Construction of a chiral quaternary carbon center by indium-catalyzed asymmetric α-alkenylation of β-ketoesters

Article abstract of DOI:10.1021/ja710408f

Construction of a nonracemic all-carbon quaternary stereocenter at the α-position of β-ketoesters was achieved by way of an indium(III)-catalyzed diastereoselective α-alkenylation reaction of chiral enamines with 1-alkynes. The enamine bearing a chiral auxiliary derived from L-isoleucine was added to the alkyne to give an α-alkenylated product in excellent yield and with a stereoselectivity better than 90% ee. One can ascribe the high selectivity to a chelate intermediate involving the auxiliary and the metal atom and the high yield to efficient interactions between the indium(III) atom and the alkyne. The selectivity increased as the reaction temperature was raised to 120°C and decreased at higher temperatures.

Full text of DOI:10.1021/ja710408f

Published on Web 03/11/2008
Construction of a Chiral Quaternary Carbon Center by
Indium-Catalyzed Asymmetric r-Alkenylation of â-Ketoesters
Taisuke Fujimoto, Kohei Endo,† Hayato Tsuji, Masaharu Nakamura,*,‡ and
Eiichi Nakamura*
Department of Chemistry, The UniVersity of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received November 18, 2007; E-mail: nakamura@chem.s.u-tokyo.ac.jp
Abstract: Construction of a nonracemic all-carbon quaternary stereocenter at the R-position of â-ketoesters
was achieved by way of an indium(III)-catalyzed diastereoselective R-alkenylation reaction of chiral enamines
with 1-alkynes. The enamine bearing a chiral auxiliary derived from L-isoleucine was added to the alkyne
to give an R-alkenylated product in excellent yield and with a stereoselectivity better than 90% ee. One
can ascribe the high selectivity to a chelate intermediate involving the auxiliary and the metal atom and the
high yield to efficient interactions between the indium(III) atom and the alkyne. The selectivity increased as
the reaction temperature was raised to 120 °C and decreased at higher temperatures.
Introduction
to achieve a high yield and high enantioselectivity. Following
the pioneering work by Meyers et al. on the reactions of chiral
We expended a considerable effort in the past decade to
achieve the addition of enolate anions or their nitrogen congeners
to unactivated olefins1 and acetylenes.2 Such reactions are unique
among the reactions that allow the formation of a C-C bond
at the R-position of carbonyl compounds because simple olefins
and acetylenes are not polarized and hence have been considered
to be unreactive toward a stabilized carbanionic nucleophile such
as enolate anions. In a series of papers, we demonstrated that
zinc(II) enolates and enamides add smoothly to simple olefins
in a stoichiometric manner1 and that zinc(II)3 or indium(III)2
enolates or enamides, generated from 1,3-dicarbonyl compounds,
react catalytically with simple 1-alkynes to produce R-alkeny-
lated or R-alkylidenated â-dicarbonyl compounds.4 One impor-
tant outcome of the former reactions is the possibility of
stereoselective synthesis of quaternary carbon centers,5 which
has attracted much attention of chemists because of the difficulty
metal enamides,6 various reactions were developed including
asymmetric R-alkylation,7,8 1,4-addition,9,10 Tsuji-Trost ally-
lation,11 and arylation.12 Introduction of an alkenyl group also
was reported, although much less frequently. For instance,
conjugated addition to alkynones13 and acylation of silyl ketene
acetals14 are such examples. A recent example by Toste and
Corkey on an enantioselective Pd-catalyzed Conia-ene reaction15
is an intramolecular variant of the R-alkenylation achieved by
the addition of a metal enolate to an alkyne. We report herein
an asymmetric indium(III)-catalyzed alkenylation of chiral
enamines to unactivated alkynes that creates an all-carbon
(5) For reviews, see: (a) Fuji, K. Chem. ReV. 1993, 93, 2037-2066. (b)
Christoffers, J.; Mann, A. Angew. Chem., Int. Ed. 2001, 40, 4591-4597.
