Copper-Catalyzed Enantioselective 1,2-Reduction of Cycloalkenones

Article abstract of DOI:10.1021/acs.orglett.1c01744

We report an asymmetric 1,2-reduction of cyclic α,β-unsaturated ketones to access various enantiomerically enriched cyclic allylic alcohols under mild conditions, catalyzed by in situ generated copper hydride ligated with (R)-DTBM-C3*-TunePhos. α-Brominated cycloalkenones were reduced with excellent enantioselectivities of up to 98% ee, while substrates that were without α-substituents were reduced chemoselectively, with moderate enantioselectivities.

Full text of DOI:10.1021/acs.orglett.1c01744

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Copper-Catalyzed Enantioselective 1,2-Reduction of Cycloalkenones
Yongjie Shi, Jingxin Wang, Qin Yin, Xumu Zhang,* and Pauline Chiu*
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ABSTRACT: We report an asymmetric 1,2-reduction of cyclic α,β-unsaturated ketones to access various enantiomerically enriched
cyclic allylic alcohols under mild conditions, catalyzed by in situ generated copper hydride ligated with (R)-DTBM-C3*-TunePhos.
α-Brominated cycloalkenones were reduced with excellent enantioselectivities of up to 98% ee, while substrates that were without α-
substituents were reduced chemoselectively, with moderate enantioselectivities.
any natural products and pharmaceuticals are chiral
allylic alcohols (Figure 1A).1 Besides being desirable
structural types with high enantioselectivity are desirable. The
asymmetric synthesis of allylic alcohols has been accomplished
by many strategies, including dynamic kinetic resolution,6
nucleophilic addition to enals,7 and allylic substitution.8
Asymmetric 1,2-reduction of α, β-unsaturated ketones is also
a straightforward way to obtain chiral allylic alcohols from
easily accessible enone substrates. The challenges of this
transformation are the chemoselectivity for competitive 1,2- or
1,4-reduction processes, as well as high facial selectivity. Ru-
catalyzed asymmetric high pressure catalytic hydrogenations of
enones and Ru-catalyzed asymmetric transfer hydrogenations
have reported considerable success.9 Probably, the most used
reduction, particularly for cyclic enones, is the Corey−Bakshi−
Shibata (CBS) reduction, which offers a predictable asym-
metric reduction.10 However, besides requiring a relatively
high catalyst loading, this reduction can be quite capricious in
practice and needs to operate within extremely stringent
reaction parameters for high enantiomeric induction.5a,10
Among the transition metals, copper is a base metal that has
one of the lowest supply risks, even lower than that of iron.11 It
is much less expensive than Ru, Ir, and Pd, as well as being
comparatively less toxic, and has a long history of promoting
reactions both stoichiometrically and catalytically. Expanding
the repertoire of copper-mediated reactions would have
M
Figure 1. Representative chiral allylic alcohols.
targets in themselves, chiral allylic alcohols are versatile starting
materials in organic synthesis for engaging in Claisen and
Overman rearrangements,2 directed epoxidations and reduc-
tions,3 SN2′, and various stereospecific substitution reactions.4
As such, allylic alcohols have been used as building blocks in
many total syntheses.1,5
Received: May 25, 2021
Published: July 13, 2021
Due to the importance of chiral allylic alcohols in synthesis,
efficient benchtop catalytic processes to generate various
https://doi.org/10.1021/acs.orglett.1c01744
© 2021 American Chemical Society
Org. Lett. 2021, 23, 5658−5663
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practical implications for laboratory-scale as well as industrial
chemistry.
(Table 1, entry 1), did not result in much improvement in the
chemoselectivity or enantioselectivity.
[(Ph3P)CuH]6 is a discrete copper hydride initially
demonstrated to be a chemoselective reagent for 1,4-reduction
of α, β-unsaturated ketones, and later as a catalyst in the
presence of various stoichiometric reductants.12 The use of
alternative ligands, together with the in situ generation of
copper hydride, modified the reduction to be chemoselective
for 1,2-reduction and carbonyl reductions, making this a very
versatile reducing system amenable to ligand tuning.13
In 2010, the Lipshutz group reported an asymmetric 1,2-
reduction of acyclic conjugated ketones, mediated by copper-
(I) hydride generated in situ from Cu(OAc)2, (R)-DTBM-
SEGPHOS, and diethoxymethylsilane (DEMS) (Scheme 1A).
