Hydrogen-bonding directed reversal of enantioselectivity

Article abstract of DOI:10.1021/ja067346f

A successful stereochemical reversal was achieved in AgOAc catalyzed [3+2] cycloaddition by the formation of hydrogen bonding between ligand and reactant. This strategy provides an efficient and convenient route to prepare both enantiomers of a chiral compound. DFT studies proposed a reasonable mechanism of the reversal of the enantioselectivity; hydrogen bonding changed the transition state. The strategy may provide some useful hints for ligand design. Copyright

Full text of DOI:10.1021/ja067346f

Published on Web 01/06/2007
Hydrogen-Bonding Directed Reversal of Enantioselectivity
Wei Zeng,† Guo-Ying Chen,† Yong-Gui Zhou,*,†,‡ and Yu-Xue Li*,‡
Dalian Institute of Chemical Physics, CAS, 457 Zhongshan Lu, Dalian 116023, China, and State Key Laboratory of
Organometallic Chemistry, Shanghai Institute of Organic Chemistry, CAS, 354 Fenglin Lu, Shanghai 200032, China
Received October 12, 2006; E-mail: ygzhou@dicp.ac.cn; liyuxue@mail.sioc.ac.cn
The preparation of both enantiomers of a chiral compound is
still a vital task in pharmaceutical and bioorganic chemistry.1
Basically, it can be achieved with the use of both enantiomers of
a chiral ligand, respectively, in a catalytic asymmetric process.
However, the two enantiomers of a chiral ligand are not always
easily available from natural chiral sources, such as amino acids,
carbohydrates, and alkaloids. Alternatively, the enantioselectivity
Figure 1. Proposed variation of transition states.
can be reversed by using different metals2 in the presence of the
same ligands, including additives,3 or changing the reaction
parameters (temperature4 and solvents5) or other methods.6 Although
the use of hydrogen bonding to accelerate or catalyze certain
reactions has been well documented recently,7 reversal of enanti-
oselectivity directed by hydrogen bonding is still rare.8 We envisage
that the formation of hydrogen bonds may reverse the enantiose-
lectivity if ligands were properly designed. The reversal could be
caused by the variation of reaction transition states (Figure 1), in
which transition state A is common. Both substrates SM1 and SM2
coordinate with the central metal M, but in transition state B, SM2
can coordinate with the central metal M, while the other substrate
SM1 has an interaction with NH2 of the ligand through hydrogen
bonding. Thus, different enantiofacial attack was afforded, leading
to the reversal of enantioselectivity. In this Communication, we
present a hydrogen-bond-directed reversal of enantioselectivity in
AgOAc-catalyzed [3+2] cycloaddition of azomethine ylides.
In our initial study, we chose the cycloaddition of iminoester 2a
with dimethyl maleate as the model reaction, which is a useful way
to form highly substituted pyrrolidine rings9 (Table 1). Ligands
1a-e could be conveniently synthesized according to the known
literature method.10 The reaction proceeded smoothly in the presence
of AgOAc/1a in Et2O, and only endo cycloaddition product was
detected with 76% ee. To our delight, the opposite absolute
configuration of adduct 3a was obtained with 83% ee when ligand
1b was used, whose substituents on the N atom are H atoms. To
achieve better enantioselectivity, we replaced phenyl groups in 1a/
1b with 3,5-dimethylphenyl (1c/1d). Both enantiomers of adduct
3a were obtained with 84% and -84% ees, respectively (entries 3
and 4). The ee was improved to 92% using 1c when the reaction
was run at -25 °C. Adduct 3a with 92% ee and opposite absolute
configuration was obtained using ligand 1d at -25 °C. Thus, both
enantiomers of adduct 3a can be obtained with excellent enanti-
oselectivity using AgOAc/1c/-25 °C and AgOAc/1d/-25 °C,
respectively.
Table 1. AgOAc-Catalyzed Asymmetric Cycloaddition of 2aa
entry
ligand
T (°
C)
yieldb (%)
eec (%)
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1c
1d
0
0
0
0
0
95
91
95
94
71
95
90
-76
83
-84
84
-19
-92
92
-25
-25
a Conditions: iminoester 2a (1.0 equiv), dimethyl maleate (1.5 equiv),
AgOAc (3 mol %), ligand (3.3 mol %), concentration ) 0.12 M. b Isolated
yields based on 2a. c Determined by HPLC.
the steric hindrance and electronic properties of the benzene ring
of iminoester 2. Other dipolarophiles such as tert-butylacrylate and
N-phenylmaleimide were also tested; successful reversal of the
absolute configuration was observed (entries 11-16).
