Enantioselective conjugate hydrocyanation of α,β-unsaturated N-acylpyrroles catalyzed by chiral lithium(I) phosphoryl phenoxide

Article abstract of DOI:10.1021/acscatal.7b02551

Enantioselective conjugate hydrocyanation of α,β-unsaturated N-acylpyrroles with the combined use of Me₃SiCN, LiCN, and HCN has been developed in the presence of a chiral lithium(I) phosphoryl phenoxide catalyst. This reaction is useful for a v

Full text of DOI:10.1021/acscatal.7b02551

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Letter
Enantioselective Conjugate Hydrocyanation of #,#-Unsaturated N-
Acylpyrroles Catalyzed by Chiral Lithium(I) Phosphoryl Phenoxide
Manabu Hatano, Katsuya Yamakawa, and Kazuaki Ishihara
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b02551 • Publication Date (Web): 30 Aug 2017
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ACS Catalysis
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Enantioselective Conjugate Hydrocyanation of α,β-Unsaturated N-
Acylpyrroles Catalyzed by Chiral Lithium(I) Phosphoryl Phenoxide
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Manabu Hatano, Katsuya Yamakawa, Kazuaki Ishihara*
Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8603, Japan
ABSTRACT: Enantioselective conjugate hydrocyanation of α,β-unsaturated N-acylpyrroles with the combined use of Me3SiCN,
LiCN, and HCN has been developed in the presence of a chiral lithium(I) phosphoryl phenoxide catalyst. This reaction is useful for
a variety of N-acylpyrroles, including previously unreported substrates, such as heteroaryl and halogen-substituted N-
cinnamoylpyrroles. A gram-scale reaction and subsequent transformations to a (R)-succinate, (S)-paraconic acid, and (R)-baclofen
demonstrate an entry for the practical synthesis of optically active β-substituted γ-aminobutyric acids (GABA).
KEYWORDS: conjugate hydrocyanation, γ-aminobutyric acid (GABA), lithium(I) catalyst, N-acylpyrrole, silicate
Previous work:
Catalytic enantioselective cyanation of α,β-unsaturated carbox-
ylic acid derivatives is one of the most useful synthetic methods
for obtaining optically active β-substituted γ-aminobutyric acids
(GABA). Due to the great importance of GABA-derived natural
(R)-1 + Me3SiCN + H2O + n-BuLi
O
Mild
Lewis acid
O
R1 R2
F
Ph
R
X
Li(H2O)n
O
O
This work:
O
1
[Li]+ [Me3Si(CN)2]–
products, pharmaceuticals, and agro-chemicals, considerable
P
O
2
E
3
attention has been devoted to this catalysis, particularly since
O
R
X
Mild
Lewis base
Much more reactive than
Me3SiCN, HCN, or LiCN
Jacobsen reported the first catalytic enantioselective cyanation of
Ph
(R)-2
α,β-unsaturated imides with the use of chiral salen-Al(III) cata-
3
lysts. By taking advantage of the comparable development of
Figure 1. Outline of conjugate hydrocyanation by using chiral
Li(I) catalyst (R)-2 and extremely reactive cyano sources.
