Copper (I)-catalyzed asymmetric addition of terminal alkynes to β-Imino esters: An efficient and direct method in the synthesis of chiral β3-alkynyl β2,2-dimethyl amino acid derivatives

Article abstract of DOI:10.1002/adsc.200900084

The first catalytic asymmetric addition of terminal alkynes to β-imino esters was carried out using chiral copper(I) complexes as catalysts under mild reaction conditions, providing an efficient and direct synthetic approach to β³-alkynyl β

Full text of DOI:10.1002/adsc.200900084

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DOI: 10.1002/adsc.200900084
Copper(I)-Catalyzed Asymmetric Addition of Terminal Alkynes
to b-Imino Esters: An Efficient and Direct Method in the
Synthesis of Chiral b3-Alkynyl b2,2-Dimethyl Amino Acid
Derivatives
Jun Wang,a Zhihui Shao,a Kai Ding Wing Yiu Yu,a,* and Albert S. C. Chana,*
a
Open Laboratory of Chirotechnology of the Institute of Molecular Technology for Drug Discovery and Synthesis and
Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, Peopleꢀs
Republic of China
Fax : (+852)-2364-9932; e-mail: bcachan@polyu.edu.hk
Received: February 6, 2009; Published online: May 28, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900084.
Abstract: The first catalytic asymmetric addition of
terminal alkynes to b-imino esters was carried out
using chiral copper(I) complexes as catalysts under
mild reaction conditions, providing an efficient and
direct synthetic approach to b3-alkynyl b2,2-dimethyl
amino esters with yields of 73–97% and 48–90% ee.
The rich chemistry of the alkynyl functionality
makes the present method a powerful and versatile
approach to a wide range of optically active b2,2-di-
methyl amino acid derivatives.
Alternatively, imino-Reformatsky reactions[5] have re-
cently been exploited for enantioselective b-amino
ester synthesis. Some notable achievements have been
made by Cozzi and co-workers in developing a one-
pot, three-component coupling protocol for enantio-
selective imino-Reformatsky reactions.[6]
Metal-catalyzed alkynylation of imines is a direct
and convenient strategy for the synthesis of propar-
gylamines.[7] Recently, we reported the catalytic asym-
metric alkynylation of a-imino esters for the prepara-
tion of optically active propargylic a-amino acids.
Using Cu(I) as catalyst and chiral bis(oxazolinyl)pyri-
dine (Pybox) as ligand, the addition of 1-octyne to a-
imino esters was achieved in up to 91% ee.[8] Based
on this finding, we anticipated that the analogous al-
kynylation of b-imino esters would afford enantioen-
riched propargylic b-amino acids. In this work, we
Keywords: asymmetric alkynylation; asymmetric
catalysis; copper; enantioselectivity; b-imino esters
b-Amino esters are useful building blocks for the syn- present our investigation on the Cu-catalyzed enan-
thesis of many nitrogen-containing biologically impor- tioselective addition of terminal alkynes to 3-(4-me-
tant compounds such as b-lactams; the development thoxyphenylimino)-2,2-dimethylpropionate, and b3-
of effective catalytic methods for the enantioselective alkyne b2,2-dimethyl amino esters were formed in up
synthesis of b-amino esters is a subject of active re- to 90% ee. According to the literature, 3-substituted-
search.[1] The asymmetric Mannich reaction consti- 2,2-dimethyl-b-amino acid residues are useful linear
tutes one of the most powerful tools for the synthesis templates for conformationally restricted peptidomi-
of chiral b-amino acids.[2] Some typical “Mannich metics, and they possess interesting pharmacological
donors” include silicon enolates, metal enolates, ke- activities.[9] For example, ethyl N-(3-{2-fluoro-4-[thi-
tones and aldehydes. Asymmetric Mannich-type reac-
tions involving addition of silyl enolates to aromatic
N
ACHTUNGTRENUN(NG imino)methyl]benzoyl}amino-2,2-dimeth-
aldimines catalyzed by chiral Lewis acid catalysts ported to be a highly potent and orally active fibrino-
have been extensively investigated, and b2,2,3-trisubsti- gen receptor antagonist (Figure 1).[10]
tuted b-amino esters can be obtained in good yields
By means of a modified Reformatsky reaction
with moderate to high enantiomeric excesses.[3] Re- (Scheme 1),[11] treatment of ethyl bromoisobutyrate
cently, proline and derivatives have emerged as effec- with zinc and triethyl orthoformate afforded 3,3-di-
tive organocatalysts for asymmetric Mannich reac- ethoxy-2,2-dimethylpropionic acid ethyl ester in 78%
tions of ketones or equivalents thereof and imines.[4] yield. Condensation of 3,3-diethoxy-2,2-dimethylpro-
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Copper(I)-Catalyzed Asymmetric Addition of Terminal Alkynes to b-Imino Esters
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Table 1. Cu-catalyzed enantioselective addition of 1-hexyne
to b-imino ester 1.[a]
Figure 1. The structure of NSL-96184.