To further understand the role of hydrogen bonding, a compu-
tational study was performed. As shown in Figure 2, the complexes
formed by 2b and Ag-1a/1b have four possible types of structures
(C1 to C4). Eight structures for 1a (R ) Me) and 1b (R ) H) of
C1 to C4 type are fully optimized by B3LYP11 method with the
Gaussian 03 program.12 For C, H and N, the 6-31G* basis set was
used; for Ag, the Lanl2DZ basis set with effective core potential
(ECP)13 was used. The results show that the most stable complexes
for both 1a and 1b are C2 type (Figure 3).
Figure 3 shows that there is large space at both sides of the
iminoester in C2-1b. The two carbonyl groups of the dimethyl
maleate can coordinate with the Ag center. Furthermore, they may
form two hydrogen bonds with the NH2 group. This interaction
can stabilize the negatively charged oxygen atom in the possible
zwitterionic intermediate and the transition state.9h This indicates
that it is favorable for C2-1b to be attacked from the top face.
While in C2-1a, the dimethylamino group cannot form hydrogen
bonds, and the methyl groups will cause steric repulsion. Therefore
the dimethyl maleate will attack from the bottom face of C2-1a,
To explore the scope of the hydrogen bond-directed reversal of
enantioselectivity in cycloaddition of azomethine ylides, a variety
of iminoester substrates derived from aldehydes with different steric
and electronic properties were examined (Table 2). All reactions
went to completion within 4 h in high isolated yields (91-98%).
Reversal of the absolute configuration was realized in the reactions
of various iminoesters 2a-f and dimethyl maleate regardless of
† Dalian Institute of Chemical Physics.
‡ Shanghai Institute of Organic Chemistry.
9
750
J. AM. CHEM. SOC. 2007, 129, 750-751
10.1021/ja067346f CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2. AgOAc-Catalyzed Asymmetric Cycloadditiona
Supporting Information Available: Spectroscopic data, experimen-
tal details, computational methods, and complete ref 12. This material
is available free of charge via the Internet at http://pubs.acs.org.
References
(1) For reviews, see: (a) Zanoni, G.; Castronovo, F.; Franzini, M.; Vidari,
G.; Giannini, E. Chem. Soc. ReV. 2003, 32, 115. (b) Sibi, M. P.; Liu, M.
Curr. Org. Chem. 2001, 5, 719.
entry
R1/R2 in 2
ligand
yieldb/3
ee (%)c
(2) For selected examples, see: (a) Du, D. M.; Lu, S. F.; Fang, T.; Xu, J. J.
Org. Chem. 2005, 70, 3712. (b) Bertozzi, F.; Pineschi, M.; Macchia, F.;
Arnold, L. A.; Minnaard, A. J.; Feringa, B. L. Org. Lett. 2002, 4, 2703.
(c) Murakami, M.; Itami, K.; Ito, Y. J. Am. Chem. Soc. 1999, 121, 4130.
(d) Yabu, K.; Masumoto, S.; Yamasaki, S.; Hamashima, Y.; Kanai, M.;
Du, W.; Curran, D. P.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 9908.
(e) Nishibayashi, Y.; Segawa, K.; Ohe, K.; Uemura, S. Organometallics
1995, 14, 5486.
(3) For selected examples, see: (a) Mao, J.; Wan, B.; Zhang, Z.; Wang, R.;
Wu, F.; Lu, S. J. Mol. Catal. A 2005, 225, 33. (b) Lutz, F.; Igarashi, T.;
Kawasaki, T.; Soai, K. J. Am. Chem. Soc. 2005, 127, 12206. (c)
Kawamura, M.; Kobayashi, S. Tetrahedron Lett. 1999, 40, 3213. (d)
Gothelf, K. V.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 1998, 63,
5483. (e) Kobayashi, S.; Ishitani, H. J. Am. Chem. Soc. 1994, 116, 4083.
(f) Kobayashi, S.; Ishitani, H.; Hachiya, I.; Araki, M. Tetrahedron 1994,
50, 11623.