Table 1. Optimizations of Asymmetric 1,2-Reductions
a
b
c
Entry
Ligand
T
Product
Conversion
ee
d
1
L3b
L4b
L5b
L5b
L3a
L4a
L5a
L3b
L4b
L5b
L5b
L5b
L5b
0 °C
0 °C
0 °C
−25 °C
rt
rt
rt
rt
2a/2a′ = 40:60
2a/2a′ = 35:65
2a/2a′ = 92:8
96%
99%
63%
99% (98%)
83%
27%
47%
>99%
>99%
>99%
67%
>99%
99% (95%)
53%
58%
68%
73%
51%
54%
56%
91%
89%
93%
93%
96%
97%
d
2
d
3
e f
,
4
5
6
7
8
9
2a
4a
4a
4a
4a
4a
4a
4a
4a
4a
Scheme 1. Asymmetric 1,2-Reduction of Enones
rt
rt
rt
10
11
12
13
d
e
−25 °C
−25 °C
e f
,
a
Reaction conditions: 1a/3a (0.1 mmol), Ligand (5 mol %),
Cu(OAc)2 (5 mol %), PhSiH3 (0.15 mmol), THF (0.5 mL).
b
Conversions determined by 1H NMR analysis; isolated yields in
c
d
brackets. Ee determined by chiral HPLC. PinBH used instead of
PhSiH3; 12 h instead of 2 h. Ligand (3.3 mol %), Cu(OAc)2 (3 mol
%), PhSiH3 (0.12 mmol). PPh3 (3 mol %) used as additive.
e
f
Both the ligand used, as well as the α-substituents of the
conjugated ketone, contributed to the high chemo- and
enantioselectivity of the reduction.14a Many β,β-disubstituted
enones were also reduced with excellent ee.14b However, as
applied to cyclic enones such as 1a, it was an unsatisfactory
solution: the reduction was not chemoselective, and 1,2- and
1,4-reduction products 2a and 2a′ in a 53:47 ratio, and with
55% ee for 2a, were obtained under the optimized conditions
(Scheme 1B).14b Using JOSIPHOS as ligand, the reduction
was neither chemoselective nor enantioselective (2a:2a′ =
75:25, 2a = 2% ee).14b Probably this was due to the greater
challenge for enantiodifferentiation of prochiral faces in these
substrates. Based on our previous research on copper hydride
chemistry15 and continued interest in copper-mediated
asymmetric reductions and ligand development,16 we
wondered whether the CuH-mediated reduction of enones
could be developed to be a robust method to access
structurally diverse cyclic allylic alcohols in particular (Scheme
1C). Herein, we report the use of DTBM-C3*-TunePhos as a
ligand,17 to achieve an improved copper catalyzed asymmetric
1,2-reduction of cyclic enones and α-brominated cyclic enones,
wherein excellent chemoselectivity and good to excellent
enantioselectivities can be achieved.
Next, we examined other ligands for this copper-mediated
reduction. After screening various ligands (Table S1), the C3*-
TunePhos family of ligands was found to be the best ligands in
terms of yield, chemo- and stereoselectivity. The Cn-TunePhos
series of ligands were designed to be more rigid than the
BIPHEP analogues by restricting the biaryl rotations through
joining the aryl units using a linker.17 In addition, through
variation of the length of the linker (C1 to C6), the bite angle
of the diphosphine could be systematically “tuned”. Finally, the
series of C3*-TunePhos ligands incorporated chirality into the
C3-linker. The use of the more bulky (R)-DTBM-C3*-
TunePhos ligand with PinBH generated 2a with an improved
conversion as well as a much higher chemoselectivity, while
maintaining an ee of 68% (Table 1, entry 3). Further
optimizations found that the use of phenylsilane as a reductant
led to a quantitative yield of (R)-2a of 73% ee at −25 °C
(Table 1, entry 4), whereas conversions were quite acceptable
with PinBH in the presence of the other ligands (Table 1,
entries 1−3). A series of β-arylated α, β-unsaturated cyclic
ketones were synthesized to be probed (1b−1d), and their
reductions under these conditions similarly provided products
2b−2d chemoselectively, and with an ee of up to 77% (Table
2). We surmise that the improved chemoselectivity and
enantioselectivity are both mainly due to additional rigidity
Our initial investigation began with studying whether
different stoichiometric reductants could improve the reduc-
tion mediated by DTBM-SEGPHOS-ligated copper hydrides.