(c) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388-
401. (d) Christoffers, J.; Baro, A. AdV. Synth. Catal. 2005, 347, 1473-
1482. (e) Denissova, I.; Barriault, L. Tetrahedron 2003, 59, 10105-10146.
(6) (a) Meyers, A. I.; Williams, D. R.; Erickson, G. W.; White, S.; Druelinger,
M. J. Am. Chem. Soc. 1981, 103, 3081-3087. (b) Meyers, A. I.; Williams,
D. R.; White, S.; Erickson, G. W. J. Am. Chem. Soc. 1981, 103, 3088-
3093. (c) Meyers, A. I.; Harre, M.; Garland, R. J. Am. Chem. Soc. 1984,
106, 1146-1148.
† Present address: Department of Chemistry and Biochemistry, School
of Advanced Science and Engineering, Waseda University, Ohkubo,
Shinjuku-ku, Tokyo 169-8555, Japan.
(7) (a) Tomioka, K.; Ando, K.; Takemasa, Y.; Koga, K. J. Am. Chem. Soc.
1984, 106, 2718-2719. (b) Enders, D.; Nu¨hring, A.; Runsink, J.; Raabe,
G. Synthesis 2001, 1406-1414.
‡ Present address: International Research Center for Elements Science,
Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011,
Japan.
(8) (a) Ooi, T.; Miki, T.; Taniguchi, M.; Shiraishi, M.; Takeuchi, M.; Maruoka,
K. Angew. Chem., Int. Ed. 2003, 42, 3796-3798. (b) Doyle, A. G.;
Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127, 62-63.
(1) (a) Kubota, K.; Nakamura, E. Angew. Chem., Int. Ed. 1997, 36, 2491-
2493. (b) Nakamura, M.; Hatakeyama, T.; Hara, K.; Nakamura, E. J. Am.
Chem. Soc. 2003, 125, 6362-6363. (c) Nakamura, M.; Hatakeyama, T.;
Nakamura, E. J. Am. Chem. Soc. 2004, 126, 11820-11825.
(2) (a) Nakamura, M.; Endo, K.; Nakamura, E. J. Am. Chem. Soc. 2003, 125,
13002-13003. (b) Nakamura, M.; Endo, K.; Nakamura, E. Org. Lett. 2005,
7, 3279-3281. (c) Endo, K.; Hatakeyama, T.; Nakamura, M.; Nakamura,
E. J. Am. Chem. Soc. 2007, 129, 5264-5271. (d) Tsuji, H.; Yamagata,
K.-i.; Itoh, Y.; Endo, K.; Nakamura, M.; Nakamura, E. Angew. Chem.,
Int. Ed. 2007, 46, 8060-8062.
(3) (a) Nakamura, M.; Liang, C.; Nakamura, E. Org. Lett. 2004, 6, 2015-
2017. (b) Nakamura, M.; Fujimoto, T.; Endo, K.; Nakamura, E. Org. Lett.
2004, 6, 4837-4840.
(4) Recently transition metal-catalyzed Conia-ene type alkenylation reactions
have been reported. (a) Au catalysis: Kennedy-Smith, J. J.; Staben, S. T.;
Toste, F. D. J. Am. Chem. Soc. 2004, 126, 4526-4527. (b) Au catalysis:
Ochida, A.; Ito, H.; Sawamura, M. J. Am. Chem. Soc. 2006, 128, 16486-
16487. (c) Re catalysis: Kuninobu, Y.; Kawata, A.; Takai, K. Org. Lett.
2005, 7, 4823-4825. (d) Ni/Yb catalysis: Gao, Q.; Zheng, B.-F.; Li, J.-
H.; Yang, D. Org. Lett. 2005, 7, 2185-2188.
(9) (a) Cristoffers, J.; Mann, A. Angew. Chem., Int. Ed. 2000, 39, 2752-2754.
(b) Hamashima, Y.; Hotta, D.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124,
11240-11241.
(10) (a) Kim, Y. S.; Matsunaga, S.; Das, J.; Sekine, A.; Ohshima, T.; Shibasaki,
M. J. Am. Chem. Soc. 2000, 122, 6506-6507. (b) Wu, F.; Li, H.; Hong,
R.; Deng, L. Angew. Chem., Int. Ed. 2006, 45, 947-950.
