Development of chiral metal amides as highly reactive catalysts for asymmetric [3 + 2] cycloadditions

Article abstract of DOI:10.3762/bjoc.12.140

Highly efficient catalytic asymmetric [3 + 2] cycloadditions using a chiral copper amide are reported. Compared with the chiral CuOTf/Et₃ N system, the CuHMDS system showed higher reactivity, and the desired reactions proceeded in high yields a

Full text of DOI:10.3762/bjoc.12.140

Development of chiral metal amides as highly reactive
catalysts for asymmetric [3 + 2] cycloadditions
Yasuhiro Yamashita, Susumu Yoshimoto, Mark J. Dutton and Shū Kobayashi*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 1447–1452.
Department of Chemistry, School of Science, The University of Tokyo,
Hongo, Bunkyo-ku, Tokyo, Japan
doi:10.3762/bjoc.12.140
Received: 28 March 2016
Accepted: 02 June 2016
Published: 13 July 2016
Email:
Shū Kobayashi* - shu_kobayashi@chem.s.u-tokyo.ac.jp
* Corresponding author
This article is part of the Thematic Series "Strategies in asymmetric
catalysis".
Keywords:
[3 + 2] cycloaddition; asymmetric reaction; catalytic reaction; low
catalyst loading; metal amide
Guest Editor: T. P. Yoon
© 2016 Yamashita et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Highly efficient catalytic asymmetric [3 + 2] cycloadditions using a chiral copper amide are reported. Compared with the chiral
CuOTf/Et3N system, the CuHMDS system showed higher reactivity, and the desired reactions proceeded in high yields and high
selectivities with catalyst loadings as low as 0.01 mol %.
Findings
Catalytic asymmetric synthesis is an ideal method to prepare catalyst activity can be reduced through Lewis acid–Lewis base
optically active compounds [1]. In this context, catalytic asym- interaction between catalysts and the formed products (product
metric carbon–carbon bond-forming reactions that can be used inhibition). To overcome such issues, the design and develop-
for the efficient construction of fundamental frameworks of ment of more reactive catalysts is required.
complex chiral molecules such as biologically active com-
pounds are particularly important. Chiral Lewis acid/Brønsted Our group has focused on the development of metal amides as
base-catalyzed carbon–carbon bond-forming reactions are one highly reactive Lewis acid/base catalysts in carbon–carbon
of the most efficient methods from the viewpoint of atom bond-forming reactions [3]. Recently, we have developed asym-
economy because only proton transfer occurs between starting metric [3 + 2] cycloadditions [4-8] and asymmetric Mannich-
materials and target products [2]. Several kinds of chiral Lewis type reactions [9] by using chiral silver or copper amides as
acid/Brønsted base-catalyst systems have been developed; how- catalysts. In these reactions, it has been revealed that the metal
ever, decreasing the catalyst loading is sometimes problematic amides have higher activity than typical silver or copper acid/
either because of the low reactivity of catalysts or because the base catalysts, and that less reactive substrates react smoothly to
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Beilstein J. Org. Chem. 2016, 12, 1447–1452.
afford the desired products in high yields with high stereoselec- endo selectivity and high enantioselectivity were obtained
tivities. Based on these results, it was considered that metal (Table 1, entry 1). On the other hand, application of CuOTf,
amide catalysts might also achieve high catalyst turnover. Here, FeSulphos, and Et3N gave only 47% yield of the product
we report chiral copper amide-catalyzed asymmetric [3 + 2] (Table 1, entry 2). This result indicated that the CuHMDS cata-
cycloadditions of Schiff bases of glycine ester that proceed with lyst had higher catalyst activity than CuOTf with the additional
low catalyst loadings (ca. 0.01 mol %).
amine base. The copper amide catalyst also showed high reac-
tivity and selectivity with 1 mol % catalyst loading (Table 1,
Catalytic asymmetric [3 + 2] cycloadditions of Schiff bases of entry 3), and similar results were obtained in other solvents
α-amino esters to olefins are useful for synthesizing optically such as Et2O and toluene, although the reactivity and enantiose-
active pyrrolidine derivatives [10-12], and many highly stereo- lectivity both decreased slightly in dichloromethane (DCM,
selective reactions have been reported; for example, Co [13], Table 1, entries 4–6). It was found that the use of the chiral
Cu [14-23], Ag [24-32], Zn [33,34], Ni [35,36], and Ca [37-39] CuHMDS catalyst also afforded the product with high enantio-
catalyst systems, and organocatalysts [40-45] have been suc- selectivity at lower catalyst loadings of 0.1 mol % (Table 1,
cessfully employed. In most cases, however, relatively high entry 7). The effect of the amide part of the structure was then
catalyst loadings (0.5–25 mol %) are required to achieve high examined. Copper dialkylamides were not as reactive as
yield and selectivities [15,45]. First, we investigated the catalyt- CuHMDS, and lower yields were obtained (Table 1, entries 8
ic asymmetric [3 + 2] cycloaddition of Schiff base 1a, prepared and 9). Interestingly, mesitylcopper also worked in a similar
from glycine methyl ester and benzaldehyde, with N-phenyl- fashion, and good yields and high selectivities were obtained
maleimide (2a) in the presence of CuN(SiMe3)2 (CuHMDS) (Table 1, entry 10). This result indicated that the reaction
and the FeSulphos ligand, with the latter being related to the proceeded through a product base mechanism [46-48]; however,
system reported by Carretero et al. [15]. The reaction produced the reactivity was lower than that of the CuHMDS system. De-
3aa smoothly with 3 mol % catalyst loading at −40 °C, and high creasing the catalyst loading further revealed that the reaction
Table 1: Chiral copper amide-catalyzed asymmetric [3 + 2] cycloadditionsa.
