Chiral and Regenerable NAD(P)H Models Enabled Biomimetic Asymmetric Reduction: Design, Synthesis, Scope, and Mechanistic Studies

Article abstract of DOI:10.1021/acs.joc.9b03054

The coenzyme NAD(P)H plays an important role in electron as well as proton transmission in the cell. Thus, a variety of NAD(P)H models have been involved in biomimetic reduction, such as stoichiometric Hantzsch esters and achiral regenerable dihydrophenantheridine. However, the development of a general and new-generation biomimetic asymmetric reduction is still a long-term challenge. Herein, a series of chiral and regenerable NAD(P)H models with central, axial, and planar chiralities have been designed and applied in biomimetic asymmetric reduction using hydrogen gas as a terminal reductant. Combining chiral NAD(P)H models with achiral transfer catalysts such as Br?nsted acids and Lewis acids, the substrate scope could be also expanded to imines, heteroaromatics, and electron-deficient tetrasubstituted alkenes with up to 99% yield and 99% enantiomeric excess (ee). The mechanism of chiral regenerable NAD(P)H models was investigated as well. Isotope-labeling reactions indicated that chiral NAD(P)H models were regenerated by the ruthenium complex under hydrogen gas first, and then the hydride of NAD(P)H models was transferred to unsaturated bonds in the presence of transfer catalysts. In addition, density functional theory calculations were also carried out to give further insight into the transition states for the corresponding transfer catalysts.

Full text of DOI:10.1021/acs.joc.9b03054

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Article
Chiral and Regenerable NAD(P)H Models Enabled Biomimetic Asymmetric
Reduction: Design, Synthesis, Scope and Mechanistic Studies
Jie Wang, Zi-Biao Zhao, Yanan Zhao, Gen Luo, Zhou-Hao Zhu, Yi Luo, and Yong-Gui Zhou
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03054 • Publication Date (Web): 30 Dec 2019
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Chiral and Regenerable NAD(P)H Models Enabled Biomimetic
Asymmetric Reduction: Design, Synthesis, Scope and
Mechanistic Studies
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Jie Wang,†§ Zi-Biao Zhao,†§ Yanan Zhao,‡ Gen Luo,‡ Zhou-Hao Zhu,† Yi Luo,*‡ and
Yong-Gui Zhou*†‡
†State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese
Academy of Sciences, Dalian 116023, P. R. China
‡ Zhang Dayu School of Chemistry, Dalian University of Technology, Dalian 116024,
P. R. China
*E-mail: luoyi@dlut.edu.cn; ygzhou@dicp.ac.cn
ABSTRACT
Chiral
NAD(P)H Model
Imines, Alkenes,
Heteroaromatics
NH
Fe
[Ru]
H2
Achiral Transfer Catalyst
Chiral NAD(P)H
Model (FENAM)
Chiral
Chiral Products
NAD(P)+ Model
Transfer Catalysts: Simple Brønsted Acids or Lewis Acids
Substrate Scope: Imines, Heteroaromatics and Electron-Deficient Olefins
The coenzyme NAD(P)H plays an important role in electron as well as proton transmission in the cell.
Thus, a variety of NAD(P)H models have been involved in biomimetic reduction, such as stoichiometric
Hantzsch esters and achiral regenerable dihydrophenantheridine. However, the development of a general and
new generation biomimetic asymmetric reduction is still a long-term challenge. Herein, a series of chiral and
regenerable NAD(P)H models with central, axial and planar chirality have been designed and applied in the
biomimetic asymmetric reduction using hydrogen gas as a terminal reductant. Combining chiral NAD(P)H
models with achiral transfer catalysts such as Brønsted acids and Lewis acids, the substrate scope could be
also expanded to imines, heteroaromatics and electron-deficient tetrasubstituted alkenes with up to 99%
yield and 99% ee. The mechanism of chiral regenerable NAD(P)H models was investigated as well. Isotope-
labeling reactions indicated that chiral NAD(P)H models were regenerated by the ruthenium complex under
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hydrogen gas firstly, and then the hydride of NAD(P)H models was transferred to unsaturated bonds in the
presence of transfer catalysts. In addition, density functional theory calculations were also carried out to give
further insight into the transition states for the corresponding transfer catalysts.
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Introduction
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As a pair of the most significant coenzymes found in the biological cell, the reduced nicotinamide adenine
dinucleotide (NADH) and nicotinamide adenine dinucleotide phosphate (NADPH) play important roles in
metabolism processes and over 400 enzyme redox reactions. All these processes and reactions entirely
depend on the interconversion of NAD(P)H and NAD(P)+ (Scheme 1a).1 Therefore, the development of
NAD(P)H models has attracted much attention and gradually become one of the most important fields in
biomimetic asymmetric reduction (BMAR).
Scheme 1. Biomimetic Asymmetric Reduction (BMAR) Based on the Coenzyme NAD(P)H
a. NAD(P)H-mediated metabolism process in the cell
Substrates
NAD(P)H
CONH2
TCA Cycle
N
Enzyme I (regeneration) Enzyme II (transfer)
RO
Glycolysis
O
.....
NAD(P)H
NAD(P)+
Products
OH OH
stoichiometric
b. Biomimetic asymmetric reduction with
NAD(P)H models
NAD(P)H Model
(Stoichiometric)
O
H H O
Substrates
R
R
Transfer Catalyst
X
N
H
Achiral NAD(P)H
Model (HEH)
NAD(P)+ Model
Products
regenerable
c. Biomimetic asymmetric reduction with
NAD(P)H models
Achiral
NAD(P)H Model
Substrates
Transfer Catalyst (chiral)
Regeneration Catalyst
NH
Achiral NAD(P)H
Model (DHPD)
Achiral
NAD(P)+ Model
H2
Products
This Work: New Generation of Biomimetic Asymmetric Reduction
chiral and regenerable
d. Biomimetic reduction with
NAD(P)H models
Chiral
NAD(P)H Model
NH
Substrates
Fe
Transfer Catalyst (achiral)
Regeneration Catalyst
Chiral
Chiral NAD(P)H
Model (FENAM)
H2
NAD(P)+ Model
Products
A general biomimetic asymmetric reduction process using hydrogen
Transfer catalysts: Brønsted acid or Lewis acid
Substrate scope: imines, heteroaromatics and alkenes
In the past decades, plenty of novel NAD(P)H models have been designed and involved in biomimetic
asymmetric reduction. Earlier NAD(P)H models mainly focused on the chiral dihydronicotinamide
derivatives and realized asymmetric reduction of ketones in the presence of the stoichiometric Lewis acids.2
Meanwhile, earlier NAD(P)H models are designed primarily by the following three aspects: introduce a
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remote sterically demanding side chain to the structure, change the different substituents at 4-position of the
dihydropyridine ring and design a special conformation to obtain stereoselectivity.2a-b Subsequently,
Hantzsch esters (HEH)3 and benzothiazolines4 as the representatives of the NAD(P)H models have been
successfully employed in biomimetic asymmetric reduction of a variety of unsaturated compounds, using the
chiral organocatalysts5 and metal catalysts6 as transfer catalysts (Scheme 1b). However, these reactions
required the stoichiometric amount of NAD(P)H models and there were inevitable limitations in
regeneration,7 leading to low atomic economy and difficulty in product isolation. Recently, our group
reported biomimetic asymmetric hydrogenation of imines and heteroaromatics with chiral phosphoric acids
and catalytic amount of achiral dihydrophenanthridine (DHPD).8 Achiral DHPD could be easily regenerated
under hydrogen gas using homogeneous ruthenium.8 Later, Beller group found that DHPD could be
regenerated under iron catalysts and realized the biomimetic asymmetric reduction of imines (Scheme 1c).9
Although much significant progress has been achieved in the design of NAD(P)H models, the development
of a general and new generation biomimetic asymmetric reduction is still a major challenge in the area of
biomimetic asymmetric catalysis.
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For early works about biomimetic asymmetric reduction concentrated on achiral regenerable NAD(P)H
models, the element of stereocontrol is the chiral transfer catalyst, mainly chiral Brønsted acids.3-6 Although
it has gained great progress, tedious screening of chiral transfer catalysts has to be carried out for every
biomimetic reduction. Recently, our group reported a chiral and regenerable NAD(P)H model which
facilitated biomimetic asymmetric reduction using the Lewis acid as transfer catalyst.10 However, there are
still some issues to be noted in these reactions. First, the detailed mechanism of the chiral regenerable
NAD(P)H model facilitated biomimetic asymmetric reduction remains to be elucidated, in terms of the
fashion of hydride transfer. Second, the interaction between NAD(P)H model, transfer catalyst and substrate
was relatively unexplored. Third, the substrate scope based on chiral regenerable NAD(P)H model should be
further investigated.
In this article, we systematically examined various chiral regenerable NAD(P)H models with central, axial
and planar chirality. Brønsted acids and Lewis acids could be regarded as transfer catalyst to realize the
biomimetric asymmetric reduction, respectively. The substrate scope could be extremely expanded to imines,
heteroaromatics and alkenes with excellent activities and enantioselectivities. In addition, we also gain
insight into the detailed mechanism of chiral regenerable NAD(P)H model facilitated biomimetic
asymmetric reduction by a combination of experimental and theoretical studies.
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Results and Discussion
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The synthesis of a chiral and regenerable NAD(P)H model with central chirality. Our previous
studies have demonstrated that the 9,10-dihydrophenanthridine is easily regenerable and efficient in hydride
transfer process. Thus, we first focused on the study about the property of the centrally chiral NAD(P)H
model 1a containing the key structure phenanthridine, which could be easily synthesized from 6-
methyphenanthridine and natural occurring chiral ketone camphor in one step with 32% yield. Next, the
regeneration was conducted under hydrogen gas with homogeneous ruthenium catalyst; the reaction
proceeded smoothly, giving the reductive form with 46% yield. However, biomimetic asymmetric reduction
could not proceed with homogeneous ruthenium complex and simple phosphoric acid as regeneration and
transfer catalyst, respectively, mainly due to the bulky steric hindrance and intramolecular hydrogen bonding
between hydroxyl and nitrogen atom resulting in the difficulty in hydride transfer process (Scheme 2). So,
for the rationale design of chiral and regenerable NAD(P)H model, there can be no substituent at the active
site of NAD(P)H model.
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Scheme 2. The Chiral and Regenerable NAD(P)H model: The Initial Experiments
OH
n-BuLi, Et2O
N
0 oC, 32%
N
O
1a
O
O
O
N
O
1a
[Ru(p-cymene)I2]2,
CHCl3, H2 (500 psi), 50 o
(4-O2NC6H4O)P(O)OH
C
N
H
Ph
Ph
The synthesis of chiral and regenerable NAD(P)H models with axial chirality. Then, we turned our
attention to NAD(P)H models with axial chirality. At first, racemic axially chiral phenanthridines 1b and 1c
(Scheme 3) could be synthesized by Suzuki-coupling of the halogen substituted phenanthridine with aryl
boronic acid, followed by chemical resolution by D-tartaric acid derivatives (D-DMTA).11 In order to
confirm the validity of axially chiral NAD(P)H models, quinoxalinone 3a was chosen as model substrate12
for biomemetic asymmetric reduction with the commercially available achiral diphenyl hydrogen phosphate
2a as transfer catalyst (Table 1). Unfortunately, no desired product was observed using (R)-1b and (R)-1c
(Table 1, entries 1-2). The reason might be that the nitrogen atom was too close to the C2 axial stereocenter,
impeding the formation of hydrogen bonding interaction with the substrate. Subsequently, axially chiral
NAD(P)H model (R)-1d involving the nitrogen far away from the axial stereogenic center was synthesized
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with the 2-amino-6-bromobenzaldehyde as starting material (Scheme 4). As expected, the desirable product
4a was afforded with poor 16% ee at 12% conversion (Table1, entry 3). Changing the methyl group to
methoxyl (S)-1e, the enantioselectivity increased to moderate 50% ee and 22% conversion, but it was still
difficult to improve the reactivity and enantioselectivity further (Table1, entry 4).
