Copper-catalyzed enantioselective conjugate reduction of α,β-unsaturated esters with chiral phenol–carbene ligands

Article abstract of DOI:10.3762/bjoc.16.50

A chiral phenol–NHC ligand enabled the copper-catalyzed enantioselective conjugate reduction of α,β-unsaturated esters. The phenol moiety of the chiral NHC ligand played a critical role in producing the enantiomerically enriched products. The catalyst worked well for various (Z)-isomer substrates. Opposite enantiomers were obtained from (Z)- and (E)-isomers, with a higher enantiomeric excess from the (Z)-isomer.

Full text of DOI:10.3762/bjoc.16.50

Copper-catalyzed enantioselective conjugate reduction of
α,β-unsaturated esters with chiral phenol–carbene ligands
Shohei Mimura1, Sho Mizushima1, Yohei Shimizu1,2 and Masaya Sawamura*1,2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2020, 16, 537–543.
1Department of Chemistry, Faculty of Science, Hokkaido University,
Kita 10 Nishi 8, Kita-ku, Sapporo, Hokkaido 060-0810, Japan and
2Institute for Chemical Reaction Design and Discovery
(WPI-ICReDD), Hokkaido University, Kita 21 Nishi 10, Kita-ku,
Sapporo, Hokkaido 001-0021, Japan
doi:10.3762/bjoc.16.50
Received: 19 November 2019
Accepted: 05 February 2020
Published: 31 March 2020
Email:
This article is part of the thematic issue "Copper-catalyzed reactions for
organic synthesis".
Masaya Sawamura* - sawamura@sci.hokudai.ac.jp
* Corresponding author
Guest Editor: O. Riant
Keywords:
© 2020 Mimura et al.; licensee Beilstein-Institut.
License and terms: see end of document.
catalyst; chiral NHC; conjugate reduction; copper catalysis;
enantioselective reaction
Abstract
A chiral phenol–NHC ligand enabled the copper-catalyzed enantioselective conjugate reduction of α,β-unsaturated esters. The
phenol moiety of the chiral NHC ligand played a critical role in producing the enantiomerically enriched products. The catalyst
worked well for various (Z)-isomer substrates. Opposite enantiomers were obtained from (Z)- and (E)-isomers, with a higher enan-
tiomeric excess from the (Z)-isomer.
Introduction
Since the leading work of Stryker and co-workers on triphenyl- [4]. Surprisingly, however, chiral ligands based on N-hetero-
phosphine-stabilized copper hydride complexes [1,2], copper cyclic carbenes (NHCs) [12] have not been applied to the
hydrides have been widely used for conjugate reductions of α,β- conjugate reduction of α,β-unsaturated carbonyl compounds,
unsaturated carbonyl compounds [3]. Especially a chiral copper while an achiral NHC/copper catalyst has successfully been
catalyst combined with a stoichiometric amount of a silane utilized in this reaction [13].
reagent, which generated copper hydride in situ, has successful-
ly been utilized for enantioselective reactions with β,β-disubsti- Meanwhile, we devoted our effort to develop novel enantiose-
tuted α,β-unsaturated carbonyl compounds [4-11]. The lective C–C bond formation reactions utilizing chiral
pioneering work of Buchwald and co-workers on the enantiose- phenol–NHC/copper catalyst systems [14-18], in which the
lective conjugate reduction of α,β-unsaturated esters using a phenol group of the NHC ligand plays crucial roles in both the
chiral p-tol-BINAP/copper catalyst established the excellent catalytic activity and stereoselectivity [19-21]. Notably, these
utility of chiral bisphosphine ligands for this type of reaction catalyst systems were also applicable for three-component
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Beilstein J. Org. Chem. 2020, 16, 537–543.
coupling reactions using hydrosilanes as hydride reagents [17]. (Table 1). When chiral NHC precursor L1·HBF4 (10 mol %)
Based on this knowledge, we decided to investigate the was used in combination with CuCl (10 mol %) and LiOt-Bu
effects of the phenol–NHC ligand on the copper-catalyzed en- (20 mol %) for the conjugate reduction of 1a with
antioselective conjugate reduction of α,β-unsaturated esters diethoxymethylsilane (4 equiv) as a reductant and t-AmOH
with hydrosilanes, placing a focus on (Z)-isomer substrates, (1 equiv) as a protonation reagent in DMA as the solvent at
which generally gave slightly lower enantiomeric excess 25 °C for 15 h, the product 2a was produced in 98% yield
with the chiral bisphosphines compared to the (E)-isomer sub- (1H NMR analysis) with a promising enantioselectivity of
strates.
