Catalytic enantioselective Hosomi-Sakurai reaction of α-ketoesters promoted by chiral copper(ii) complexes

Article abstract of DOI:10.1039/c9cc01159e

A catalytic enantioselective Hosomi-Sakurai reaction of α-ketoesters has been developed. A copper(ii) complex with a chiral bis(oxazoline) ligand bearing methanesulfonamide groups shows excellent catalytic activity to give α,α-disubstituted α-hydroxyesters in high yields with high enantioselectivities. This is the first successful method for the catalytic enantioselective 1,2-addition of α-ketoesters with allylic silanes.

Full text of DOI:10.1039/c9cc01159e

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DOI: 10.1039/C9CC01159E
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Catalytic Enantioselective Hosomi–Sakurai Reaction of -
Ketoesters Promoted by Chiral Copper(II) Complexes
Received 00th January 20xx,
Accepted 00th January 20xx
Yutaro Niwa, Mayu Miyake, Ichiro Hayakawa, Akira Sakakura*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A
catalytic enantioselective Hosomi–Sakurai reaction of - knowledge, an efficient method for the asymmetric addition of
ketoesters has been developed. A copper(II) complex with a chiral -ketoesters with allylic silanes has not yet been reported.
bis(oxazoline) ligand bearing methanesulfonamide groups shows Previously, Ishihara and Sakakura’s group developed a new
excellent catalytic activity to give ,-disubstituted - chiral bis(oxazoline) ligand 1a bearing methanesulfonamide
hydroxyesters in high yields with high enantioselectivities. This is groups (Table 1).8 A copper(II) complex of 1a, which is called
the first successful method for the catalytic enantioselective 1,2- n-cation catalyst, catalytically promotes the hetero-Diels–Alder
addition of -ketoesters with allylic silanes.
reaction of ,-unsaturated -ketoesters with allylsilanes to
give the corresponding adducts in high yields with high
diastereo- and enantioselectivities.8c
Since 1a·CuX2
Catalytic asymmetric allylations of ketones are useful methods
for the synthesis of chiral tertiary alcohols.1 Several effective
methods that use chiral catalysts have been developed.
Among these methods, the Hosomi–Sakurai reaction2,3 is
promising, since it employs inexpensive and nontoxic allylic
silanes as carbon nucleophiles. However, little is known about
the catalytic enantioselective Hosomi–Sakurai reaction of
ketones,4,5 because ketones generally show lower reactivity
and selectivity than aldehydes. In addition, the use of a chiral
Lewis acid catalyst sometimes initiates undesired background
reactions through a non-enantioselective silylium ion catalysis
to decrease the enantioselectivity.6
-Ketoesters are useful substrates for asymmetric 1,2-addition
with a carbon nucleophile, since the reaction affords optically
active ,-disubstituted -hydroxyesters, which are important
structural motifs in biologically active compounds.
Accordingly, methods for the catalytic asymmetric allylation of
-ketoesters have been reported.7 For example, Feng and
successfully activates ,-unsaturated -ketoesters, this
catalyst may also be suitable for promoting the asymmetric
1,2-addition of -ketoesters. We report herein the first
catalytic enantioselective Hosomi–Sakurai reaction of -
ketoesters.
Our study commenced with an examination of the catalytic
activities of 1a·Cu(NTf2)2 in the Hosomi–Sakurai reaction of -
ketoester 2a (Table 1).
