Cu-catalyzed asymmetric Michael addition of glycine derivatives to α,β-unsaturated malonates

Article abstract of DOI:10.1002/cjoc.201090297

Michael addition of glycine imines with alkylidene and arylidene malonates has been developed using Cu/FcPhox as catalyst, providing corresponding Michael products in high yields with high diastereo- and enanti-oselectivities.

Full text of DOI:10.1002/cjoc.201090297

FULL PAPER
Cu-Catalyzed Asymmetric Michael Addition of Glycine
Derivatives to α,β-Unsaturated Malonates†
Hou, Xuelong*,a,b(侯雪龙)
b Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
Li, Qinga(李青)
Yao, Junb(姚俊)
Dai, Lixina(戴立信)
a State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Road, Shanghai 200032, China
Michael addition of glycine imines with alkylidene and arylidene malonates has been developed using
Cu/FcPhox as catalyst, providing corresponding Michael products in high yields with high diastereo- and enanti-
oselectivities.
Keywords asymmetric catalysis, Michael addition, glycine derivatives, Cu-catalysis, alkylidene malonate
Introduction
Michael addition products in high diastereo- and enan-
tioselectivities. In this paper, we would like to disclose
our preliminary results on this reaction.
Michael reaction as an versatile protocol to form
carbon-carbon and carbon-heteroatom bond in organic
synthesis attracted the attention of synthetic chemists
for a long time.1 Because the products are easily con-
verted to the relevant α-amino acids when the glycine
derivatives are used as donor, the Michael addition of
them with α,β-unsaturated compound has widely been
studied since Stork and co-workers reported the first
example of Michael addition of glycine derivative with
α,β-unsaturated ester in 1976.2,3 Since then, many pro-
cedures have been developed and optically active prod-
ucts were afforded in some cases, however, catalytic
asymmetric version of the reaction appeared only in
recent years. Most of them employed chiral
phase-transfer catalysts,4 chiral organo bases,5 and
chiral crown-ethers6 as catalyst, more excess of sub-
strate and base as well as high catalytic loading some-
time were needed. Transition-metal catalysts have suc-
cessfully been used in the asymmetric cycloaddition
reaction of glycine derivatives with many types of un-
saturated compounds,7,8a,9,10 to our surprise that there
were a few reports on the use of transition-metal cata-
lyst in the asymmetric Michael addition reaction of gly-
cine derivatives.9,11 As a program aimed at the synthesis
and applications of chiral ligands in asymmetric cataly-
sis,12 we studied the use of glycine derivatives in
asymmetric reaction.8 Further studies revealed that
Cu/P,N-ferrocene ligands are effective catalysts in the
Michael addition reaction of glycine derivatives with
α,β-unsaturated malonates, affording corresponding
Results and discussion
Initially the reaction of glycine derivative 1a with
methyl cinnamate 2a using Cu-ligand L1 as the catalyst
was investigated (Scheme 1). After 3 d, 60% yield of
Michael addition product 3a was obtained, dr ratio be-
ing 1∶ 3 while ee value being 24%/42%. To increase
the reaction efficiency, more electron-deficient alkene,
benzylidene malonate 2b was used as Michael acceptor.
To our delight, quantitative product 3b was provided by
the reaction of 1a with 2b under the condition of Eq. 1
after 8 h, but the diastereoselectivities was still low (dr
being 2∶ 1 with 84%/99% ee).
Scheme 1
Based upon the above results, the influence of cop-
per salts on the reaction was studied (Table 1). It can be
seen that all reactions using different copper salts pro-
*
E-mail: xlhou@mail.sioc.ac.cn
Received July 25, 2010; revised and accepted September 16, 2010.
Project supported by the Major Basic Research Development Program (No. 2010CB833300), the National Natural Science Foundation of China
(Nos. 20872161, 20821002, 20932008), the External Cooperation Program of Chinese Academy of Sciences (No. GJHZ200816), the Chinese
Academy of Sciences, Shanghai Committee of Science and Technology and Croucher Foundation of Hong Kong.
† Dedicated to the 60th Anniversary of Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences.
Chin. J. Chem. 2010, 28, 1761— 1764
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1761

Hou et al.