(11) (a) Nakamura, M.; Hajra, A.; Endo, K.; Nakamura, E. Angew. Chem., Int.
Ed. 2005, 44, 7248-7251. (b) Behenna, D. C.; Stoltz, B. M. J. Am. Chem.
Soc. 2004, 126, 15044-15045. (c) Nemoto, T.; Fukuda, T.; Matsumoto,
T.; Hitomi, T.; Hamada, Y. AdV. Synth. Catal. 2005, 347, 1504-1506.
(12) (a) Åhman, J.; Wolfe, J. P.; Troutman, M. V.; Palucki, M.; Buchwald, S.
L. J. Am. Chem. Soc. 1998, 120, 1918-1919. (b) Spielvogel, D. J.;
Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 3500-3501.
(13) Bella, M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 5672-5673.
(14) (a) Mermerian, A. H.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 4050-
4051. (b) Mermerian, A. H.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 5604-
5607.
(15) Corkey, B. K.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 17168-17169.
9
4492
J. AM. CHEM. SOC. 2008, 130, 4492-4496
10.1021/ja710408f CCC: $40.75 © 2008 American Chemical Society

Indium-Catalyzed
R
-Alkenylation of
â
-Ketoesters
A R T I C L E S
Table 1. Catalyst Screening
quaternary stereocenter with high efficiency. The synthetic
scheme is summarized in eq 1: the addition reaction of an
R-substituted â-enaminoester to an alkyne takes place in the
presence of an indium(III) catalyst, and acidic workup affords
optically active â-ketoesters. This reaction was inspired by a
stoichiometric analogue of the reaction that utilized an optically
active zinc(II) enamide and an unactivated olefin as reaction
partners,1b which, however, cannot be applied to quaternary
carbon center construction because of our inability to regiose-
lectively generate the necessary but sterically encumbered
enolate from R,R-disubstituted ketone or imine starting materials.
entry
catalysta
temp (
°
C)
time (h)
% yieldb
% eec
1
2
3
4
5
6
7
8
Et2Zn
Zn(OTf)2/Et3N
In(OTf)3
In(OTf)3/Et3N
In(OTf)3/BuLi
In(OTf)3/LiOTf
In(OTf)3/LiOTfd
In(OTf)3/Mg(OTf)2
70
100
120
120
120
120
120
120
8
18
6
12
8
12
12
12
96
98
95
12
92
88
75
90
15
53
89
53
94
93
95
94
a Ratio of zinc or indium salt and additive is 1:1 unless otherwise noted.
b Isolated yield. c Determined by HPLC analysis. d 2.5 equiv of LiOTf vs
indium salt was used.
Table 2. Temperature Effect on Stereoselectivity
Entry
temp (
°C)
% yielda
% eeb
Results and Discussion
1
2
3
4
70
100
120
140
87
94
92
93
68
83
94
91
General. A variety of enamines 1 bearing a chiral auxiliary
was synthesized in 80-90% yield by dehydrative condensation
of a dicarbonyl compound and a chiral amine derived from an
R-amino acid. They were obtained mostly as a single isomer, a
Z-enamine form, but no further structure determination was
carried out because this geometry is of no consequence in the
subsequent reaction.
a Isolated yield. b Determined by HPLC analysis.