Scheme 1. Synthesis of 3-(4-methoxyphenylimino)-2,2-dime-
thylpropionic acid ethyl ester 1.
Entry
Ligand
Yield [%][b]
ee [%][c]
1
2
3
4
5
4
5
6
7
8
87
68
89
87
73
69
67
87
69
1
pionic acid ethyl ester with p-anisidine in the presence
of p-toluenesulfonic acid monohydrate (PTSA) gave
3-(4-methoxyphenylimino)-2,2-dimethylpropionic acid
ethyl ester 1 in 91% yield.
[a]
All the reactions were carried out in a 0.25 mmol scale of
1 using 2 equiv. of alkyne 2a in 1.0 mL CH2Cl2 with 10
mol% Pybox and 10 mol% CuOTf·0.5toluene at room
temperature.
When b-imino ester 1 (0.25 mmol) was treated with
1-hexyne
2a
(0.5 mmol),
CuOTf.0.5toluene
(0.025 mmol) and pybox ligand 4 (0.025 mmol) in
CH2Cl2 (1 mL) at room temperature for 72 h, 3a was
produced in 87% yield and 69% ee (Table 1, entry 1).
The activity of other pybox derivatives for the alkyny-
lation reaction has also been examined. As shown in
Table 1, the best results (89% yield, 87% ee) were ob-
[b]
[c]
Isolated yield.
Determined by chiral HPLC using a Chiralpak AD-H
column.
tained when pybox ligand 6 containing t-Bu substitu- yield after seven days of reaction (entry 1). Interest-
ents was used (entry 3). Other pybox derivatives bear- ingly, when a ligand-to-metal ratio of 0.75:1 was em-
ing i-Pr (ligand 5) or indanyl (ligand 7) groups pro- ployed, 3a was obtained in 88% yield on day 1 and
duced 3a in lower enantioselectivity (ca. 68%, en- 97% yield on day 2. An optimum ligand-to-metal
tries 2 and 4), while the bidentate bis(oxazoline) ratio was found to be 0.5:1 and 3a was produced
ligand 8 gave 73% yield but a racemic product (<1% quantitatively after two days of reaction (entry 5).
ee). Analogous to our previous work,[8] other ligands Notably, ligand-to-metal ratios <0.5:1 also led to
such as Binap, Quinap and MonoPhos phosphorami- sluggish reactions (entries 6 and 7). However, the
dites failed to give comparable results.
