α-Chiral acetylenes having an all-carbon quaternary center: Phase transfer catalyzed enantioselective a alkylation of a-alkyl-a-alkynyl esters

Full text of DOI:10.1002/anie.200901977

Communications
DOI: 10.1002/anie.200901977
Asymmetric Synthesis
a-Chiral Acetylenes Having an All-Carbon Quaternary Center: Phase
Transfer Catalyzed Enantioselective a Alkylation of a-Alkyl-a-alkynyl
Esters**
Takuya Hashimoto, Kazuki Sakata, and Keiji Maruoka*
Owing to the synthetic versatility and modularity of acety-
lenes, chiral building blocks bearing acetylene moieties are
widely used as valuable intermediates.[1] Accordingly, tre-
mendous efforts have been devoted to the development of
catalytic asymmetric approaches to enable facile access to
Scheme 2. Phase transfer catalyzed asymmetric functionalization of
these attractive materials. The asymmetric transition metal
mediated addition of terminal acetylenes (asymmetric alky-
nylations) to various prochiral electrophiles (Scheme 1,
left),[2] such as aldehydes,[3] ketones,[4] aldimines,[5] and
a-alkyl-a-alkynyl esters. Q=ammonium.
catalyzed asymmetric alkylation, taking advantage of its well-
established practicality in analogous transformations, as well
as our broad interest in phase-transfer catalysis.[16]
The starting materials, a-alkyl-a-alkynyl esters, could be
synthesized from a-iodoalkanoates and monosubstituted
acetylenes by using the protocol reported by Oshima and
co-workers.[17] In an exploratory study, the asymmetric
benzylation of the a-silylethynyl esters 3 was investigated
under conventional phase transfer catalyzed alkylation reac-
tion conditions using (S)-1a as the catalyst (Table 1).[18] To our
delight, the reaction of a-(tert-butyldimethylsilyl)ethynyl
ester cleanly provided the desired compound in 87% yield
with 63% ee (Table 1, entry 1). Examination of the steric
Scheme 1. Common tactics for the catalytic asymmetric synthesis of
a-chiral acetylenes.
electron-deficient alkenes,[6] as well as asymmetric additions
to prochiral alkynyl substrates (Scheme 1, right),[7–11] have
been successfully adopted for this purpose.[12,13]
Table 1: Screening of the reaction conditions.[a]
However, most of these procedures are only applicable to
the synthesis of a-chiral acetylenes having one hydrogen atom
at the a position.[14] We envisaged that asymmetric a func-
tionalization of racemic a-alkyl-a-alkynyl esters via prochiral
a-alkynyl enolates would offer a distinctive solution in this
realm, providing a-chiral acetylenes having a quaternary
À
stereogenic center (Scheme 2). The asymmetric C C bond
formation with these substrates is highly appealing since it is
expected to generate an enantioenriched all-carbon quater-
nary center having both an appended acetylene and ester as
useful functionalities;[15] such a substrate is hardly accessible
by use of the existing catalytic asymmetric methods.
Entry Cat. Si
Solvent
toluene
T [8C], t [h] Yield [%][b] ee [%][c]
As a suitable benchmark catalytic system to evaluate the
viability of such a transformation, we selected phase transfer
1
2
3
4
5
6
7
8
1a
1a
1a
1b
1c
2
TBS
0, 5
0, 20
0, 2
0, 2
0, 2
0, 5
0, 5
87
92
68
62
48
49
78
70
63
18
78
74
11
14
83
86
TIPS toluene
TMS toluene
TMS toluene
TMS toluene
TMS toluene
TMS mesitylene
[*] Dr. T. Hashimoto, K. Sakata, Prof. Dr. K. Maruoka
Department of Chemistry, Graduate School of Science
Kyoto University
1a
1a
TMS mesitylene À20, 12
Sakyo, Kyoto, 606-8502, (Japan)
Fax: (+81)75-753-4041
E-mail: maruoka@kuchem.kyoto-u.ac.jp
[a] Reactions conditions:
3
(0.10 mmol) and benzyl bromide
(0.12 mmol) in the presence of 2 mol% phase-transfer catalyst
(0.002 mmol) and powdered KOH (0.25 mmol). [b] Yield of isolated
product. [c] Determined by chiral HPLC analysis after desilylation of the
product. TBS=tert-butyldimethylsilyl. TIPS=triisopropylsilyl, TMS=tri-
methylsilyl.