chiral catalysts for the cyanation of aldehydes, ketones, imines,
2,4,5
3,6
7
8
and nitroolefins,
chiral Al(III), Al(III)/Er(III), Gd(III),
9
10
11
12
13
Na(I), Sr(II), Ru(II)/Li(I), Mg(II), and Ti(IV) complexes
and chiral phase transfer catalysts (PTC) have been shown to
14
We initially examined the reaction of highly synthetically useful
α,β-unsaturated N-acylpyrrole 4a , unlike less practical chal-
cones or phenyl vinyl ketone derivatives, through the use of chi-
ral BINOL (1,1’-bi-2-naphthol)-derived lithium(I) phosphoryl
phenoxide (R)-2 (10 mol%) in toluene at 25 °C for 7 h (Table 1,
also see the Supporting Information (SI)). Fortunately, under
be effective for the cyanation of α,β-unsaturated carboxylic acid
derivatives. In these reports, the combined use of trimethylsilyl
cyanide (Me3SiCN) and alcohols/phenols (i.e., in situ generation
of HCN), ethyl cyanoformate, acetone cyanohydrin, KCN, and
20
15
K4[Fe(CN)6] were used as cyanide sources. In this regard, we
have recently developed the catalytic enantioselective cyanosi-
lylation of ketones with the combined use of Me3SiCN, LiCN,
17a
the same reaction conditions as in our previous report (with
15 mol% of n-BuLi, 250 mol% of Me3SiCN, and 120 mol% of
H2O), the corresponding product 5a was obtained in 67% yield
with 91% ee (entry 2). The yield was slightly improved when
350 mol% of Me3SiCN was used (entry 3). 60 mol% of water
increased the yield but decreased the enantioselectivity to 66%
ee (entry 4). On the other hand, the reaction did not proceed
when 200 mol% of H2O was used, where the majority of
Me3SiCN would be converted to HCN (entry 5). The use of 20
mol% of n-BuLi was highly effective for improving the yield, and
5a was obtained in 90% yield with 91% ee and (R)-1 was fully
recovered through the workup procedure (entry 6). In contrast,
shortage of Li(I)-source for 3 greatly decreased the yield (entry 1,
also see the SI). Further investigation of the reaction tempera-
ture at 15 °C decreased the yield to 52% (entry 7). The use of
extra HCN (100 mol%), which was prepared in advance from
and HCN in the presence of chiral lithium(I) phosphoryl phe-
16,17a
noxide (R)-2 (Figure 1).
Indeed, highly nucleophilic lithi-
um(I) dicyanotrimethylsilicate(IV) 3 would be readily generated
16,17a
in situ from Me3SiCN and LiCN,
and the catalytic activity of
18
Li(I) aqua complex (R)-2 as an acid–base cooperative catalyst
was dramatically increased in the presence of HCN. In this
context, we are currently interested in whether or not our cata-
lytic system can be applied to the enantioselective conjugate
hydrocyanation of α,β-unsaturated carboxylic acid derivatives
instead of ketones (Figure 1). From the viewpoint of poor abun-
dances of lanthanoid and late transition metals in the Earth’s
7
crust (worldwide mining production per year; Er: 500 tons,
8
11
19
Gd: 400 tons, Ru: 12 tons), a sole use of the lightest Li
(39,000 tons)-catalysts might be helpful in environmental and
economical reasons.
21
Me3SiCN and 2-propanol, was not effective, and the yield was
slightly decreased (entry 8). Moreover, racemic 1 showed
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Page 2 of 6
a
Table 1. Optimization of the Reaction Conditions
significantly low catalytic activity (entry 9), which indicates the
hetero-dimerization of (R)-2/(S)-2 (Also see the positive non-
17a
1
2
3
4
Ph
linear effect in the SI). Overall, the present reaction system with
+
–
O
O
the use of chiral Li(I) catalyst 2 and [Li] [Me3Si(CN)2] 3 was
effective for the catalytic enantioselective cyanation of α,β-
unsaturated N-acylpyrrole 4a.
P
OH
O
5
Ph
6
7
8
9
With the optimized reaction conditions in hand, we next exam-
ined the scope of N-(3-aryl)acryloylpyrroles 4a−j (Scheme 1).
We first investigated o-, m-, and p-tolyl-substituted substrates
(4b–d). As a result, m-tolyl 5c and p-tolyl 5d were obtained
with 92% ee and 93% ee, respectively, whereas o-tolyl 5b was
obtained in only moderate yield (59%) and enantioselectivity
(71% ee). Substrate 4e with a p-anisyl moiety as an electron-
donating group gave the corresponding product 5e in 85% yield
with 90% ee. On the other hand, substrates 4f and 4g with
haloaryl moieties as electron-withdrawing groups gave the cor-
responding products 5f with 71% ee and 5g with 73% ee, re-
spectively. Although the enantioselectivities of 5f and 5g were
moderate, to the best of our knowledge, this is the first example
(R)-1 (10 mol%)
O
O
CN
Ph
n-BuLi (10–20 mol%)
+
N
Ph
Me3SiCN
N
(S)
H2O (60–200 mol%)
toluene, 25 °C, 7 h
(250 or 350 mol%)
4a
5a
10
11
12
13
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15
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n-BuLi
(mol%)
Me3SiCN
(mol%)
H2O
(mol%)
5a, yield
(%)
5a, ee
(%)
entry
1
2
3
4
5
10
15
15
15
15
20
20
20
20
250
250
350
250
250
250
250
250
250
120
120
120
60
200
120
120
120
120
7
53
91
90
66
–
91
89
90
0
67
85
97
0
90
52
76
14
6
7b
8c
9d
of the use of halogen-substituted N-cinnamoylpyrroles in enanti-
a
The reaction was carried out with 4a (0.30 mmol), Me3SiCN
(250 or 350 mol%), (R)-1 (10 mol%), n-BuLi (10–20 mol%), and
H2O (60–200 mol%) in toluene at 25 °C for 7 h unless otherwise
Reaction temperature was 15 °C. Extra HCN (100
mol%) was added. d Racemic 1 was used instead of (R)-1.
