Unprecedented effects of additives and ligand-to-metal ratio on the enantiofacial selection of copper-catalyzed alkynylation of a-imino ester with arylacetylenes

Article abstract of DOI:10.1002/adsc.200700237

The first catalytic asymmetric addition of arylacetylenes to α-imino esters was carried out using chiral copper(I) complexes as catalysts under mild reaction conditions, providing the corresponding alkynylation products in good yields with 67-74% ee value

Full text of DOI:10.1002/adsc.200700237

UPDATES
DOI: 10.1002/adsc.200700237
Unprecedented Effects of Additives and Ligand-to-MetalRatio
on the Enantiofacial Selection of Copper-Catalyzed Alkynylation
of a-Imino Ester with Arylacetylenes
Zhihui Shao,a Jun Wang,a Kai Ding,a and Albert S. C. Chana,*
a
Open Laboratory of Chirotechnology, 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)-23-649-932; e-mail: bcachan@polyu.edu.hk
Received: May 12, 2007; Revised: July 25, 2007
Supporting information for thisarticle isavailable on the WWW under http://asc.wiley-vch.de/home/.
Abstract: The first catalytic asymmetric addition of
arylacetylenesto a-imino esters was carried out
using chiral copper(I) complexes as catalysts under
mild reaction conditions, providing the correspond-
ing alkynylation productsin good yieldswith 67–
74% ee values. Profound effects of the ligand-to-
metal ratio and additives on the stereofacial selec-
tion were observed. Both enantiomers of a given
product can be obtained with almost identical enan-
tiomeric excess using the same chiral ligand by ad-
justing the ligand-to-metal ratio.
per(I) complexes with 48–91% enantiomeric excess-
es.[11] From a synthetic standpoint, an efficient and
flexible approach to enantiomerically pure aromatic
alkynyl-a-amino acid derivativesishighly deisrable.
In this paper, we report the first enantioselective ad-
dition of arylacetylenesto an a-imino ester, and
reveal unprecedented effectsof the ligand-to-metal
ratio and additiveson the enantiofacial eslection of
the Cu-catalyzed alkynylation of an a-imino ester
with arylacetylenes.
The experimentswere carried out under ismilar
conditions to those used in our previous study of Cu-
catalyzed addition of aliphatic alkynesto the a-imino
ester.[11] The reaction of phenylacetylene 2a and a-
imino ester 1 wasperformed in dichloromethane
(DCM) at À108C using 10 mol% CuOTf·0.5C6H6 as
a precatalyst, Pybox 10 (Figure 1) asa chiral ligand
and 0.1 equivalent of PMP-NH2 asadditive. The de-
sired product 3a wasobtained with moderate yield
(51%) and low enantiomeric excess (41% ee) after
Keywords: asymmetric alkynylation; asymmetric
catalysis; copper; enantioselectivity; a-imino ester;
ligand-to-metal ratio
Optically active non-proteinogenic a-amino acidsare
important compounds in biological systems and chiral 48 h. Although the cause of this phenomenon was not
building blocks in drug syntheses.[1–6] A special class immediately clear, thisresult indicated the difference
of these compounds are chiral b,g-alkynyl-a-amino in reactivity between aliphatic and aromatic alkynes
acid derivatives.[7] It isrecognized that compounds
containing carbon/carbon triple bondsserve to deacti-
in the Cu-catalyzed akynylation of the a-imino ester,
and that new reaction conditions must be established
vate a variety of enzymes.[8] However, the synthesis of for arylacetylenes. To our delight, further experiments
enantiomerically enriched b,g-alkynyl-a-amino acid indicated that, in the absence of an additive, the yield
derivativesisa challenging undertaking.
and enantiomeric excess of the addition product 3a
increased significantly to 64% and 61%, respectively,
at À108C after 48 h. After further optimization, we
obtained the product 3a in 75% yield and 60% ee at
Metal-catalyzed addition of terminal alkynesto
iminesrepreesntsone of the mots convenient meth-
ods for the synthesis of propargylamines.[9] Thisreac-
tion wasextended to a-imino esters and an efficient room temperature after 24 h.
synthesis of b,g-alkynyl-a-amino acid derivativeswas
These interesting results led us to examine the
developed by the direct addition of phenylacetylene effect of a variety of chiral ligands(Figure 1) in the
and alkylacetylenesto an a-imino ester in the pres- Cu-catalyzed asymmetric addition of phenylacetylene
ence of silver(I) salts.[10] Based on this method, we re- 2a to the a-imino ester 1. Similar to the previously re-
alized the first catalytic asymmetric synthesis of ali- ported results in the enantioselective addition of ali-
phatic alkynyl-a-amino acid derivativesby using cop-
phatic alkynesto the a-imino ester,[11] BINAP was
Adv. Synth. Catal. 2007, 349, 2375 – 2379
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2375