69% ee (Table 1, entry 1). When the phenolic hydroxy group of
L1 was changed to a methoxy group (in L2), the enantioselec-
tivity drastically dropped to −10% ee, while the yield remained
99% (Table 1, entry 2). Similarly, N,N'-dimesityl-NHC L3,
Results and Discussion
Optimization
The initial investigation of the reaction conditions was carried which lacked an oxygen functionality in the N-aryl group,
out with ethyl (Z)-3-phenylbut-2-enoate (1a) as a substrate showed poor enantioselectivity (9% ee) with high yield (99%
Table 1: Optimization of the copper-catalyzed enantioselective conjugate reduction of 1a.a
entry
ligand
silane
alcohol
yield (%)
ee (%)
1
2
3
4
5
6
7
8
(S,S)-L1·HBF4
(S,S)-L2·HBF4
(S,S)-L3·HBF4
(S,S)-L4·HBF4
(S,S)-L5·HBF4
(S,S)-L6·HBF4
(S,S)-L4·HBF4
(S,S)-L4·HBF4
(S,S)-L4·HBF4
(S,S)-L4·HBF4
(S,S)-L4·HBF4
(S,S)-L4·HBF4
(S,S)-L4·HBF4
(EtO)2MeSiH
(EtO)2MeSiH
(EtO)2MeSiH
(EtO)2MeSiH
(EtO)2MeSiH
(EtO)2MeSiH
(MeO)2MeSiH
(TMSO)2MeSiH
(EtO)3SiH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-BuOH
iPrOH
98
99
99
97
99
97
98
94
0
69
−10
9
90
26
58
84
71
–
9
10
11
12
13
PMHS
5
99
7
–
82
–
(EtO)2MeSiH
(EtO)2MeSiH
(EtO)2MeSiH
MeOH
4
–
aThe yield was determined by 1H NMR analysis using 1,1,2,2-tetrachloroethane as an internal standard. The enantiomeric excess (ee) was deter-
mined by HPLC analysis with a chiral stationary phase column CHIRALCEL® OD-H.
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Beilstein J. Org. Chem. 2020, 16, 537–543.
yield, Table 1, entry 3). Thus, the hydroxy group of L1 was The nature of the alcoholic protonation reagent also had a
essential for the enantioselectivity by the catalyst. When the strong impact. The presence of a tertiary alcohol, t-AmOH or
mesityl group of L1 was changed to a bulkier 2-Me-4,6-Cy2- t-BuOH, was essential for the reaction to occur with a reason-
C6H2 group in L4, the enantioselectivity was markedly im- able yield, while iPrOH and MeOH markedly suppressed the
proved to 90% ee, with a high yield (97%, Table 1, entry 4). A reaction (Table 1, entries 12 and 13). However, the bulkier
naphthol substituent on the nitrogen atom of the NHC (in L5 t-AmOH was superior to t-BuOH in terms of enantioselectivity
and L6) instead of the phenol substituent was not suitable, (Table 1, entries 4 and 11).
giving significantly lower enantioselectivities (Table 1, entry 5,
99% yield, 26% ee; entry 6, 97% yield, 58% ee).
Substrate scope
Having established optimized conditions for the reaction of 1a
Further optimization of the conditions was conducted with L4. (2a, 97% yield, 90% ee (R), Table 2, entry 1), the scope of α,β-
Changing the silane group affected both the reactivity and unsaturated carbonyl compounds was examined. Because the
selectivity (Table 1, entries 7–10), while the replacement of the separation of the product from silicon-based byproducts was
ethoxy groups of (EtO)2MeSiH with methoxy or trimethylsilyl- troublesome, the isolated yields were lower than the yields de-
oxy groups resulted in only moderate reductions in the enantio- termined by NMR spectroscopy (2a, 52%, Table 2, entry 1).
selectivity and high yields. At the same time, trialkoxysilane
(EtO)3SiH and polymeric silane PMHS gave only trace When (E)-1a was used as the substrate, the opposite enantio-
amounts of the product.
mer (S)-2a was obtained in >99% yield, with slightly lower en-
Table 2: Substrate scope of the copper-catalyzed enantioselective conjugate reduction.a
entry
1
substrate
product
yield (%)
97 (52)
ee (%)
90
1a
2a
2
>99 (75)
>99 (60)
82
75
(E)-1a
(S)-2a
3b
1b
1c
1d
2b
2c
2d
4
5
>99 (44)
96 (74)
84
76
539

Beilstein J. Org. Chem. 2020, 16, 537–543.