FULL PAPER
vided excellent yields of product (Table 1, Entries 1— 4
and Entry 6) except that using CuI, which gave product
in 34% yield only (Table1, Entry 5). However, there
was almost no diastereoselectivity in all cases and enan-
tioselectivity was also lower with exceptions when Cu-
ClO4 and Cu(OTf)2 were used (Entries 1, 3). We have
found that electronic factor of ligands has great impact
on the selectivity of the reaction.8,13,14 We also found
that regio- and diastereoselectivities of the reaction were
switched by ligands with different electronic prop-
erty.8,14a Thus, the ligands having the phenyl ring with
different substituent on P atom were tested and the re-
sults are also compiled in Table 1. It can be seen that L4
with two electron-withdrawing group, CF3, at 3,5-posi-
tion of phenyl ring gave the best diastereoselectivities
(Entry 9) though the enantioselectivity is low, while
ligands L2 and L3 with electron-donating group, Me
and MeO, at phenyl ring provided the product with
lower diastereoselectivity (Entries 7 and 8). THF proved
to be the best among the common solvents, such as
CH2Cl2, toluene, Et2O and DME, while t-BuOK be the
best among the bases screened (Et3N, DABCO, DMAP,
BuOLi, CsOH, LiOH) in terms of yields, diastereo- and
enantioselectivities (not showed in Table). It was re-
ported that i-PrOH has great effect in some reactions.15
So under the condition of 10 mol% Cu(OTf)2, 11 mol%
L4, 4 Å MS, 10 mol% t-BuOK and THF as solvent, we
added 100 mol% of i-PrOH as additive, finding that the
enantioselectivity increased from 64% to 84% (Entry
11), however, the enantioselectivity was not improved
when CuClO4 was used as lewis acid under the same
condition (Entry 12 vs. Entry 13).
Under the optimized condition, the substrate scope
was investigated (Table 2). All arylidene malonates 2, in
which R was phenyl ring with either electron-with-
drawing or donating substituent at para- or meta-posi-
tion and naphthyl, delivered the products in high yields
(Entries 1— 6). The diastereoselectivity was between 7
— 10∶ 1 (Entries 1— 3, 5 and 6), but malonate 2e with
methoxy group at meta-position of phenyl ring gave 3e
in a dr ratio of 5∶ 1 (Entry 4). High ee was realized
when substituent was phenyl (Entry 1), para-substituted
phenyl (Entries 2, 3) and naphthyl (Entry 6), while
meta-substituted benzylidene malonates 2e and 2f pro-
vided the products in 64% and 68% ee respectively (En-
tries 4 and 5). The reaction is also suitable for alky-
lidene malonates, providing corresponding products in
high yields and high ee (Entries 7— 10). When malonate
2l with cyclohexyl as substituent was used the dr ratio
was 10∶ 1 and the ee was 95% but the yield was
Table 1 Influence of copper salts and electronic factor of
ligands on the selectivities of the reactiona,16
Table 2 Cu-catalyzed Michael addition of glycine imine with
α,β-Unsaturated Malonatesa
Entry
CuX
Ligand Yieldb/%
drc
eed/%
1
2
3
4
5
6
7
8
9
CuClO4
CuOTf
L1
L1
L1
L1
L1
L1
L2
L3
L4
PPh3
L4
L4
L4
97
93
98
96
34
97
96
94
94
95
98
98
98
2∶1 84/99
Entry 2, R
Product Yieldb/%
drc eed/%
1∶
1∶
1∶
1∶
1∶
1
1
1
1
1
7/35
80/84
63/41
13/43
53/44
1
2
3
4
5
6
7
8
9
2b, Ph
3b
3c
3d
3e
3f
91
93
8∶
7∶
1
1
1
1
84
80
81
64
68
79
86
82
83
86
95
Cu(OTf)2
CuPF6
2c, p-BrC6H4
2d, p-NO2C6H4
2e, m-MeOC6H4
2f, m-ClC6H4
2g, 1-Naphtyl
2h, i-Bu
89
7∶
CuI
100
100
100
100
88
5∶
Cu(OAc)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
10∶
9∶
1
1∶ 1.5 99/—
3g
3h
3i
1
1
1
1
1
4∶
11∶
1∶
1
84/—
64/—
—
2∶
1
2i, i-Pr
9∶
10 Cu(OTf)2
11 Cu(OTf)2
12 CuClO4
3
1
2j, n-Pr
3j
100
100
42
4∶
e
8∶
84/—
66/99
66/99
10 2k, Et
3k
2∶
12∶
12∶
1
11 2l, c-Hexyl
3l
＞10∶
1
e
13 CuClO4
1
a Run at 0 ℃ under Ar in 8 h, using 11 mol% of ligand and 10
a Run at 0 ℃ under Ar, using 11 mol% of ligand, 10 mol% of
mol% of Cu(OTf)2, 4 Å MS, 100 mol% of i-PrOH as additive.