The reaction of 2a with an
allyltrimethylsilane was conducted in the presence of
1a·Cu(NTf2)2 (5 mol%) at ambient temperature. Since the
crude product included a small amount of TMS ether of 3a,‡
the crude product was treated with TBAF to remove the TMS
group. As a result, the reaction proceeded smoothly in EtNO2
at ambient temperature to give 3a in 78% yield with 74% ee
(entry 1). In sharp contrast, the reaction in other solvents such
as dichloromethane, acetonitrile, THF and isopropyl alcohol
did not proceed at all even under heating conditions.‡ The use
colleagues
tetraallylstannane
complexes.7a Yoda and colleagues developed an asymmetric
reported
asymmetric
by
addition
N,N’-dioxide–In(III)
with
of allyltriisopropylsilane gave 3a with
a slightly better
catalyzed
enantioselectivity (80% ee), but the yield of 3a was
significantly decreased (50%) (entry 2). We next evaluated
other chiral bis(oxazoline) ligands.9
Ligand 1b bearing
addition with -amido-functionalized allylstannanes catalyzed
by chiral In(III) complexes.7b
Aminophenol-catalyzed
trifluoromethanesulfonamide groups is also effective for the
Diels–Alder reaction of N-acryloyloxazolidinones.8a However,
the use of 1b in the present reaction significantly decreased
the enantioselectivity (53% ee), although the reactivity was
improved (90% yield) (entry 3). When the reaction was
conducted in the presence of ligand 1c, which has sterically
bulky tert-butyl groups at the 4,4’-positions, only a trace
amount of 3a was obtained (entry 4). In contrast, the use of
1d bearing benzyl groups at the 4,4’-positions gave 3a in 83%
asymmetric addition with allylboronates was also reported by
Hoveyda and colleagues.7c However, to the best of our
Graduate School of Natural Science and Technology, Okayama University, 3-1-1,
Tsushima-naka, Kita-ku, Okayama, Japan.
Electronic Supplementary Information (ESI) available: Experimental procedures
and characterization data for all new compounds (PDF). See
DOI: 10.1039/x0xx00000x
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yield, while the enantioselectivity was poor (–7% ee)§ (entry 5).
The use of ligand 1e or 1f, which have four phenyl groups at
the 4,4’,5,5’-positions, gave 3a in moderate yields (68 and
67%) in low enantioselectivity (–16 and –35% ee)§ (entries 6
and 7).
Table 2 1a·Cu(NTf2)2-catalyzed Hosomi–Sakurai reaction of 2 with allyltrimethylsilanea
View Article Online
DOI: 10.1039/C9CC01159E
1. 1a·Cu(NTf2)2
(5 mol%)
R1 OH
O
EtNO2, rt
TMS
+
CO2R2
R1
CO2R2
*
2. TBAF
THF, rt
3
2
Table 1 Catalytic activities of chiral copper(II) complexes in the addition reaction of 2a
Entry
2
R1
Me
R2
Bn
Et
Et
Et
Et
Et
Me
Et
Yield (%)b
3b, 71
3c, 74
3d, 41
3e, 75
3f, 67
3g, 0
Ee (%)c
65 (R)
74
74
73
69
—
—
79
with allylsilanesa
1
2
3
4
5
6
7
8
2b
2c
2d
2e
2f
2g
2h
2i
CH3(CH2)5
CH2=CH(CH2)2
BnO(CH2)3
c-C5H9
c-C6H11
Ph
O
R3Si
+
Ph
CO2Et
2a
Ph
1. 1·Cu(NTf2)2 (5 mol%)
3h, 0
3j, 72
OH
CO2Et
EtNO2, rt
4-CF3C6H4
*
3a
2. TBAF, THF, rt
a The reaction of 2 (0.2 mmol) was conducted with allyltrimethylsilane (3 equiv) in
the presence of 1·Cu(NTf2)2 (5 mol%) in EtNO2 at ambient temperature for 1–24
h. The crude product was treated with TBAF (1 equiv) in THF at ambient
temperature. b Isolated yield. c Evaluated by chiral HPLC analysis.
O
O
O
O
N
N
N
N
R’
R’
R’HN
NHR’
Me
O
1a: R’ = Ms
1b: R’ = Tf
1c: R’ = t-Bu
1d: R’ = Bn
S
O
O
N
O
N
N
O
O
O
O
H
Cu2+
Ph
Ph
Ph
Ph
Ph
H
O
Tf
N
N
N
N
N
O
S
2b
(R)-3b
O
Ph
Ph
Ph
Ph
Tf
Tf
N
1e
1f
O
N
Me
Entry
1
R
Yield (%)b
Ee (%)c
74
80
53
ND
–7
–16
–35
Tf
O
1
2
3
4
5
6
7
1a
1a
1b
1c
1d
1e
1f
Me
i-Pr
Me
Me
Me
Me
Me
78
50
90
3
83
68
67
Re face approach
Me
TMS
Scheme 1 Proposed transition state assembly for the 1a·Cu(NTf2)2-catalyzed
allylation of 2b
a
The reaction of 2a (0.2 mmol) was conducted with allylsilane (3 equiv) in the
The reaction of primary alkyl-substituted -ketoesters such as
presence of 1·Cu(NTf2)2 (5 mol%) in EtNO2 at ambient temperature for 20 h. The
crude product was treated with TBAF (1 equiv) in THF at ambient temperature for
0.5 h. b Isolated yield. c Evaluated by chiral HPLC analysis.
