic
data for 3j as a CIF file. This material is available free of
charge via the Internet at http://pubs.acs.org.
external amine. AgOAc/TCF also catalyzed the conjugate
addition to R-enones with high enantioselectivity. This
reaction was accompanied by the formation of the cy-
cloadduct as a byproduct; nevertheless, the yield of the
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 17, 2013
4421