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Scheme 3. The Chiral NAD(P)H Model: The N Atom Close to the C2 Axis
The synthesis route of NAD(P)H model (R)-1b
a)
Pd-Cat., KOtBu
Arylboronic acid
Cl
Br NH2
Pd(OAc)2, Cs2CO3
PPh3, Norbornene
I
+
N
20% (2 steps)
Cl
N
N
Ar
Ar
Cl Pd Cl
N
1) D-DMTA, acetone
N
N
2) NaOH (aq.), 12%
Cl
Ar = 2,6-iPr2C6H3
Pd-Cat.
1b
(+/-)-
1b
(R)-(+)-
The synthesis route of NAD(P)H model (R)-1c
b)
B(OH)2
Pd(PPh3)4, K2CO3
DME/H2O, 97%
N
+
N
Br
1c
(+/-)-
CO2H
ArCOO
H
H
1) D-DMTA, acetone
N
OCOAr
2) NaOH (aq.), 45%
CO2H
Ar = 4-MeOC6H4
D-DMTA
1c
(R)-(-)-
Although only moderate enantioselectivity and reactivity were obtained, these experimental results
demonstrated the feasibility in biomimetic asymmetric reduction with the regenerable and chiral NAD(P)H
models. Achiral and simple phosphoric acid derivatives could be also used as transfer catalyst. The next step
is to design and synthesize new and more efficient chiral and regenerable NAD(P)H models.
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Scheme 4. The Chiral NAD(P)H Model: The N Atom Far Away from the C2 Axis
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The synthesis route of (R)-1d
a)
Br
1) Pd(PPh3)4, K2CO3
ArB(OH)2, 44%
CHO
NH2
HCl, NaNO2, KI
75%
N
N
N
I
2) Fe, HCl, 80%
9
NH2
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Pd(PPh3)4, K2CO3
ArB(OH)2, 34%
1) D-DMTA, acetone
N
2) NaOH (aq.), 13%
1d
(+/-)-
1d
(R)-(+)-
The synthesis route of (S)-1e
b)
O2N
Br
CHO
Pd(PPh3)4, K2CO3
Fe, HCl (aq.)
39%
N
CHO
ArB(OH)2, 14%
Br
Br
Br
N
N
Pd(PPh3)4, K2CO3
ArB(OH)2, 99%
1) D-DMTA, acetone
OMe
MeO
2) NaOH (aq.), 22%
1e
(S)-(+)-
1e
(+/-)-
The synthesis of chiral and regenerable NAD(P)H models with planar chirality. Since the discovery
of ferrocene in the 1950s13a-b, chiral ferrocenyl compounds have been extensively applied in asymmetric
catalysis. Among various areas, chiral ferrocene ligands are most prominent. A wide variety of chiral
ferrocenyl ligands are known today such as Josiphos ligand, Walphos and phosphite-oxazoline ligands based
ferrocene structure13d-f. Besides, planar chiral heterocycles have been used in not only the transition metal
catalysis but also the nucleophilic catalysis13c,f. Inspired by the extensive application of the planar chirality in
asymmetric synthesis, we wondered if the planar chiral framework would achieve a better stereoselective
control, taking advantage of steric resistance between its two sides. Therefore, NAD(P)H models with planar
chirality based on the ferrocene framework were designed. Combined with previous experience, new
NAD(P)H models should be no substituents on the active site. In addition, the nitrogen atom should be far
away from the planar stereogenic center. According to the known literature10,14, starting with the readily
available ferrocenealdehyde, a series of chiral regenerable ferrocene-based NAD(P)H models (abbreviated as
FENAM) (R)-1f-i with various electronic properties could be synthesized in moderate total yields.(Scheme
5).
Scheme 5. NAD(P)H Models with Planar Chirality
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N
CHO
1f
(R)- : R = H
ref. 10,14
1g
R
(R)- : R = Me
1h
(R)- : R = OMe
1i
(R)- : R = F
Fe
Fe
(R)-FENAM
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7
8
9
Brønsted acid promoted BMAR. Gratifyingly, employing (R)-1f as the chiral and regenerable NAD(P)H
model, the enantioselectivity could be dramatically improved to 97% ee. In this reaction, the homogeneous
ruthenium complex could be as regeneration catalyst and simple phosphoric acid could be as transfer catalyst
(Table 1. entry 5). Then, various solvents such as ethyl acetate, toluene, chloroform and methanol were
examined, the solvent chloroform proved to be the best (entries 5-10). After this, an array of Brønsted acids
were extensively tested (entries 11-14). Besides, the planar chiral NAD(P)H models with different electronic
property have a marginal beneficial effect (entries 15-18). The full conversion would be achieved while
prolonging time. Thus, the optimal protocol was identified: imine 3a (1.0 equiv.), [Ru(p-cymene)I2]2 (0.5
mol%), chiral NAD(P)H model (R)-1g (10 mol%), achiral transfer catalyst Brønsted acid 2a (4 mol%), H2
(500 psi), CHCl3 and 40 oC.
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Table 1. Optimization of Brønsted Acid Promoted BMAR of Quinoxalinones a
[Ru(p-cymene)I2]2
Chiral NAD(P)H Model
N
O
N
O
1
H2
(500 psi)
+
*
Acid , Solvent, 40 oC
N
H
Ph
2
N
Ph
3a
4a
O2N
NO2
 H2O
O
O
O
O
O
O
O
O
O
P
P
OH
P
OH
OH
S
OH
O
O
COOH
O2N
2a
2b
2c
2d
2e
Entry
Solvent
Acid 2
1
Conv. %b
Ee %c
1
2
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
THF
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2a
2a
2a
2a
(R)-1b
(R)-1c
(R)-1d
(S)-1e
(R)-1f
(R)-1f
(R)-1f
(R)-1f
(R)-1f
(R)-1f
(R)-1f
(R)-1f
(R)-1f
(R)-1f
(R)-1f
(R)-1g
(R)-1h
(R)-1i
<5
<5
-
-
3
12
16
50
97
95
-
4
22
5
78
6
70
7
<5
8
EtOAc
Toluene
MeOH
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
<5
-
9
35
90
20
98
97
-
10
11
12
13
14
15d
16d
17d
18d
86
62
53
<5
69
98
97
98
98
96
>95
>95 (96)e
>95
92
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aReaction conditions: 3a (0.1 mmol), [Ru(p-cymene)I2]2 (0.5 mol%), 1 (10 mol%),
Acid 2 (4 mol%), Solvent (2 mL), H2 (500 psi), 40 oC, 22 h. bConversion was
c
measured by analysis of 1H NMR spectra. The ee values were determined by chiral
HPLC. dReaction time was prolonged to 48 h. eIsolated yield.
6
7
8
9
With the optimized conditions in hand, the substrate scope of the biomimetic asymmetric reduction was
investigated using a catalytic amount of the chiral and regenerable NAD(P)H model. Gratifyingly, this
strategy was suitable for a series of quinoxalinones with high activities and excellent enantioselectivities (92-
98% yield, 96-99% ee). As depicted in Scheme 6, the electronic nature and steric effect on the phenyl of the
substrate rarely influenced the reactivity and enantioselectivity, giving the desired reductive products in high
enantioselectivities and yields (4a-4f, 97-99% ee). Furthermore, benzyl or allyl protected substrates
performed well with excellent results (4g, 4h). In the previous reports, the 3-alkyl substituted quinoxalinones
were much more challengeable and low enantioselectivities were obtained (4i, 8% ee in ref. 12b). It should
be pointed out that the substituents at 3-position of quinoxalinones were not confined to the aryl groups, and
3-alkyl groups could also be tolerated to afford the desirable products with excellent activities and
enantioselectivities (4i-4l, 96-99% ee).
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Scheme 6. Brønsted Acid Promoted BMAR of Quinoxalinones
R2
N
R2
N
O
O
NAD(P)H Model (R)- , 40 oC
1g
H2
(500 psi)
+
R1
R1
2a
[Ru(p-cymene)I2]2, , CHCl3
N
H
4
N
3
N
O
N
O
N
O
N
O
(R)
N
H
N
H
N
H
N
H
OMe
Br
4a
4d
4c
4b
96% yield, 98% ee
97% yield, 97% ee
95% yield, 98% ee
95% yield, 98% ee
Bn
Allyl
N
O
N
O
N
O
N
O
OMe
N
H
N
H
N
H
N
H
4e
4f
4g
4h
F
96% yield, 99% ee 95% yield, 98% ee 93% yield, 99% ee
93% yield, 99% ee
N
O
N
O
N
O
N
O
N
H
N
H
N
H
N
H
Me
4i
4j
4k
4l
94% yield, 96% ee 98% yield, 97% ee 92% yield, 99% ee
98% yield, 96% ee
Scheme 7. Brønsted Acid Promoted the BMAR of Benzoxazinones
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O
O
O
O
NAD(P)H Model (R)- , 40 oC
1f
H2
+
(500 psi)
R1
N
R2
R1
N
H
6
R2
2b
[Ru(p-cymene)I2]2, , CHCl3
5
6
O
O
O
O
O
O
O
O
7
8
9
N
H
N
H
N
H
N
H
OMe
F
6a
94% yield, 98% ee
6b
94% yield, 98% ee
6c
97% yield, 97% ee
6d
94% yield, 97% ee
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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50
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O
O
O
O
O
O
O
O
OCH3
F
N
H
N
H
N
H
N
H
Cl
Br
6e
97% yield, 93% ee
6f
6g
96% yield, 98% ee
6h
97% yield, 99% ee
96% yield, 92% ee
O
O
O
O
O
O
O
O
S
N
H
N
H
Cl
N
H
N
H
6i
92% yield, 97% ee
6j
84% yield, 94% ee
6k
97% yield, 99% ee
6l
97% yield, 99% ee
O
O
O
O
O
O
O
O
N
H
N
H
N
H
N
H
Ph
Me
6m
83% yield, 97% ee
6n
92% yield, 98% ee
6o
92% yield, 99% ee
6p
97% yield, 99% ee
To expand the generality of this strategy, we next focused on the synthesis of the optically pure
dihydrobenzoxazinones which represent the crucial structural motif of bioactive molecules and clinical
pharmaceuticals.15 High activities and excellent enantio-selectivities were obtained with most substrates
(Scheme 7, 6a-6p). The steric hindrance of the substituents on the phenyl appeared to have marginal effect
on the results. Besides, this protocol was also suitable for the substrates bearing halogen atoms (6d-6f, 92-97%
ee), which provides an opportunity for the late-stage transformations. In addition, introducing a heteroaryl
group onto 3-position, the reaction also proceeded smoothly with excellent enantioselectivity (6j, 94% ee).
Gratifyingly, switching aryl to alkyl groups, the substrates also participated well regardless of the length of
the alkyl chain (6m-6p, 97-99% ee).
Scheme 8. Brønsted Acid Promoted the BMAR of other Imines and Heteroaromatics
O
O
1f 2b,
(R)-
,
[Ru(p-cymene)I2]2
H2 (500 psi), CHCl3, 40 oC, 48 h
N
H
Ph
N
Ph
7
8
85% yield, 91% ee
NPMP
CF3
NHPMP
1f 2b,
, [Ru(p-cymene)I2]2
(R)-
CF3
H2 (500 psi), CHCl3, 40 oC, 48 h
Ar
Ar
10
9
Ar
yield (%) ee (%)
10a
Ph (
4-CH3C6H4
)
(
98
97
93
97
93
99
10b
10c
)
)
4-FC6H4
[Ru(p-cymene)I2]2
(
1f 2b,
(R)-
,
N
Ar
N
Ar
H2 (500 psi), CHCl3/THF (3:1)
40 oC, 48 h
H
11
12
Ar
12a
yield (%) ee (%)
Ph (
)
96
99
94
83
83
90
12b
12c
4-ClC6H4
3-BrC6H4
(
(
)
)
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To further showcase the utility of this strategy, we expanded the biomimetic asymmetric reduction to the
benzoxazine,16 linear alkynyl ketimines17 and heteroaromtic quinolines18 (Scheme 8). The reactions
transformed smoothly, affording the corresponding chiral dihydrobenzoxazine 8, alkynyl amines 10 and
tetrahydroquinolines 12 in good to excellent enantioselectivities.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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Lewis acid promoted BMAR. Lewis acids could efficiently promote various organic reactions by
coordination activation.19 Combined with chiral ligands, chiral Lewis acid catalysts could realize a myriad of
asymmetric reactions. However, owing to electron-donating properties of chiral ligands, the decrease of the
Lewis acidity ineluctably results in low coordination activation with the substrates, which limited its further
application. Encouraged by the excellent results achieved by chiral and regenerable NAD(P)H model with
achiral bench stable Brønsted acid as transfer catalyst, we postulated that the chiral regenerable NAD(P)H
models would provide a new opportunity to simple Lewis acid, which may be regarded as the transfer
catalyst as well to realize the biomimetic asymmetric reduction without the combination with chiral ligands
to provide the chiral environment.