copper salt and 4 Å MS. b Separated yield. c Determined by H
1
b Separated yield. c Determined by H NMR. d ee of the major
1
NMR. d Determined by HPLC using chiral column. e 100 mol% of
diasteroisomer, determined by HPLC using chiral column.
i-PrOH as additive.
1762
www.cjc.wiley-vch.de
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2010, 28, 1761— 1764

Asymmetric Michael Addition of Glycine Derivatives to α,β-Unsaturated Malonates
42% only (Entry 11). The substrates with substituent at
α-position gave the products in high diastereoselectivity
(Entries 8 and 11) while that with no substituent pro-
vided the products in lower diastereoselectivity (Entries
7, 9 and 10). X-Ray diffraction analysis of 3c showed it
has syn-stereochemistry.
dation of Hong Kong for a Studentship.
References and notes
1
(a) Krause, N. Angew. Chem., Int. Ed. 1998, 37(3), 283.
(b) Leonard, J.; Diez-Barra, E.; Merino, S. Eur. J. Org.
Chem. 1998, 10, 2051.
(c) Krause, N.; Hoffmann-Roder, A. Synthesis 2001, 171.
(d) Lewandowska, E. Tetrahedron 2007, 63(10), 2107.
(e) Vicario, J. L.; Badia, D.; Carrillo, L. Synthesis 2007,
2065.
2
3
Stork, G.; Ambrose, Y. W.; Touzin, A. J. Org. Chem. 1976,
21, 3491.
Some reviews and examples:
(a) Gothelf, K. V.; Jørgensen, K. A. Chem. Rev. 1998, 98,
863.
(b) O’Donnell, M. J. Acc. Chem. Res. 2004, 37, 506.
(c) Coldham, I.; Hufton, R. Chem. Rev. 2005, 105, 2765.
(d) Pandey, G.; Banerjee, P.; Gadre, S. R. Chem. Rev. 2006,
106, 4484.
(e) Hashimoto, T.; Maruoka, K. Chem. Rev. 2007, 107,
5656.
Figure 1 ORTEP drawing of 3c.
(f) Najera, C.; Sansano, J. M. Chem. Rev. 2007, 107, 4584.
(g) Akiyama, T.; Hara, M.; Fuchibe, K.; Sakamoto, S.; Ya-
maguchi, K. Chem. Commun. 2003, 1734.
(h) Zhang, F. Y.; Corey, E. J. Org. Lett. 2000, 2, 1097.
(i) Lygo, B.; Allbutt, B.; Kirton, E. H. M. Tetrahedron Lett.
2005, 46, 4461.
The steric factor of glycine ester also influences the
stereochemistry of the reaction. When tert-butyl esters
1c were used, even better stereoselectivities were
achieved while the reaction of ethyl ester 1b provided
the same stereoselectivities (Scheme 2).
(i) Arai, S.; Takahashi, F.; Tsuji, R.; Nishida, A. Heterocy-
cles 2006, 67, 495.
Scheme 2
4
(a) Corey, E. J.; Noe, M. C.; Xu, F. Tetrahedron Lett. 1998,
39, 5347.
(b) O'Donnell, M. J.; Bennett, W. D.; Wu, S. D. J. Am.
Chem. Soc. 1989, 111, 2353.
(c) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997,
119, 12414.
(d) Shibuguchi, T.; Fukuta, Y.; Akachi, Y.; Sekine, A.; Oh-
shima, T.; Shibasaki, M. Tetrahedron Lett. 2002, 43, 9539.
(e) Arai, S.; Tsuji, R.; Nishida, A. Tetrahedron Lett. 2002,
43, 9535.
5
6
Ma, D. W.; Cheng, K. J. Tetrahedron: Asymmetry 1999, 10,
713.
(a) Itoh, T.; Shirakami, S. Heterocycles 2001, 55, 37.