8a,b,11b,14a
oselective conjugate hydrocyanation.
Moreover, previ-
ously non-applicable substrates 4h with 3-furyl, 4i with 3-thienyl,
and 4j with 3-inolyl moieties as heteroaryl groups gave products
5h with 94% ee, 5i with 90% ee, and 5j with 85% ee. Fortu-
nately, recrystallization of the products 5a, 5f, 5g, and 5j with
moderate enantio-purities increased these values to 94–99% ee
without any serious loss of yield (see the results in brackets b in
Scheme 1). During this crystallization, a crystal of 5g that was
suitable for X-ray analysis was obtained, and the absolute stere-
ochemistry of 5g was determined to be S-configuration (See the
SI).
b
c
noted.
Scheme 1. Substrate Scope of N-Cinnamoylpyrroles
O
(R)-1 (10 mol%)
n-BuLi (20 mol%)
O
CN
Ar
+
Ar
Me3SiCN
N
N
(S)
H2O (120 mol%)
(250 mol%)
4a–j
5a–j
toluene, 25 ºC, 7–26 h
Product 5, yield, enantioselectivity, and reaction time:a
CN CN
Scheme 2. Substrate Scope of α,β-Unsaturated N-(3-
Alkyl)acylpyrroles
O
CN
O
O
N
N
N
O
(R)-1 (2.5–10 mol%)
n-BuLi (5–20 mol%)
O
CN
R2
5a
90%, 91% ee (7 h)
[68%, >99% ee]b
5c
79%, 92% ee (26 h)
[94%, 90% ee (21 h)]c
5b
59%, 71% ee (18 h)
R2
+
Me3SiCN
N
N
H2O (120 mol%)
toluene, 3–22 h
R1
4k–t
R1
(250 mol%)
5k–t
O
CN
O
CN
O
CN
F
Product 5, yield, enantioselectivity, and reaction time:a
N
N
N
O
CN O CN
O
CN
5d
94%, 93% ee (16 h)
OMe
5e
85%, 90% ee (17 h)d
5f
N
N
N
84%, 71% ee (7 h)
[46%, 94% ee]b
5k
97%, 90% ee (25 ºC, 3 h)
92%, 90% ee (25 ºC, 22 h)b
5l
99%, 92% ee (0 ºC, 6 h)
5m
86%, 94% ee (–20 ºC, 7 h)
O
N
CN
O
CN
N
O
CN
O
CN
O
CN
O
Br
OBn
N
OBn
N
5g
85%, 73% ee (8 h)
[55%, >99% ee]b
N
Ph
5h
70%, 94% ee (19 h)
[93%, 91% ee (20 h)]c
5n
5o
5p
94%, 95% ee (0 ºC, 4 h) 90%, 97% ee (–20 ºC, 16 h) 73%, 96% ee (–20 ºC, 11 h)
O
CN
O
CN
S
O
CN
O
CN
O
CN
O
CN
N
N
N
N
N
N
N
S
5i
62%, 90% ee (16 h)
5q
91%, 95% ee (0 ºC, 18 h)
5r
98%, 91% ee
(0 ºC, 7 h)
5s
93%, 92% ee
(0 ºC, 7 h)
5t, 90% (25 ºC, 7 h)
trans: 56%, 93% ee
cis: 34%, 84% ee
5j
73%, 85% ee (60 ºC, 12 h)
[55%, 99% ee]b
a The reaction was carried out with 4 (0.30 mmol), Me3SiCN (250
mol%), (R)-1 (10 mol%), n-BuLi (20 mol%), and H2O (120 mol%)
in toluene at –20, 0, or 25 °C for 3–22 h unless otherwise noted.