Table 2. Optimization of Lewis Acid-Promoted BMAR of Tetrasubstituted Alkenesa
[Ru(p-cymene)I2]2, CHCl3
O
O
O
O
O
*
O
1
Chiral NAD(P)H Model
+
LA, H2 (800 psi), 50 o
C
CO2Et
CO2Et
Ph
Ph
Ph
13a
14a
14aa
14a:
14aa
14a
Entry
LA
1
Conv.(%)b
Ee (%)c
1
2
3
4
5
6
7
8
9
Sm(OTf)3
Sm(OTf)3
Sm(OTf)3
Sm(OTf)3
Sm(OTf)3
Cu(OTf)2
Sc(OTf)3
Yb(OTf)3
-
(R)-1c
(S)-1e
(R)-1f
(R)-1g
(R)-1h
(R)-1f
(R)-1f
(R)-1f
(R)-1f
4
>20:1
>20:1
10:1
6.3:1
11:1
-
42
40
38
87
84
76
-
11
7
8
<5
<5
-
-
>95 (97d)
>20:1
90
<5
-
-
aReaction conditions 13a (0.10 mmol), [Ru(p-cymene)I2]2 (0.5 mol%), 1 (10 mol%),
Lewis acid (20 mol%), CHCl3 (2 mL), H2 (800 psi), 50 oC. bConversion was
measured by analysis of 1H NMR spectra of unpurified mixtures and 14a d.r. >20:1.
d
cThe ee values were determined by HPLC analysis. Isolated yield for the reaction
with 0.15 mmol scale for 80 h.
As challenging substrates in the asymmetric catalysis, tetrasubstituted alkenes have attracted widespread
attention for scientific researchers, especially in the biomimetic asymmetric reduction.20 To our delight,
simple commercially available Lewis acid could enable biomimetic asymmetric reduction of the
tetrasubstituted alkenes 13. Different Lewis acids have different acidity, so the product ratio of 14a:14aa is
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different. After extensive screening of various Lewis acids, we found that readily available rare-earth
ytterbium triflate [Yb(OTf)3] afforded the optimal results in view of both activity and enantioselectivity
(Table 2). It was observed that the thermodynamically controlled product, 3,4-trans-disubstituted
dihydrocoumarins, could be achieved for aryl groups in excellent diastereoselectivities (d.r. >20:1) and
enantioselectivities. The ratio of main product 14a to deacidified product 14aa was >20:1 with Yb(OTf)3 as
transfer catalyst. As for the alkyl-substituted substrate, the desired products with moderate diastereo- and
enantioselectivity could also be obtained.10 In addition, this strategy was also suitable for the biomimetic
asymmetric reduction of 3-aryl and 3-alkyl substituted benzoxazinones using Lewis acid Sm(OTf)3 instead
of Yb(OTf)3 as the transfer catalyst, giving the desired product up to 98% ee and up to 98% yield.10
10
11
12
13
14
15
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Scheme 9. Lewis Acid Promoted BMAR of Tetrasubstituted Alkenes and Benzoxazinones.
5
6
7
8
R3
O
O
R3
O
O
1f
(R)- , [Ru(p-cymene)I2]2
H2
(800 psi)
+
CO2R2
3, CHCl3, 50 o
C
Yb(OTf)
CO2R2
R1
13
R1
14
9
12 examples, 48-97% yield
69-92% ee, d.r = 9.2:1-20:1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
O
N
O
1f
(R)- , [Ru(p-cymene)I2]2
H2
(500 psi)
+
3, CHCl3, 50 o
C
R1
N
H
R2
R1
R2
Sm(OTf)
5
6
12 examples, 57-98% yield
92-98% ee
MECHANISTIC STUDY
The nonlinear effect. To further understand the mechanism of the detailed reaction process, we examined
the relationship between the ee value of chiral NAD(P)H model and the reduced product 6a. It was indicated
that the enantiomeric excess of the reductive product 6a was completely proportional to the enantiomeric
excess of chiral NAD(P)H model (R)-1f. The linear effect supported that the chiral NAD(P)H model for
asymmetric induction was consistent with 1:1 ratio of the substrate in transition state.
Isotope-labeling experiments. In order to investigate the reaction pathway, several interrelated isotopic-
labeling experiments were also conducted, as summarized in Scheme 10. Substrate 5a could be reduced
under D2 atmosphere, affording the reductive deuterium product 6a-D. It was indicated that D2 was the
terminal reductant in the biomimetic reduction reaction (Scheme 10a). Meanwhile, the chiral and
regenerable NAD(P)H model (R)-1f could be mildly regenerated with 56% conversion in the presence of D2,
and deuterium atom was added to the less steric face (Scheme 10b). No deuterium atom incorporation was
observed in the recovered NAD(P)H model (R)-1f. Treatment of substrate 5a with the reductive NAD(P)H
model (R)-1f-D lead to the reductive product 6a-D with 95% deuterium incorporation and 99% ee (Scheme
10c). The result showed that the deuterium incorporated chiral reductive NAD(P)H model (R)-1f-D could
enantioselectively transfer deuterium to the imine 5a in the presence of Brønsted acid, and deuterium atom
on the less steric face was selectively transferred, leading to the excellent enantioselectivity.
Isotopic labeling experiments and the nonlinear effect have revealed the hydride transfer process in
biomimetic asymmetric reduction. However, the detailed interaction among the chiral NAD(P)H models,
substrates and transfer catalyst was not fully understood. Thus, the detailed mechanism was further studied
by density functional theory calculations.
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Scheme 10. Isotopic Labeling Experiments
O
O
[Ru(p-cymene)I2]2, 50 o
C
O
N
O
+
a)
D2 (400 psi)
Ph
D (>95%)
2b,
1f
Acid
(R)- , CHCl3,
N
H
6a-D
Ph
7
5a
Conv. >95%, 99% ee
8
9
H (D <5%)
N
D (>95%)
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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52
53
54
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56
57
58
59
60
[Ru(p-cymene)I2]2
NH
CHCl3, D2
b)
Fe
Fe
1f
(R)-
1f-D
(R)-
Conv. = 56%
D (>95%)
H
NH
O
O
O
O
Acid , 50 oC
2b
c)
+
Ph
D (>95%)
Fe
N
H
N
Ph
CHCl3
6a-D
35% yield, 99% ee
5a
1f-D
(R)-
Density functional theory calculations. On the basis of density functional theory calculations (see SI for
more details) and aforementioned experimental data, a plausible mechanism21 and optimized stationary
points together with their relative energies are illustrated in Scheme 11. The optimized stationary points and
relative energies mainly involved in the chiral and regenerable NAD(P)H-model facilitated biomimetic
asymmetric reduction of C=N and C=C bonds. At first, chiral NAD(P)H model (R)-1f could be reduced to (R)-
1f-H in situ by ruthenium complex and hydrogen gas. Then, the reduced chiral NAD(P)H model (R)-1f-H
could realize biomimetic asymmetric reduction of C=C, C=N and heteroaromatics with achiral transfer
catalysts (Brønsted acid and Lewis acid). In the case of C=N bond reduction by Brønsted acid
(ArO)2P(O)OH (Scheme 11a), the transfer catalyst assists asymmetric reduction via forming O∙∙∙H and N∙∙∙H
dual hydrogen bond interactions with chiral NAD(P)H model and 5a, respectively. This process has an
energy barrier of 15.9 kcal/mol and is exergonic by 2.5 kcal/mol. In comparison, if the transfer catalyst is
replaced by Lewis acid Yb(OTf)3, the coordination of 5a via its N atom to Yb center of Yb(OTf)3 forms
complex C-LA-C=N with a relative energy of 7.3 kcal/mol, which surmounts an energy barrier of 10.6
kcal/mol (TS-LA-C=N) to give P-LA-C=N with a relative energy of 11.4 kcal/mol. Similarly, there are
also some O∙∙∙H interaction between counteranion (OTf) of Yb(OTf)3 and chiral NAD(P)H model and 5a in
the reduction process. In contrast, in the case of Yb(OTf)3-assisted C=C bond reduction (Scheme 10b), the
corresponding energy barrier (TS-LA-C=C, 8.9 kcal/mol) is obviously lower than that of C=N bonds (15.9
and 10.6 kcal/mol), mainly due to coordination interaction between Yb(OTf)3 and double carbonyl groups of
substrate. Double functions of NAD(P)H model and transfer catalyst play an important role for formation of
cyclic transition state and enantioselective control.
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Scheme 11. The Probable Reaction Mechanism, Optimized Stationary Points and the Corresponding Free
Energy in Solution Relative to Separated Reactants.
5
6
N
7
Fe
8
9
Chiral Products
-1f
NH
(R)
Ru(II)
H2
Transfer Catalyst
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Imines
Heteroaromatics
Alkenes
Fe
-1f-H
(R)
a)
Brønsted Acids as Transfer Catalyst
Fe
Fe
Fe
O
N
N
N
Hb
Hb
Hb
O
O
O
O
H
O
P
H
O
Ha
H
O
P
P
O
Ha
O
O
O
O
O
N
H
O
O
O
N
O
Ha
Ph
N
Ph
Ph
H
H
TS-BA-C=N
15.9
P-1-C=N
-2.5
C-BA-C=N
8.0
G‡ = 15.9
Lewis Acids as Transfer Catalyst
X = OTf
O
Fe
Fe
O
3
Fe
O
CF3
N
CF
S
S
O
CF3
N
S
Hb
O
N
H
O
Hb
Hb
H
H
H
Ha
O
YbX
O
YbX
Ha
O
O
O
O
Ha
O
N
O
O
YbX
N
O
S
O
O
S
N
Ph
Ph
O
O
O
Ph
H
H
S
CF3
CF3
CF3
O
O
O
C-LA-C=N
TS-LA-C=N
P-LA-C=N
-7.3
3.3
-11.4
G‡ = 10.6
Lewis Acids as Transfer Catalyst
b)
Fe
Fe
Fe
O
O
S
N
O
S
N
N
Hb
Ha
Hb
Ha
CF3
CF3
CF3
S
Hb
O
H
H
O
H
O
O
O
O
O
O
YbX2
O
O
O
O
YbX2
YbX2
O
O
O
OEt
Ar
Ha
OEt
OEt
Ar
Ar
C-LA-C=C
TS-LA-C=C
-20.0
G‡ = 8.9
P-LA-C=C
-31.1
-46.8
CONCLUSION
In conclusion, we designed and synthesized a series of chiral and regenerable NAD(P)H with central,
axial and planar chirality, and applied them in biomimetic asymmetric reduction. In this process, the
hydrogen gas was as terminal reductant. Readily available and bench-stable achiral Brønsted acid or Lewis
acid ytterbium/samarium triflate could be used as the transfer catalysts. This biomimetic asymmetric
reduction features broad substrate scope, including various imines, electron-deficient alkenes and
heteroaromatic compounds with up to 99% yield and 99% ee. In addition, the detailed mechanism of chiral
and regenerable NAD(P)H models enabled biomimetic asymmetric reduction has been investigated by
combination of experimental and theoretical studies. The isotope-labeling reactions indicated that the
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process suffered from the NAD(P)H models regeneration under hydrogen gas, and then the hydride
transferred to the unsaturated bond, similar to coenzyme NAD(P)H mediated redox reaction process.