Table 2: Substrate scope of the copper-catalyzed enantioselective conjugate reduction.a (continued)
6b,c
>99 (75)
>99 (45)
84
85
1e
2e
7
1f
1g
1h
2f
2g
2h
8b,c
9
>99 (55)
>99 (79)
70
83
10
81 (59)
79
1i
2i
aThe yields were determined by 1H NMR analysis using 1,1,2,2-tetrachloroethane as an internal standard. Isolated yields are shown in parentheses.
bt-BuOH was used instead of t-AmOH. c(EtO)2MeSiH (1 equiv) was used.
antioselectivity (Table 2, entry 2, 82% ee (S) vs 90% ee (R) in The structure of the ester moiety affected the stereoselectivities:
entry 1). The inversion of the absolute configuration of the Lower enantioselectivities were observed with benzyl ester 2g
product depended on the E/Z geometry of the substrates, and (Table 2, entry 8, >99% yield, 70% ee) and isopropyl ester 2h
this was analogous to the reported results obtained with the (Table 2, entry 9, >99% yield, 83% ee). In addition to the α,β-
chiral bisphosphine ligand systems, while the observation of a unsaturated esters, an α,β-unsaturated Weinreb amide 1i
higher enantioselectivity for the (Z)-isomer substrate 1a was afforded the corresponding product 2i with comparable results
characteristic for the phenol–NHC chiral ligand [4,6,8]. The (Table 2, entry 10, 81% yield, 79% ee).
result suggested that the chiral catalyst may mainly discrimi-
nate the hydrogen atom and the ethoxycarbonyl group at the
Proposed catalytic cycle
α-position rather than the two substituents at the β-position. In
good agreement with this assumption is the reaction of sub-
strate 1b, carrying a phenyl group and a p-tolyl group as β-sub-
stituents, which seemed to be difficult for the catalyst to differ-
entiate, both sterically and electronically, affording the product
2b in good enantioselectivity (Table 2, entry 3, >99% yield,
75% ee).
Based on the experimental observations and previous know-
ledge of the catalysis of phenol–NHC chiral ligands [14-18], we
propose a catalytic cycle as shown in Scheme 1. LiOt-Bu
abstracts the two protons of the acidic imidazolium C–H and
phenol O–H groups of the L4·HBF4 adduct in the presence of
CuCl to generate a phenoxy copper(I) species A. As a result, all
LiOt-Bu (20 mol %) is consumed in this step. Thus, the system
is neutral. Transmetalation between A and (EtO)2MeSiH
Next, the effects of the β-substituent (R1) were examined. Both produces the copper hydride species B. This transmetalation
electron-donating and -withdrawing substituents on the para- adds the silyl group to the phenoxy oxygen atom of the NHC
position of the β-aryl substituent gave excellent reactivities and ligand. The coordination of an α,β-unsaturated carbonyl com-
good enantioselectivities (Table 2, entry 4, 2c: >99% yield, pound 1 to the copper atom occurs in such a way that the bulky
84% ee; entry 5, 2d: 96% yield, 76% ee). Further, a heteroaryl O-silyl group of the copper catalyst can avoid steric repulsions
substituent, 2-ethoxycarbonylthiophene, was tolerated (Table 2, with the alkoxycarbonyl group of the substrate 1, forming
entry 6, 2e: >99% yield, 84% ee), and a β-alkyl-substituted π-complex C, and thus explaining the marked influence of the
substrate 1f was also competent (entry 7, 2f: >99% yield, hydrosilane structure on the enantioselectivity. During this
85% ee).
stereodetermining step, coordination of the phenoxy oxygen
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Beilstein J. Org. Chem. 2020, 16, 537–543.