Table 3. Chiral Auxiliary Screening
Screening of the catalyst was carried out for the reaction of
a â-enaminoester 1a derived from L-isoleucine (Table 1). The
addition reaction of the enamine 1a and phenylacetylene 2 was
carried out using various catalysts, some of which are shown
in Table 1, and subsequent acidic hydrolysis provided the
R-alkenylated products. It is noteworthy that the reaction does
not require the use of a solvent, although it tolerates the use of
aromatic solvents (e.g., toluene; Table 5, entries 5 and 6) when
necessary. The reaction in the presence of diethylzinc (10 mol
%)3b at 70 °C for 8 h gave the corresponding product 3 in 96%
yield with 15% ee (entry 1 in Table 1). A combination of zinc-
(II) bis(trifluoromethanesulfonate), Zn(OTf)2 (10 mol %), and
triethylamine, Et3N (10 mol %),3a at 100 °C for 18 h improved
the selectivity to 53% ee (entry 2 in Table 1). The reaction with
an In(OTf)3 catalyst2 took place faster than the zinc reaction
and gave better enantioselectivity (entry 3 in Table 1). However,
the presence of triethylamine reduced the activity of the In-
(OTf)3 catalyst (entry 4 in Table 1). When a small amount of
butyllithium in hexane (10 mol %) was added,2c the reaction
became faster, and the product was obtained in 92% yield with
94% ee (entry 5 in Table 1). Such beneficial effects of basic
additives were also observed for LiOTf (10 mol %, 93% ee)
(entry 6 in Table 1). A larger amount of LiOTf (25 mol %)
slightly improved the enantioselectivity to 95% ee at the expense
of the reaction rate (entry 7 in Table 1). Mg(OTf)2 (10 mol %)
behaved similarly to LiOTf (entry 8 in Table 1).
Entry
R
% yielda
% eeb
1
2
3
4
5
6
Bn (1b)
i-Bu (1c)
Ph (1d)
s-Bu (1a)
i-Pr (1e)
t-Bu (1f)
93
92
87
92
89
91
68
70
81
94
89
91
a Isolated yield. b Determined by HPLC analysis.
(entries 1-3 in Table 2) and decreased again when heated
further up to 140 °C (entry 4 in Table 2). Such a temperature
effect suggests that the selectivity is controlled by an entropy
factor.
Chiral auxiliary screening was performed using the reaction
of â-aminocrotonate 1a-1f and phenylacetylene 2 (2.0 equiv)
in the presence of In(OTf)3 (10 mol %) and butyllithium (10
mol %) at 120 °C for 8 h (Table 3). All substrates examined
herein afforded the desired product 3 in high yields while the
enantioselectivity was dependent on the structure of the chiral
auxiliaries. Selectivity was low with chiral auxiliaries lacking
a branched substituent (68% ee with 1b, entry 1 in Table 3,
and 70% ee with 1c, entry 2 in Table 3), and the enantioselec-
tivity slightly increased with a phenyl group (derived from
L-phenylglycine; 81% ee, entry 3 in Table 3). We finally found
Interestingly, the selectivity increased markedly as the tem-
perature was raised (Table 2f). It increased from 70 to 120 °C
9
J. AM. CHEM. SOC. VOL. 130, NO. 13, 2008 4493

A R T I C L E S
Fujimoto et al.
Table 4. Reaction of Various Ketoester Derivatives with
Table 5. Reaction with Various Alkynes
Phenylacetylene
entry
R
product
time (h)
% yielda
% eeb
Enamine
1
2
3
Ph (2)
n-Hex (20)
1-cyclohexenyl (22)
4-MeOC6H4 (24)
4-MeOCOC6H4 (26)
4-BrC6H4 (28)
13
21
23
25
27
29
8
24
12
4
24
24
93
78
88
82
91
93
94
94
88
96
94
94
entry
R1
R2
R3
product
time (h)
% yielda
% eeb
1
2
3
4
5
6
7
8
9
Me
Me
Me
Me
allyl
Bn
Et (1a)
Et (4)
Et (6)
3
5
7
8
18
18
8
8
8
8
8
8
92
82
85
92
94
93
93
84
81
94
94
95
97
96
94
94
92
81
4
5c
6c
-(CH2)4-
Et (8)
9
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
Me (10)
Et (12)
i-Pr (14)
allyl (16)
Bn (18)
11
13
15
17
19
a Isolated yield. b Determined by HPLC analysis. c Reaction was carried
out in toluene.