Furthermore, density functional theory (DFT) calculations revealed the detailed transition state for the
corresponding transfer catalyst and showed that the excellent enantioselectivity in the reaction resulted from
the diastereotopic transfer of hydrogen atom. The above mechanistic study may provide some useful hints
for design of biomimetic catalytic system and extend the scope of chiral and regenerable NAD(P)H models
enabled biomimetic asymmetric reduction.
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11
12
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EXPERIMENTAL SECTION
General: Unless otherwise noted, all reactions were carried out under an atmosphere of nitrogen using the
standard Schlenk techniques. Commercially available reagents were used without further purification.
1
Solvents were treated prior to use according to the standard methods. H NMR, 13C NMR spectra were
recorded at 400 MHz and 100 MHz with the Brucker spectrometer. 19F NMR spectra were recorded at 376
MHz with Brucker spectrometer. Chemical shifts are reported in ppm using tetramethylsilane as internal
1
standard when using CDCl3 as solvent for H NMR spectra. The following abbreviations were used to
symbolize the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. Flash
column chromatography was performed on silica gel (200-300 mesh). All reactions were monitored by TLC
analysis. Optical rotations were measured by the polarimeter. Enantiomeric excess was determined by HPLC
analysis using chiral column described below in detail. The heat source for all heating reactions is the oil
bath. High-resolution mass spectrometry (HRMS) was measured on an electrospray ionization (ESI)
apparatus using time-of-flight (TOF) mass spectrometry.
Procedures for Synthesis of NAD(P)H Models with Central Chirality: Under the nitrogen, 6-
methylphenanthridine (0.386 g, 2.0 mmol) was dissolved in ether (10 mL), followed by dropwise addition of
o
n-butyllithium (1.6 M solution in hexanes) (1.40 mL, 2.2 mmol) at 0 C. The mixture was stirred for 5
o
minutes at 0 C. Then the reaction was stirred for one hour at ambient temperature. To a solution of D-
o
camphor (0.304 g, 2.0 mmol) in ether (5 mL) under nitrogen was added at 0 C. Next, the reaction was
stirred at ambient temperature. When TLC indicated that the reaction was finished, the mixture was cooled
o
to 0 C. The reaction was quenched with water (15 mL), extracted with ether (10 mL×3). The combined
organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was removed under the
reduced pressure, and the residue was purified by flash column chromatography to give the corresponding
product 1a.
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1,7,7-trimethyl-2-(phenanthridin-6-ylmethyl)bicyclo[2.2.1]heptan-2-ol (1a): 0.220 g, 32% yield, white
solid, mp 123-124 oC, new compound, Rf = 0.75 (hexanes/ethyl acetate 10/1), 1H NMR (400 MHz, CDCl3) δ
8.63 (d, J = 7.8 Hz, 1H), 8.52 (d, J = 7.7 Hz, 1H), 8.26 (d, J = 8.0 Hz, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.89-
7.79 (m, 1H), 7.76-7.66 (m, 2H), 7.65-7.58 (m, 1H), 7.32 (s, 1H), 3.55 (s, 2H), 2.29 (d, J = 12.9 Hz, 1H),
1.85-1.70 (m, 2H), 1.69-1.57 (m, 1H), 1.55-1.43 (m, 2H), 1.27 (s, 3H), 1.19-1.08 (m, 1H), 0.89 (s, 3H), 0.85
(s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 161.0, 142.0, 132.9, 130.8, 129.4, 128.8, 127.6, 126.8, 126.0,
125.9, 123.4, 122.7, 122.0, 81.0, 52.9, 49.4, 47.9, 45.4, 40.0, 30.9, 27.3, 21.8, 21.2, 11.5. HRMS (ESI-TOF)
m/z Calculated for C24H28NO [M+H]+ 346.2165, found: 346.2165.
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48
49
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60
Procedures for Synthesis of NAD(P)H Model 1b with Axial Chirality: Under nitrogen, a mixture of 2-
chloro-1-iodo-3-methylbenzene (7.94 g, 32 mmol), 2-bromobenzylamine (6.44 g, 35 mmol), cesium
carbonate (21.52 g, 66 mmol), triphenylphosphine (0.82 g, 3.1 mmol), palladium diacetate (1.10 g, 4.5 mmol)
and norbornene (1.48 g, 16 mmol) in N,N-dimethylformamide (DMF, 120 mL) was stirred for 24 h at 160
oC . When TLC indicated that the reaction was finished, the mixture was cooled to ambient temperature and
extracted with ethyl acetate (30 mL×3). Then the combined organic layer was dried over anhydrous sodium
sulfate and concentrated in vacuo. The crude product was afforded by flash column chromatography.
Under nitrogen, a mixture of potassium tert-butoxide (59 mg, 0.53 mmol) and Pd-Cat (5 mg, 0.007 mmol)
in 1,4-dioxane (2 mL) was stirred for 10 mins. After naphthalen-1-yl-boronic acid (90 mg, 0.53 mmol) was
added and stirred for 20 mins, the above crude compound (80 mg, 0.38 mmol) was added and stirred at 100
oC for 16 h. The mixture was cooled to ambient temperature and extracted with ethyl acetate (20 mL×3).
Then, the combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The
solid obtained was purified by flash column chromatography to achieve product (+/-)-1b (white solid 52 mg,
o
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20% yield for 2 steps). m.p. = 136-137 C, Rf = 0.40 (hexanes/ethyl acetate 10/1). H NMR (400 MHz,
CDCl3) δ 9.08 (s, 1H), 8.61 (dd, J = 19.1, 8.4 Hz, 2H), 7.98-7.88 (m, 3H), 7.86-7.79 (m, 1H), 7.70-7.60 (m,
3H), 7.45-7.39 (m, 2H), 7.28-7.17 (m, 2H), 2.15 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 153.3, 143.9,
139.2, 138.2, 137.9, 133.8, 132.7, 132.7, 130.8, 129.3, 128.7, 128.4, 127.6, 127.4, 127.2, 126.1, 125.9, 125.8,
125.7, 125.6, 122.1, 121.8, 121.6, 20.8. HRMS (ESI-TOF) m/z Calculated for C24H18N [M+H]+ 320.1434,
found: 320.1438.
o
The compound (+/-)-1b (634 mg, 2 mmol) was dissolved in acetone (8 mL) with heating to 40 C. The
(+)-di-p-methoxylbenzoyl-D-tartaric acid (D-DMTA, 573 mg, 1.2 mmol) in acetone (6 mL) was added and
the mixture was stirred for 20 minutes. Then 50 mL of hexanes was added slowly. After stirring for 5
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minutes, the mixture was cooled to ambient temperature. The crystals were filtered, washed with cold
hexanes for three times and dried to afford the solid diastereo- isomeric salt. Workup of the
diastereoisomeric salt was as follows: The crystal was added to sodium hydroxide aqueous solution and
stirred for 30 min. The mixture was extracted with dichloromethane. Then combined organic phase was
dried over anhydrous sodium sulfate and the solvent was removed in vacuo to afford the product. Repeating
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this operation three times gave the chiral compound (R)-(+)-1b. (78 mg, 12% yield, new compound, []20
=
D
+76.36 (c 0.66, CHCl3), 94% ee HPLC (OD-H, elute: n-hexane/i-PrOH =97/3, detector: 220 nm, 30 oC, flow
rate: 0.7 mL/min), t1 = 15.0 min (major), t2 = 18.0 min.
Procedures for Synthesis of NAD(P)H Model 1c with Axial Chirality: Under the nitrogen, a mixture of
4-bromophenanthridine (0.994 g, 3.9 mmol), (2-methylnaphthalen-1-yl)boronic acid (1.040 g, 5.6 mmol),
potassium carbonate (0.953 g, 6.8 mmol), tetrakis(triphenylphosphine)palladium (0.199 g, 0.17 mmol) in
o
dimethoxyethane/water (50 mL/25 mL) was stirred at 95 C for 24 h. The mixture was cooled to ambient
temperature and extracted with ethyl acetate (30 mL×3). Then the combined organic layer was dried over
anhydrous sodium sulfate and concentrated in vacuo. The crude product obtained was purified by flash
column chromatography using hexanes and ethyl acetate as eluent to achieve racemic product (+/-)-1c (white
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solid, 1.20 g, 97% yield). m.p. = 156-157 C, Rf = 0.40 (hexanes/ethyl acetate 10/1). H NMR (400 MHz,
CDCl3) δ 9.15 (s, 1H), 8.73 (d, J = 8.3 Hz, 2H), 7.99 (d, J = 7.9 Hz, 1H), 7.97-7.85 (m, 3H), 7.81 (t, J = 7.7
Hz, 1H), 7.71 (t, J = 7.5 Hz, 1H), 7.62 (d, J = 7.1 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.36 (dd, J = 10.6, 3.9
Hz, 1H), 7.23-7.14 (m, 2H), 2.14 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 153.5, 143.4, 140.0, 136.7,
134.0, 133.4, 132.8, 132.1, 131.1, 130.9, 128.8, 128.7, 127.9, 127.6, 126.8, 126.3, 125.7, 124.6, 124.5, 122.1,
122.0, 20.9. HRMS (ESI-TOF) m/z Calculated for C24H18N [M+H]+ 320.1434, found: 320.1436.
o
The compound (+/-)-1c (2.17 g, 6.8 mmol) was dissolved in acetone (6 mL) with heating to 40 C. The
(+)-di-p-methoxylbenzoyl-D-tartaric acid (D-DMTA, 1.80 g, 3.7 mmol) in acetone (3 mL) was added and
the mixture was stirred for 20 minutes. Then 20 mL of hexanes was added slowly. After stirring for 5
minutes, the mixture was cooled to ambient temperature. The crystals were filtered, washed with cold
hexanes for three times and dried to afford the solid diastereoisomeric salt. Workup of the diastereoisomeric
salt was as follows: The crystal was added to sodium hydroxide aqueous solution and stirred for 30 min. The
mixture was extracted with dichlorome- thane. Then combined organic phase was dried and the solvent was
removed in vacuo to afford the product. Repeating this operation three times gave the chiral compound (R)-
(-)-1c. (981 mg, 45% yield, []20D = -27.24 (c 0.58, CHCl3), 99% ee HPLC (OD-H, elute: n-hexane/i-PrOH
=99/1, detector: 254 nm, 30 oC, flow rate: 0.4 mL/min), t1 = 21.7 min (major), t2 = 25.9 min.
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Procedures for Synthesis of NAD(P)H Model 1d with Axial Chirality: Under the nitrogen, a mixture of
2-amino-6-bromobenzaldehyde (4.10 g, 20 mmol), (2-nitrophenyl)boronic acid (3.76 g, 23 mmol),
potassium carbonate (5.76 g, 41 mmol) and tetrakis(triphenylphosphine)palladium (2.13 g, 1.84 mmol) in
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DME/water (35 mL/20 mL) was stirred at 95 C for 48 h. The mixture was cooled to ambient temperature
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and extracted with ethyl acetate (30 mL×3). Then the combined organic layer was dried over anhydrous
sodium sulfate and concentrated in vacuo. The crude product was afforded by flash column chromatography
1
(grey oil, 2.17 g, 44% yield). Rf = 0.60 (hexanes/ethyl acetate 2/1). H NMR (400 MHz, CDCl3) δ 9.65 (s,
1H), 8.01 (dd, J = 8.1, 1.2 Hz, 1H), 7.66-7.61 (m, 1H), 7.58-7.53 (m, 1H), 7.39 (dd, J = 7.5, 1.5 Hz, 1H),
7.29-7.24 (m, 1H), 6.69 (d, J = 8.4 Hz, 1H), 6.55-6.35 (m, 1H; brs, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ
192.6, 150.8, 149.2, 143.3, 134.6, 134.0, 132.7, 132.3, 129.0, 124.2, 117.2, 117.0, 116.1.
