A ferrocenyl-DHIPOH/Cu(OAc)2 complex for diastereo- and enantioselective catalysis of the 1,4-addition of glycine derivatives to alkylidene malonates

Article abstract of DOI:10.1021/ol202466v

A planar chiral ferrocene derivative Fc-DHIPOH served as an excellent N,O- chiral ligand for asymmetric copper catalyzed 1,4-addition of glycine derivatives to alkylidene malonates. The corresponding 1,4-adducts were obtained in high yields with excellent enantioselectivities up to 95% ee.

Full text of DOI:10.1021/ol202466v

ORGANIC
LETTERS
2011
Vol. 13, No. 22
6010–6013
A Ferrocenyl-DHIPOH/Cu(OAc)2 Complex
for Diastereo- and Enantioselective
Catalysis of the 1,4-Addition of Glycine
Derivatives to Alkylidene Malonates
Yu-Hua Shi,† Zheng Wang,† Bin Hu,† Ming Wang,† John S. Fossey,†,‡ and
Wei-Ping Deng*,†
Shanghai Key Laboratory of Functional Materials Chemistry & School of Pharmacy,
East China University of Science and Technology, Shanghai, China, 200237, and School of
Chemistry, University of Birmingham, Edgbaston, Birmingham, B15 2TT, England, U.K.
weiping_deng@ecust.edu.cn
Received September 12, 2011
ABSTRACT
A planar chiral ferrocene derivative Fc-DHIPOH served as an excellent N,O- chiral ligand for asymmetric copper catalyzed 1,4-addition of glycine
derivatives to alkylidene malonates. The corresponding 1,4-adducts were obtained in high yields with excellent enantioselectivities up to 95% ee.
New skeletal types and concepts in the design of novel
chiral ligands have been a significantly stimulating topic in
asymmetric catalysis over the past half century.1 Yet, only
a small number of ligands truly deserve the moniker of
“privileged ligands”.2 Despite impressive progress in this
area, discovery often relies on serendipity and systematic
screening, with the design of suitable chiral ligands for
particular tasks remaining challenging.
Recently we designed a planar chiral ferrocene deriva-
tive for nucleophilic catalysis,3 through a combination of
† East China University of Science and Technology.
‡ University of Birmingham.
(2) (a) Yoon, T. P.; Jacobsen, E. N. Science 2003, 299, 1691. (b)
Asymmetric Catalysis, Privileged Ligands and Complexes, 8, no. 2,
Aldrich Chemical Co., 2008. (c) Benessere, V.; Del Litto, R.; De Roma,
A.; Ruffo, F. Coord. Chem. Rev. 2010, 254, 390.
(3) Hu, B.; Meng, M.; Wang, Z.; Du, W.; Fossey, J. S.; Hu, X.; Deng,
W.-P. J. Am. Chem. Soc. 2010, 132, 17041.
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119, 1492. (b) Ruble, J. C.; Tweddell, J.; Fu, G. C. J. Org. Chem. 1998,
63, 2794.
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J. Am. Chem. Soc. 2004, 126, 12226. (b) Birman, V. B.; Li, X. Org. Lett.
2006, 8, 1351. (c) Birman, V. B.; Jiang, H. Org. Lett. 2005, 7, 3445.
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Wiley & Sons: New York, 2010. (b) Supramolecular Catalysis; van
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metric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer:
New York, 1999. (d) Chiral Ferrocenes in Asymmetric Catalysis: Synth-
esis and Applications; Dai, L.-X., Hou, X.-L., Eds.; Wiley-VCH: Weinheim,
2010. (e) Dai, L.-X.; Tu, T.; You, S.-L.; Deng, W.-P.; Hou, X.-L. Acc. Chem.
Res. 2003, 36, 659. (f) Pfaltz, A.; Drury, W. J., III. Proc. Natl. Acad. Sci.
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r
10.1021/ol202466v
Published on Web 10/18/2011
2011 American Chemical Society