2c [R1 = CH3(CH2)5], 2d [R1 = CH2=CH(CH2)2] and 2e [R1
=
BnO(CH2)2] also gave the corresponding adducts 3c–e in
moderate to good yields (41–75%) with good
enantioselectivities (73–74% ee) (entries 2–4).
The reactivity of the present allylation highly depended on the
size of the R1 group. For example, the reaction of cyclopentyl-
substituted -ketoester 2f gave the corresponding adduct 3f in
67% yield with 69% ee (entry 5), while cyclohexyl-substituted
-ketoester 2g (R1 = c-C6H11) and methyl benzoylformate (2h,
R1 = Ph) were inert under the present reaction conditions, and
the starting materials were completely recovered (entries 6
and 7). The introduction of an electron-withdrawing CF3 group
on the phenyl group of 2h successfully improved the reactivity
to give 3i in 72% yield with 79% ee (entry 8).
We next examined the catalytic enantioselective Hosomi–
Sakurai reaction with methallyltrimethylsilane, which is more
nucleophilic than allyltrimethylsilane10 (Scheme 2). As a result,
the reaction proceeded rapidly even at –30 °C to give the
corresponding adduct 4a with high enantioselectivity (97% ee).
The optimized reaction conditions could be applied to the
allylation of various -ketoesters 2 (Table 2). The reaction of
benzyl pyruvate 2b gave the corresponding adduct 3b in 71%
yield with 65% ee (entry 1). The absolute configuration of 3b
was assigned to be R from the sign of the measured optical
rotation, compared to that of the reported S-isomer.7a This
enantioselectivity could be explained by the proposed
transition state assembly (Scheme 1).
Intramolecular
interaction of the sulfonamide groups of 1a with copper(II)
cation would preferentially shield the Si face of the
coordinated 2b.8 Allyltrimethylsilane would approach the Re
face of 2b to give (R)-3b as the major enantiomer.
2 | J. Name., 2012, 00, 1-3
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Table 3 Enantioselective addition reaction of 2 with methallyltrimethylsilanea
However, the yield of 4a was low (48%) and a significant
amount (32%) of 5a was also formed as a byproduct. This
byproduct should be generated via deprotonation of the
tertiary cation intermediate, while desilylation of the same
cationic intermediate gives the desired product 4a. According
to previous reports,11 5a could be converted into 4a under
acidic conditions via formation of the tertiary cation
intermediate. Indeed, treatment of 5a with 5 mol% of
1a·Cu(NTf2)2 at ambient temperature gave 4a in 75% yield
without any loss of enantiomeric excess (97% ee) (Scheme 2).
View Article Online
DOI: 10.1039/C9CC01159E
O
+
TMS
R1
CO2R2
2
1. 1a·Cu(NTf2)2 (5 mol%)
R1 OH
EtNO2, –30 °C then rt
CO2R2
*
4
2. TBAF, THF, rt
Entry
1
2
3
4d
5
6
7
8
9
10
11
12
13e
14
2
R1
Ph(CH2)2
Me
CH3(CH2)5
CH2=CH(CH2)2
BnO(CH2)3
c-C5H9
R2
Et
Bn
Et
Et
Et
Et
Et
Me
Et
Et
Et
Et
Et
Et
Yield (%)b
4a, 90
4b, 73
4c, 79
4d, 75
4e, 53
4f, 53
4g, 81
4h, 99
4i, 81
4j, 95
4k, 80
4l, 78
4m, 14
4n, 75
Ee (%)c
96
94
94
96
98
88
78
98
97
93
96
95
ND
97
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
O
+
TMS
Ph
CO2Et
2a
Ph
1a·Cu(NTf2)2
(5 mol%)
c-C6H11
Ph
Ph
EtNO2, –30 °C
4-CF3C6H4
4-MeOC6H4
4-MeC6H4
3-MeC6H4
2-MeC6H4
2-FC6H4
+
OH
CO2Et
OH
CO2Et
*
TMS
*
4a: 48%, 97% ee
5a: 32%
1a·Cu(NTf2)2 (5 mol%), EtNO2, rt
a
The reaction of 2 (0.2 mmol) with methallyltrimethylsilane (3 equiv) was
conducted in EtNO2 (1 mL) in the presence of 1a·Cu(NTf2)2 at –30 °C for 1 h, and
then the reaction mixture was warmed to ambient temperature. The crude
75%, 97% ee
Scheme
2
1a·Cu(NTf2)2-catalyzed addition reaction of 2a with
methallytrimethylsilane
b
c
product was treated with TBAF (0.5–3 equiv) in THF at 0 °C. Isolated yield.