However, the use of alternative silanes (Table S1), or PinBH
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enone, they were all reduced to the corresponding optically
enriched allylic alcohols with excellent enantioselectivities
(93−97% ee) and yields of up to 99% (Table 3). Alkynylated
Table 2. Substrate Scope for Asymmetric 1,2-Reduction of
β-Substituted Cyclohexenones
a
Table 3. Substrate Scope for Asymmetric 1,2-Reduction of
a
α-Substituted Enones
a
Isolated yields are shown.
of (R)-DTBM-C3*-TunePhos over the (R)-DTBM-SEG-
PHOS and the (R)-MeO-BIPHEP, as the electronics of
these ligands are relatively similar.
Although both the chemoselectivity and enantioselectivity of
the reduction of cyclohexenones have been improved
compared with the previous results,14b the absolute enantio-
meric excess of 71−77% is moderate by today’s standards.
Thus, another solution for a more enantioselective reduction of
cyclohexenones was still needed.
We next considered the installation of a bromo-substituent
to the α, β-unsaturated cyclic ketones and to examine this
reduction. α-Brominated enones have been reduced with
higher enantioselectivities under various conditions, including
the CBS reduction.5c The α-bromo allylic alcohols obtained
upon reduction could be subsequently debrominated to access
the parent allylic alcohols,5b,c or the vinylic bromide functional
group can be exploited for functionalization in various ways, as
in the synthetic studies of calyciphylline A or taxezopidine A
(Figure 1B).18 The confluence of reactivity over three
contiguous functionalized carbons of α-bromo allylic alcohols
facilitates elaborations to furnish densely functionalized
molecular constructs.
a
Isolated yields are shown.
Using 3a as a standard substrate, of the chiral diphosphine
ligands that were screened (Table S2), reduction in the
presence of (R)-DTBM-SEGPHOS (L3b), (R)-DTBM-
BIPHEP (L4b), and (R)-DTBM-C3*-TunePhos (L5b), all
proceeded to full conversion over 2 h with exclusive 1,2-
reduction, and concurrently with good enantioselectivities
(Table 1, entries 8−10). The reductions were both higher
yielding and more enantioselective than those with their less
hindered, non-DTBM analogues having the same backbones
(L3a, L4a, L5a). The enantiocontrol achieved for 4a in the
presence of (R)-DTBM-C3*-TunePhos was slightly superior
(93% ee). Using HBPin as a stoichiometric reductant did not
facilitate full conversion (Table 1, entries, 10, 11). The catalyst
loading could be further decreased to 3 mol % along with 1.2
equiv of PhSiH3, with no detriment to the yield or the
enantioselectivity. The ee of the reduction was further
enhanced when the temperature was decreased to −25 °C
(Table 1, entry 12). The addition of 3 mol % PPh3 increased
the ee of the reduction to 97% (Table 1, entry 13).
3g having a further extended conjugated system was
chemoselectively reduced to alcohol 4g in high yield and ee.
Enone 3h bearing a skipped diene and enone 3i with a benzyl
group were reduced to the corresponding alcohols in excellent
yields and enantioselectivities. Various 3-alkyl substituted
cyclohexenones (3j−l) were also reduced in high yields and
with up to 98% ee.
We extended the substrate scope to other cycloalkenones.
Reduction under the optimized conditions provided both β-
aryl and β-alkyl substituted cyclopent-2-en-1-ols 4m, 4n and
cyclohept-2-en-1-ol 4o with excellent ee (96%−98% ee).
