Catalytic Biomimetic Asymmetric Reduction of Alkenes and Imines Enabled by Chiral and Regenerable NAD(P)H Models

Article abstract of DOI:10.1002/anie.201813400

The development of biomimetic chemistry based on the NAD(P)H with hydrogen gas as terminal reductant is a long-standing challenge. Through rational design of the chiral and regenerable NAD(P)H analogues based on planar-chiral ferrocene, a biomimetic asymm

Full text of DOI:10.1002/anie.201813400

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Accepted Article
Title: Catalytic Biomimetic Asymmetric Reduction of Alkenes and
Imines Enabled by Chiral and Regenerable NAD(P)H Models
Authors: Yong-Gui Zhou, Jie Wang, Zhou-Hao Zhu, Mu-Wang Chen,
and Qing-An Chen
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201813400
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10.1002/anie.201813400
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Catalytic Biomimetic Asymmetric Reduction of Alkenes and
Imines Enabled by Chiral and Regenerable NAD(P)H Models
Jie Wang, Zhou-Hao Zhu, Mu-Wang Chen, Qing-An Chen, and Yong-Gui Zhou*
Dedication to 70th Anniversary of Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Abstract: The development of biomimetic chemistry based on the
NAD(P)H with hydrogen gas as terminal reductant is a long-standing
challenge. Through rational design of the chiral and regenerable
NAD(P)H models based on planar chiral ferrocene skeleton, a
biomimetic asymmetric reduction has been realized using bench-
stable Lewis acids as transfer catalysts, a broad set of alkenes and
imines could be reduced with up to 98% yield and 98% ee, likely
enabled by enzyme-like cooperative bifunctional activation. This
represents the first general biomimetic asymmetric reduction (BMAR)
process enabled by chiral and regenerable NAD(P)H models. This
concept demonstrates catalytic utility of chiral coenzyme NAD(P)H in
asymmetric catalysis.
Scheme 1. Biomimetic Asymmetric Reduction (BMAR) Based on Coenzyme
NAD(P)H
The development of biomimetic approaches plays an important
role in agrochemicals, materials and pharmaceuticals. In the cell,
For previous works on biomimetic asymmetric reduction
based on the achiral NAD(P)H model, chiral Brønsted acids are
used as dominant transfer catalyst to control the
enantioselectivity. Owing to the inherent activation pattern
(protonation or hydrogen bonding) of chiral Brønsted acids, its
substrate scope is mostly confined within the asymmetric
reduction of C=N bonds. Obviously, increase the diversity of
activation pattern will further expand the generality of biomimetic
asymmetric reduction. For example, tetrasubstituted alkenes are
the challenging substrates in asymmetric hydrogenation,
especially in the biomimetic asymmetric reduction (Scheme 2).10
Owing to the inherent activation pattern of Brønsted acids, not
surprisingly, no desired biomimetic reduction was observed
using phosphoric acid as transfer catalyst in the presence of
phenanthridine (PD). Gratifyingly, the switch of transfer catalyst
to Lewis acid Sm(OTf)3 delivered the desired product 2a in 42%
yield. Without the transfer catalyst, no reaction occurred. To
further increase the diversity of activation pattern, we envisioned
that the development of chiral and regenerable NAD(P)H model
might provide a general biomimetic asymmetric reduction with
other transfer catalyst (Scheme 1). Herein, we reported a
biomimetic asymmetric reduction based on the ferrocene-
derived chiral and regenerable NAD(P)H models with the readily
available Lewis acids as achiral transfer catalysts, alongside
wide substrate scope, excellent activities and enantioselectivities.
the reduced nicotinamide adenine dinucleotide (NADH) and
nicotinamide adenine dinucleotide phosphate (NADPH) are
recognized as a couple of crucial enzymes and over 400
enzyme redox reactions depend on the interconversion of
NAD(P)H and NAD(P)+ such as citric acid cycle, glycolysis and
amino acid decomposition.1 Therefore, efficient methods to
realize biomimetic asymmetric reduction (BMAR) have been
studied intensively, and the design of NAD(P)H models, transfer
catalysts and regeneration catalysts is important topic2 (Scheme
1). As the simplest achiral NAD(P)H models, Hantzsch esters
(HEH)3 and benzothiazolines4 have been widely and
successfully applied in biomimetic asymmetric reduction of a
series of unsaturated compounds in the presence of chiral
organocatalysts5 and metal catalysts.6 However, these reactions
required the stoichiometric NAD(P)H models and suffered from
intractable limitations in regeneration.7 Recently, a catalytic
amount of achiral dihydrophenanthridine (DHPD) was employed
to realize biomimetic asymmetric hydrogenation of imines and
heteroaromatics with chiral phosphoric acid, which is easy to be
regenerated under hydrogen gas using homogeneous
ruthenium8 or iron catalyst.9 Despite these remarkable progress,
the development of a chiral and regenerable NAD(P)H models
for BMAR is still a long-standing challenge in biomimetic
asymmetric catalysis.