Table 6. Reaction of Various Ketoester Derivatives with Gaseous
Acetylene
a Isolated yield. b Determined by HPLC analysis.
that the L-isoleucine derivative 1a gave the best enantioselec-
tivity (94% ee, entry 4 in Table 3). The isopropyl (1e) and t-butyl
(1f) substituents are of comparable efficiency: 89% ee (entry
5 in Table 3) and 91% ee (entry 6 in Table 3), respectively.
The importance of the methoxy group in the chiral auxiliary
already has been documented for a long time6 and is illustrated
here experimentally by the very poor enantioselectivity for the
auxiliary without the methoxy group (eq 2).16 The reaction rate
was found to be rather insensitive to the absence of the methoxy
group.
Enamine
entry
R1
R2
R3
time (h)
product
% yielda
% eeb
1
2
3
4
Me
Bn
-(CH2)4-
-(CH2)3-
-(CH2)3-
Et (6)
Et (8)
Et (12)
Bn (18)
48
32
33
34
31
32
33
34
72
81
84
79
28
39
86
64
a Isolated yield. b Determined by HPLC analysis.
2 in Table 5). We found no evidence of either isomerization of
the terminal alkene produced to internal alkenes.2d The reaction
of 1-ethynylcyclohexene (22) took place to form the C-C bond
in the internal carbon atom to give a diene product 23 that
survived nicely under the reaction conditions (88% yield with
88% ee, entry 3 in Table 5). The reaction with electron-donating
p-methoxyphenylacethylene (24) was completed in 4 h to afford
the product 25 in 82% yield with 96% ee (entry 4 in Table 5).
The electron-withdrawing p-methoxycarbonylphenylacetylene
(26) and p-bromoethynylbenzene (28) required longer reaction
times to provide the corresponding products in 91% yield with
94% ee (27) and 93% yield with 94% ee (29), respectively
(entries 5 and 6 in Table 5). Comparison of the electron-rich
and deficient alkynes indicated that the electron-rich alkyne
reacts faster than the deficient alkyne, while the yield and
enantioselectivity of the product were unaffected by the sub-
stituent. This rate profile suggests strongly that Lewis acidic
activation of the alkyne by the indium metal is an important
step in this reaction.
The addition to acetylene posed some problems due to the
gaseous nature of the compound and the low purity of the
acetylene gas that are cheaply available. The reaction, however,
took place smoothly under conditions previously developed for
the corresponding racemic reaction (Table 6).2b Thus, the
reaction was carried out under an atmospheric pressure of
acetylene gas (welding grade) in the presence of In(OTf)3 (10
mol %), butyllithium (10 mol %), and molecular sieves 3A (100
wt % for the indium catalyst). While the reaction of an acyclic
substrate 6 and cyclohexanone derivative 8 resulted in being
poorly selective (28% ee, entry 1 in Table 6 and 39% ee, entry
Next, we examined the scope of the â-enaminoester substrates
under optimized conditions (Table 4). The reactions took place
in high yield and with a high enantioselectivity whether or not
the enamine moiety was a part of the ring structure. For acyclic
substrates 1a, 4, and 6, the substrates with a bulkier R-substituent
were rather unreactive but showed higher selectivities (up to
95% ee, entries 1-3 in Table 4). Cyclic substrates underwent
the addition reaction as well. The cyclohexanone derivative 8
furnished the product 9 with a higher yield and selectivity (92%
yield, 97% ee, entry 4 in Table 4). The 2-oxocyclopentancar-
boxylate derivatives 10, 12, and 14 provided the products 11,
13, and 15, respectively, in good yields with high enantiose-
lectivities (entries 5-7 in Table 4). The allyl ester 16 and the
benzyl ester 18 afforded the corresponding product in 84% yield
with 92% ee (entry 8 in Table 4) and 81% yield with 81% ee
(entry 9 in Table 4), respectively.
Table 5 summarizes the scope of the alkyne substrates. The
reaction of 12 with an alkyne (2.0 equiv) was carried out under
standard conditions with the use of In(OTf)3 and butyllithium
at 120 °C. The reaction with a simple aliphatic alkyne, 1-octyne
(20), required a somewhat longer reaction time (24 h) to give
the corresponding product 21 in 78% yield with 94% ee (entry
(16) This auxiliary is used for a diastereoselective 1,4-addition reaction. (a)
Guingant, A. Tetrahedron: Asymmetry 1991, 2, 415-418. (b) Cave´, C.;
Desmae¨le, D.; d’Angelo, J. J. Org. Chem. 1996, 61, 4361-4368.