Zhihui Shao et al.
UPDATES
Figure 1. Chiral ligandstested in the addition of aromatic alkynesto an a-imino ester.
less effective in this reaction (Table 1, entry 8). Given (entry 5). Pybox 10, which wasthe mots effective
that chiral copper-bis(oxazoline) (box) complexes ligand used in the enantioselective addition of aliphat-
have been successfully applied in numerous enantio- ic alkynesto the a-imino ester,[11] gave slightly lower
selective addition reactions,[12–14] a variety of chiral bi- yield (75% yield) and enantiomeric excess (60% ee)
s(oxazolinyl) ligands were tested. Among the chiral li- (entry 7).
gandsthat we have invetsigated, the commercially
Other Cu(I) pre-catalysts in combination with
available chiral ligand Pybox 8 furnished the target ligand 8 were also investigated in this reaction
product 3a with the best result (80% yield, 63% ee) (Table 2). CuPF6·4MeCN gave relatively lower yield
(62% yield) and enantiomeric excess (54% ee) under
the same conditions (entry 1), and CuBr and CuCl
Table 1. Effectsof different chiral ligandson reactivity and
did not show any catalytic activity (entries 2 and 3).
We then studied the effect of ligand-to-metal ratio
in thisCuOTf·0.5C 6H6-catalyzed reaction (Table 3).
enantioselectivity.[a]
Table 2. Effectsof different Cu(I) pre-catalystson reactivity
and enantioselectivity.[a]
Entry
Ligand
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
4
5
6
7
8
9
10
11
68
65
trace
66
80
65
75
54
<5
<5
not determined
49
63
61
60
<5
Entry
Cu(I) pre-catalyst
Yield [%][b]
ee [%][c]
1
2
3
CuPF6·4MeCN
CuBr
CuCl
62
0
0
54
[a]
[a]
All the reactionswere carried out in a 0.25-mmol csale
of 1 using 2 equivs. of phenylacetylene 2a in 1.5 mL
DCM with 10 mol% catalyst at room temperature.
Isolated yield.
Determined by chiral HPLC using a Chiralpak AD-H
column.
All the reactionswere carried out in a 0.25-mmol csale
of 1 using 2 equivs. of phenylacetylene 2a in 1.5 mL
DCM with 10 mol% catalyst at room temperature.
Isolated yield.
Determined by chiral HPLC using a Chiralpak AD-H
column.
[b]
[c]
[b]
[c]
2376
asc.wiley-vch.de
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 2375 – 2379