A mixture of the above crude product (1.91 g, 7.9 mmol), iron powder (1.76 g, 31.6 mmol) in ethanol (10
mL) was stirred at 75 oC and conc. HCl (5.30 mL) was added slowly. When TLC indicated that the reaction
was finished, the mixture was cooled to ambient temperature and saturated sodium hydrogen carbonate
solution was added. The mixture was extracted with dichloromethane (30 mL×3). Then the combined
organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was
afforded by flash column chroma- tography (orange solid, 1.22 g, 80% yield).
To a solution of above product (615 mg, 3.15 mmol) in water (10 mL) was added conc. HCl (4.2 mL) and
stirred for 5 min. A solution of sodium nitrite (283 mg，4.10 mmol) in H2O (8 mL) was added slowly. After
stirred for 3 h at ambient temperature, a solution of potassium iodide (837 mg，5.04 mmol) in water (10 mL)
was added to the reaction. After stirred for 3 hours at 60 oC, the mixture was cooled to ambient temperature
and saturated sodium hydrogen carbonate solution was added. The mixture was extracted with
dichloromethane (30 mL×3). Then the combined organic layer was dried over anhydrous sodium sulfate and
concentrated in vacuo. The crude product was afforded by flash column chromatography (purple solid, 0.717
g, 75% yield); 1H NMR (400 MHz, CDCl3) δ 9.48 (s, 1H), 8.59-8.48 (m, 2H), 8.23-8.16 (m, 2H), 7.79-7.74
(m, 1H), 7.71-7.66 (m, 1H), 7.51-7.45 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 157.1, 144.6, 139.0, 134.3,
131.7, 130.3, 129.4, 127.6, 126.1, 122.8, 122.5, 122.0, 99.6.
Under the nitrogen, a mixture of the above crude product (516 mg, 1.7 mmol), potassium carbonate (467
mg,
3.4
mmol),
(2-methylnaphthalen-1-yl)-boronic
acid
(629
mg,
3.4
mmol)
and
tetrakis(triphenylphosphine)palladium (195 mg, 0.17 mmol) in DME/water (30 mL/15 mL) was stirred at 95
oC for 24 h. The mixture was cooled to ambient temperature and extracted with ethyl acetate (30 mL×3).
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Then the combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The
product (+/-)-1d was afforded by flash column chromatography (white solid, 186 mg, 34% yield). m.p. =
165-166 oC, Rf = 0.40 (hexanes/ethyl acetate 10/1). 1H NMR (400 MHz, CDCl3) δ 8.79-8.67 (m, 3H), 8.19-
8.10 (m, 1H), 8.04-7.95 (m, 1H), 7.94-7.87 (m, 2H), 7.78-7.68 (m, 2H), 7.58 (d, J = 7.1 Hz, 1H), 7.51 (d, J =
8.5 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H), 7.28-7.19 (m, 1H), 7.10 (d, J = 8.5 Hz, 1H), 2.14 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 152.0, 144.4, 139.6, 134.6, 134.1, 133.5, 133.0, 132.0, 130.8, 130.2, 129.7, 128.8,
128.5, 128.3, 128.0, 127.2, 126.3, 125.9, 125.2, 125.1, 124.2, 122.4, 121.4, 20.7. HRMS (ESI-TOF) m/z
Calculated for C24H18N [M+H]+ 320.1434, found: 320.1438.
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The compound (+/-)-1d (306 mg, 1 mmol) was dissolved in acetone (3 mL) with heating to 40 C. The
(+)-di-p-methoxylbenzoyl-D-tartaric acid (D-DMTA, 254 mg, 0.5 mmol) in acetone (1 mL) was added and
the mixture was stirred for 20 minutes. Then 20 mL of hexanes was added slowly. After stirring for 5
minutes, the mixture was cooled to ambient temperature. The crystals were filtered, washed with cold
hexanes for three times and dried to afford the solid diastereo- isomeric salt. Workup of the
diastereoisomeric salt was as follows: The crystal was added to sodium hydroxide aqueous solution and
stirred for 30 min. The mixture was extracted with dichloromethane. Then combined organic phase was
dried and the solvent was removed in vacuo to afford the product. Repeating this operation three times gave
the chiral (R)-(-)-1d. (39 mg, 13% yield, []20 = +11.33 (c 0.15, CHCl3), 92% ee HPLC (OD-H, elute: n-
D
hexane/i-PrOH =95/5, detector: 254 nm, 30 oC, flow rate: 0.5 mL/min), t1 = 15.2 min (major), t2 = 17.9 min.
Procedures for synthesis of NAD(P)H Model 1e with Axial Chirality: Under the nitrogen, a mixture of
2,6-dibromobenzaldehyde (729 mg, 2.77 mmol), (2-nitrophenyl)boronic acid (507 mg, 3.05 mmol),
potassium carbonate (763 mg, 5.54 mmol) and tetrakis(triphenylphosphine)palladium (96 mg, 0.08 mmol) in
DME/water (15 mL/8 mL) was stirred at 95 oC for 24 h. The mixture was cooled to ambient temperature and
extracted with ethyl acetate (30 mL×3). Then the combined organic layer was dried over anhydrous sodium
sulfate and concentrated in vacuo. The crude product (118 mg, 14% yield) was afforded by flash column
chromatography.
A mixture of above crude product (118 mg, 0.4 mmol), iron powder (65 mg, 1.2 mmol) in ethanol (10 mL)
was stirred at 75 oC and conc. HCl (0.30 mL) was added. When TLC indicated that the reaction was finished,
the mixture was cooled to ambient temperature and saturated sodium hydrogen carbonate solution was added.
The mixture was extracted with dichloromethane (30 mL×3). Then the combined organic layer was dried
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over anhydrous sodium sulfate and concentrated in vacuo. The crude product was afforded by flash column
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chromatography (39 mg, 39% yield).
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Under the nitrogen, a mixture of above product (1.85 g, 7.2 mmol), (2-methoxynaphthalen-1-yl)boronic
acid (1.88 g, 9.36 mmol), potassium carbonate (1.98 g, 14.4 mmol) and tetrakis(triphenylphos-
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phine)palladium (414 mg, 0.36 mmol) in DME/water (40 mL/20 mL) was stirred at 95 C for 4 h. The
mixture was cooled to ambient temperature and extracted with ethyl acetate (30 mL×3). Then the combined
organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The product (+/-)-1e was
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afforded by flash column chromatography (2.40 g, 99% yield). White solid, mp = 155-156 C, Rf = 0.10
(hexanes/ethyl acetate 10/1). 1H NMR (400 MHz, CDCl3) δ 8.84 (s, 1H), 8.75-8.65 (m, 2H), 8.13 (d, J = 7.8
Hz, 1H), 8.06-7.93 (m, 2H), 7.88 (d, J = 8.1 Hz, 1H), 7.76-7.66 (m, 2H), 7.62 (d, J = 7.2 Hz, 1H), 7.44 (d, J
= 9.1 Hz, 1H), 7.33 (t, J = 7.4 Hz, 1H), 7.28-7.22 (m, 1H), 7.20-7.16 (m, 1H), 3.76 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 154.6, 152.4, 144.4, 136.7, 134.2, 132.9, 130.6, 130.5, 130.3, 130.1, 129.0, 128.6,
128.1, 127.0, 126.9, 125.5, 125.0, 124.4, 123.8, 122.4, 121.4, 120.9, 113.1, 56.5. HRMS (ESI-TOF) m/z
Calculated for C24H18NO [M+H]+ 336.1383, found: 336.1389.
o
The compound (+/-)-1e (2.24 g, 6.7 mmol) was dissolved in acetone (40 mL) with heating to 40 C. The
(+)-di-p-methoxylbenzoyl-D-tartaric acid (D-DMTA, 1.93 g, 4.0 mmol) in acetone (10 mL) was added and
the mixture was stirred for 20 minutes. The mixture was cooled to ambient temperature. The crystals were
filtered, washed with cold hexanes for three times and dried to afford the solid diastereoisomeric salt.
Workup of the diastereoisomeric salt was as follows: The crystal was added to sodium hydroxide aqueous
solution and stirred for 30 min. The mixture was extracted with dichloromethane. Then combined organic
phase was dried over anhydrous sodium sulfate and the solvent was removed in vacuo to afford the product.
Repeating this operation four times gave the chiral compound (R)-(+)-1e. (490 mg, 22% yield, []20
=
D
o
+115.29 (c 0.66, CHCl3), 99% ee HPLC (OD-H, elute: n-hexane/i-PrOH =96/4, detector: 220 nm, 30 C,
flow rate: 0.6 mL/min), t1 = 16.1 min, t2 = 29.9 min (major).
Brønsted Acid-Promoted Biomimetic Asymmetric Reduction:
The Synthesis of the Substrates:. Quinoxalinones 312b, benzoxazinones 512b, benzoxazine 712b and
alkynyl ketimines 98b could be conveniently prepared according to the known literature procedure. All
compounds 3, 5, 7 and 9 are the known.
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Procedures for Biomimetic Asymmetric Reduction of Quinoxalinones: A mixture of [Ru(p-
cymene)I2]2 (0.7 mg, 0.00075 mmol), diphenyl hydrogen phosphate 2a (1.5 mg, 0.006 mmol), NAD(P)H
model (R)-1g (4.5 mg, 0.015 mmol) and quinoxalinone 3 (0.15 mmol) in chloroform (3 mL) was stirred at
room temperature for 5 min in glove box and then the mixture was transferred to an autoclave. The
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hydrogenation was performed at 40 C under hydrogen gas (500 psi) for 48 h. After careful release of the
hydrogen gas, the autoclave was opened and the reaction mixture was directly purified by column
chromatography on silica gel using hexanes and ethyl acetate as eluent to give the chiral reductive products 4.
(-)-(R)-1-Methyl-3-phenyl-3,4-dihydroquinoxalin-2(1H)-one (4a): 23 mg for 0.1 mmol, 96% yield,
white solid, known compound, Rf = 0.41 (hexanes/ethyl acetate 5/1), 98% ee, []20 = -134.86 (c 0.39,
D
CHCl3), [lit.12b: []20 = +153.0 (c 0.4, CHCl3) for 92% ee]; H NMR (400 MHz, CDCl3) δ 7.40-7.35 (m,
1
D
2H), 7.33-7.26 (m, 3H), 6.97-6.91 (m, 2H), 6.88-6.83 (m, 1H), 6.73 (dd, J = 7.6, 1.2 Hz, 1H), 5.04 (s, 1H),
4.36 (brs, 1H), 3.37 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.3, 139.3, 134.7, 128.9, 128.5, 128.5,
127.3, 124.0, 119.7, 115.0, 114.2, 61.0, 29.4. HPLC (AD-H, elute: n-hexane/i-PrOH = 80/20, detector: 254
nm, 30 oC, flow rate: 1.0 mL/min), t1 = 12.2 min, t2 = 15.6 min (major).
(-)-(R)-1-Methyl-3-(p-tolyl)-3,4-dihydroquinoxalin-2(1H)-one (4b): 36 mg, 95% yield, white solid,
known compound, Rf = 0.56 (hexanes/ethyl acetate 5/1), 98% ee, []20 = -127.63 (c 0.72, CHCl3), [lit.
:
12b
D
[]20D = +106.2 (c 0.4, CHCl3) for 89% ee]; 1H NMR (400 MHz, CDCl3) δ 7.27 (d, J = 8.0 Hz, 2H), 7.13 (d,
J = 8.0 Hz, 2H), 6.99-6.92 (m, 2H), 6.90-6.84 (m, 1H), 6.74 (dd, J = 7.6, 0.9 Hz, 1H), 5.01 (s, 1H), 4.38 (brs,
1H), 3.39 (s, 3H), 2.33 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.4, 138.2, 136.3, 134.8, 129.6, 128.6,
127.2, 123.9, 119.6, 114.9, 114.2, 60.8, 29.4, 21.3. HPLC (AD-H, elute: n-hexane/i-PrOH = 80/20, detector:
230 nm, 30 oC, flow rate: 1.0 mL/min), t1 = 11.2 min, t2 = 14.9 min (major).