9
4494 J. AM. CHEM. SOC. VOL. 130, NO. 13, 2008

Indium-Catalyzed
R
-Alkenylation of
â
-Ketoesters
A R T I C L E S
tolerates a considerable range of functional groups. We therefore
consider that indium(III), which serves as a Lewis acid, activates
specifically a C-C triple bond toward nucleophiles in the
presence of certain basic functional groups.
Experimental Procedures
Representative Procedure for Preparation of Chiral Enamine.
(Z)-Ethyl 3-[(2S,3R)-1-Methoxy-3-methylpentan-2-ylamino]-2-me-
thylbut-2-enoate (1a). Molecular sieves 4A (5.0 g) was added to a
hexane solution (30 mL) of ethyl 2-methylacetoacetate (4.32 g, 30.0
mmol) and (S)-1-methoxypentan-2-amine19 (4.32 g, 33.0 mmol), and
the mixture was heated at 50 °C for 12 h. The resulting suspension
was cooled to ambient temperature and was filtered through a pad of
Celite. The residue was washed with ethyl acetate, and the filtrate was
concentrated. The crude product was purified by distillation (13 Pa,
76-77 °C) to afford compound 1a as a colorless liquid (5.1 g, 93%).
1H NMR (CDCl3, 500 MHz) δ 0.89 (d, J ) 6.8 Hz, 3H), 0.91 (t, J )
7.4 Hz, 3H), 1.19 (m, 1H), 1.24 (t, J ) 6.8 Hz, 3H), 1.55 (m, 1H),
1.62 (m, 1H), 1.79 (s, 3H), 1.97 (s, 3H), 3.32 (m, 1H), 3.33 (s, 3H),
3.45 (dd, J ) 9.2 Hz, 6.9 Hz, 1H), 3.52 (m, 1H), 4.23 (m, 2H), 9.42
(d, J ) 9.2 Hz, 1H). 13C NMR (CDCl3, 125 MHz) δ 11.9, 12.8, 14.6,
15.5, 15.6, 24.7, 37.4, 57.4, 58.6, 59.2, 74.5, 86.5, 159.6, 171.0. IR
(cm-1) 3249 (br), 2970 (w), 2894 (w), 1640 (m), 1590 (s), 1478 (m),
1250 (vs), 1173 (w), 1102 (vs), 780 (m). Anal. calcd for C14H27NO3:
C, 65.33; H, 10.57; N, 5.44; Found: C, 65.26; H, 10.75; N, 5.31.
Representative Procedure for Asymmetric Alkenylation Reac-
tion. (R)-Isopropyl 2-Oxo-1-(1-phenylvinyl)cyclopentanecarboxylate
(15). Indium(III) triflate was dried under reduced pressure (26 Pa) at
60 °C for 2 h and then at 160 °C for 10 h before use. To the dried
indium triflate (16.8 mg, 0.030 mmol) was added 19 µL of butyllithium
(1.60 M hexane solution, 0.030 mmol) to afford a white paste. To this
mixture was added enamine 14 (849 mg, 3.0 mmol) and phenylacetylene
2 (612 mg, 6.0 mmol) successively to afford a pale-yellow homoge-
neous liquid. This mixture was heated immediately at 120 °C. The color
of the reaction mixture gradually turned orange. The reaction was
monitored by TLC analysis. After stirring for 8 h, enamine 14 was
completely consumed. The mixture was cooled to room temperature
and diluted with THF (3.0 mL). To the mixture was added an aqueous
solution of acetic acid (ca. 1 M, 3.0 mL). After stirring for 6 h, the
solution was neutralized by a saturated aqueous solution of NaHCO3
and extracted with AcOEt, and the combined organic layer was dried
over Na2SO4. Concentration and silica gel column chromatography
afforded pure product 15 as a pale-yellow oil (741 mg, 91% yield).