(R)-1 could be fully recovered (>99%) in all the cases through the
a The reaction was carried out with 4 (0.30 mmol), Me3SiCN (250
mol%), (R)-1 (10 mol%), n-BuLi (20 mol%), and H2O (120 mol%)
in toluene at 25 °C for 7–26 h unless otherwise noted. (R)-1 could
be fully recovered (>99%) in all the cases through the routine
b
b
routine purification on silica gel column chromatography. 2.5
purification on silica gel column chromatography.
Yield and
c
mol% of catalyst was used.
enantio-purity after a recrystallization. 270 mol% of Me3SiCN
was used. d 300 mol% of Me3SiCN was used.
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Encouraged by the relatively wide scope of N-(3-
Scheme 4. Synthesis of GABA, (R)-Baclofen 12 and
(S)-Pregabalin
1
2
3
4
5
6
7
8
aryl)acryloylpyrroles 4a–j in Scheme 1, we next examined N-(3-
alkyl)acryloylpyrroles 4k–t (Scheme 2). Compared to 4a–j, 4k–
t showed better reactivity, and sometimes the reaction could be
conducted at –20 or 0 °C. As a result, substrates 4k–n with
simple n-alkyl chains gave the corresponding products 5k–n in
high yields with high enantioselectivities (90–95% ee). Although
we consistently used 10 mol% of catalyst due to an experimental
reason in a small scale, 5k was obtained indeed in 92% yield
with 90% ee even with the use of 2.5 mol% of catalyst. A ben-
zyloxy group could be used in the alkyl chains (i.e., 4o and 4p),
and the corresponding products 5o and 5p were obtained with
high enantioselectivities. Substrate 4q with a terminal thienyl
moiety gave 5q in 91% yield with 95% ee. Substrates 4r and
4s with sterically hindered cyclohexyl and tert-butyl moieties
gave 5r and 5s in high yields with 91–92% ee. Moreover, α,β-
disubstituted substrate 4t could be used, and the corresponding
5t was obtained with high enantioselectivities. The lack of dia-
stereoselectivity in 5t might be due to non-stereoselective proto-
Me3SiCN (250 mol%)
(S)-1 (10 mol%)
O
CN
O
N
n-BuLi (20 mol%)
N
5u
Cl
H2O (120 mol%)
toluene, 25 °C, 7 h
Cl
95%, 85% ee
79%, 99% ee
4u
recrystallization
1) H2, PtO2 (10 mol%)
HCl, MeOH
25 °C, 5 h
O
CN
Ar
O
TBSOTf
Cl
MeO
NH
9
MeOH
40 ºC, 39 h
2) NaOMe, MeOH
25 °C, 17 h
(Ar = p-ClC6H4)
11
10
11
12
13
14
15
16
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60
68% (3 steps), 99% ee
10
CO2H
6 M HCl aq
(4)
Cl
reflux, 12 h
NH2·HCl
(R)-baclofen (12), 96%
Me3SiCN (250 mol%)
O
CN
O
N
(S)-1 (10 mol%)
n-BuLi (20 mol%)
N
H2O (120 mol%)
toluene, 0 °C, 10 h
5v
4v
8a,b
nation of the lithium(I) enolate intermediates.
82%, 90% ee
73%, >99% ee
recrystallization
CO2H
To demonstrate the synthetic utility of the present catalysis, we
conducted a >1 g-scale synthesis of 5n (Scheme 3, eq. 1). The
reaction proceeded smoothly at 0 °C with the use of 1.13 g (5
mmol) of 4n. In such a large scale, we could easily reduce (R)-1
to 5 mol%, and, moreover, LiOH instead of n-BuLi could be
used. Consequently, 1.20 g of 5n was obtained in 95% yield
with 95% ee. It is noted that chemically stable and non-polar
(R)-1, unlike the regarded catalysts such as unstable chiral salens,
ref. 8a,b
(5)
NH2
(S)-pregabalin
conditions (Scheme 3, eq. 3). Hydrolysis of 8 provided biologi-
cally active (S)-(–)-paraconic acid 9 in 98% yield, which is a key
23
2
intermediate of microbial hormone (3R)-(–)-A-factor. To the
polar sugar-derivatives and amino acids, could be almost re-
best of our knowledge, this is the first example for the catalytic
covered (96%) without any practical difficulties through the
routine purification on silica gel column chromatography, alt-
hough our catalyst’s turnover number was not extremely high.