(-)-(R)-3-(4-Methoxyphenyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (4c): 38 mg, 95% yield,
white solid, known compound, Rf = 0.50 (hexanes/ethyl acetate 5/1), 98% ee, []20 = -138.15 (c 0.76,
D
CHCl3), [lit. 12b: []20D = +120.9 (c 0.4, CHCl3) for 90% ee]; 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 8.7
Hz, 2H), 6.99-6.92 (m, 2H), 6.91-6.82 (m, 3H), 6.76-6.71 (m, 1H), 5.00 (s, 1H), 4.32 (brs, 1H), 3.78 (s, 3H),
3.40 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 165.6, 158.8, 133.8, 130.5, 127.6, 122.9, 118.7, 114.0,
113.3, 113.2, 59.6, 54.5, 28.4. HPLC (AD-H, elute: n-hexane/i-PrOH = 80/20, detector: 230 nm, 30 oC, flow
rate: 1.0 mL/min), t1 = 16.7 min, t2 = 19.7 min (major).
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(-)-(R)-3-(4-Bromophenyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (4d): 46 mg, 97% yield, white
solid, known compound, Rf = 0.60 (hexanes/ethyl acetate 5/1), 97% ee, []20D = -140.32 (c 0.92, CHCl3), [lit.
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12b: []20 = +122.1 (c 0.4, CHCl3) for 94% ee]; H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 8.4 Hz, 2H),
D
8
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7.31-7.24 (m, 2H), 7.01-6.85 (m, 3H), 6.79-6.73 (m, 1H), 5.01 (s, 1H), 4.37 (brs, 1H), 3.38 (s, 3H); 13C{1H}
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NMR (100 MHz, CDCl3) δ 164.8, 137.1, 133.4, 131.0, 128.1, 127.4, 123.1, 121.6, 119.0, 114.1, 113.3, 59.5,
o
28.5. HPLC (OD-H, elute: n-hexane/i-PrOH = 80/20, detector: 230 nm, 30 C, flow rate: 1.0 mL/min), t1 =
10.4 min (major), t2 = 16.5 min.
(-)-(R)-3-(3-Fluorophenyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (4e): 37 mg, 96% yield, white
solid, known compound, Rf = 0.45 (hexanes/ethyl acetate 5/1), 99% ee, []20D = -161.75 (c 0.74, CHCl3), [lit.
12b: []20D = +121.8 (c 0.4, CHCl3) for 91% ee]; 1H NMR (400 MHz, CDCl3) δ 7.34-7.25 (m, 1H), 7.18 (d, J
= 7.8 Hz, 1H), 7.12 (d, J = 9.7 Hz, 1H), 7.02-6.93 (m, 3H), 6.91-6.86 (m, 1H), 6.77 (d, J = 7.8 Hz, 1H), 5.06
(s, 1H), 4.44 (brs, 1H), 3.39 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 165.7, 163.8 (d, 1JF-C = 245.0 Hz),
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141.7 (d, JF-C = 6.3 Hz), 134.3, 130.4 (d, JF-C = 7.8 Hz), 128.4, 124.1, 123.0, 120.0, 115.4 (d, JF-C = 21.1
Hz), 115.1, 114.4 (d, 2JF-C = 21.1 Hz), 114.3, 60.5, 29.5; 19F{1H} NMR (376 MHz, CDCl3) δ -112.17. HPLC
(AD-H, elute: n-hexane/i-PrOH = 85/15, detector: 230 nm, 30 oC, flow rate: 1.0 mL/min), t1 = 13.3 min, t2 =
17.2 min (major).
(+)-(R)-3-(2-Methoxyphenyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (4f): 38 mg, 95% yield,
white solid, known compound, Rf = 0.40 (hexanes/ethyl acetate 5/1), 98% ee, []20 = +107.36 (c 0.76,
D
1
CHCl3), [lit. 12b: []20 = -168.4 (c 0.4, CHCl3) for 74% ee]; H NMR (400 MHz, CDCl3) δ 7.29-7.22 (m,
D
1H), 7.03 (dd, J = 7.5, 1.3 Hz, 1H), 6.97 (dd, J = 7.6, 1.4 Hz, 1H), 6.92-6.80 (m, 4H), 6.60 (dd, J = 7.3, 1.5
Hz, 1H), 5.46 (s, 1H), 4.52 (brs, 1H), 3.87 (s, 3H), 3.50 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.6,
157.4, 134.9, 129.6, 129.0, 127.7, 126.9, 123.8, 120.9, 119.6, 114.8, 114.6, 111.1, 56.0, 55.8, 29.3. HPLC
(OD-H, elute: n-hexane/i-PrOH = 80/20, detector: 230 nm, 30 oC, flow rate: 1.0 mL/min), t1 = 13.6 min, t2 =
16.4 min (major).
(-)-(R)-1-Benzyl-3-phenyl-3,4-dihydroquinoxalin-2(1H)-one (4g): 44 mg, 93% yield, yellow solid,
known compound, Rf = 0.45 (hexanes/ethyl acetate 5/1), 99% ee, []20 = -150.33 (c 0.88, CHCl3), [lit. 12b
:
D
[]20D = +79.0 (c 0.2, CHCl3) for 91% ee]; 1H NMR (400 MHz, CDCl3) δ 7.48-7.44 (m, 2H), 7.38-7.32 (m,
3H), 7.30-7.22 (m, 3H), 7.18 (d, J = 7.3 Hz, 2H), 6.96-6.92 (m, 1H), 6.87-6.83 (m, 1H), 6.78-6.71 (m, 2H),
5.31 (d, J = 16.1 Hz, 1H), 5.18 (s, 1H), 5.10 (d, J = 16.1 Hz, 1H), 4.50 (brs, 1H); 13C{1H} NMR (100 MHz,
CDCl3) δ 166.4, 139.1, 136.8, 134.9, 129.0, 128.9, 128.6, 127.7, 127.3, 127.3, 126.6, 124.1, 119.7, 115.8,
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114.4, 61.0, 46.0. HPLC (AD-H, elute: n-hexane/i-PrOH = 80/20, detector: 230 nm, 30 C, flow rate: 1.0
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mL/min), t1 = 18.4 min, t2 = 20.2 min (major).
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(-)-(R)-1-Allyl-3-phenyl-3,4-dihydroquinoxalin-2(1H)-one (4h): 37 mg, 93% yield, yellow solid,
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known compound, Rf = 0.45 (hexanes/ethyl acetate 5/1), 99% ee, []20 = -112.29 (c 0.74, CHCl3), [lit. 12b
:
D
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[]20D = +93.0 (c 0.2, CHCl3) for 91% ee]; 1H NMR (400 MHz, CDCl3) δ 7.43-7.38 (m, 2H), 7.36-7.29 (m,
3H), 6.98-6.91 (m, 2H), 6.87-6.81 (m, 1H), 6.77 (d, J = 7.7 Hz, 1H), 5.93-5.83 (m, 1H), 5.19-5.07 (m, 2H; s,
1H), 4.72-4.63 (m, 1H), 4.55- 4.47 (m, 1H), 4.42 (brs, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 165.9, 139.1,
134.8, 132.2, 128.9, 128.5, 127.7, 127.2, 124.0, 119.8, 116.9, 115.6, 114.4, 61.0, 44.9. HPLC (AD-H, elute:
o
n-hexane/i-PrOH = 80/20, detector: 230 nm, 30 C, flow rate: 1.0 mL/min), t1 = 10.6 min, t2 = 16.3 min
(major).
(-)-(R)-1,3-Dimethyl-3,4-dihydroquinoxalin-2(1H)-one (4i): 25 mg, 94% yield, yellow oil, known
compound, Rf = 0.41 (hexanes/ethyl acetate 5/1), 96% ee, []20D = -367.57 (c 0.50, CHCl3), [lit. 12b: []20
=
D
+65.0 (c 0.2, CHCl3) for 8% ee]; 1H NMR (400 MHz, CDCl3) δ 6.95-6.90 (m, 2H), 6.89-6.83 (m, 1H), 6.74-
6.69 (m, 1H), 4.02-3.92 (m, 1H; brs 1H), 3.36 (s, 3H), 1.44 (d, J = 6.6 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 168.6, 135.2, 129.3, 123.6, 119.8, 114.8, 114.4, 52.4, 29.2, 18.0. HPLC (AD-H, elute: n-hexane/i-
PrOH = 85/15, detector: 230 nm, 30 oC, flow rate: 1.0 mL/min), t1 = 7.7 min, t2 = 8.2 min (major).
(-)-(R)-3-Ethyl-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (4j): 28 mg, 98% yield, colorless oil,
known compound23, Rf = 0.50 (hexanes/ethyl acetate 5/1), 97% ee, []20D = -59.82 (c 0.56, CHCl3), 1H NMR
(400 MHz, CDCl3) δ 6.95-6.88 (m, 2H), 6.87-6.80 (m, 1H), 6.71 (d, J = 7.8 Hz, 1H), 4.06 (brs, 1H), 3.84-
3.78 (m, 1H), 3.36 (s, 3H), 1.91-1.79 (m, 1H), 1.78-1.67 (m, 1H), 1.01 (t, J = 7.5 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 168.0, 134.8, 129.1, 123.7, 119.6, 114.7, 114.4, 58.0, 29.2, 25.0, 10.0. HPLC (AD-H,
elute: n-hexane/i-PrOH = 85/15, detector: 230 nm, 30 oC, flow rate: 1.0 mL/min), t1 = 7.8 min, t2 = 9.1 min
(major).
(-)-(R)-3-Isopropyl-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (4k): 28 mg, 92% yield, yellow oil,
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new compound, Rf = 0.52 (hexanes/ethyl acetate 5/1), 99% ee, []20 = -18.03 (c 0.56, CHCl3), H NMR
D
(400 MHz, CDCl3) δ 6.94-6.86 (m, 2H), 6.83-6.77 (m, 1H), 6.71-6.66 (m, 1H), 4.10 (brs, 1H), 3.71-3.66 (m,
1H), 3.37 (s, 3H), 2.25-2.10 (m, 1H), 1.01 (d, J = 7.0 Hz, 3H), 0.93 (d, J = 6.7 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 167.1, 135.0, 128.7, 123.7, 119.2, 114.7, 113.9, 62.4, 30.6, 29.2, 19.3, 17.9. HPLC (AD-H,
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elute: n-hexane/i-PrOH = 85/15, detector: 230 nm, 30 oC, flow rate: 1.0 mL/min), t1 = 7.6 min, t2 = 9.4 min
(major). HRMS (ESI-TOF) m/z Calculated for C12H17N2O [M+H]+ 205.1335, found: 205.1339.
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(-)-(R)-3-Butyl-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (4l): 32 mg, 98% yield, yellow oil, new
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compound, Rf = 0.52 (hexanes/ethyl acetate 5/1), 96% ee, []20 = -35.15 (c 0.64, CHCl3), H NMR (400
D
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MHz, CDCl3) δ 6.95-6.88 (m, 2H), 6.87-6.81 (m, 1H), 6.71 (d, J = 7.8 Hz, 1H), 4.03 (brs, 1H), 3.88-3.83 (m,
1H), 3.36 (s, 3H), 1.86-1.76 (m, 1H), 1.73-1.61 (m, 1H), 1.47-1.28 (m, 4H), 0.91 (t, J = 7.0 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 168.2, 134.8, 129.1, 123.7, 119.6, 114.7, 114.5, 56.9, 31.5, 29.2, 27.8, 22.7, 14.2.
o
HPLC (AD-H, elute: n-hexane/i-PrOH, detector: 230 nm, 30 C, flow rate: 1.0 mL/min), t1 = 7.7 min, t2 =
9.4 min (major). HRMS (ESI-TOF) m/z Calculated for C13H19N2O [M+H]+ 219.1492, found: 219.1493.
Procedures for Biomimetic Asymmetric Reduction of Benzoxazinones: A mixture of [Ru(p-
cymene)I2]2 (0.7 mg, 0.00075 mmol), bis(4-nitro- phenyl)hydrogen phosphate 2b (2.6 mg, 0.0075 mmol),
NAD(P)H model (R)-1f (4.3 mg, 0.015 mmol) and benzoxazinone 5 (0.15 mmol) in chloroform (3 mL) was
stirred at room temperature for 5 min in glove box and then the mixture was transferred to an autoclave. The
o
hydrogenation was performed at 50 C under hydrogen gas (500 psi) for 48 h. After careful release of the
hydrogen gas, the autoclave was opened and the reaction mixture was directly purified by column
chromatography on silica gel using hexanes and ethyl acetate as eluent to give the corresponding chiral
reductive products 6. The enantiomeric excesses were determined by chiral HPLC.