[a]
J. Wang, Z. H. Zhu, M. W. Chen, Q. A. Chen, Prof. Dr. Y. G. Zhou
State Key Laboratory of Catalysis, Dalian Institute of Chemical
Physics, Chinese Academy of Sciences
457 Zhongshan Road, Dalian 116023, China
E-mail: ygzhou@dicp.ac.cn
Homepage: http://lac.dicp.ac.cn/index.php
J. Wang
University of Chinese Academy of Sciences, Beijing, China
Prof. Dr. Y. G. Zhou
[b]
[c]
State Key Laboratory of Fine Chemicals, Zhang Dayu School of
Chemistry, Dalian University of Technology, Dalian, China
Scheme 2. Initial results about the biomimetic reduction of tetrasubstituted
alkenes
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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2
3
Sm(OTf)3
-
CHCl3
CHCl3
CH2Cl2
Toluene
THF
(R)-6a
(R)-6a
(R)-6a
(R)-6a
(R)-6a
(R)-6a
(R)-6a
(R)-6a
(R)-6a
(R)-6b
(R)-6c
(R)-6d
(R)-6a
11
<5
11
31
>95
<5
41
<5
88
80
63
17
97d
10:1
-
87
-
Considering that the dihydropyridine is the key structural
moiety for regeneration of NAD(P)H model under hydrogen gas
with ideal atom economy, we sought to explore the chiral
NAD(P)H model containing dihydropyridine moiety. In addition,
the chiral and regenerable NAD(P)H model should be
conveniently prepared from the commercially available materials
and finely tuned. Inspired by the application of the planar
chirality in asymmetric synthesis,11 we design a chiral NAD(P)H
model 6 with planar chirality containing the key structure
phenanthridine (Scheme 3). Through three simple operations
(reduction, Suzuki coupling, and oxidative cyclization), a series
of NAD(P)H models FENAM (R)-6a-d were easily synthesized
4
Sm(OTf)3
Sm(OTf)3
Sm(OTf)3
Cu(OTf)2
La(OTf)3
Sc(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
4.5:1
5.2:1
4.5:1
-
85
86
83
-
5
6
7
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
8
>20:1
-
92
-
9
10
11
12
13
14
>20:1
>20:1
>20:1
>20:1
>20:1
90
89
87
89
90
from
the
readily
available
chiral
(S)-2-
iodoferrocenecarboxaldehyde 3 (Scheme 3).12
[a] Reactions were carried with 1a (0.10 mmol), [Ru(p-cymene)I2]2 (0.5 mol%),
6 (10 mol%), Acid (20 mol%), Solvent (2 mL), H2 (800 psi), 50 oC, 23 h. [b]
Conversion and selectivity was measured by analysis of 1H NMR spectra. [c]
Determined by chiral HPLC. [d] Isolated yield for the reaction with 0.15 mmol
scale for 80 h.
With optimal condition in hand, the substrate scope of
biomimetic asymmetric reduction of tetrasubstituted alkenes 1
using a catalytic amount of FENAM (R)-6a was explored
(Scheme 4). It is noteworthy that the thermodynamically
preferred product, 3,4-trans-disubstituted dihydrocoumarins,
could be obtained for aryl-substituted substrates 1a-1k in a
highly diastereo-selective manner (d.r. >20:1) with high
enantioselectivities and activities (2a-2k).13 The absolute
configuration of 2e was assigned as (3R,4R) by X-ray diffraction
analysis (for the details, see the Supporting Imformation). As for
the methyl-substituted substrate, moderate diastereo- and
enantioselectivity could be obtained (2l).
Scheme 3. Synthesis of NAD(P)H Models FENAM (R)-6 with planar chirality
To verify the efficiency of planarly chiral NAD(P)H models,
tetrasubstituted alkene 1a was chosen as model substrate for
biomimetic asymmetric reduction (Table 1). Ruthenium (II) and
acid were employed as the regeneration and transfer catalyst,
respectively. As the same as the result of achiral NAD(P)H
model phenanthridine (Scheme 2), Lewis acid displayed higher
reactivity over Brønsted acid and gave the desired product 2a in
high enantioselectivity (87%, entries 1-3). Small amount of side
products 2a' was detected resulting from the decarboxylation.
According to the investigations of solvent effect, better reactivity
but lower selectivity was observed in THF (entries 2, 4-6). The
evaluation of transfer catalyst suggests Yb(OTf)3 was optimal
with regard to reactivity and enantioselectivity (entries 7-10). No
improvement of enantioselectivity was observed using NAD(P)H
models FENAM (R)-6b-d with different steric and electronic
properties (entries 11-13). Excellent isolated yield of 2a was
achieved by prolonging the reaction time (97% yield, entry 14).