[**] This work was partially supported by a Grant-in-Aid for Scientific
Research from the MEXT (Japan).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200901977.
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effect of the silyl moiety revealed that the use of the bulky
triisopropylsilyl group reduced the enantioselectivity to
18% ee (Table 1, entry 2), whereas the small trimethylsilyl-
substituted ester was converted into the desired product with
a promising level of asymmetric induction (Table 1, entry 3).
Although the screening of other catalysts could not improve
the selectivity (Table 1, entries 4–6), use of mesitylene as a
solvent at lower temperature had a positive effect, furnishing
the target material with 86% ee (Table 1, entries 7 and 8).
Having the optimized conditions in hand, the scope of this
alkylation was then examined (Table 2). Irrespective of the
electronic nature and substituent pattern of the benzylic
Scheme 3. Alkylation of a-methyl-a-phenylethynyl ester.
g-hydrogen atom of the allenyl ester, thereby making the
generation of the reactive enolate far less feasible.[20] Notably,
under our catalytic reaction conditions, the g-alkylated allenyl
ester was not observed at all.
Table 2: Alkylation of a-alkyl-a-(trimethylsilyl)ethynyl esters.[a]
At this point, we turned our attention to the use of cesium
hydroxide monohydrate, as a stronger base to overcome this
deficiency, under otherwise identical reaction conditions. As a
result, the alkylated compound could be obtained in 88%
yield within 27 hours without the loss of the enantioselectivity
(Table 3, entry 1).[21] This newly developed set of reaction
conditions had a broad substrate scope with respect to alkyl
Entry
R2
R3
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
10
Me
Me
Me
Me
Me
Me
Me
Et
Bn
70
72
74
79
59
89
73
85
81
78
86
90
82
83
90
87
84
89
87
90
3-MeC6H4CH2
4-MeOC6H4CH2
2-ClC6H4CH2
H2C C(CH3)CH2
(CH3)2C CHCH2
(E)-PhCH CHCH2
Bn
2-MeC6H4CH2
(E)-PhCH CHCH2
Table 3: Alkylation of a-aryl-, alkenyl-, and alkylethynyl esters.[a]
=
=
=
Et
Et
Entry R1
R2
R3
Yield [%][b] ee [%][c]
=
1
2
3
4
5
6
7
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me Bn
88
85
81
88
94
94
90
92
96
90
90
82
93
95
94
95
96
[a] Reactions conditions: the alkynyl ester (0.10 mmol) and alkyl halide
(0.12 mmol) in the presence of 2 mol% (S)-1a (0.002 mmol) and
powdered KOH (0.25 mmol). [b] Yield of the isolated product. [c] Deter-
mined by chiral HPLC or GC analysis after desilylation of the product.
Bn=benzyl.
Me 3-MeC6H4CH2
Me 4-MeOC6H4CH2
Me 2-ClC6H4CH2
Me H2C C(CH3)CH2 92
Me H2C CHCH2
=
=
ꢀ
81
84
90
88
Me HC CCH2
Me tBuO2CCH2
8[d]
9
10
11
12
13
halides, the alkylation gave the products in good yields and
ee values (Table 2, entries 2–4).[19] Excellent levels of enan-
tioselectivity were attained in the reactions involving prenyl
and methallyl bromides (Table 2, entries 5 and 6). Cinnamyl
bromide could be utilized as well (Table 2, entry 7). To
investigate the tolerance of the other a-alkyl group of the
ester, a-ethyl-a-(trimethylsilyl)ethynyl ester was subjected to
this enantioselective alkylation and resulted in the formation
of the desired compounds in satisfactory yields and having
ee values ranging from 87% to 90% (Table 2, entries 8–10).