(-)-(R)-3-Phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (6a): 32 mg, 94% yield, white solid,
known compound, Rf = 0.50 (hexanes/ethyl acetate 5/1), 98% ee, []20 = -134.92 (c 0.75, CHCl3), [lit. 12b
:
D
[]20D = +106.5 (c 0.4, CHCl3) for 97% ee]; 1H NMR (400 MHz, CDCl3) δ 7.42-7.31 (m, 5H), 7.05-6.97 (m,
2H), 6.88-6.82 (m, 1H), 6.81-6.77 (m, 1H), 5.03 (d, J = 1.7 Hz, 1H), 4.28 (brs, 1H); 13C{1H} NMR (100
MHz, CDCl3) δ 165.3, 140.9, 136.4, 132.4, 129.0, 127.5, 125.2, 120.4, 117.0, 114.9, 59.3. HPLC (OD-H,
elute: n-hexane/i-PrOH = 70/30, detector: 230 nm, 30 oC, flow rate: 0.7 mL/min), t1 = 11.9 min (major), t2 =
15.8 min.
(-)-(R)-3-(p-Tolyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (6b): 34 mg, 94% yield, white solid,
known compound, Rf = 0.50 (hexanes/ethyl acetate 5/1), 98% ee, []20 = -127.20 (c 0.68, CHCl3), [lit. 12b
D
[]20D = +85.0 (c 0.4, CHCl3) for 86% ee]; 1H NMR (400 MHz, CDCl3) δ 7.26 (d, J = 8.1 Hz, 2H), 7.15 (d, J
= 8.0 Hz, 2H), 7.04-6.97 (m, 2H), 6.87-6.81 (m, 1H), 6.78 (d, J = 7.8 Hz, 1H), 4.98 (d, J = 1.4 Hz, 1H), 4.24
(brs, 1H), 2.32 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 165.5, 141.0, 138.9, 133.4, 132.5, 129.7, 127.4,
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125.2, 120.3, 116.9, 114.9, 59.0, 21.2. HPLC (OD-H, elute: n-hexane/i-PrOH = 70/30, detector: 230 nm, 30
oC, flow rate: 0.7 mL/min), t1 = 9.4 min (major), t2 = 23.8 min.
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(-)-(R)-3-(4-Methoxyphenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (6c): 37 mg, 97% yield, white
solid, known compound, Rf = 0.20 (hexanes/ethyl acetate 10/1), 97% ee, []20D = -98.91 (c 0.74, CHCl3), [lit.
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12b: []20D = +69.0 (c 0.2, CHCl3) for 80% ee]; 1H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 8.6 Hz, 2H), 7.01
(t, J = 8.5 Hz, 2H), 6.92-6.81 (m, 3H), 6.78 (d, J = 7.8 Hz, 1H), 4.95 (d, J = 0.6 Hz, 1H), 4.26 (brs, 1H), 3.77
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 165.6, 160.0, 141.0, 132.6, 128.8, 128.4, 125.2, 120.3, 116.9,
114.9, 114.4, 58.8, 55.3. HPLC (OD-H, elute: n-hexane/i-PrOH = 70/30, detector: 230 nm, 30 oC, flow rate:
0.7 mL/min), t1 = 11.5 min (major), t2 = 24.9 min.
(-)-(R)-3-(4-Fluorophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (6d): 34 mg, 94% yield, known
compound, white solid, Rf = 0.40 (hexanes/ethyl acetate 10/1), 97% ee, []20D = -124.84 (c 0.68, CHCl3), [lit.
12b: []20D = +107.0 (c 0.2, CHCl3) for 89% ee]; 1H NMR (400 MHz, CDCl3) δ 7.43-7.33 (m, 2H), 7.10-6.99
(m, 4H), 6.91-6.84 (m, 1H), 6.83-6.79 (m, 1H), 5.02 (d, J = 1.2 Hz, 1H), 4.27 (brs, 1H); 13C{1H} NMR (100
1
4
3
MHz, CDCl3) δ 165.2, 163.0 (d, JF-C = 246.6 Hz), 140.9, 132.3, 132.1 (d, JF-C = 3.3 Hz), 129.4 (d, JF-C
=
2
8.3 Hz), 125.3, 120.6, 117.0, 116.0 (d, JF-C = 21.7 Hz), 115.0, 58.7; 19F{1H} NMR (376 MHz, CDCl3) δ -
112.46. HPLC (AD-H, elute: n-hexane/i-PrOH = 80/20, detector: 230 nm, 30 oC, flow rate: 0.8 mL/min), t1 =
10.9 min, t2 = 13.5 min (major).
(-)-(R)-3-(4-Chlorophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (6e): 38 mg, 97% yield, white
solid, known compound, 93% ee, Rf = 0.40 (hexanes/ethyl acetate 10/1), []20 = -119.99 (c 0.76, CHCl3),
D
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[lit. 12b: []20 = +90.0 (c 0.2, CHCl3) for 87% ee]; H NMR (400 MHz, CDCl3) δ 7.36-7.32 (s, 4H), 7.07-
D
6.98 (m, 2H), 6.91-6.85 (m, 1H), 6.84-6.79 (m, 1H), 5.01 (d, J = 2.0 Hz, 1H), 4.28 (brs, 1H); 13C{1H} NMR
(100 MHz, CDCl3) δ 164.9, 140.9, 135.0, 134.8, 132.1, 129.2, 128.9, 125.3, 120.7, 117.0, 115.0, 58.7. HPLC
(AD-H, elute: n-hexane/i-PrOH = 80/20, detector: 230 nm, 30 oC, flow rate: 0.8 mL/min), t1 = 11.4 min, t2 =
13.2 min (major).
(-)-(R)-3-(4-Bromophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (6f): 43 mg, 96% yield, white
solid, known compound, Rf = 0.20 (hexanes/ethyl acetate 10/1), 92% ee, []20 = -108.83 (c 0.86, CHCl3),
D
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[lit. 12b: []20 = +83.0 (c 0.2, CHCl3) for 90% ee]; H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 8.4 Hz, 2H),
D
7.28 (d, J = 8.4 Hz, 2H), 7.06-7.00 (m, 2H), 6.91-6.85 (m, 1H), 6.84-6.80 (m, 1H), 5.01 (d, J = 1.7 Hz, 1H),
4.26 (brs, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 164.8, 140.9, 135.3, 132.2, 132.1, 129.2, 125.3, 123.2,
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120.7, 117.1, 115.0, 58.8. HPLC (AD-H, elute: n-hexane/i-PrOH = 80/20, detector: 230 nm, 30 oC, flow rate:
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0.8 mL/min), t1 = 12.1 min, t2 = 13.2 min (major).
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(-)-(R)-3-(3-Fluorophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (6g): 35 mg, 96% yield, white
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solid, known compound, Rf = 0.30 (hexanes/ethyl acetate 10/1), 98% ee, []20 = -128.71 (c 0.70, CHCl3),
D
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[lit. 12b: []20D = +100 (c 0.2, CHCl3) for 89% ee]; 1H NMR (400 MHz, CDCl3) δ 7.36-7.29 (m, 1H), 7.19 (d,
J = 7.8 Hz, 1H), 7.15-7.10 (m, 1H), 7.07-7.00 (m, 3H), 6.91-6.79 (m, 2H), 5.05 (d, J = 1.6 Hz, 1H), 4.32 (brs,
1H); 13C{1H} NMR (100 MHz, CDCl3) δ 164.7, 163.0 (d, 1JF-C = 246.0 Hz), 140.8, 138.7 (d, 3JF-C = 6.9 Hz),
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4
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132.0, 130.6 (d, JF-C = 8.1 Hz), 125.4, 123.2 (d, JF-C = 3.1 Hz), 120.7, 117.0, 116.0 (d, JF-C = 21.0 Hz),
115.0, 114.6 (d, 2JF-C = 22.6 Hz), 58.8 (d, 4JF-C = 1.8 Hz); 19F{1H} NMR (376 MHz, CDCl3) δ -111.53. HPLC
(AD-H, elute: n-hexane/i-PrOH = 80/20, detector: 230 nm, 30 oC, flow rate: 0.8 mL/min), t1 = 9.9 min, t2 =
13.4 min (major).
(+)-(R)-3-(2-Methoxyphenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (6h): 37 mg, 97% yield,
yellow oil, known compound, Rf = 0.28 (hexanes/ethyl acetate 10/1), 99% ee, []20 = +151.88 (c 0.74,
D
CHCl3), [lit. 12b: []20 = -110.5 (c 0.44, CHCl3) for 48% ee]; H NMR (400 MHz, CDCl3) δ 7.33-7.27 (m,
1
D
1H), 7.22 (d, J = 6.6 Hz, 1H), 7.07-7.03 (m, 1H), 6.97-6.87 (m, 3H), 6.84-6.78 (m, 1H), 6.68-6.65 (m, 1H),
5.42 (s, 1H), 4.29 (brs, 1H), 3.82 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 165.5, 157.1, 141.1, 132.5,
130.2, 128.2, 125.0, 124.9, 120.9, 120.0, 116.7, 115.1, 111.2, 55.7, 54.6. HPLC (AD-H, elute: n-hexane/i-
PrOH = 80/20, detector: 230 nm, 30 oC, flow rate: 0.8 mL/min), t1 = 12.4 min, t2 = 16.3 min (major).
(-)-(R)-3-(3,4-Dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (6i): 35 mg, 92% yield,
yellow solid, known compound, Rf = 0.50 (hexanes/ethyl acetate 10/1), 97% ee, []20 = -104.99 (c 0.70,
D
CHCl3), [lit. 8a: []16D = -85.1 (c 0.96, CHCl3) for 90% ee]; 1H NMR (400 MHz, CDCl3) δ 7.16 (s, 1H), 7.13-
7.06 (m, 2H), 7.05-6.96 (m, 2H), 6.87-6.81 (m, 1H), 6.80-6.75 (m, 1H), 4.95 (s, 1H), 4.22 (brs, 1H), 2.23 (s,
6H); 13C{1H} NMR (100 MHz, CDCl3) δ 165.6, 141.0, 137.6, 137.4, 133.8, 132.6, 130.2, 128.8, 125.1,
124.8, 120.3, 116.9, 114.9, 59.1, 19.9, 19.5. HPLC (OD-H, elute: n-hexane/i-PrOH = 70/30, detector: 230
nm, 30 oC, flow rate: 0.7 mL/min), t1 = 12.9 min (major), t2 = 28.5 min.
(-)-(S)-3-(Thiophen-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (6j): 29 mg, 84% yield, yellow
solid, known compound, Rf = 0.30 (hexanes/ethyl acetate 10/1), 94% ee, []20D = -40.17 (c 0.59, CHCl3), [lit.
1
12b: []20 = +32 (c 0.2, CHCl3) for 86% ee]; H NMR (400 MHz, CDCl3) δ 7.26 (d, J = 5.2 Hz, 1H), 7.09-
D
7.00 (m, 3H), 6.98-6.93 (m, 1H), 6.92-6.86 (m, 1H), 6.82 (d, J = 7.6 Hz, 1H), 5.36 (s, 1H), 4.39 (brs, 1H);
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13C{1H} NMR (100 MHz, CDCl3) δ 164.1, 141.0, 138.7, 131.5, 127.1, 126.9, 126.5, 125.3, 120.9, 117.0,
115.5, 55.2. HPLC (AD-H, elute: n-hexane/i-PrOH = 80/20, detector: 230 nm, 30 oC, flow rate: 0.8 mL/min),
t1 = 12.0 min, t2 = 28.1 min (major).