(b) Cram, D. J.; Sogah, G. D. Y. J. Chem. Soc., Chem.
Commun. 1981, 625.
(c) Alonso-López, M.; Martin-Lomas, M.; Penadés, S. Tet-
rahedron Lett. 1986, 27, 3551.
(d) Aoki, S.; Sasaki, S.; Koga, K. Tetrahedron Lett. 1989,
30, 7229.
(e) Töke, L.; Fenichel, L.; Albert, M. Tetrahedron Lett. 995,
36, 5951.
For some of examples:
(a) Gothelf, A. S.; Gothelf, K. V.; Hazell, R. G.; Jφrgensen,
K. A. Angew. Chem., Int. Ed. 2002, 41, 4236.
(b) Longmire, J. M.; Wang, B.; Zhang, X. J. Am. Chem. Soc.
2002, 124, 13400.
Conclusion
In conclusion, Cu-catalyzed asymmetric Michael
addition of glycine imine with α,β-unsaturated malo-
nates has been developed, providing Michael adducts in
high yields, high diastereo- and enantioselectivities.
Both alkylidene and arylidene malonates are suitable
substrates. Electronic factor of the ligand plays the role
in the stereochemistry of the reaction. Investigations on
the reaction using other Michael reaction acceptors as
well as the applications of the products in organic syn-
thesis and the determination of absolute configuration of
adduct 3 are in progress.
7
Acknowledgement
(c) Chen, C.; Li, X.; Schreiber, S. L. J. Am. Chem. Soc.
2003, 125, 10174.
Jun, YAO gratefully acknowledged Croucher Foun-
Chin. J. Chem. 2010, 28, 1761— 1764
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1763

Hou et al.
FULL PAPER
(d) Oderaotoshi, Y.; Cheng, W.; Fujitomi, S.; Kasano, Y.;
Minakata, S.; Komatsu, M. Org. Lett. 2003, 5, 5043.
(e) Zeng, W.; Zhou, Y.-G. Org. Lett. 2005, 7, 5055.
(f) Carbrera, S.; Gómez Arrayás, R.; Carretero, J. C. J. Am.
Chem. Soc. 2005, 127, 16394.
(g) Nájera, C.; de Gracia Retamosa, M.; Sansano, J. M.
Tetrahedron: Asymmetry 2006, 17, 1985.
(h) Zeng, W.; Chen, G.-Y.; Zhou, Y.-G.; Li, Y.-X. J. Am.
Chem. Soc. 2007, 129, 750.
(i) Nájera, C.; De Gracia Retamosa, M.; Sansano, J. M. Org.
Lett. 2007, 9, 4025.
(j) Zeng, W.; Zhou, Y.-G. Tetrahedron Lett. 2007, 48, 4619.
(k) Lopez-Perez, A.; Adrio, J.; Carretero, J. C. J. Am. Chem.
Soc. 2008, 130, 10084.
(l) Nájera, C.; Retamosa, M. D.; Sansano, J. M. Angew.
Chem., Int. Ed. 2008, 47, 6055.
(a) Yan, X.-X.; Peng, Q.; Zhang, Y.; Zhang, K.; Hong, W.;
Hou, X.-L.; Wu, Y.-D. Angew. Chem., Int. Ed. 2006, 45,
1979.
Lett. 2010, 12, 1688
12 (a) Dai, L.-X.; Tu, T.; You, S.-L.; Deng, W.-P.; Hou, X.-L.
Acc. Chem. Res. 2003, 36, 659.
(b) Hou, X.-L.; You, S.-L.; Tu, T.; Deng, W.-P.; Wu, X.-W.;
Li, M.; Yuan, K.; Zhang, T.-Z.; Dai, L. X. Top. Catal. 2005,
35, 87.
(c) Hou, X.-L.; Dong, D.-X.; Yuan, K. Tetrahedron:
Asymmetry 2004, 15, 2189.
(d) Wu, W. Q.; Peng, Q.; Dong, D. X.; Hou, X. L.; Wu, Y.
D. J. Am. Chem. Soc. 2008, 130, 9717.
13 For excellent review on electronic factor in asymmetric ca-
talysis: Flanagan, S. P.; Guiry, P. J. J. Organomet. Chem.
2006, 691, 2125.
