Diastereo- And enantioselective synthesis of α,γ-diaminobutyric acid derivatives via Cu-catalyzed asymmetric michael reaction

Article abstract of DOI:10.1021/ol100060t

(Figure Presented) The first highly diastereo- and enantioselective catalytic asymmetric Michael addition of glycine derivatives to nitroalkenes have been developed. The enantioselectivity of ortho-substituted products can be significantly improved by using a new 1,2-P,N-ferrocene ligand L5. The α,γdiaminoacid derivative was obtained without the loss of optical activity from the adduct.

Full text of DOI:10.1021/ol100060t

ORGANIC
LETTERS
2010
Vol. 12, No. 5
1080-1083
Diastereo- and Enantioselective
Synthesis of r,γ-Diaminobutyric Acid
Derivatives via Cu-Catalyzed
Asymmetric Michael Reaction
Qing Li, Chang-Hua Ding, Xue-Long Hou,* and Li-Xin Dai
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
xlhou@mail.sioc.ac.cn
Received January 11, 2010
ABSTRACT
The first highly diastereo- and enantioselective catalytic asymmetric Michael addition of glycine derivatives to nitroalkenes have been developed.
The enantioselectivity of ortho-substituted products can be significantly improved by using a new 1,2-P,N-ferrocene ligand L5. The r,γ-
diaminoacid derivative was obtained without the loss of optical activity from the adduct.
R,γ-Diaminobutyric acid as a subunit is found in natural
products,1 and it also possesses wide biological activities.2
In addition, NR-protected derivatives of R,γ-diaminobutyric
acid serve as important precursors for the synthesis of
structurally diverse analogues of biologically active peptides
such as cyclic peptide antibiotics gramicidin S3a and the
immunosuppressant cyclosporin A.3b However, only a limited
number of procedures for its synthesis have been reported.4
Very recently, an enantioselective synthesis of R,γ-diami-
nobutyric acids appeared, based on the chiral auxiliary
strategy.5 Thus development of a catalytic asymmetric route
to R,γ-diaminobutyric acid derivative is highly desirable.
It is conjectured that optically active R,γ-diaminobutyric
acids could be obtained via a metal-catalyzed asymmetric
Michael addition of glycine derivatives to nitroalkenes.6 The
asymmetric conjugate addition of glycine derivatives to
electron-deficient olefins is a highly versatile reaction to
afford the relevant R-amino acids.7 Acrylates,8 R,ꢀ-unsatur-
ated carbonyl compounds,9 and nitriles10 have been success-
fully applied as Michael acceptors in such reaction. The
racemic addition of glycine derivatives to nitroalkenes has
also been documented;11,14b,c however, no catalytic diastereo-
and enantioselective version of the reaction appeared. Previ-
(1) (a) Sasaki, J.; Chijimatsu, M.; Suzuki, K. Int. J. Syst. Bacteriol. 1998,
48, 403. (b) Storm, D. R.; Rosenthal, K. S.; Swanson, P. E. Annu. ReV.
Biochem. 1977, 46, 723.
(2) (a) Lambein, F.; Vos, B. Arch. Int. Physiol. Biochim. 1981, 89, B66.
(b) Ronquist, G.; Hugosson, R.; Westermark, B. J. Cancer Res. Clin. Oncol.
1980, 96, 259. (c) O’Neal, R. M.; Chen, C. H.; Reynolds, C. S.; Meghal,
S. K.; Koeppe, R. E. Biochem. J. 1968, 106, 699.
10.1021/ol100060t  2010 American Chemical Society
Published on Web 02/09/2010

ously, we developed an asymmetric 1,3-dipolar cycloaddition
of azomethine ylides with nitroalkenes using Cu catalyst.12,13
The cycloaddition proceeded through stepwise process,
specifically, Michael addition followed by cyclization.12c,14
On that basis we considered the possibility to obtain only
the Michael addition product by changing the substrate
structure and reaction conditions. Herein, we disclosed the
first example of such reaction using Cu/P,N-ferrocene ligands
as catalysts. The transformation of the resulted product to
the highly valuable ꢀ-substituted-R,γ-diaminobutyric acid
derivative is also demonstrated.
yield with 94/6 dr and 90% ee (entry 3 vs entries 1 and 2).