Reiser reported the Michael addition of indole to rather insensitive to the ligand-to-metal ratio.
benzylidene malonate catalyzed by a copper catalyst Table 3 depicts the effect of solvent on the Cu-cata-
enantioselectivity of the alkynylation reaction was
containing bis(oxazoline) ligands in which the excess lyzed enantioselective addition of 1-hexyne to b-
of ligand with respect to the metal was detrimental to imino ester 1. When toluene and EtOAc were em-
enantioselectivity.[12] According to our earlier reports ployed, 3a was obtained in ca. 65% yield. Other sol-
on the alkynylation of a-imino esters, the ligand-to- vents such as THF, hexane, DCE and CH2Cl2 afforded
metal ratio was found to have a profound influence better yields (>80%) of 3a. Considering both the
on the enantioselctivity.[8c] In this work, the effect of yield and enantioselectivity, we chose CH2Cl2 as the
the ligand-to-metal ratio on the alkynylation of b- solvent for further studies.
imino ester 1 has been investigated. As shown in
With the optimized conditions in hand, the scope of
Table 2, a ligand-to-metal ratio> 1:1 resulted in slug- alkynes in the reaction system was examined, and the
gish reactions. For instance, with a ligand-to-metal results are summarized in Table 4. Both aliphatic
ratio=1.5:1, the product 3a was obtained in 53% alkynes and aromatic alkynes reacted smoothly with
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Jun Wang et al.
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Table 2. Effects of different ligand-to-Cu(I) ratio on reactivity and enatioselectivity.[a]
Entry
Ratio of 6 to Cu
Yield[b] [%]
3 Days
ee [%][c]
1 Day
2 Days
7 Days
1
2
3
4
5
6
7
1.5:1
1.25:1
1:1
0.75:1
0.5:1
0.25:1
0.125:1
14
26
60
88
94
66
43
29
48
88
97
100
90
72
36
60
95
/
/
95
83
53
90
/
/
/
88
88
87
87
87
85
83
/
84
[a]
All the reactions were carried out in a 0.25-mmol scale of 1 using 2 equiv. of alkyne 2a in 1.0 mL CH2Cl2 with 10 mol%
CuOTf·0.5toluene at room temperature.
Determined by GC with tetradecane as internal standard.
[b]
[c]
Determined by chiral HPLC using a Chiralpak AD-H column.
Table 3. Effects of the choice of solvent on the reactivity ly alkynes with some functional groups, makes this re-
and enantioselectivity.[a]
action attractive.
In conclusion, we have investigated the addition of
terminal alkynes to b-imino esters, and developed the
first catalytic enantioselective addition of terminal
alkynes to b-imino esters. This reaction provides an
efficient and direct synthetic approach to b3-alkynyl
b2,2-dimethyl amino esters with 73–97% yields and
48–90% ee. The rich chemistry of alkynyl functionali-
ty makes the present method a powerful and versatile
approach to a wide range of optically active b2,2-di-
Entry
Solvent
Yield [%][b]
ee [%][c] methyl amino acid derivatives. The mechanism and
synthetic applications of this efficient addition reac-
tion are currently under investigation in our laborato-
ry.
54
1
2
3
4
5
6
THF
80
68
82
60
87
97
90
86
Toluene
Hexane
EtOAc
DCE
90
87
87
CH2Cl2
[a]
All the reactions were carried out in a 0.25-mmol scale
of 1 using 2 equiv. of alkyne 2a in 1.0 mL solvent with 10
mol% CuOTf·0.5toluene at room temperature.
Determined by GC with tetradecane as internal stan-
dard.
Experimental Section
Typical Procedure for Catalytic Asymmetric
Alkynylation of b-Imino Esters
[b]
[c]
Pybox
6 (4.1 mg, 0.0125 mmol) and CuOTf·0.5toluene
Determined by chiral HPLC using a Chiralpak AD-H
column.
(6.5 mg, 0.025 mmol) were added to a dried 5-mL reaction
flask containing a magnetic stirring bar. CH2Cl2 (1.0 mL)
was added, and the mixture was stirred at room temperature
for 1 h. Then b-imino ester 1 (62 mg, 0.25 mmol) and alkyne
(0.5 mmol) were sequentially added under vigorous stirring.
The resulting solution was stirred at room temperature until
the completion of the reaction, as monitored by TLC. The
mixture was then passed through a short plug of silica gel
which was subsequently washed with ether. The combined
solutions were concentrated under vacuum. The purification
b-imino ester, providing the corresponding alkynyla-
tion products with excellent yields and good ee.