14 (a) Tu, T.; Deng, W.-P.; Hou, X.-L.; Dai, L.-X.; Dong, X.-C.
Chem. Eur. J. 2003, 9, 3073.
(b) Wu, X.-W.; Yuan, K.; Sun, W.; Zhang, M.-J.; Hou, X.-L.
Tetrahedron: Asymmetry 2003, 14, 107.
(c) Tu, T.; Hou, X.-L.; Dai, L.-X. J. Organomet. Chem.
2004, 689, 3847.
8
9
(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.
Ca-catalyzed reactions were reported:
(a) Saito, S.; Tsubogo, T.; Kobayashi, S. J. Am. Chem. Soc.
2007, 129, 5364.
15 Opio, J. O.; Labidalle, S.; Galons, H.; Miocque, M.;
Zaparucha, A.; Loupy, A. Syn. Commun. 1991, 21, 1743.
16 Typical procedure for the Michael addition of 1 and 2. To a
flame-dried Schlenk tube containing activated 4 Å MS were
added Cu(OTf)2 (3.6 mg, 0.01 mmol) and ligand L4 (8.2 mg,
0.011 mmol) then freshly distilled anhydrous THF (1 mL)
subsequently under argon atmosphere. Stirred for 30 min,
the solution was cooled to 0 ℃ the glycine derivatives 1a
(0.1 mmol) was added, followed by t-BuOK (10 µL, 1
mol/L in THF, 0.01 mmol) and 2b (0.11 mmol). The reac-
tion mixture was stirred at 0 ℃ until the reaction com-
pleted (monitored by TLC), then filtered through a short
plug of silica gel. After evaporation of the solvent, the crude
(b) Kobayashi, S.; Tsubogo, T.; Saito, S.; Yamashita, Y.
Org. Lett. 2008, 10, 8079.
10 There are also some reports by using organocatalysts. For
examples:
(a) Alemparte, C.; Blay, G.; Jørgensen, K. A. Org. Lett.,
2005, 7, 4569.
(b) Vicario, J. L.; Reboredo, S.; Badia, D.; Carrillo, L.
Angew. Chem., Int. Ed. 2007, 46, 5168.
(c) Xue, M. X.; Zhang, X. M.; Gong, L. Z. Synlett 2008,
691.
(d) Liu, Y. K.; Liu, H.; Du, W.; Yue, L.; Chen, Y. C. Chem.
Eur. J. 2008, 14, 9873.
(e) Kano, T.; Kumano, T.; Maruoka, K. Org. Lett. 2009, 11,
2023.
1
product was analyzed by H NMR spectroscopy to deter-
mine the diastereomeric ratio, and then purified by chroma-
tography on silica gel (EtOAc/petroleum mixtures). Ana-
lytical data for 3b: Major diastereomer: 84% ee; m.p. 119—
121 ℃; 1H NMR (300 MHz, CDCl3) δ: 3.39 (s, 3H), 3.57 (s,
3H), 3.64 (s, 3H), 4.32—4.43 (m, 3H), 6.84—7.70 (m, 15H);
13C NMR (CDCl3) δ: 48.50, 51.99, 52.25, 52.57, 54.01,
68.77, 127.20, 127.25, 128.03, 128.20, 128.35, 128.52,
128.99, 130.65, 135.75, 138.92, 139.21, 1＋68.24, 168.50,
170.82, 171.89; MS (ESI) m/z: 474.2 (M＋H ), 496.2 (M＋
Na＋); HRMS (ESI) calcd for C28H27NNaO6, 496.17127,
found 496.17306; HPLC (Chiral AD, hexane/2-propanol＝
90/10, flow rate＝1.0 mL/min), tR＝11.46 min, 17.77 min.
(f) Wang, Y. G.; Kumano, T.; Kano, T.; Maruoka, K. Org.
Lett. 2009, 11, 2027.
11 (a) Chen, C. G.; Hou, X. L.; Pu, L. Org. Lett. 2009, 11,
2073.
(b) Li, Q.; Ding, C. H.; Hou, X. L.; Dai, L. X. Org. Lett.
2010, 12, 1080.
(c) Zheng, B. H.; Ding, C. H.; Hou, X. L.; Dai, L. X. Org.
(E1007251 Lu, Y.)
1764
www.cjc.wiley-vch.de
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2010, 28, 1761— 1764