The evaluation of ferrocene ligands L1-4 with different
electronic properties revealed that the electronic factor of
ligands did not influence the diastereoselectivity but rather
the enantioselectivity of the reaction (entries 5 and 6 vs
entries
3 and 4). This differs from our previous
observation,12b,c presumably due to the steric factor of the
glycine esters 1c. The solvents have a strong effect on the
stereochemistry of the reaction, and THF was the best among
the solvents screened, including toluene, CH3CN, Et2O, and
CH2Cl2 (entry 6 vs entries 7-10). The screening of Lewis
acid showed that CuPF6 and AgOAc were also able to
smoothly catalyze the Michael reaction albeit with poor
selectivity, whereas CuI and Cu(OTf)2 retarded the reaction
(not shown in Table 1).
The substrate scope of nitroalkenes 2 was examined under
optimized conditions (Table 2). Reactions of glycine imine 1c
Initially, the reaction of glycine imine 1a with nitroalkene
2a using CuClO4/ligand L1 as catalyst was tested at room
temperature (eq 1), with the expectation that the Michael
addition would dominate over the cycloaddition reaction
because of the great steric hindrance of the diphenyl
methylene group. The source material was consumed com-
pletely in 1 h, and a mixture of Michael addition product
and cycloaddition product was obtained in the ratio of 2:1.
Considering the temperature effect on this reaction, we then
ran this reaction at -10 °C and obtained the Michael reaction
adduct as only product; the cycloaddition product was not
detected.
Table 2. Substrate Scope for the CuClO4-Catalyzed Reaction of
Glycine Imine 1c with Nitroalkenes 2a
entry
2, R
2a, Ph
yield (%)b anti:sync ee (%) antid
1
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
94:6
95:5
98:2
98:2
98:2
95:5
92:8
96:4
94:6
90:10
82:18
90:10
97
97
98
97
98
97
98
97
95
76
64
89
2
2b, p-Br-C6H4
2c, p-Cl-C6H4
2d, p-F-C6H4
2e, p-OMe-C6H4
2f, p-Me-C6H4
2g, m-Br-C6H4
2h, m-OMe-C6H4
2i, 2-fural
Encouraged by the results above, we set out to optimize
the reaction conditions (Table 1). Investigation of the glycine
imine 1 led to the bulky tert-butyl esters 1c as the optimal
substrate, and the adduct 6a was provided in quantitative
3
4
5
6
7
8
9
10
11
12
2j, o-Br-C6H4
2k, o-CF3-C6H4
2l, o-Cl-C6H4
a Molar ratio of 1c/2/CuClO4/L3/Et3N ) 1/1/0.1/0.1/0.1. b Isolated yields.
Table 1. Optimization of Reaction Conditions for the CuClO4-
Catalyzed Reaction of Glycine Imine 1 with Nitroalkene 2aa
c
Determined by H NMR. d Determined by chiral HPLC.
1
with various (E)-2-aryl-1-nitroalkenes with substituents at the
para- and meta-positions of the phenyl ring proceeded with
quantitative yields, the diastereoselectivity being 92:8-98:2 and
the enantioselectivity being 95-98% (entries 1-8). The
electronic properties of the substituents exerted limited impact
on the diastereo- and enantioselectivity. Notably, the (E)-2-
(furan-2-yl)-1-nitroalkene 2i underwent Michael addition in
ee (%)
(3) (a) Mant, C. T.; Kondejewski, L. H.; Hodges, R. S. J. Chromatogr.
A 1998, 816, 79. (b) Galpin, I. J.; Mohammed, A. K. A.; Patel, A.