Finally, while these studies were mainly focused on cyclic
substrates in connection with our total synthesis work, we also
considered the reduction of the only brominated enone, (Z)-3-
bromo-4-phenylbut-3-en-2-one 3p, examined in the previous
report.14a Asymmetric reduction using (R)-DTBM-C3*-
TunePhos (L5b) as ligand provided 4p in 81% yield and
86% ee, compared with 77% ee and 91% yield using (R)-
DTBM-SEGPHOS (L3b) in the Lipshutz work. The reduction
of two α-methylated enones afforded 4q, 4r with comparable
or slightly improved enantioselectivities.14a
With the optimized conditions in hand, we next evaluated
the substrate scope. For 3-arylated or 3-naphthylated 3a−f
bearing various substituents on the aromatic ring, for which
there is conjugation and potential electronic influence on the
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We evaluated the limits of this reduction separately in larger
scale TON experiments. It was found that, with S/C as high as
1000, enone 3j was reduced to 4j with full conversion and 98%
ee without any loss of enantioselectivity or yield (Scheme 2,
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01744.
■
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Experimental procedures, spectral and analytical data,
Scheme 2. TON Experiments and Derivatizations
1
copies of H and 13C NMR spectra for new compounds
(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Xumu Zhang − Guangdong Provincial Key Laboratory of
Catalysis, Southern University of Science and Technology,
Shenzhen 518055, China; orcid.org/0000-0001-5700-
0608; Email: zhangxm@sustech.edu.cn
Pauline Chiu − Department of Chemistry and State Key
Laboratory of Synthetic Chemistry, The University of Hong
Kong, Hong Kong, China; orcid.org/0000-0001-5081-
4756; Email: pchiu@hku.hk
Authors
Yongjie Shi − Department of Chemistry and State Key
Laboratory of Synthetic Chemistry, The University of Hong
Kong, Hong Kong, China; Guangdong Provincial Key
Laboratory of Catalysis, Southern University of Science and
Technology, Shenzhen 518055, China; orcid.org/0000-
0003-3845-5505
Jingxin Wang − Guangdong Provincial Key Laboratory of
Catalysis, Southern University of Science and Technology,
Shenzhen 518055, China
Qin Yin − Academy for Advanced Interdisciplinary Studies,
Southern University of Science and Technology, Shenzhen
518000, China; Guangdong Provincial Key Laboratory of
Catalysis, Southern University of Science and Technology,
Shenzhen 518055, China; orcid.org/0000-0003-3534-
3786
Table S3). Such a high TON represents economies for both
the amount of metal and ligand required for the asymmetric
reduction. To demonstrate the practicality of this reduction, a
gram-scale synthesis was accomplished using 0.1% catalyst, to
convert 3a to 4a in 91% yield and 96% ee (Scheme 2). This
reduction can be readily operated as a benchtop synthesis
without requiring the use of a glovebox. It was also possible to
work up the reaction such that most of the THF solvent could
be recovered or, alternatively, 2-MeTHF from renewable
resources could be used instead as solvent.
The α-bromo-substituted allylic alcohols are versatile
intermediates in organic synthesis, and several derivatizations
are shown using 4a (Scheme 2). Metalation and protonation
resulted in debromination to generate 2a in high yield with
retention of optical purity.5b Alternatively, after MOM
protection, metalation and then treatment with DMF provided
aldehyde 5 in 80% yield over 2 steps.18b Finally, the vinylic
bromide can be a handle to engage in cross-coupling reactions,
such as a palladium-catalyzed Heck reaction, providing
dienoate 6 in 83% yield.
In summary, we have developed a convenient and effective
asymmetric reduction catalyzed by a base metal, copper, to
provide α-substituted allylic alcohols with excellent enantiose-
lectivities. A TON of at least 1000 was observed, and the
reduction is robust and reliable. The optimized reaction
conditions tolerated a fairly broad substrate scope, and various
β-aryl, alkyl, allyl, alkynyl-substituted brominated cyclohex-
enones, and bromo-cyclopentenones and cycloheptenones
were reduced with good enantioselectivities. For cyclo-
hexenones that are α-protonated, a highly chemoselective
1,2-reduction occurred, with improved, albeit moderate,
enantiomeric excesses over other chiral ligands thus far
studied. This also represents the first application of the Cn-
Tunephos ligands in copper-mediated chemistry. The reduc-
tion is readily scalable for multigram-scale preparations.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01744
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The Guangdong Provincial Key Laboratory of Catalysis
(2020B121201002), the State Key Laboratory of Synthetic
Chemistry, and the Laboratory for Synthetic Chemistry and
Chemical Biology under the Health@InnoHK Program of the
Innovation and Technology Commission, The Government of
Hong Kong Special Administrative Region of the People’s
Republic of China, are acknowledged for funding support.
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