Methyl propiolate 2g is very active and the reaction
was complete within several hours. However, the ee is
only 48% (entry 8), and a lower reaction temperature
did not improve the enantioselectivity, but just drop-
ped the yield. The wide scope of the alkynes, especial- of the residue by flash silica gel column chromatography
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Copper(I)-Catalyzed Asymmetric Addition of Terminal Alkynes to b-Imino Esters
Table 4. Cu-catalyzed addition of alkynes to b-imino ester.[a]
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Entry
Alkyne
Product
Yield [%][b]
ee [%][c]
1
2
2a
2b
3a
3b
97
93
87
75
3
4
2c
2c
3c
3c
96
83
84
84[d]
5
6
2d
2e
3d
3e
92
82
70
77
7
8
2f
2g
3f
3g
73
86
77
48
9
2h
3h
90
88
10
2h
2i
3h
3i
32[e]
81
85
77
11
[a]
All the reactions were carried out in a 0.25-mmol scale of 1 using 2 equiv. of alkyne 2a–i in 1.0 mL CH2Cl2 with 5 mol%
Pybox 6 and 10 mol% CuOTf·0.5toluene at room temperature.
Isolated yield.
Determined by chiral HPLC using a Chiralpak AD-H or OD-H column.
Reaction was performed in THF instead of CH2Cl2.
[b]
[c]
[d]
[e]
Reaction was performed in THF and 60% 1 recovered.
yielded the corresponding alkynylation product (see Sup-
porting Information for details).
Amino Acids, (Eds.: E. Juaristi, V. A. Soloshonok),
Wiley-VCH, New York, 2005, and references cited
therein; b) D. Seebach, T. Kimmerlin, R. Sebesta,
M. A. Campo, A. K. Beck, Tetrahedron 2004, 60, 7455;
c) N. Sewald, Angew. Chem. 2003, 115, 5972; Angew.
Chem. Int. Ed. 2003, 42, 5794; d) J. A. Ma, Angew.
Chem. 2003, 115, 4426; Angew. Chem. Int. Ed. 2003, 42,
4290; e) A. E. Taggi, A. M. Hafez, T. Lectka, Acc.
Chem. Res. 2003, 36, 10; f) M. Liu, M. P. Sibi, Tetrahe-
dron 2002, 58, 7991; g) S. Abele, D. Seebach, Eur. J.
Org. Chem. 2000, 1; h) G. Cardillo, C. Tomasini, Chem.
Soc. Rev. 1996, 25, 117.
Acknowledgements
We thank the Hong Kong Research Grants Council (PolyU
5003/06P), the University Grants Committee Areas of Excel-
lence Scheme in Hong Kong (AoE P/10–01) and the Hong
Kong Polytechnic University Areas of Strategic Development
Fund for financial support.
[2] Reviews: a) M. Ueno, S. Kobayashi, Catalytic enantio-
selective Mannich reactions, in: Enantioselective Synthe-
sis of b-Amino Acids, (Eds.: E. Juaristi, V. A. Solosho-
nok), Wiley-VCH, New York, 2005, pp 139–158, and
references cited therein; b) K. Brinner, J. A. Ellman,
Asymmetric synthesis of b-amino acids by enolate addi-
References
[1] For a discussion of the synthesis and biology of b-
amino acids see: a) Enantioselective Synthesis of b-
Adv. Synth. Catal. 2009, 351, 1250 – 1254
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1253

Jun Wang et al.
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tions to tert-butanesulfinyl imines, in: Enantioselective
Synthesis of b-Amino Acids, (Eds.: E. Juaristi, V. A. So-
loshonok), Wiley-VCH, New York, 2005, pp 181–194,
and references cited therein; c) F. Tanaka, C. F. Barbas
III, Organocatalytic approaches to enantioenriched b-
amino acids, in: Enantioselective Synthesis of b-Amino
Acids, (Eds.: E. Juaristi, V. A. Soloshonok), Wiley-
VCH, New York, 2005, pp 195–214, and references
cited therein; d) M. R. Saidi, N. Azizi, Tetrahedron:
Asymmetry 2002, 13, 2523; e) S. Hata, M. Iguchi, T.