When the reaction was run in a 0.3 mmol scale, the yield was 93%,
Figure 1. ORTEP drawing of single-crystal structure of 29.
Figure 2. Proposed transition state structure.
2 in Table 6), the cyclopentanone derivatives 12 and 18 afforded
the corresponding R-vinyl product in high yield with acceptable
selectivity (entries 3 and 4 in Table 6). The poor selectivity
with acetylene gas indicates in turn that the steric bulk of the
substituent of the 1-alkyne plays a key role in the highly
enantioselective reactions described previously.
Absolute Configuration and Mechanistic Considerations.
A single crystal of compound 29 was obtained, and its absolute
configuration was determined to be R by X-ray structural
analysis using anomalous dispersion effects (Figure 1).17 The
Flack parameter of the R enantiomer was 0.015(7), while that
of the S enantiomer was close to 1.0.18
We previously proposed a transition state model of the
racemic version of the present reaction (â-ketoester addition to
alkyne) on the basis of a computational study.2c Considering
this model and the observed R configuration of the product to
the present system, we can build a reasonable transition state
structure as shown in Figure 2. The methoxy group forms a
rigid bicyclic ring system with the indium(III) center, which
forces the alkyne substituent away from the side chain (R) on
the chiral auxiliary. The poor selectivity with acetylene gas
conforms to this analysis. The electrophilic nature of the reaction
suggested by the data in Table 5 supports the proposed
mechanism that is driven by the strong interaction between the
indium(III) atom and an alkyne carbon atom.
1
which is shown in Table 4 (entry 7). H NMR (CDCl3, 500 MHz) δ
1.13 (d, J ) 6.3 Hz, 3H), 1.23 (d, J ) 6.3 Hz, 3H), 1.73-1.82 (m,
1H), 1.86-1.94 (m, 1H), 2.09-2.14 (m, 1H), 2.33-2.44 (m, 2H), 2.64
(ddd, J ) 13.2 Hz, 8.9 Hz, 6.9 Hz, 1H), 5.04 (hept, J ) 6.3 Hz, 1H),
5.27 (s, 1H), 5.46 (s, 1H), 7.23-7.32 (m, 5H). 13C NMR (CDCl3, 125
MHz) δ 18.9, 21.2, 21.5, 34.0, 37.2, 66.7, 69.4, 118.8, 127.5 (2C),
127.6 (2C), 128.1, 140.0, 144.9, 169.8, 212.1. IR (cm-1) 3057 (w),
2980 (m), 2897 (w), 1749 (vs), 1714 (vs), 1621 (w), 1494 (w), 1455
(w), 1374 (w), 1251 (vs), 1181 (m), 1139 (m), 1104 (vs), 1031 (w),
992 (w), 957 (w), 911 (s), 826 (m), 776 (s), 730 (m), 703 (w). Anal.
calcd for C17H20O3: C, 74.97; H, 7.40; Found: C, 75.21; H, 7.59. Chiral
HPLC: CHIRALPAK AD-H (Daicel), hexane/i-PrOH ) 95:5, 1 mL/
Conclusion
We have developed an asymmetric indium(III)-catalyzed
R-alkenylation reaction of â-ketoesters through the addition of
enamides bearing a chiral auxiliary to unactivated 1-alkynes.
While the reaction is a catalytic alkyne version of the stoichio-
metric reaction of the enamides derived from ketones that add
to unactivated 1-alkenes, we have so far been unable to apply
this catalytic reaction to unactivated alkenes. The origin of the
high reactivity is the strong electrophilic interaction of the
indium(III) atom to the alkyne that makes the reaction electro-
philic in its character and makes the transition state tight enough
to attain high enantioselectivity. Despite the high temperature
and Lewis acidity of the indium(III) metal atom, the reaction
min, 20 °C, 254 nm, 9.4 min (major)/14.3 min (minor). [R]29 -61.0
D
(c 0.30, CHCl3, 94% ee).