Entry
Cu catalyst
Solvent
X
Time (h)
Yield (%)
endo/exo
ee (%, endo)
1
CuHMDS
CuOTf + Et3N
CuHMDS
CuHMDS
CuHMDS
CuHMDS
CuHMDS
CuNMe2e
CuTMPe
THF
THF
THF
Et2O
toluene
DCM
THF
THF
THF
THF
THF
3
6
99
47
98
91
95
67
94
53
46
86
94
>99:1
98:2
99
99
>99
98
99
93
96
94
98
97
95
2b
3c
4c
5c
6c
7d
8d
9d
10d
11f
3
6
1
6
>99:1
99:1
1
6
1
6
99:1
1
6
99:1
0.1
0.1
0.1
0.1
0.01
18
18
18
18
48
>99:1
>99:1
>99:1
>99:1
>99:1
Cu(mesityl)
CuHMDS
aThe [3 + 2] cycloaddition reaction of 0.5 M 1a (0.30 mmol) with 2a (1.1 equivalents, 0.33 mmol) were conducted at −40 °C in the presence of the
copper amide prepared from CuOTf·0.5toluene complex/KHMDS/FeSulphos (1.1:1.0:1.1) in situ unless otherwise noted. bCuOTf·0.5toluene complex
(0.0090 mmol) and Et3N (0.0090 mmol) were used. cThe reaction was conducted with 1a (1.0 mmol). dThe reaction was conducted with 1a
(10 mmol). eThe copper amides were prepared in situ by mixing CuOTf·0.5toluene complex, FeSulphos and LiNMe2 or lithium 2,2,6,6,-tetramethyl-
piperidide (LiTMP). fThe reaction was conducted with 1.25 M 1a (50 mmol).
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Beilstein J. Org. Chem. 2016, 12, 1447–1452.
proceeded with 0.01 mol % loading of chiral CuHMDS catalyst lectivities. The reaction with methyl acrylate also proceeded in
without significant loss of selectivity (Table 1, entry 11).
high yield with high enantioselectivity; however, in this case the
exo/endo selectivity was moderate. Methyl vinyl ketone and
We then examined the substrate scope of the [3 + 2] cycloaddi- methyl methacrylate reacted with 1a to afford the desired
tion with respect to the Schiff base (Table 2). The Schiff bases [3 + 2] adducts in high yields with high selectivities. Notably,
prepared from tolualdehydes were successfully employed in the the chiral CuHMDS catalyst worked well with catalyst load-
reaction with 2a, and high reactivities and enantioselectivities ings of both 0.1 and 0.01 mol %.
were observed by using 0.1 mol % catalyst loading (Table 2,
entries 1–4). The Schiff base from p-methoxybenzaldehyde was A proposed catalytic cycle is shown in Figure 1. Thus, the
a good substrate (Table 2, entry 5) and reacted even in the pres- chiral CuHMDS deprotonates Schiff base 1a to generate the
ence of 0.01 mol % catalyst loading, albeit with a slight de- corresponding chiral Cu enolate B through the efficient forma-
crease in the enantioselectivity (Table 2, entry 6). The use of tion of pseudo-intramolecular transition state A. Intermediate B
Schiff bases bearing either electron-donating or electron-with- reacted with maleimide 2a to form Cu-pyrrolidine intermediate
drawing substituents were also suitable, and high yields and en- C. H-HMDS then reacted with the latter to regenerate the chiral
antioselectivities were obtained with both 0.1 and 0.01 mol % CuHMDS and release the product to complete the catalytic
catalyst loading (Table 2, entries 5–9). Sterically hindered sub- cycle. The result obtained by using a mesitylcopper catalyst
strates were also viable, and high enantioselectivities were ob- suggests that the reaction could also proceed through a product
tained with 0.01 mol % catalyst loading (Table 2, entries base mechanism in which the Cu-pyrrolidine intermediate C
10–13).
deprotonates the Schiff base 1a directly; however, the higher re-
activity observed upon catalysis by CuHMDS and the basicity
Other electrophiles were also successfully employed with of the intermediate indicates that the proposed cycle is reason-
0.1 mol % catalyst loading (Scheme 1). N-Methylmaleimide able when CuHMDS is used as catalyst. The high catalyst
reacted with 1a in high yield with high diastereo- and enantiose- turnover may be due to the stronger Brønsted basicity of
Table 2: Scope of the reaction with respect to Schiff basesa.