Iwasawa, K. Yamada, K. Tomioka, Org. Lett. 2004, 6,
1721; f) Y. Wang, Q. F. He, H. W. Wang, X. Zhou, Z. Y.
Huang, Y. Qin, J. Org. Chem. 2006, 71, 1588; g) A. Cor-
dova, Acc. Chem. Res. 2004, 37, 102.
Shankar, M. P. Kirkup, S. W. McCombie, J. W. Clader,
A. K. Ganguly, Tetrahedron Lett. 1996, 37, 4095;
d) J. C. Adrian, J. L. Barkin, L. Hassib, Tetrahedron
Lett. 1999, 40, 2457; e) A. Sorochinsky, N. Voloshin, A.
Markovsky, M. Belik, N. Yasuda, H. Uekusa, T. Ono,
D. O. Berbasov, V. A. Soloshonok, J. Org. Chem. 2003,
68, 7448; f) N. A. Ross, R. R. MacGregor, R. A.
Bartsch, Tetrahedron 2004, 60, 2035.
[6] a) P. G. Cozzi, E. Rivalta, Angew. Chem. 2005, 117,
3666; Angew. Chem. Int. Ed. 2005, 44, 3600; b) P. G.
Cozzi, E. Rivalta, Pure Appl. Chem. 2006, 78, 287;
c) P. G. Cozzi, Adv. Synth. Catal. 2006, 348, 2075.
[7] For a review, see: L. Zani, C. Bolm, Chem. Commun.
2006, 4263; for excellent examples, see: a) C. M. Wei,
C. J. Li, J. Am. Chem. Soc. 2002, 124, 5638; b) C. Kora-
din, K. Polborn, P. Knochel, Angew. Chem. 2002, 114,
2651; Angew. Chem. Int. Ed. 2002, 41, 2535; c) N. Gom-
mermann, C. Koradin, K. Polborn, P. Knochel, Angew.
Chem. 2003, 115, 5941; Angew. Chem. Int. Ed. 2003, 42,
5763; d) T. F. Knopfel, P. Aschwanden, T. Ichikawa, T.
Watanabe, E. M. Carreira, Angew. Chem. 2004, 116,
6097; Angew. Chem. Int. Ed. 2004, 43, 5971; e) C. M.
Wei, J. T. Mague, C. J. Li, Proc. Natl. Acad. Sci. USA,
2004, 101, 5749; f) R. Dodda, C. J. Zhao, J. Org. Lett.
2007, 9, 165; g) M. Irmak; M. M. K. Boysen Adv.
Synth. Catal. 2008, 350, 403; h) A. Labonne, L. Zani, L.
Hintermann, C. Bolm J. Org. Chem. 2007, 72, 5704;
i) L. Zani, S. Alesi, P. G. Cozzi, C. Bolm J. Org. Chem.
2006, 71, 1558; j) L. Zani, T. Eichhorn, C. Bolm, Chem.
Eur. J. 2007, 13, 2587.
[8] a) J. X. Ji, T. T. L. Au-Yeung, J. Wu, C. W. Yip, A. C. S.
Chan, Adv. Synth. Catal. 2004, 346, 42; b) J. X. Ji, J.
Wu, A. C. S. Chan, Proc. Natl. Acad. Sci. USA 2005,
102, 11196; c) Z. H. Shao, J. Wang, K. Ding, A. C. S.
Chan, Adv. Synth. Catal. 2007, 349, 2375.
[9] a) T. Harada, J. Katada, A. Tachiki, T. Asari, K. Iijima,
I. Uno, I. Ojima, Y. Hayashi, Bioorg. Med. Chem. Lett.
1997, 209; b) Y. Hayashi, T. Harada, J. Katada, I. Uno,
Drugs Future 1997, 22, 1367.