1
2
3
4
5
6
7
8
9
10
11d
12d
13d
14d
15e
16e
Ph/Me (2b)
Ph/Me (2b)
1d
1c
1d
1c
1d
1c
1d
1c
1d
1c
1d
1c
1d
1c
1d
1c
95 (3b)
96 (3b)
93 (3c)
98 (3c)
96 (3d)
91 (3d)
95 (3e)
95 (3e)
98 (3f)
91 (3f)
90 (3g)
90 (3g)
96 (3h)
89 (3h)
98 (3i)
98 (3i)
90
-85
90
-87
88
-91
88
-85
91
-87
97
-78
94
-79
36
-92
p-anisyl/Me (2c)
p-anisyl/Me (2c)
4-chlorophenyl/Me (2d)
4-chlorophenyl/Me (2d)
o-toluyl/Me (2e)
o-toluyl/Me (2e)
2-naphthyl/Me (2f)
2-naphthyl/Me (2f)
Ph/Me (2b)
Ph/Me (2b)
o-toluyl/Me (2e)
o-toluyl/Me (2e)
Ph/Me (2b)
(4) For selected examples, see: (a) Berkessel, A.; Mukherjee, S.; Lex, J.
Synlett 2006, 41. (b) Trost, B. M.; Fettes, A.; Shireman, B. T. J. Am.
Chem. Soc. 2004, 126, 2660. (c) Casey, C. P.; Martins, S. C.; Fagan, M.
A. J. Am. Chem. Soc. 2004, 126, 5585. (d) Sibi, M. P.; Gorikunti, U.;
Liu, M. Tetrahedron 2002, 58, 8357.
Ph/Me (2b)
a Conditions: iminoesters 2 (1.0 equiv), dimethyl maleate (1.5 equiv),
AgOAc (3 mol %), ligand (3.3 mol %), concentration ) 0.12 M, at -25 °C.
b Isolated yields. c Determined by HPLC. d t-Butylacrylate was used. e N-
phenylmaleimide was used.
(5) For selected examples, see: (a) Arseniyadis, S.; Valleix, A.; Wagner, A.;
Mioskowski, C. Angew. Chem., Int. Ed. 2004, 43, 3314. (b) Zhou, J.; Ye,
M. C.; Huang, Z. Z.; Tang, Y. J. Org. Chem. 2004, 69, 1309. (c) Kanai,
M.; Koga, K.; Tomioka, K. J. Chem. Soc., Chem. Commun. 1993, 1248.
(d) Johannsen, M.; Jørgensen, K. A. Tetrahedron 1996, 52, 7321.
(6) Selected examples of reversal due to steric effect, pressure, substituents
on coordination atoms, and metal/ligand ratio, see: (a) Kitagawa, O.;
Matsuo, S.; Yotsumoto, K.; Taguchi, T. J. Org. Chem. 2006, 71, 2524.
(b) Kuwano, R.; Sawamura, M.; Ito, Y. Bull. Chem. Soc. Jpn. 2000, 73,
2571. (c) Danjo, H.; Higuchi, M.; Yada, M.; Imamoto, T. Tetrahedron
Lett. 2004, 45, 603. (d) Clyne, D. S.; Mermet-Bouvier, Y. C.; Nomura,
N.; RajanBabu, T. V. J. Org. Chem. 1999, 64, 7601. (e) Nomura, N.;
Mermet-Bouvier, Y. C.; RajanBabu, T. V. Synlett 1996, 745. (f) Evans,
D. A.; Kozlowski, M. C.; Murray, J. A.; Burgey, C. S.; Campos, K. R.;
Connell, B. T.; Staples, R. J. J. Am. Chem. Soc. 1999, 121, 669 and
references cited therein.
Figure 2. The four types of complexes formed by 2b and Ag-1a/1b.
(7) (a) Pihko, P. M. Angew. Chem., Int. Ed. 2004, 43, 2062. (b) Dalko, P. I.;
Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138. (c) Noyori, R.;
Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97. (d) Taylor, M. S.; Jacobsen,
E. N. Angew. Chem., Int. Ed. 2006, 45, 1520 and references cited therein.
(e) Noyori, R.; Ohkuma, T. Angew. Chem., Int. Ed. 2001, 40, 40. (f)
Huang, Y.; Unni, A. K.; Thadani, A. N.; Rawal, V. H. Nature 2003, 424,
146. (g) Du, H.; Zhao, D.; Ding, K. Chem.sEur. J. 2004, 10, 5964. (h)
Deng, X. M.; Cai, P.; Ye, S.; Sun, X. L.; Liao, W. W.; Li, K.; Tang, Y.;
Wu, Y. D.; Dai, L. X. J. Am. Chem. Soc. 2006, 128, 9730. (i) Breit, B.;
Seiche, W. J. Am. Chem. Soc. 2003, 125, 6608. (j) Weis, M.; Waloch,
C.; Seiche, W.; Breit, B. J. Am. Chem. Soc. 2006, 128, 4188.