5n (95% ee) was transformed to synthetically useful 2-alkyl-
substituted succinic acid diester 6, which is usually difficult to
synthesize by asymmetric hydrogenation, unlike 2-aryl-
24
asymmetric synthesis of paraconic acid 9.
25,26
Moreover, we synthesized (R)-baclofen 12,
an inhibitory
neurotransmitter as a GABA receptor agonist marketed by No-
vartis and Daiichi-Sankyo (Scheme 4, eq. 4). By taking advan-
tage of our catalyst over halogen-substituted N-
cinnamoylpyrroles, substrate 4u was used in the presence of (S)-
1. Fortunately, the corresponding product 5u was obtained in
22
substituted succinic acid derivatives, in 85% yield without
epimerization by using Me3SiOTf in ethanol at 110 °C (Scheme
3, eq. 2). Moreover, compound 5o (97% ee) was transformed to
γ-butyrolactone 8 (97% ee) through removal of the Bn moiety
by treatment with BBr3 and then cyclization under acidic
95% yield with 85% ee, even though 4u is a previously disfa-
11b
voured chloro-substituted N-cinnamoylpyrrole.
Recrystalliza-
tion of 5u improved the optical purity up to 99% ee. Subse-
quently, non-epimerized TBSOTf-catalyzed esterification of 5u
gave 10, followed by PtO2-catalyzed hydrogenation of 10 and
cyclization under basic conditions to give 11 in 68% yield in
three steps (Also see the SI for other reaction conditions.). Final-
Scheme 3. Synthesis of Succinic Acid Diester 6 and
(S)-(–)-Paraconic Acid 9
ly, hydrolysis of 11 provided (R)-baclofen 12 in 96% yield.
O
O
CN
(R)-1 (5 mol%)
LiOH (10 mol%)
3,8a,8b
Moreover, a key intermediate of (S)-pregabalin,
which is an
+
Ph
Me3SiCN
N
N
Ph
(1)
H2O (120 mol%)
toluene
anticonvulsant GABA receptor agonist by Pfizer, was synthe-
sized from substrate 4v in 82% yield with 90% ee (Scheme 4, eq.
5). In this case, recrystallization of 5v also improved the optical
purity up to >99% ee.
5n
(250 mol%)
4n, 5 mmol, 1.13 g
95%, 95% ee, 1.20 g
[(R)-1: 96% recovery]
0 ºC, 7 h
CO2Et
Recovered
(R)-1
Me3SiOTf
5n
EtO2C
Ph (2)
EtOH
110 ºC, 48 h
Although further investigation of the actual catalysts is required
95% ee
6
85%, 94% ee
27
to fully understand the reaction mechanism, a postulated
monomeric structure was considered as a working model, as
shown in Figure 2. In TS-13, attractive bonding between the
Lewis basic phenoxide oxygen of the catalyst and the Li(I)-ion of
the pentacoordinate silicate 3 might be possible. In this regard,
Olah previously reported that ab initio calculations show that
O
CN
BBr3
5n (1.20 g)
OH
5o
N
CH2Cl2
97% ee
–78 ºC, 3 h
7
CN
CO2H
ref. 23
OH
p-TsOH
CH3CN
70 ºC, 15 h
6 M HCl
the pentacoordinate silicate has two N-bonded diaxial cyano
O
O
O
O
O
(3)
28
40 ºC
23 h
groups with the lowest energy.
More importantly, trans-
8
9
O
O
(3R)-(–)-A-factor
(microbial hormone)
coordination of amide to an acid center (i.e., trans-N–C=O···Li)
is more likely than cis-coordination (i.e., cis-N–C=O···Li) due to
98%
91%, 97% ee
(2 steps)
29
steric and electronic constraints. In fact, the reactivity of (Z)-
4n was quite low (eq. 6), and this result might strongly support
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Page 4 of 6
the trans-coordination of amide to the lithium(I) center. Overall,
Notes
1
2
3
4
5
6
7
8
the re-face attack to 4a by 3 via TS-13 would preferentially lead
to (S)-product 5a after protonation of the corresponding lithi-
um(I) enolate intermediate 14 with HCN (Also see the SI).
The authors declare no competing financial interest.