Tetrahedron 1988, 44, 1783.
entry
1, R
L
solvent yield (%)b anti:sync (anti/syn)d
1
2
3
4
5
6
7
8
9
10
1a, Me L1 THF
>99
>99
>99
>99
>99
>99
>99
>99
65
78:22
78:22
94:6
79/88
85/-
90/-
84/-
97/-
95/-
93/80
91/95
96/84
92/89
(4) (a) Yamada, K.; Urakawa, H.; Oku, H.; Katakai, R. J. Peptide Res.
2004, 64, 43. (b) Solladie´-Cavallo, A.; Simon, M. C. Tetrahedron Lett.
1989, 30, 6011.
1b, Et
L1 THF
1c, tBu L1 THF
1c, tBu L2 THF
1c, tBu L3 THF
1c, tBu L4 THF
1c, tBu L3 toluene
1c, tBu L3 CH3CN
1c, tBu L3 Et2O
1c, tBu L3 CH2Cl2
92:8
94:6
94:6
86:14
85:15
76:14
65:35
(5) Huang, Y.; Li, Q.; Liu, T. L.; Xu, P. F. J. Org. Chem. 2009, 74,
1252.
(6) Metal catalysis: (a) Christoffers, J.; Koripelly, G.; Rosiak, A.; Ro¨ssle,
M. Synthesis 2007, 1279. Organocatalysis: (b) Tsogoeva, S. B. Eur. J. Org.
Chem. 2007, 1701. (c) Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org.
Chem. 2002, 1877.
82
a Molar ratio of 1/2a/CuClO4/L/Et3N ) 1/1/0.1/0.1/0.1. b Isolated yields.
(7) (a) Hashimoto, T.; Maruoka, K. Chem. ReV. 2007, 107, 5656. (b)
Na´jera, C.; Sansano, J. M. Chem. ReV. 2007, 107, 4584. (c) O’Donnell,
M. J. Acc. Chem. Res. 2004, 37, 506.
c
Determined by H NMR. d Determined by chiral HPLC.
1
Org. Lett., Vol. 12, No. 5, 2010
1081

quantitative yield with 96:4 dr and 95% ee (entry 9). The
versatility of furan in several types of reactions such as the
Diels-Alder reaction will provide the resulted Michael product
as a useful intermediate in organic synthesis. Disappointingly,
much lower enantioselectivities were obtained when (E)-2-(o-
substituted aryl)-1-nitroalkenes 2j-l were the substrates (entries
1.49 g of 2a using L3 as ligand still afforded product 6a in
>99% yield with 94:6 dr and 97% ee, which established the
practical utility of the reaction.
Hydrolysis of the adduct 6a afforded a free amino ester
7a, which was subjected to hydrogenation of the nitro group
followed by protection of the free amino groups. The R,γ-
diaminobutanoate 8 was provided without the loss of optical
activity in 79% overall yield (Scheme 2).
10-12).15 Aliphatic nitroalkene 2 (R ) Pr) was investigated
i
in the same conditions above, and unexpectedly, we obtained
the sole cycloaddition product (dr > 99:1, ee ) 97%).
Scheme 2
.
Transformation of Adduct 6a to R,γ-Diaminobutyric
Acid Derivative 8
Scheme 1. Improvement of Enantioselectivity for the Reaction
of Glycine Imine 1c with Nitroalkenes 2a, 2j-2l Using L5a
The absolute configuration of Michael addition product 6b was
assigned as (2R,3R) by conversion of the adduct 6b to free amino
ester 7b followed by the X-ray diffraction analysis (Figure 1).
To circumvent the aforementioned problem that stemmed
from ortho-substituents on the phenyl ring of nitroalkenes 2,
we designed and synthesized a novel type of 1,2-P,N-ferrocene
ligands L5 with a P-bound pyrrole group because pyrrole
features strong π-acceptor and weak σ-donor properties and
N-pyrrolylphosphine ligands have shown greatly improved
selectivity in some reactions.16 We then utilized L5 in the
Michael addition of glycine ester 1c to nitroalkenes 2j-l, which
showed amazing positive effect for the stereocontrol in the
Michael reaction of (E)-2-(ortho-substituted aryl)-1-nitroalkenes.
