possesses extensive biological activity.9 To the best of our
knowledge, only two examples of metal-catalyzed enantio-
selective reactions have so far been reported:10 Hou et al.
reported anti- and enantioselective conjugate addition of
benzophenone imino ester to nitroalkene using the copper/
FcFOX complex,11 and Oh succeeded with the syn-
and anti-stereocontrolled reaction using the copper/bru-
cine derived amino alcohol complex.12 We previously
reported the silver/ThioClickFerrophos-catalyzed asym-
metric Mannich reaction of glycine imino esters with tosyl
imines where syn-adducts were produced preferentially
with high enantioselectivities.13 Our current efforts expand
the use of this catalyst to other asymmetric reactions with
glycine imino esters. Thus, weappliedthe silver/ThioClick-
Ferrophos complex to the asymmetric conjugate addition
of benzophenone glycine imino ester to β-nitrostyrene and
found that the conjugate addition proceeded accompanied
by a small amount of [3 þ 2] cycloaddition to give an anti-
adduct in high enantioselectivity. In the course of our
research, we found that a [3 þ 2] cycloaddition proceeded
by modifying the reaction conditions to afford the opti-
cally active pyrrolidine derivative as a major product in
high enantioselectivity.14
to produce anti-3 and endo-4 as the sole diastereomers.
Although the conjugate adduct was a minor product, ee of
this adduct reached 98%. Encouraged by high ee%, we
attempted to optimize the reaction conditions to obtain the
conjugate adduct 3 as a major product. The results from
the optimization experiment for the conjugate adduct are
shown in Table 1. When the reaction temperature was
lowered to ꢀ25 °C, the selectivity for the conjugate adduct
was slightly improved, and the ratio of 3 to 4 was 31:69
(entry 2). The addition of triethylamine (18 mol % to
glycine imino ester) to the reaction mixture dramatically
increased the selectivity for the conjugate adduct, and the
ratio of 3 to 4 was 97:3 (entry 3). The conjugate adduct was
obtained selectively with high enantioselectivity (98% ee)
in the presence of triethylamine. The use of a more
sterically hindered amine such as diisopropylethylamine
(DIPEA) had the opposite effect on selectivity, and the
ratio of 3 to 4 changed to 62:38 (entry 4). We used the
glycine imino tert-butyl ester 1b instead of the methyl ester
in order toimprovethe selectivity for the conjugateadduct;
however, the selectivity decreased in the opposite direction
(entry 5). THF was chosen as the best choice for solvent
since other solvents such as toluene, diethyl ether, and
dichloromethane afforded reduced selectivity for the con-
jugate adduct, even though they also favored the conjugate
adduct (entries 6ꢀ8). Other silver salts such as AgOTf,
AgPF6, and AgBF4 were examined; however, AgOAc
produced the best result with respect to selectivity for
the conjugate addition and enantioselectivity of the
product (entries 9ꢀ11). The combination of CuOAc/
ClickFerrophos (CF) also produced the conjugate adduct
selectively but with lower ee% (70% ee) than the combina-
tion of AgOAc/TCF (entry 12).
Thus, we determined that optimum reaction conditions
were obtained when using THF as the solvent, AgOAc as
the metal salt, Et3N as the base, and the methyl ester 1a as
the glycine imino ester at ꢀ25 °C. Here, the relative and
absolute configuration of a conjugate adduct was con-
firmed by X-ray analysis of methyl 3-ferrocenyl butanoate
3j; the configuration was revealed to be anti-(2S,3S) (see
Supporting Information (SI)). The substrate scope of
nitroalkenes was examined with respect to the electronic
property and the position of the substituents under the
optimized conditions. The results of the reaction with
(E)-2-aryl-1-nitroalkenes are summarized in Table 2. The
selectivity for the conjugate adduct was almost indepen-
dent of the substituents, with the ratio of the conjugate
adducttothecycloadductbeinginthe rangeof93:7to97:3.
Theanti-conjugateadducts wereproduced exclusively with
excellent enantioselectivities (97ꢀ99% ee) regardless of the
electronic properties and position of the substituents. The
reaction with (E)-2-(2-nitrovinyl)naphthalene 2i and 2-ni-
trovinylferrocene2j alsogavethe anti-adducts (3i and 3j) in
good yields with excellent ee’s (entries 9 and 10).
Figure 1. ClickFerrophos and ThioClickFerrophos.
Initially, we examined the silver-catalyzed asymmetric
conjugate addition of glycine imino methyl ester 1a to β-
nitrostyrene under the following reaction conditions: 5 mol
% of AgOAc and 5.5 mol % of the ThioClickFerrophos
ligand (TCF, Figure 1) in THF at room temperature for
3 h. 1H NMR of the crude product revealed the presence
of a mixture of R-imino-γ-nitrobutyrate 3 (the conjugate
adduct) and 3-nitropyrolidine4 (thecycloadduct) ina ratio
of 25:75. The reaction proceeded diastereoselectively
(9) (a) Huang, Y.; Li, q.; Liu, T.-L.; Xu., P.-F. J. Org. Chem. 2009, 74,
1252. (b) Perkins, H. R. Biochem. J. 1971, 121, 417. (c) O’Neal, R. M.;
Chen, C.-H.; Reynols, C. S.; Meghal, S. K.; Koeppe, R. E. Biochem. J.
1968, 106, 699.
(10) Metal catalyzed nonasymmetric reactions have been reported.
(a) Li, W.; Liu, H.; Du, D.-M. Synlett 2009, 925. (b) Vivanco, S.; Lecea,
B.; Arrieta, A.; Prieto, P.; Morao, I.; Linden, A.; Cossı
Chem. Soc. 2000, 122, 6078.
(11) Li, Q.; Ding, C.-H.; Hou, X.-L.; Dai, L.-X. Org. Lett. 2010, 12,
1080.
(12) Kim, H. Y.; Li, J.-Y.; Kim, S.; Oh, K. J. Am. Chem. Soc. 2011,
133, 20750.
´
o, F. P. J. Am.
In the initial experiment, the pyrrolidine cycloadduct
was obtained as a major product with high ee% when
the reaction was carried out at rt in the absence of tri-
ethylamine (Table 1, entry 1). Since the optically active
(13) Imae, K.; Shimizu, K.; Ogata, K.; Fukuzawa, S.-i. J. Org. Chem.
2011, 76, 3604.
(14) (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) Fukuzawa, S.-i.; Oki, H. Org. Lett. 2008, 10,
1747.
pyrrolidine is
a
biologically and pharmaceutically
B
Org. Lett., Vol. XX, No. XX, XXXX