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(-)-(R)-6-Methyl-3-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (6k): 35 mg, yellow oil, 97%
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yield, known compound, Rf = 0.30 (hexanes/ethyl acetate 10/1), 99% ee, []20 = -139.56 (c 0.70, CHCl3),
D
[lit.8a: []16D = -104.9 (c 0.74, CHCl3) for 87% ee]; 1H NMR (400 MHz, CDCl3) δ 7.41-7.32 (m, 5H), 6.90 (d,
J = 8.2 Hz, 1H), 6.64 (d, J = 8.2 Hz, 1H), 6.60 (s, 1H), 5.01 (d, J = 1.2 Hz, 1H), 4.20 (brs, 1H), 2.27 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 165.4, 138.9, 136.6, 135.1, 132.0, 129.0, 128.9, 127.5, 121.0, 116.6,
o
115.4, 59.3, 21.0. HPLC (OD-H, elute: n-hexane/ i-PrOH = 70/30, detector: 230 nm, 30 C, flow rate: 0.7
mL/min), t1 = 9.6 min (major), t2 = 12.4 min.
(-)-(R)-6-Chloro-3-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (6l): 38 mg, 97% yield, white
solid, known compound, Rf = 0.50 (hexanes/ethyl acetate 10/1), 99% ee, []20 = -158.80 (c 0.76, CHCl3),
D
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[lit. 8a: []15 = -109.9 (c 0.90, CHCl3) for 89% ee]; H NMR (400 MHz, CDCl3) δ 7.40-7.32 (m, 5H), 6.93
D
(d, J = 8.2 Hz, 1H), 6.84-6.75 (m, 2H), 5.05 (d, J = 1.6 Hz, 1H), 4.41 (brs, 1H); 13C{1H} NMR (100 MHz,
CDCl3) δ 164.5, 139.3, 136.0, 133.2, 130.2, 129.2, 129.1, 127.3, 120.1, 118.0, 114.7, 58.8. HPLC (OD-H,
elute: n-hexane/i-PrOH = 70/30, detector: 230 nm, 30 oC, flow rate: 0.7 mL/min), t1 = 10.3 min (major), t2 =
14.8 min.
(-)-(R)-3-Methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (6m): 20 mg, 83% yield, yellow oil,
known compound, Rf = 0.30 (hexanes/ethyl acetate 10/1), 97% ee, []20 = -41.00 (c 0.40, CHCl3), [lit.15b
:
D
[]20D = -38.4 (c 0.24, CHCl3) for 97% ee]; 1H NMR (400 MHz, CDCl3) δ 7.04-6.95 (m, 2H), 6.89-6.80 (m,
1H), 6.80-6.76 (m, 1H), 4.02-3.84 (m, 1H; brs 1H), 1.54 (d, J = 6.6 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 167.4, 141.4, 133.0, 125.0, 120.5, 116.9, 115.1, 50.6, 17.2. HPLC (OD-H, elute: n-hexane/i-PrOH
= 70/30, detector: 230 nm, 30 oC, flow rate: 0.7 mL/min), t1 = 6.8 min (major), t2 = 7.9 min.
(-)-(R)-3-Ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (6n): 24 mg, 92% yield, colorless oil, known
compound, Rf = 0.40 (hexanes/ethyl acetate 5/1), 98% ee, []20D = -51.04 (c 0.48, CHCl3), [lit.15b: []20D = -
23.4 (c 0.22, CHCl3) for 79% ee]; 1H NMR (400 MHz, CDCl3) δ 6.99 (t, J = 7.6 Hz, 2H), 6.83 (t, J = 7.7 Hz,
1H), 6.78 (d, J = 7.8 Hz, 1H), 3.98 (brs, 1H), 3.90-3.85 (m, 1H), 2.03-1.89 (m, 1H), 1.89-1.77 (m, 1H), 1.07
(t, J = 7.5 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.6, 141.0, 132.5, 125.0, 120.2, 116.7, 115.1, 56.0,
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24.5, 9.6. HPLC (OD-H, elute: n-hexane/i-PrOH = 90/10, detector: 230 nm, 30 oC, flow rate: 0.7 mL/min), t1
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= 14.1min (major), t2 = 17.6 min.
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(-)-(R)-3-Butyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (6o): 28 mg, 92% yield, yellow oil, known
compound 9b, Rf = 0.50 (hexanes/ethyl acetate 10/1), 99% ee, []20D = -43.75 (c 0.56, CHCl3), 1H NMR (400
MHz, CDCl3) δ 7.02-6.96 (m, 2H), 6.87-6.81 (m, 1H), 6.80-6.74 (m, 1H), 4.03-3.87 (m, 1H; brs 1H), 1.98-
1.86 (m, 1H), 1.83-1.70 (m, 1H), 1.52-1.31 (m, 4H), 0.92 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 166.7, 141.1, 132.4, 125.0, 120.2, 116.8, 115.1, 54.8, 30.9, 27.4, 22.4, 13.9. HPLC (OD-H, elute:
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n-hexane/i-PrOH = 95/5, detector: 230 nm, 30 C, flow rate: 0.7 mL/min), t1 = 21.4 min (major), t2 = 24.7
min.
(-)-(R)-3-Phenethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (6p): 37 mg, 97% yield, yellow solid,
known compound 9b Rf = 0.50 (hexanes/ethyl acetate 10/1), 99% ee, []20 = -12.84 (c 0.74, CHCl3), 1H
D
NMR (400 MHz, CDCl3) δ 7.33-7.27 (m, 2H), 7.25-7.18 (m, 3H), 7.03-6.93 (m, 2H), 6.83 (t, J = 7.7 Hz, 1H),
6.68-6.62 (m, 1H), 3.97-3.86 (m, 1H), 3.79 (brs, 1H), 2.91-2.73 (m, 2H), 2.35-2.21 (m, 1H), 2.13-2.01 (m,
1H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.5, 141.1, 140.4, 132.3, 128.8, 128.5, 126.5, 125.0, 120.4, 116.8,
o
115.3, 54.5, 32.7, 31.7. HPLC (OD-H, elute: n-hexane/i-PrOH = 70/30, detector: 230 nm, 30 C, flow rate:
0.7 mL/ min), t1 = 8.5 min (major), t2 = 12.7 min.
Procedures for Biomimetic Asymmetric Reduction of Benzoxazine: A mixture of [Ru(p-cymene)I2]2
(0.5 mg, 0.0005 mmol), bis(4-nitrophenyl) hydrogen phosphate 2b (1.4 mg, 0.004 mmol), NAD(P)H model
(R)-1f (2.9 mg, 0.01 mmol) and benzoxazine 7 (0.10 mmol) in chloroform (2 mL) was stirred at room
temperature for 5 min in glove box and then the mixture was transferred to an autoclave. The hydrogenation
o
was performed at 40 C under hydrogen gas (500 psi) for 48 h. After careful release of the hydrogen, the
autoclave was opened and the reaction mixture was directly purified by column chromatography on silica gel
using hexanes and ethyl acetate as eluent to give the reductive products 8. The enantiomeric excesses were
determined by chiral HPLC.
(-)-(S)-3-Phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (8): 18 mg, 85% yield, yellow oil, the known
compound, Rf = 0.70 (hexanes/ethyl acetate 20/1), 91% ee, []20D = -105.99 (c 0.20, CHCl3), [lit.15a: []RT
=
D
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-118.1 (c 1.0, CHCl3) for 98% ee]; H NMR (400 MHz, CDCl3) δ 7.43-7.30 (m, 5H), 6.89-6.76 (m, 2H),
6.72-6.64 (m, 2H), 4.53-4.45 (m, 1H), 4.30-4.24 (m, 1H), 4.03-3.95 (m, 1H; brs, 1H); 13C{1H} NMR (100
MHz, CDCl3) δ 143.1, 138.7, 133.4, 128.3, 127.9, 126.7, 121.0, 118.4, 116.1, 114.9, 70.5, 53.7. HPLC (OD-
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H, elute: n-hexane/i-PrOH = 70/30, detector: 230 nm, 30 oC, flow rate: 0.7 mL/min), t1 = 11.6 min (major), t2
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= 15.4 min.
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8
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Procedures for Biomimetic Asymmetric Reduction of Alkynyl Ketimines: A mixture of [Ru(p-
cymene)I2]2 (0.5 mg, 0.0005 mmol), bis(4-nitrophenyl) hydrogen phosphate 2b (1.4 mg, 0.004 mmol), N
AD(P)H model (R)-1f (2.9 mg, 0.01 mmol) and alkynyl ketimines 9a-c (0.10 mmol) in chloroform (2 mL)
was stirred at room temperature for 5 min in glove box and then the mixture was transferred to an autoclave.
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The hydrogenation was performed at 40 C under hydrogen gas (500 psi) for 48 h. After careful release of
hydrogen, the autoclave was opened and the reaction mixture was directly purified by column
chromatography on silica gel using hexanes and ethyl acetate as eluent to give the products 10a-c. The
enantiomeric excesses were determined by chiral HPLC.
(+)-(S)-4-Methoxy-N-(1,1,1-trifluoro-4-phenylbut-3-yn-2-yl)aniline (10a): 30 mg, 98% yield, yellow
oil, known compound, Rf = 0.60 (hexanes/ethyl acetate 20/1), 97% ee, []20 = +229.98 (c 0.60, CHCl3),
D
[lit.8b: []20 = = -231.28 (c 1.16, CHCl3) for 95% ee]; H NMR (400 MHz, CDCl3) δ 7.50-7.41 (m, 2H),
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D
7.40-7.29 (m, 3H), 6.83 (dd, J = 21.2, 8.8 Hz, 4H), 4.84-4.72 (m, 1H), 3.79 (s, 3H; brs 1H); 13C{1H} NMR
(100 MHz, CDCl3) δ 154.4, 139.1, 132.2, 129.3, 128.6, 124.0 (q, J = 280.0 Hz), 121.6, 117.1, 115.1, 86.5,
81.0 (q, J = 2.3 Hz), 55.9, 52.4 (q, J = 33.8 Hz); 19F{1H} NMR (376 MHz, CDCl3) δ -75.69. HPLC (AD-H,
o
elute: n-hexane/i-PrOH = 95/5, detector: 254 nm, 30 C, flow rate: 0.8 mL/min), t1 = 15.2 min (major), t2 =
16.1 min.
(+)-(S)-4-Methoxy-N-(1,1,1-trifluoro-4-(p-tolyl)but-3-yn-2-yl)aniline (10b): 31 mg, 97% yield, yellow
oil, known compound, Rf = 0.60 (hexanes/ethyl acetate 10/1), 93% ee, []20 = +231.82 (c 0.60, CHCl3),
D
[lit.8b: []20D = -288.76 (c 0.90, CHCl3) for 95% ee]; 1H NMR (400 MHz, CDCl3) δ 7.24 (d, J = 8.1 Hz, 2H),
7.03 (d, J = 7.9 Hz, 2H), 6.80-6.73 (m, 2H), 6.73-6.67 (m, 2H), 4.71-4.61 (m, 1H), 3.69 (s, 3H), 3.66 (brs,
1H), 2.26 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 154.2, 139.4, 139.0, 131.9, 129.1, 123.8 (q, J = 279.9
Hz), 118.4, 116.9, 114.9, 86.5, 80.2 (q, J = 2.3 Hz), 55.7, 52.2 (q, J = 33.7 Hz), 21.5; 19F{1H} NMR (376
MHz, CDCl3) δ -75.74. HPLC (AS-H, elute: n-hexane/i-PrOH = 95/5, detector: 254 nm, 30 oC, flow rate: 0.8
mL/min), t1 = 9.7 min (major), t2 = 10.7 min.
(+)-(S)-4-Methoxy-N-(1,1,1-trifluoro-4-(4-fluorophenyl)but-3-yn-2-yl)aniline (10c): 30 mg, 93% yield,
yellow oil, known compound, Rf = 0.50 (hexanes/ethyl acetate 10/1), 99% ee, []20 = +203.65 (c 0.60,
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CHCl3), [lit.8b: []20 = -204.91 (c 1.26, CHCl3) for 95% ee]; H NMR (400 MHz, CDCl3) δ 7.38-7.29 (m,
D
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