In the process of expanding the substrate scope of this
phase transfer catalyzed alkylation to include other a-alkynyl
esters having either an aryl, alkenyl, or alkyl substituent at the
acetylene terminus, we became aware of the significantly
decreased reactivity of these substrates. For example, benzy-
lation of the a-phenylethynyl ester 5 under the aforemen-
tioned reaction conditions led to the formation of product 6 in
only 28% yield after 10 days, even though the enantioselec-
tivity was remarkably high (Scheme 3). Examination of the
remaining components revealed the complete disappearance
of the starting a-alkynyl ester 5 and the formation of the
allenyl ester 7 in a racemic form. This fact indicated the facile
base-mediated isomerization of the a-alkynyl ester, which has
a rather acidic a-hydrogen atom relative to the poorly acidic
Et
Et
Bn
=
H2C C(CH3)CH2 87
92
4-MeOC6H4 Me H2C C(CH3)CH2 87
4-MeOC6H4 Me Bn
=
4-ClC6H4
Me Bn
Me Bn
Me Bn
85
82
69
14[e]
15[e]
93
90
nBu
[a] Reactions conditions: the alkynyl ester (0.10 mmol) and alkyl halide
(0.12 mmol) in the presence of 2 mol% (S)-1a (0.002 mmol) and
powdered CsOH·H2O (0.50 mmol). [b] Yield of the isolated product.
[c] Determined by chiral HPLC analysis. [d] Performed at À308C.
[e] 10 equiv of CsOH·H2O.
halides and a-alkyl-a-alkynyl esters as showcased in Table 3.
Use of benzylic and allylic halides in the reaction with
a-methyl-a-phenylethynyl ester furnished the corresponding
products in high yields and with enantioselectivities ranging
from 90 to 96% ee (Table 3, entries 1–7). Alkylation with
bromoacetate gave the product with slightly lower enantio-
selectivity (Table 3, entry 8). Alkylation of other a-aryl-
ethynyl esters with different steric and electronic properties
also worked very efficiently (Table 3, entries 9–13). Further-
more, this method was applicable to alkynyl esters having an
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Communications
Jiang, W. Liu, L. Qiu, Z. Xu, J. Xu, A. S. C. Chan, R. Wang, Org.
Lett. 2007, 9, 2329.
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To investigate further the appearance of the allenyl ester
in this reaction system, phase transfer catalyzed alkylation of
the separately synthesized allenyl esters was implemented as
shown in Scheme 4. As expected, alkylation of the g-phenyl-
allenyl ester 7[22] proceeded by using cesium hydroxide
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Scheme 4. Phase transfer catalyzed enantioselective alkylation of
allenyl esters.
monohydrate and the result was comparable to that of the
ethynyl ester, whereas the reaction of g-(trimethylsilyl)allenyl
ester 8[23] only required the use of potassium hydroxide. This
finding led us to conclude that the reactivity difference
between a-silylethynyl esters and other a-alkynyl esters stems
from the facile g deprotonation of g-silylallenyl esters gen-
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In summary, we demonstrated the feasibility of a-alkyl-a-
alkynyl esters to undergo highly enantioselective a alkylation
under phase-transfer reaction conditions, furnishing a-chiral
acetylenes having an all-carbon quaternary center. A detailed
investigation of this reaction system revealed the formation of
an allenyl ester prior to the alkylation. Considering the
increase in the number of various asymmetric catalysis
reactions which rely on the in situ deprotonation of
a-hydrogen atoms on the esters, the protocol reported
herein will have broad applicability beyond phase-transfer
catalysis as a means to afford an array of a-chiral acetylenes
having a quaternary stereogenic center.
À
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Received: April 14, 2009
Published online: June 2, 2009
Keywords: alkylation · alkynes · asymmetric synthesis ·
.
phase-transfer catalysis · synthetic methods
À
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À
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À
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[19] For the determination of the absolute configuration, see the
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reaction conditions led to the formation of the benzylated
compound in 66% yield and 78% ee within 2 hours.
[22] R. W. Lang, H.-J. Hansen, Org. Synth. 1984, 62, 202.
[23] Prepared as a mixture of the allenyl ester and the ethynyl ester
(71:29); see the Supporting Information for details.
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