■ACKNOWLEDGMENT
Financial support was partially provided by JSPS KAKENHI
Grant Numbers 17H03054 and 15H05755. KY thanks the JSPS
Research Fellowships for Young Scientists and the Program for
Leading Graduate Schools: IGER Program in Green Natural
Sciences (MEXT).
re-face attack
C
Ph
Li
HCN
O
CN
Ln
Me
N
(S)-5a
N
O
9
N
Ph
(91% ee)
Me
O
O
Si
Me
14
Li
■REFERENCES
P
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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25
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30
31
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34
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42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+ Me3SiCN
O
(R)-2
C
N
O
Li CN
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2016, 27, 999–1055.
(2) Reviews for asymmetric cyanation of aldehydes, ketones, imines,
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Khan, N. H.; Kureshy, R. I.; Abdi, S. H. R.; Agrawal, S.; Jasra, R. V.
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Young, C. Chem. Rev. 2008, 108, 5146–5226. (h) Denmark, S. E.;
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2016, 6, 989–1023.
Li
3
Ln
TS-13
(Ln = H2O, HCN, solvent, etc.)
4a
trans-N-C=O-Li
coordination
Figure 2. Possible transition state 13 to (S)-5a.
(R)-1 (10 mol%)
n-BuLi (20 mol%)
O
CN
O
Ph
+
Me3SiCN
(6)
N
Ph
H2O (120 mol%)
toluene, 0 ºC, 4 h
N
(250 mol%)
(Z)-4n
5n, 2%
P
P
O
O
*
*
O
Li
O
Li
P=O
O
Ph
*
O
=
(R)-1
OH
N
N
Ph
(Z)
(E)
disfavored
favored
In summary, we have developed the enantioselective conjugate
hydrocyanation of α,β-unsaturated N-acylpyrroles with the use
of highly practical and heavy metal-free chiral lithium(I) phos-
phoryl phenoxide catalyst. A mixture of Me3SiCN, LiCN, and
HCN is a key to promote the reaction. A variety of N-
acryloylpyrroles were used, some of which have been unsuitable
for use with previous catalysts. A gram-scale reaction and trans-
formations of (R)-succinic acid derivative, (S)-paraconic acid, (R)-
baclofen, and a key intermediate of (S)-pregabalin were demon-
strated. Overall, a variety of optically active β-substituted
GABA compounds would be accessed much more easily with
this powerful conjugate hydrocyanation.
(3) Sammis, G. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125,
4442–4443.
(4) Asymmetric cyanation of nitroolefins: With PTC: (a) Bernal, P.;
Fernández, R.; Lassaletta, J. M. Chem. Eur. J. 2010, 16, 7714–7718.
With Ti(IV) catalyst: (b) Lin, L.; Yin, W.; Fu, X.; Zhang, J.; Ma, X.;
Wang, R. Org. Biomol. Chem. 2012, 10, 83–89. With V(V) catalyst: (c)
North, M.; Watson, J. M. ChemCatChem 2013, 5, 2405–2409.
(5) Recent selected papers on catalytic enantioselective cyanation of
aldehydes and ketones: (a) Zeng, X.-P.; Cao, Z.-Y.; Wang, X.; Chen,
L.; Zhou, F.; Zhu, F.; Wang, C.-H.; Zhou, J. J. Am. Chem. Soc. 2016,
138, 416–425. (b) Zhao, Y.-L.; Cao, Z.-Y.; Zeng, X.-P.; Shi, J.-M.; Yu,
Y.-H.; Zhou. J. Chem. Commun. 2016, 52, 3943–3946. (c) Zeng, X.-P.;
Zhou, J. J. Am. Chem. Soc. 2016, 138, 8730–8733. (d) Zhu, C.; Xia, Q.;
Chen, X.; Liu, Y.; Du, X.; Cui, Y. ACS Catal. 2016, 6, 7590–7596. (e)
Brodbeck, D.; Broghammer, F.; Meisner, J.; Klepp, J.; Garnier, D.;
Frey, W.; Kästner, J.; Peters, R. Angew. Chem. Int. Ed. 2017, 56, 4056–
4060.
■ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.xxxxxxxxx.