[3] a) H. Ishitani, M. Ueno, S. Kobayashi, J. Am. Chem.
Soc. 1997, 119, 7153; b) H. Ishitani, M. Ueno, S. Ko-
bayashi, J. Am. Chem. Soc. 2000, 122, 8180; c) M.
Ueno, H. Ishitani, S. Kobayashi, Org. Lett. 2002, 4,
3395; d) T. Akiyama, J. Itoh, K. Yokota, K. Fuchibe,
Angew. Chem. 2004, 116, 1592; Angew. Chem. Int. Ed.
2004, 43, 1566; e) Y. Ihori, Y. Yamashita, H. Ishitani, S.
Kobayashi, J. Am. Chem. Soc. 2005, 127, 15528; f) S.
Kobayashi, K. Arai, H. Shimizu, Y. Ihori, H. Ishitani,
Y. Yamashita, Angew. Chem. 2005, 117, 771; Angew.
Chem. Int. Ed. 2005, 44, 761; g) K. Saruhashi, S. Ko-
bayashi, J. Am. Chem. Soc. 2006, 128, 11232; h) A. Ha-
segawa, Y. Naganawa, M. Fushimi, K. Ishihara, H. Ya-
mamoto, Org. Lett. 2006, 8, 3175; i) M. Yamanaka, J.
Itoh, K. Fuchibe, T. Akiyama, J. Am. Chem. Soc. 2007,
129, 6756; j) J. Xiao, T. P. Loh, Synlett 2007, 5, 815.
[4] a) J. W. Yang, C. Chandler, M. Stadler, D. Kampen, B.
List, Nature 2008, 452, 453; b) Y. G. Chi, E. P. English,
W. C. Pomerantz, W. S. Horne, L. A. Joyce, L. R.
Alexander, W. Fleming, E. A. Hopkins, S. H. Gellman,
J. Am. Chem. Soc. 2007, 129, 6050; c) J. W. Yang, M.
Stadler, B. List, Angew. Chem. 2007, 119, 615; Angew.
Chem. Int. Ed. 2007, 46, 609; d) J. W. Yang, M. Stadler,
B. List, Nature Protocols, 2007, 2, 1937; e) J. Vesely, R.
Rios, I. Ibrahem, A. Cordova, Tetrahedron Lett. 2007,
48, 421; f) Y. G. Chi, S. H. Gellman, J. Am. Chem. Soc.
2006, 128, 6804; g) N. S. Chowdari, J. T. Suri, C. F.
Barbas, Org. Lett. 2004, 6, 2507; h) W. Notz, F. Tanaka,
S. Watanabe, N. S. Chowdari, J. M. Turner, R. Thayu-
manavan, C. F. Barbas, III, J. Org. Chem. 2003, 68,
9624.
[10] Y. Hayashi, J. Katada, T. Harada, A. Tachiki, K. Iijima,
Y. Takiguchi, M. Muramatsu, H. Miyazaki, T. Asari, T.
Okazaki, Y. Sato, E. Yasuda, M. Yano, I. Uno, I.
Ojima, J. Med. Chem. 1998, 41, 2345.
[11] a) N. C. Deno, J. Am. Chem. Soc. 1947, 69, 2233; b) Y.
Yang, F. Y. Wang, F. D. Rochon, M. M. Kayser, Can. J.
Chem. 2005, 83, 28.
[5] a) H. Gilman, M. Speeter, J. Am. Chem. Soc. 1943, 65,
2255; b) C. Baldoli, P. DelButtero, E. Licandro, A. Pa-
pagni, T. Pilati, Tetrahedron 1996, 52, 4849; c) B. B.
[12] R. Rasappan, M. Hager, A. Gissibl, O. Reiser, Org.
Lett. 2006, 8, 6099.
1254
asc.wiley-vch.de
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 1250 – 1254