Thus, the optimal reaction condition was identified: Alkenes 1
(1.0 equiv.), [Ru(p-cymene)I2]2 (0.5 mol%), FENAM (R)-6a (10
mol%), achiral transfer catalyst Lewis acid Yb(OTf)3 (20 mol%),
H2 (800 psi), CHCl3 and 50 oC.
Table 1. Conditions Optimizationa
Scheme 4.
Substrate Scope for Lewis Acid-Promoted the BMAR of
Tetrasubstituted alkenes
Conv.
(%)b
Ee
Entry
1
Acid
Slovent
CHCl3
Model
2a:2a'b
(%)c
Due to Lewis acid's ability on the activation of imines, this
strategy might be suitable for biomimetic asymmetric reduction
(PhO)2PO2H
(R)-6a
<5
-
-
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10.1002/anie.201813400
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Scheme 6. Dependence of enantioselectivity of the product 8a on ee of
NAD(P)H model (R)-6a
C=N bonds. Substituted benzoxazinones 7 were chosen as
model substrate14 to validate our hypothesis (Scheme 5).
Through conditions optimization, Lewis acid Sm(OTf)3 emerged
as the best transfer catalyst in terms of reactivity and
enantioselectivity (conditions optimization see Supporting
Information). Generally, excellent yields (89-98%) and
enantioselectivities (92−98%) were obtained in this biomimetic
asymmetric hydrogenation system regardless of the electronic
property of the substituent on 3-aryl-benzoxazinones 7 (7a-7k).
As for the alkyl-substituted substrate, moderate yield and high
enantioselectivity (96%) could be obtained (8l).
Based on the experimental results and putative mechanism of
NAD(P)H model-promoted biomimetic asymmetric reduction,8a
a
plausible mechanism for the chiral and regenerable NAD(P)H
model-enabled biomimetic asymmetric reduction of C=N and
C=C unsaturated bonds is illustrated (Scheme 7). Just like the
cofactor NAD(P)H-mediated reduction, this catalytic biomimetic
asymmetric reduction comprises two cascade redox cycles
promoted by two achiral catalysts. For the Lewis acid-catalyzed
reaction, coordination interaction of the activation mode plays a
major role in the biomimetic asymmetric reduction process.
Scheme 5.
Substrate Scope for Lewis Acid-Promoted the BMAR of
Benzoxazinones
Configuration stability of chiral NAD(P)H model FENAM (R)-6a
Scheme 7. Proposed Mechanism and Transition State
o
was obtained by heating it in THF (at 60 C), ClCH2CH2Cl (at 80
o
oC) and toluene (at 100 C) for 4 h, respectively, and the HPLC
In summary, through rational design of chiral regenerable
NAD(P)H model based on planar chiral ferrocene skeleton, we
have successfully developed a new generation biomimetic
asymmetric reduction with hydrogen gas as terminal reductant.
Using the readily available and bench-stable achiral Lewis acid
ytterbium or samarium triflate as the transfer catalysts, the
substrate scope could be significantly extended. A broad set of
electron deficient tetrasubstituted alkenes and imines could be
reduced with up to 98% yield and 98% ee. It is worth mentioning
that this is the first successful chiral and regenerable NAD(P)H
model enabling the general biomimetic asymmetric reduction.
From the view of organic synthesis, the above biomimetic
reactions provide a direct access a variety of chiral amines and
dihydrocoumarins which are prevalent in natural products,
synthetic intermediates and pharmaceuticals. We anticipate that
this concept will open a new horizon for the development of
asymmetric biomimetic chemistry of coenzyme NAD(P)H in
other fields.
analysis showed the ee values were retained.15 Thus, the planar
chiral NAD(P)H model would provide a potential application
under harsh conditions in organic synthesis. Furthermore, the
enantioselectivity of product was proportional to the
enantiomeric excess of chiral NAD(P)H model (R)-6a (Scheme
6). The observed linear dependence indicates that only a
monomeric chiral catalyst rather than an aggregate of two or
more catalysts is catalyzing the reaction.
Acknowledgements
Financial support from the National Natural Science Foundation
of China (21532006, 21690074) and Dalian Institute of Chemical
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Conflict of interest
The authors declare no conflict of interest
Keywords: Asymmetric Reduction • Chiral NAD(P)H Model •
Biomimetic Chemistry • Regeneration • Alkenes
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
Jie Wang, Zhou-Hao Zhu, Mu-Wang
Chen, Qing-An Chen, and Yong-Gui
Zhou*
Page No. – Page No.
Catalytic Biomimetic Asymmetric
Reduction of Alkenes and Imines
Enabled by Chiral and Regenerable
NAD(P)H Models
Through rational design of chiral and regenerable NAD(P)H models based on
planar chiral ferrocene skeleton, a biomimetic asymmetric reduction has been
realized using bench-stable Lewis acids as transfer catalysts, a broad set of
tetrasubstituted alkenes and imines could be reduced with up to 98% yield and 98%
ee. This represents the first general biomimetic asymmetric reduction process
enabled by the chiral and regenerable NAD(P)H models.
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