two inspirational catalyst systems of Fu4 and Birman5
(Figure 1). Our new nonenzymatic catalyst showed selec-
tivity factors S of up to 1892 in the kinetic resolution of
secondary alcohols.
Due totheir biological importance, muchefforthas been
made toward efficient synthesis of β-alkyl substituted
glutamic acid derivatives through diastereoselective7 or
catalytic8 1,4-additions of glycine derivatives to R,β-un-
saturated esters or amides. The products serve not only as
essential components of peptides and proteins but also as
signal mediators.9 In view of the biological and synthetic
importance of optically active glutamic acids and their
β-substituted derivatives, versatile and practical approaches
to their synthesis are still required. Consequently, in order
to further improve the stereoselectivity of this newly estab-
lished catalytic asymmetric reaction, we set out to de-
sign novel ferrocene-based planar chiral N,O-ligands (Fc-
DHIPOH) containing both planar and centrally chiral
architectural features of the aforementioned Fc-PIP and
DHIPOH respectively (Figure 2).
Herein we report on the newly designed and synthesized
N,O-ligand Fc-DHIPOH which was found to offer im-
proved enantioselectivities in the aforementioned ligand/
Cu(OAc)2 catalyzed asymmetric Michael reactions of
glycine derivatives to alkylidene malonates giving 3-aryl
glutamic acid derivatives with high enantioselectivities
(89%À95% ee).
Figure 1. Design of Fc-PIP as the novel nucleophilic catalyst.
Additionally, we also reported that further elaboration
of the DHIP core with a diphenylmethanol pendant group
on the stereogenic position of the imidazole ring provided
novel N,O-ligands (DHIPOHs).6 Among these DHIPOHs,
N,O-ligand 5 was found to efficiently catalyze the 1,
4-Michael addition of glycine derivative 2a to alkylidene
malonates 1 to afford the corresponding 1,4-adducts 3 in
excellent yields and good enantioselectivities (79À83%)
for the major anti-3 adducts. The corresponding 1,4-
adducts 3 were readily converted to 3-aryl glutamic acids,
exemplified by the one-pot conversion of one substrate to
chlorpheg, a selective L-homocysteic acid (HCA) uptake
inhibitor, in 72% yield.6b
Scheme 1. Synthesis of N,O- Ligands 6a and 6b
Figure 2. Design features of Fc-DHIPOH.
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Deng, W.-P. Angew. Chem., Int. Ed. 2011, 50, 4897. (b) Wang, M.; Shi,
Y.-H.; Luo, J.-F.; Du, W.; Shi, X.-X.; Fossey, J. S.; Deng, W.-P. Catal.
Sci. Technol. 2011, 1, 100.
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2009, 20, 2629. (c) Oba, M.; Saegusa, T.; Nishiyama, N.; Nishiyama, K.
Tetrahedron 2009, 65, 128. (d) Soloshonok, V. A.; Cai, C.; Yamada, T.;
Ueki, H.; Ohfune, Y.; Hruby, V. J. J. Am. Chem. Soc. 2005, 127, 15296.
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Araki, Y.; Kumamoto, T.; Seki, H.; Fukuda, K.; Isobe, T. Chem.
Commun. 2001, 245. (g) Zhang, F.-Y.; Corey, E. J. Org. Lett. 2000, 2,
1097.
The synthesis of planar chiral Fc-DHIPOHs 6a,b
(Scheme 1) was accomplished as follows: The preparation
(8) (a) Hou, X.; Li, Q.; Yao, J.; Dai, L. Chin. J. Chem. 2010, 28, 1761.
(b) Arai, S.; Takahashi, F.; Tsuji, R.; Nishida, A. Heterocycles 2006, 67,
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Org. Lett., Vol. 13, No. 22, 2011
6011