Experimental procedure, characterization data, copies of 1H
NMR and 13C NMR spectra of all new compounds (PDF)
CIF file of 5g (CIF)
(6) (a) Mazet, C.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2008, 47,
1762–1765. (b) Madhavan, N.; Weck, M. Adv. Synth. Catal. 2008, 350,
419–425. (c) Jakhar, A.; Sadhukhan, A.; Khan, N. H.; Saravanan, S.;
Kureshy, R. I.; Abdi, S. H. R.; Bajaj, H. C. ChemCatChem 2014, 6,
2656–2661.
■AUTHOR INFORMATION
Corresponding Author
(7) Sammis, G. M.; Danjo, H.; Jacobsen, E. N. J. Am. Chem. Soc.
2004, 126, 9928–9929.
*E-mail: ishihara@cc.nagoya-u.ac.jp
(8) (a) Mita, T.; Sasaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 2005, 127, 514–515. (b) Fujimori, I.; Mita, T.; Maki, K.; Shiro,
M.; Sato, A.; Furusho, S.; Kanai, M.; Shibasaki, M. Tetrahedron 2007,
63, 5820–5831. (c) Tanaka, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 2008, 130, 6072–6073.
ORCID
Manabu Hatano: 0000-0002-5595-9206
Kazuaki Ishihara: 0000-0003-4191-3845
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(26) Baclofen has not been synthesized by enantioselective conju-
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synthesis of baclofen. (a) Herdeis, C.; Hubmann, H. P. Tetrahedron:
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13
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22
23
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31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
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48
49
50
51
52
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G.; Ma, Y. Synlett 2010, 2010, 2164–2168. (b) Li, Z.; Liu, C.; Zhang,
Y.; Li, R.; Ma, B.; Yang, J. Synlett 2012, 23, 2567–2571. (c) Hu, X.; Li,
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(16) Dicyanotrimethylsilicates(IV) are known as highly reactive CN–
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W. B.; Davidson, F. Inorg. Chem. 1988, 27, 4012–4018. (b) Sassaman,
M. B.; Prakash, G. K. S.; Olah, G. A. J. Org. Chem. 1990, 55, 2016–
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Chem. Soc. 2005, 127, 10776–10777. (c) Hatano, M.; Ikeno, T.;
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Catal. 2016, 6, 4699–4709.
(19) (a) CRC Handbook of Chemistry and Physics, 97th ed, Haynes, W.
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(http://geology.com/metals/)
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McErlean, C. S. P. Eur. J. Org. Chem. 2012, 1877–1888. Also see, refs.
8a, 8b, 11b, and 14a.
(21) In our previous study in ref. 17a, use of additional HCN was
effective for increasing the catalytic activity. In contrast, no significant
positive effect on either the yield or enantioselectivity of the product
was observed, although the reason for this finding is still not clear.
(22) Recent reports on asymmetric hydrogenation to provide 2-
alkyl-substituted succinic acid diesters: (a) Bernasconi, M.; Müller, M.-
(27) Possible active species in the enantioselective cyanosilylation of
ketones have been discussed in our previous paper, see ref. 17a.
Moreover, in this reaction, we also found a positive non-linear effect
of 1 and 5a, which supports the notion that the active species might
be monomeric structures in this reaction. The preliminary results are
shown in the SI.
(28) Sassaman, M. B.; Prakash, G. K. S.; Olah, G. A. J. Org. Chem.
1990, 55, 2016–2018.
(29) In previous reports, Lewis acids (LA) have been considered to
coordinate α,β-unsaturated N-acylpyrroles in a trans-N–C=O···LA
manner. (a) Ohshima, T.; Nemoto, T.; Tosaki, S.; Kakei, H.;
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title, should give the reader a representative idea of one of the following: A key structure, reaction, equation, concept, or the-
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1
2
3
4
5
6
O
CN
O
chiral Li(I) aqua catalyst
(2.5–10 mol%)
N
R
N
R
Me3SiCN + LiCN + HCN in situ
7
8
9
up to 1.2 g scale
up to 97% ee
toluene, 25 ºC, 3–26 h
R = alkyl, aryl
Ph
R
OH2
Key intermediates for
(R)-Succinate
(3R)-(–)-A-factor
(R)-Baclofen
O
O
Li
O
10
11
12
13
14
15
16
17
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N
P
O
O
[Li]+ [Me3Si(CN)2]–
(S)-Pregabalin
Ph
Keywords: conjugate hydrocyanation; γ-aminobutyric acid (GABA); lithium(I) catalyst; N-acylpyrrole; silicate
6
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