Entry
Ar
1
FeSulphos (mol %)
3
Yield (%)
Endo/exo
ee (%, endo)
1
p-MeC6H4
p-MeC6H4
m-MeC6H4
o-MeC6H4
p-MeOC6H4
p-MeOC6H4
p-ClC6H4
1b
1b
1c
1d
1e
1e
1f
0.1
3ba
3ba
3ca
3da
3ea
3ea
3fa
92
91
93
92
91
91
96
96
96
94
87
76
91
>99:1
>99:1
>99:1
97:3
>99
85
2
0.01
0.1
3
>99
>99
99
4
0.1
5
0.1
97:3
6
0.01
0.1
>99:1
98:2
93
7
92
8
p-FC6H4
1g
1g
1h
1h
1i
0.1
3ga
3ga
3ha
3ha
3ia
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
99
9
p-FC6H4
0.01
0.1
98
10
11
12
13
2-naphthyl
2-naphthyl
1-naphthyl
1-naphthyl
99
0.01
0.1
97
99
1i
0.01
3ia
98
aReaction conditions: For 0.1 mol % catalyst loading: the [3 + 2] cycloaddition reactions of 0.5 M 1 (10 mmol) with 2a (11 mmol) were conducted at
−40 °C for 18 h by using the chiral copper amide prepared from CuOTf·0.5toluene complex (0.011 mmol), KHMDS (0.010 mmol), and FeSulphos
(0.011 mmol) in situ. For 0.01 mol % catalyst loading: the [3 + 2] cycloaddition reactions of 1.25 M 1 (50 mmol) with 2a (55 mmol) were conducted at
−40 °C for 48 h by using the chiral copper amide prepared from CuOTf·0.5toluene complex (0.0055 mmol), KHMDS (0.0050 mmol), and FeSulphos
(0.0055 mmol) in situ.
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Scheme 1: Scope of the reaction with other electrophiles. The [3 + 2] cycloaddition reaction of 0.5 M 1a (10 mmol) with 2 (11 mmol) was conducted at
−40 °C for 18 h by using the chiral copper amide prepared from CuOTf·0.5toluene complex (0.011 mmol), KHMDS (0.010 mmol), and FeSulphos
(0.011 mmol) in situ.
CuHMDS, which enables rapid deprotonation of the Schiff pared with catalysis by using the CuOTf/Et3N system, the Cu
base.
amide system showed higher reactivity, and the reactions
proceeded with high enantioselectivities even with 0.01 mol %
catalyst loading. Further investigations that are focused on the
Conclusion
In conclusion, highly efficient asymmetric [3 + 2] cycloaddi- application of metal amide catalysts in other reactions are
tions catalyzed by chiral CuHMDS have been described. Com- ongoing.
Figure 1: Proposed catalytic cycle.
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Beilstein J. Org. Chem. 2016, 12, 1447–1452.
10.Adrio, J.; Carretero, J. C. Chem. Commun. 2011, 47, 6784–6794.
doi:10.1039/c1cc10779h
Experimental
A general experimental procedure for conducting catalytic
asymmetric [3 + 2] cycloaddition reactions with 0.01 mol %
catalyst loading is described. Under an Ar atmosphere, a solu-
tion of the preformed chiral CuHMDS catalyst [prepared from
KHMDS (1.0 mg, 0.0050 mmol), CuOTf·0.5toluene (1.3 mg,
0.0055 mmol) and FeSulphos (2.3 mg, 0.0050 mmol) in an-
hydrous THF (5 mL) with heating at 40 °C for 1 h] was trans-
ferred into a well-dried 50 mL single-necked flask attached to a
three-way cock (sealed with grease). The solution was cooled at
−40 °C, and a mixture of 1 (50 mmol) and 2a (55 mmol) in an-
hydrous THF (35 mL) was added by using a cannula. The
whole was stirred for 48 h at −40 °C, then the reaction was
quenched by the addition of H2O, and the mixture was extracted
with dichloromethane. The organic layers were combined and
dried over anhydrous Na2SO4. The selectivities were deter-
mined by 1H NMR analysis and HPLC analysis after purifica-
tion of a small amount of the separated crude solution. After
filtration and concentration under reduced pressure, the crude
product obtained was purified by recrystallization and column
chromatography to determine the isolated yield of the desired
product. Obtained compounds were characterized by 1H and
13C NMR and by HPLC analyses using HPLC with chiral
columns. The physical data for the products were consistent
with reported values [49-54].
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Acknowledgements
This work was partially supported by a Grant-in-Aid for
Science Research from the Japan Society for the Promotion of
Science (JSPS), Global COE Program, the University of Tokyo,
MEXT, Japan, and the Japan Science and Technology Agency
(JST). S. Y. thanks the MERIT program, University of Tokyo,
for financial support.
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See for product 3ca.
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1452