Scheme 1: Proposed catalytic cycle.
atom to the copper atom may render the chiral environment Experimental
better defined. Then, the π-complex C undergoes 1,4- A typical procedure for the copper-catalyzed enantioselec-
hydrocupration to afford copper enolate D. During our initial tive conjugate reduction (Table 1, entry 4; Table 2, entry 1):
investigations, we observed configurational isomerization from In a glove box, CuCl (1.5 mg, 0.015 mmol), L4⋅HBF4 (9.8 mg,
1a to (E)-1a when the reaction was conducted in the absence of 0.015 mmol), and LiOt-Bu (2.4 mg, 0.03 mmol) were placed in
alcoholic protonation reagents. This observation implied that a vial containing a magnetic stirring bar. The vial was sealed
the 1,4-hydrocupration step (C to D) is reversible. Finally, pro- with a teflon-coated silicon rubber septum. N,N-Dimethylacet-
tonation of D by t-AmOH gives the product 2 and silyl ether amide (0.90 mL) was added to the vial, and then the mixture
(EtO)2MeSiOt-Am, regenerating the phenoxy copper(I) com- was stirred at room temperature for 5 min. Next, t-AmOH
plex A. Due to the reversibility of the 1,4-hydrocupration, the (16.3 μL, 0.15 mmol) was added, and the vial was taken out of
choice of the alcoholic protonation reagent affects both the re- the glove box. To the reaction mixture was added 1a (28.5 mg,
activity and enantioselectivity.
0.15 mmol). After stirring for 5 min at room temperature,
diethoxymethylsilane (101 μL, 0.60 mmol) was added to the
mixture. After stirring for 15 h at 25 °C, the reaction mixture
Conclusion
A chiral phenol–NHC ligand efficiently promoted the enantio- was diluted with diethyl ether (1.0 mL) and quenched with H2O
selective conjugate reduction of α,β-unsaturated esters with a (0.6 mL). The organic layer was separated, and the aqueous
hydrosilane. To the best of our knowledge, this is the first layer was extracted three times with diethyl ether. The com-
demonstration of the applicability of chiral NHC ligands in bined organic layer was filtered through a short plug of silica
Cu-catalyzed enantioselective conjugate reductions. The gel by using diethyl ether as an eluent. After the solvent was re-
phenolic N-substituent of the chiral NHC ligand was essential moved under reduced pressure, the yield of the product was de-
for the high enantioselectivity. Good enantioselectivities were termined to be 97% by 1H NMR analysis with 1,1,2,2-tetra-
observed for the various (Z)-configured substrates with differ- chloroethane as an internal standard. After a rough purification
ent β-substituents. Further investigations on the catalyst of the crude product by silica gel chromatography (eluent: 0 to
development based on this knowledge are ongoing in our labo- 1% EtOAc/hexane), the collected residue was further purified
ratory.
by GPC (eluent: CHCl3) to afford the pure product 2a as color-
541

Beilstein J. Org. Chem. 2020, 16, 537–543.
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The ee value was determined by HPLC analysis with a chiral
stationary column CHIRALCEL® OD-H (Daicel Chemical
Industries, 4.6 mm, 250 mm, hexane/2-propanol, 98:2, v/v,
0.5 mL/min, 40 °C, 220 nm UV detector, retention time =
9.1 min for the (R)-isomer and 13.3 min for the (S)-isomer).
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Supporting Information
doi:10.1002/anie.201600619
16.Yasuda, Y.; Ohmiya, H.; Sawamura, M. Angew. Chem., Int. Ed. 2016,
55, 10816–10820. doi:10.1002/anie.201605125
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18.Yasuda, Y.; Ohmiya, H.; Sawamura, M. Synthesis 2018, 50,
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Supporting Information File 1
Experimental procedures, characterization data, HPLC
charts, and NMR spectra (1H, 13C) for the new compounds.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-16-50-S1.pdf]
19.Clavier, H.; Coutable, L.; Guillemin, J.-C.; Mauduit, M.
Tetrahedron: Asymmetry 2005, 16, 921–924.
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Acknowledgements
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Alexakis, A. J. Am. Chem. Soc. 2006, 128, 8416–8417.
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The Institute for Chemical Reaction Design and Discovery
(ICReDD) was established by the World Premier International
Research Initiative (WPI), MEXT, Japan.
Funding
doi:10.1002/anie.201103581
22.Guo, S.; Zhou, J. Org. Lett. 2016, 18, 5344–5347.
doi:10.1021/acs.orglett.6b02662
This work was supported by the JSPS KAKENHI grant-in-aid
for Scientific Research (A) to M.S. (No. JP18H03906), JSPS
KAKENHI grant-in-aid for Early-Career Scientists (No.
18K14207) to Y.S.
ORCID® iDs
Yohei Shimizu - https://orcid.org/0000-0001-8797-9757
Masaya Sawamura - https://orcid.org/0000-0002-8770-2982
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