(8) For examples of reversal of enantioselectivity due to OH or NH2, see:
(a) Hoarau, O.; A¨ıt-Haddou, H.; Daran, J. C.; Cramaile`re, D.; Balavoine,
G. G. A. Organometallics 1998, 18, 4718. (b) Beliczey, J.; Giffels, G.;
Kragl, U.; Wandrey, C. Tetrahedron: Asymmetry 1997, 8, 1529.
(9) For successful examples using Ag, Cu, Zn catalysts, see: (a) Bonini, B.
F.; Boschi, F.; Comes-Franchini, M.; Fochi, M.; Fini, F.; Mazzanti, A.;
Ricci, A. Synlett 2006, 543. (b) Zeng, W.; Zhou, Y.-G. Org. Lett. 2005,
7, 5055. (c) Stohler, R.; Wahl, F.; Pfaltz, A. Synthesis 2005, 1431. (d)
Alemparte, C.; Blay, G.; Jørgensen, K. A.; Org. Lett. 2005, 7, 4569. (e)
Chen, C.; Li, X.; Schreiber, S. L. J. Am. Chem. Soc. 2003, 125, 10174.
(f) Longmire, J. M.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2002, 124,
13400. (g) Liamas, T.; Arraya´s, R. G.; Carretero, J. C. Org. Lett. 2006, 8,
1795. (h) Yan, X.-X.; Peng, Q.; Zhang, Y.; Zhang, K.; Hong, W.; Hou,
X.-L.; Wu, Y.-D. Angew. Chem., Int. Ed. 2006, 45, 1979. (i) Catrera, S.;
Arraya´s, R. G.; Carretero, J. C. J. Am. Chem. Soc. 2005, 127, 16394. (j)
Gao, W.; Zhang, X.; Raghunath, M. Org. Lett. 2005, 7, 4241. (k)
Oderaotoshi, Y.; Cheng, W.; Fujitomi, S.; Kasano, Y.; Minakata, S.;
Komatsu, M. Org. Lett. 2003, 5, 5043. (l) Gothelf, A. S.; Gothelf, K. V.;
Hazell, R. G.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2002, 41, 4236.
(10) Hayashi, T.; Mise, T.; Fukushima, M.; Kagotani, M.; Nagashima, N.;
Hamada, Y.; Matsumoto, A.; Kawakami, S.; Konishi, M.; Yamamoto,
K.; Kumada, M. Bull. Chem. Soc. Jpn. 1980, 53, 1138.
Figure 3. The optimized structures of C2-1b and C2-1a. The hydrogen
atoms that are not involved in the reactions are omitted for clarity. Calculated
at B3LYP/6-31*/Lanl2DZ level.
hence, the enantioselectivity is reversed. According to the above
model, addition of competitive hydrogen-bond donors should
destroy the hydrogen binding, decrease of enantioselectivity should
be observed, and so, cycloaddition of 2a and dimethyl maleate was
performed using AgOAc-1b as catalyst in the presence of additives
(t-amyl alcohol, EtOH) at 0 °C, enantioselectivity was decreased
to 79% and 78% from 83%.14
1H NMR titration experiments and Job’s method were employed
to probe the hydrogen binding between the complex AgOAc-1b
and dimethyl maleate. A significant change of the N-H chemical
shift was observed, and an approximate 1:1 complex was indi-
cated.14
In summary, a successful stereochemical reversal was achieved
in AgOAc catalyzed [3+2] cycloaddition of azomethine ylides by
the formation of hydrogen bonding between ligand and reactant.
Density-functional theory studies proposed a reasonable mechanism
of the reversal of the enantioselectivity. The strategy may provide
some useful hints for ligand design.
(11) (a) Becke, A. D. Phys. ReV. A: At., Mol., Opt. Phys. 1988, 38, 3098. (b)
Becke, A. D. J. Chem. Phys. 1993, 98, 1372, 5648. (c) Lee, C.; Yang,
W.; Parr, R. G. Phys. ReV. B: Condens. Matter Mater. Phys. 1988, 37,
785.
(12) The calculations were performed with Gaussian 03 program: Frisch, M.
J.; et al. Gaussian 03, revision C.02; Gaussian, Inc.: Wallingford, CT,
2004.
(13) Wadt, W. R.; Hay, P. J. J. Chem. Phys. 1985, 82, 284.
(14) See Supporting Information for details.
Acknowledgment. We are grateful for the financial support
from National Science Foundation of China (Grant 20532050).
JA067346F
9
J. AM. CHEM. SOC. VOL. 129, NO. 4, 2007 751