The ee values of the Michael products 6j, 6k, and 6l increased
from 76%, 64%, and 89% to 93%, 86%, and 93%, respectively,
by employing L5 as ligand (Scheme 1), while the excellent
diastereo- and enantioselectivity was still maintained at the
expense of chemical yield when 2a was the substrate.
The reaction proceeded smoothly even on a 10 mmol scale
under the same condition. Treatment of 2.95 g of 1c with
(8) (a) Kano, T.; Kumano, T.; Maruoka, K. Org. Lett. 2009, 11, 2023.
(b) Saito, S.; Tsubogo, T.; Kobayashi, S. J. Am. Chem. Soc. 2007, 129,
5364. (c) Ryoda, A.; Yajima, N.; Haga, T.; Kumamoto, T.; Nakanishi, W.;
Kawahata, M.; Yamaguchi, K.; Ishikawa, T. J. Org. Chem. 2008, 73, 133.
(d) Soloshonok, V. A.; Cai, C.; Yamada, T.; Ueki, H.; Ohfune, Y.; Hruby,
V. J. J. Am. Chem. Soc. 2005, 127, 15296. (e) Shibuguchi, T.; Fukuta, Y.;
Akachi, Y.; Sekine, A.; Ohshima, T.; Shibasaki, M. Tetrahedron Lett. 2002,
43, 9539. (f) Arai, S.; Tsuji, R.; Nishida, A. Tetrahedron Lett. 2002, 43,
9535. (g) Ishikawa, T.; Araki, Y.; Kumamoto, T.; Isobe, T.; Seki, H.;
Fukuda, K. Chem. Commun. 2001, 245. (h) Ma, D. W.; Cheng, K. J.
Tetrahedron Asymmetry 1999, 10, 713. (i) Corey, E. J.; Xu, F.; Noe, M. C.
J. Am. Chem. Soc. 1997, 119, 12414. (j) O’Donnell, M. J.; Bennett, W. D.;
Wu, S. J. Am. Chem. Soc. 1989, 111, 2353.
Figure 1. ORTEP drawing of the amino ester 7b.
(9) (a) Wang, Y. G.; Kumano, T.; Kano, T.; Maruoka, K. Org. Lett.
2009, 11, 2027. (b) Tsubogo, T.; Saito, S.; Seki, K.; Yamashita, Y.;
Kobayashi, S. J. Am. Chem. Soc. 2008, 130, 13321. (c) Elsner, P.; Bernardi,
L.; Salla, G. D.; Overgaard, J.; Jørgensen, K. A. J. Am. Chem. Soc. 2008,
130, 4897. (d) Saito, S.; Tsubogo, T.; Kobayashi, S. J. Am. Chem. Soc.
2007, 129, 5364. (e) Bernardi, L.; Lo´pez-Cantarero, J.; Niess, B.; Jørgensen,
K. A. J. Am. Chem. Soc. 2007, 129, 5772. (f) Shibuguchi, T.; Mihara, H.;
Kuramochi, A.; Sakuraba, S.; Ohshima, T.; Shibasaki, M. Angew. Chem.,
Int. Ed. 2006, 45, 4635.
In summary, we report the first catalytic asymmetric
Michael addition of glycine derivatives to nitroalkenes by
using Cu/1,2-P,N-ferrocene ligand as catalyst, providing
ꢀ-substituted-R,γ-diaminobutyric acid derivatives in high
diastereo- and enantioselectivities. A novel type of 1-dipyr-
rolylphosphanes Fc-Phox L5 was designed and synthesized
1082
Org. Lett., Vol. 12, No. 5, 2010

for the first time. The Fc-Phox L5 dramatically improved
the enantioselectivity for the Michael reaction of (E)-2-
(ortho-substituted aryl)-1-nitroalkenes. Further studies on the
applications of this new ligand in asymmetric catalysis are
in progress.