Representative Procedure for Addition to Acetylene Gas. (R)-
Ethyl 2-Benzyl-2-ethanoylbut-3-enoate (31). Dried indium(III) triflate
(12.9 mg, 0.024 mmol) and molecular sieves 3A (12.9 mg) were placed
into a flame-dried reaction vessel (15 mL) equipped with a balloon
(17) Flack, H. D. Acta Crystallogr., Sect. A: Found. Crystallogr. 1983, 39,
876-881.
(18) Single crystal used for the X-ray structural analysis was analyzed by HPLC
to provide the same retention time as the major enantiomer.
(19) (S)-1-Methoxypentan-2-amine was prepared by methylation of L-(+)-
isoleucinol with NaH/MeI according to Meyers et al.’s procedure: Meyers,
A. I.; Williams, D. R.; Erickson, G. W.; White, S.; Druelinger, M. J. J.
Am. Chem. Soc. 1981, 103, 3081-3087.
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A R T I C L E S
Fujimoto et al.
filled with 1 atm pressure of welding-grade acetylene gas. The solids
were treated with butyllithium (1.6 M, 15 µL, 0.024 mmol) under argon,
and the vessel was evacuated and then acetylene was introduced via
the balloon. Under acetylenic atmosphere, enamine 6 (0.24 mmol) and
toluene (240 µL) were added, and the resulting suspension was heated
at 120 °C for 48 h. The resulting mixture was cooled to room
temperature, diluted with THF (500 µL), and treated with an aqueous
solution of acetic acid (ca. 1 M, 500 µL). After stirring for 6 h, the
mixture was neutralized with an aqueous NaHCO3 solution, extracted
with ethyl acetate, and concentrated. The crude product was purified
by silica gel column chromatography to afford pure product 31 as a
pale-yellow oil (43 mg, 72%). 1H NMR (CDCl3, 500 MHz) δ 1.22 (t,
J ) 7.5 Hz, 3H), 2.12 (s, 3H), 3.23 (d, J ) 13.7 Hz, 1H), 3.39 (d, J )
13.7 Hz, 1H), 4.14 (dq, J ) 10.9 Hz, 7.5 Hz, 1H), 4.20 (dq, J ) 10.9
Hz, 7.5 Hz, 1H), 5.15 (d, J ) 17.7 Hz, 1H), 5.38 (d, J ) 10.9 Hz, 1H),
6.31 (dd, J ) 17.7 Hz, 10.9 Hz, 1H), 7.09 (dd, J ) 7.2 Hz, 1.8 Hz,
2H), 7.19-7.26 (m, 3H). 13C NMR (CDCl3, 125 MHz) δ 13.9, 27.3,
41.3, 61.5, 67.3, 117.9, 126.7, 128.0 (2C), 130.0 (2C), 135.3, 136.1,
170.5, 201.8. IR (cm-1) 3031 (w), 2983 (w), 2939 (w), 1713 (vs), 1497
(w), 1455 (w), 1355 (w), 1260 (m), 1173 (s), 1084 (m), 1017 (m), 996
(m), 928 (m), 857 (w), 739 (w), 700 (vs). Anal. calcd for C15H18O3:
C, 73.15; H, 7.37; Found: C, 73.17; H, 7.62. Chiral HPLC: CHIRAL-
PAK OJ-H (Daicel), hexane/i-PrOH ) 99.9:0.1, 0.5 mL/min, 20 °C,
275 nm, 34.1 min (major)/39.3 min (minor). [R]23 -4.28 (c 0.73,
D
CHCl3, 28% ee).
Acknowledgment. This research was supported by KAK-
ENHI provided by MEXT/JSPS (E.N., No. 18105004) and by
a Grant-in-Aid for the 21st Century COE Program for Frontiers
in Fundamental Chemistry provided by MEXT, Japan.
Supporting Information Available: Experimental details and
HPLC analysis data. This material is available free of charge
via the Internet at http://pubs.acs.org.
JA710408F
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4496 J. AM. CHEM. SOC. VOL. 130, NO. 13, 2008