Evaluated by chiral HPLC analysis. The reaction in the first step was conducted
at –50 °C. e The reaction in the first step was conducted at 60 °C.
d
The above results implied that when the reaction mixture,
which was obtained from the reaction of 2a with
methallyltrimethylsilane at –30 °C, was allowed to warm to
ambient temperature, then the corresponding adducts 4a
would be formed as a single product. As we expected, the
reaction of 2a with methallyltrimethylsilane under these
conditions (–30 °C, 1 h; then rt, 2 h) gave 4a in 90% yield with
96% ee (Table 3, entry 1).
N
N
Mes
Mes
Ph
Cl
Ru
Cl
PCy3
(2 mol%)
CH2Cl2, reflux
R
OH
OH
R
CO2Et
CO2Et
Since adduct 4a was obtained in high yield with high
enantioselectivity, we next examined the substrate scope and
limitations. As in the reaction with allyltrimethylsilane, the
crude products included a small amount of TMS ether of 4, so
the crude products were treated with TBAF to remove the TMS
group. The reaction of 2b–f gave the corresponding adducts
4b–f in good yields (53–79%) with high enantioselectivity (88–
98% ee) (entries 2–6). However, the reaction of 2g, which has
a rather bulky cyclohexyl group, showed a slightly low
enantioselectivity (78% ee), although the yield of 4g was good
(81%) (entry 7). The aryl-substituted -ketoesters 2h–l were
3d (R = H)
6 (R = H): 82% (75% ee)
7 (R = Me): 83% (95% ee)
4d (R = Me)
Scheme 3 Ring-closing metathesis of adducts 3d and 4d.
,-Disubstituted -hydroxyesters 3 and 4, the adducts of the
present Hosomi–Sakurai reaction, are synthetically useful
chiral building blocks. For example, ring-closing metathesis of
3d and 4d using Grubbs’ 2nd-generation catalyst (2 mol%)
gave the corresponding cyclohexenes 6 and 7 in respective
yields of 82 and 83% without loss of enantiomeric excess
(Scheme 2). Compound 6 is a key chiral intermediate for the
synthesis of quinic acid.12
In conclusion, we developed a catalytic enantioselective
Hosomi–Sakurai reaction of -ketoesters 2. Chiral copper(II)
complex with bis(oxazoline) ligand 1a showed high catalytic
activity, and chiral ,-disubstituted -hydroxyesters 3 and 4
were obtained in high yields with high enantioselectivities.
Financial support for this project was partially provided by a
Grant-in-Aid from JSPS KAKENHI (18K05123), the Sumitomo
also
good
substrates
for
the
reaction
with
methallyltrimethylsilane, and gave the corresponding adducts
4h–l in high yields (78–99%) with high enantioselectivity (93–
98% ee) (entries 8–12). The introduction of a methyl group at
the ortho-position of the phenyl group significantly decreased
the reactivity, probably due to steric hindrance (14% yield,
entry 13). In contrast to the 2-methylphenyl substituted 2m,
2-fluoro-derivative 2n showed good reactivity (75% yield) and
high enantioselectivity (97% ee) (entry 14).
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40; (c) R. Hunter, C. D. Simon, Tetrahedron Lett., 1988, 29,
Foundation and the Okayama Foundation for Science and
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Instrumental Analysis, Department of Instrumental Analysis &
Cryogenics, Advanced Science Research Center, Okayama
University for the NMR and HRMS measurements.
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Conflicts of interest
There are no conflicts to declare.
Notes and references
‡ See the Electronic Supplementary Information for details.
§ The minus sign indicates that the opposite enantiomer was
obtained as a major product.
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