(10) Akiyama, T.; Hara, M.; Fuchibe, K.; Sakamoto, S.; Yamaguchi,
K. Chem. Commun. 2003, 1734.
Acknowledgment. Financially supported by the Major
Basic Research Development Program (2010CB833300),
National Natural Science Foundation of China (20872161,
20821002, 20932008), Chinese Academy of Sciences, and
Science and Technology Commission of Shanghai Munici-
pality.
(11) (a) Li, W.; Liu, H.; Du, D. M. Synlett 2009, 925. (b) Rowley, M.;
Leeson, P. D.; Williams, B. J.; Moore, K. W.; Baker, R. Tetrahedron 1992,
48, 3557.
(12) (a) Chen, C. G.; Hou, X. L.; Pu, L. Org. Lett. 2009, 11, 2073. (b)
Yan, X. X.; Peng, Q.; Li, Q.; Zhang, K.; Yao, J.; Hou, X. L.; Wu, Y. D.
J. Am. Chem. Soc. 2008, 130, 14362. (c) Yan, X. X.; Peng, Q.; Zhang, Y.;
Zhang, K.; Hong, W.; Hou, X. L.; Wu, Y. D. Angew. Chem., Int. Ed. 2006,
45, 1979.
(13) Another report on the 1,3-cycloaddition of nitroalkenes with glycine
derivatives: Xue, M. X.; Zhang, X. M.; Gong, L. Z. Synlett 2008, 691.
(14) (a) Arrieta, A.; Otaegui, D.; Zubia, A. Coss´; io, F. P.; D´ıaz-Ortiz,
A.; de la Hoz, A.; Herrero, M. A.; Prieto, P.; Foces-Foces, C.; Pizarro,
J. L.; Arriortua, M. I. J. Org. Chem. 2007, 72, 4313. (b) Vivanco, S.; Lecea,
B.; Arrieta, A.; Prieto, P.; Morao, I.; Linden, A.; Coss´ıo, F. P. J. Am. Chem.
Soc. 2000, 122, 6078. (c) Ayerbe, M.; Arrieta, A.; Coss´ıo, F. P.; Linden,
A. J. Org. Chem. 1998, 63, 1795.
Supporting Information Available: General experimen-
tal procedure, spectral data for 6a-6l and 7a, 7b, and 8,
and X-ray analysis data of 7b in CIF format. This material
isavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
OL100060T
(15) The ortho-substituent of the substrate decreasing stereoselectivity
in asymmetric catalysis is also observed by other groups. For some
examples, see: (a) Trost, B. M.; Hitce, J. J. Am. Chem. Soc. 2009, 131,
4572. (b) Kato, Y.; Furutachi, M.; Chen, Z.; Mitsunuma, H.; Matsunaga,
S.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 9168. (c) Cheng, L.; Liu,
L.; Jia, H.; Wang, D.; Chen, Y. J. J. Org. Chem. 2009, 74, 4650. (d)
Hamashima, Y.; Suzuki, T.; Takano, H.; Shimura, Y.; Sodeoka, M. J. Am.
Chem. Soc. 2005, 127, 10164. (e) Reference 12b.
(16) (a) Yan, Y. J.; Zhang, X. W.; Zhang, X. M. J. Am. Chem. Soc.
2006, 128, 16058. (b) van der Slot, S. C.; Duran, J.; Luten, J.; Kamer,
P. C. J.; van Leeuwen, P. W. N. M. Organometallics 2002, 21, 3873. (c)
Jackstell, R.; Klein, H.; Beller, M.; Wiese, K. D.; Ro¨ttger, D. Eur. J. Org.
Chem. 2001, 3871. (d) Breit, B. J. Mol. Catal. 1999, 143, 143. (e) Trzeciak,
A. M.; Glowiak, T.; Grzybek, R.; Zio´lkowski, J. J. J. Chem. Soc., Dalton
Trans. 1997, 1831. (f) Breit, B. Chem. Commun. 1996, 2071.
Org. Lett., Vol. 12, No. 5, 2010
1083