(see Supporting Information (SI)). With these two Fc-
DHIPOHs 6a,b in hand, our recently developed asym-
metric copper-catalyzed 1,4-Michael addition of glycine
derivative 2a to alkylidene malonate 1a was tested under
the optimal reaction conditions.6b To our delight, N,O-
ligand (S,Sp)-6a permitted the reaction to proceed
smoothly affording the corresponding adducts in 94%
yield, 91:9 diastereoisomer ratio, and 93% ee. Compar-
ing this result with that obtained when a ligand 4 that
does not bear a pentaphenyl ferrocene moiety revealed a
22% improvement in ee.
Significantly, the diastereoisomer (S,Sp)-6b was comple-
tely inactive for the same reaction. Further screening of
reaction conditions confirmed the optimal reaction proto-
col to be in line with that we previously disclosed;6b details
of the metal salts and solvents tried are summarized in the
SI, where it can be seen that selection of the ester moiety of
glycine derivative 2, ethyl ester 2b, gave similar diastereo-
selectivity but lower enantioselectivity (81% ee) and the
bulkier tert-butyl ester 2c gave corresponding adduct 3ac
with an excellent diastereoisomeric ratio (>99:1), but in
almost racemic form (3% ee). When diisopropyl ester 1b
was used instead of dimethyl ester 1a in a reaction with 2a,
none of the desired adduct was formed, perhaps due to the
steric influence of the bulky isopropyl group. Therefore,
methyl glycine derivative 2awas used for probing the scope
of methyl alkylidene malonates 1.
A range of β-(hetero)aryl alkylidene malonates 1cÀm
were next employed in reactions with methyl glycine
derivative 2a in the presence of (S,Sp)-6a/Cu(OAc)2 in
THF at room temperature. As shown in Table 1, all the
reactions of aryl alkylidene malonate substrates contain-
ing both electron-withdrawing and -donating groups pro-
ceeded smoothly giving similar enantioselectivities (Table 1,
89À93% ee, entries 1À8). The p-bromophenyl alkylidene
malonate gave the highest dr up to 96:4 (Table 1, entry 2).
Hetereoaryl alkylidene malonates 1i and 1j also reacted
smoothly with 2a to afford the corresponding Michael
adducts in excellent yields and the same levels of enantio-
selectivity, albeit with lower diastereoselectivities (Table 1,
entries 9À10). Larger naphthyl alkylidene malonate 1l
gave high enantioselectivity for both anti (93% ee) and
syn isomers (90% ee), but with a slightly lower yield and
Table 1. Scope of Alkylidene Malonates 1 in Asymmetric
1,4-Michael Additiona
yield
dr
ee (anti/syn)
entry
R
(%)b (anti/syn)
(%)c
noted
1
4-Cl-C6H4 (1a)
4-Br-C6H4 (1c)
4-NO2-C6H4 (1d)
C6H5 (1e)
94
98
94
85
87
92
82
91
95
91
71
25
91/9
93/57 (99)
93/95 (98)
90/55
81
81
80
83
82
80
81
79
81
78
À
2
96/4
3
85/15
83/17
87/13
94/6
4
91/81 (99)
e
5
4-CH3-C6H4 (1f)
4-CF3-C6H4 (1g)
4-CH3O-C6H4 (1h)
3-Cl-C6H4 (1i)
2-furyl (1j)
90/À
6
91/63
e
7
88/12
87/13
67/33
77/23
80/20
>98/2
89/À
8
89/84
9
93/91(99)
90/84
10
11
12
3-pyridinyl (1k)
1-naphthyl (1l)
iBu (1m)
93/90
e
95/À
À
a All reactions performed in anhydrous THF at room temperature,
using 11 mol % of ligand 6a, 10 mol % of Cu(OAc)2, and 10 mol % of
KOtBu. b Isolated yields of diastereomer mixtures. c All ee values were
determined by HPLC, and data in parentheses were the ee of the anti
adduct after simple crystallization. d The ee values given by DHIPOH 5 in
previous report. e The ee of syn product was not determined.
of racemic 7 according to Fu’s protocol,4a followed by a
Pd-catalyzed CÀN coupling of (S)-oxazolidinone 8 to 7,
gave two chromatographically separable diastereoisomers
(S,Sp)-9a and (S,Rp)-9b in 38% and 40% yields respec-
tively (78% overall yield).3 Hydrolysis of the resultant
isomers in the presence of methanolic sodium hydroxide
afforded the corresponding alcohols 10a and 10b, which
were then treated with MsCl/Et3N to furnish the two
diastereoisomers (S,Sp)-6a and (S,Rp)-6b in 74% and
69% yields respectively. The relative configurations of
the two isomers were assigned on the basis of single-
crystal X-ray diffraction analysis of the isomer (S,Rp)-6b
Figure 3. Proposed Transition States for Steric Control Mode of 6a and 6b.
6012
Org. Lett., Vol. 13, No. 22, 2011

diastereoselectivity (Table 1, entry 11). The aliphatic
alkylidene malonate 1m showed low reactivity to give
corresponding adduct 3ma in only 25% yield, but with
excellent diastereo- and enantioselectivity (Table 1, entry
12, >98:2 dr, 95% ee). The relative and absolute config-
uration of major adducts of 3 were assigned as the
anti-(2R,3S) isomer by the comparison of the retention
times of anti enantiomers to those reported in our previous
report.6b
Based on these results, we reasoned that the stereocon-
trolling modes for both DHIPOH and Fc-DHIPOH sys-
tems are similar (Figure 3, transition state I), and the
central and planar chirality features of N,O-ligand Fc-
DHIPOH 6a are well matched. Furthermore, the complete
inactivity of diastereoisomer 6b in the same 1,4-Michael
addition implies that two chiral elements of 6b are mis-
matched. A possible transition state II was proposed to
account for this result (Figure 3), in which both “upper”
and “lower” faces (as drawn) are blocked by the diphe-
nylmethanol group and η5-C5Ph5 moiety, respectively.
In summary, we have developed a novel planar chiral N,
O-ligandÀcopper catalyst construct, Fc-DHIPOH 6a/Cu-
(OAc)2, which has proved to be a highly efficient catalyst
for the 1,4-Michael addition of glycine derivatives to
alkylidene malonates to afford 3-substituted glutamic acid
derivatives in moderate to excellent yields (25À98%), with
good diastereoselectivities (up to >98/2) and excellent
enantioselectivities (up to 95% ee for the anti adducts).10
We expect that this new DHIP-based planar chiral N,O-ligand
architecture could open the door to new developments
in the area of asymmetric catalysis. Further studies on
the mechanism and applications of this reaction are
now in progress.
Acknowledgment. W.P.D. thanks the “Shu Guang”
project of Shanghai Education Development Foundation
(No. 09SG28) and Natural Science Foundation of China
(No. 21172068) for financial support. J.S.F. and W.P.D.
thank the CAtalysis and Sensing for our Environment
(CASE) network and the Natural Science Foundation of
China for young foreign scientist (No. 21050110426).
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Supporting Information Available. Procedure for the
synthesis of N,O-Ligand 6a,b, table of optimization data,
general procedures for 1,4-Michael addition and charac-
terization of corresponding products, copies of 400 MHz
1H and 100 MHz 13C NMR of all ligands and products as
well as their HPLC data. This material is available free of
charge via Internet at http://pubs.acs.org.
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