Unprecedented Effectsof Additivesand Ligand-to-Metal Ratio on the Enantiofacial Selection
UPDATES
Table 3. Effectsof different ratio of CuOTf·0.5C 6H6 to
chiral ligand 8 on reactivity and enantioselectivity.[a]
available. Our finding offersan interesting alternative
to provide both enantiomersof a chiral compound.
Interestingly, the addition of 4 Š molecular sieve to
the reaction system also resulted in the switch of the
enantioselectivity of product 3a (entry 9). When 4 Š
MS wascombined with CuOTf·0.5C 6H6/Pybox 8
(1:1.5), À70% ee wasobtained (entry 10). The switch
of the stereofacial selection might be due to a differ-
ent mode of coordination. However, further studies
certainly are needed to elucidate thisinteresting phe-
nomenon.
A profound solvent effect on the yield and enantio-
selectivity of the reaction was also observed (Table 4).
For example, when toluene was used as solvent, only
30% ee wasobtained (entry 1). DCM wasthe bets
choice of solvent for reactivity and enantioselectivity
(entry 5).
Entry Ratio of 8 to CuOTf·0.5C6H6 Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
9
10
1:1
80
74
64
60
57
54
34
70
71
60
63[d]
1.1:1
1.2:1
1.25:1
1.3:1
1.5:1
2:1
1:1.2
1:1
1.5:1
60[d]
23[e]
2[e]
À36[e]
À62[f]
À63[f]
50[d]
À23[g]
À70[h]
[a]
Table 4. Effectsof the choice and concentration of oslvent
All the reactionswere carried out in a 0.25-mmol csale
on the reactivity and enantioselectivity.[a]
of 1 using 2 equivs. of phenylacetylene 2a in 1.5 mL
DCM with 10 mol% catalyst at room temperature.
Isolated yield.
Determined by chiral HPLC using a Chiralpak AD-H
[b]
[c]
column.
24 h.
36 h.
6 days.
24 h, 4 Š MS added.
6 days, 4 Š MS added.
[d]
[e]
[f]
Entry Solvent Solvent volume [mL] Yield [%][b] ee [%][c]
[g]
[h]
1
2
3
4
5
6
7
toluene 1.5
81
40
80
78
80
76
65
30
44
63
66
70
69
57
THF
1.5
1.5
1.2
1.0
0.8
0.6
DCM
DCM
DCM
DCM
DCM
When the ratio of Pybox 8 to CuOTf·0.5C6H6 was
changed from 1:1 to 1.1:1, a slightly lower ee wasob-
tained (entry 2). The observation that a small excess
of ligand isdetrimental to enantioselectivity isin con-
trast to the usual observation in asymmetric catalysis
that an excess of chiral ligand is beneficial to suppress
the background reaction catalyzed by uncomplexed
metal. When the ratio of Pybox 8 to CuOTf·0.5C6H6
waschanged from 1:1 to 1.25:1, the ee value dramati-
cally decreased to almost 0% (entry 4). This observa-
tion indicated that the ligand-to-metal ratio might
have a decisive influence on the enantioselectivity of
[a]
All the reactionswere carried out in a 0.25-mmol csale
of 1 using 2 equivs. of phenylacetylene 2a with 10 mol%
catalyst at room temperature.
[b]
[c]
Isolated yield.
Determined by chiral HPLC using a Chiralpak AD-H
column.
Under the optimized conditions, the scope of nucleo-
the reaction. Further increase of the ratio of Pybox 8 philes in the reaction system was examined, and the
to CuOTf·0.5C6H6 to 1.5:1 dramatically switched the results are summarized in Table 5. The electronic
product enantioselectivity to the opposite sense. The property of the substituents on the aromatic ring did
product 3a wasobtained with almots identical
ee not show significant effects on the reactivity and ste-
(62% ee) but with opposite enantiofacial selection reoselectivity of Cu-catalyzed alkynylation of the a-
(entry 6). This is surprising yet most interesting since imino ester. The arylacetylenes bearing either an elec-
both enantiomersof a given product with almots the
tron-donating group or an electron-withdrawing
same enantiomeric excess can be prepared with the group reacted smoothly with the a-imino ester, pro-
same chiral ligand by simply adjusting the ligand-to- viding the corresponding alkynylation products with
metal ratio. Although usually both enantiomers of a good yieldsand 67–74% ee values.
chiral compound can be prepared by using the oppo-
site enantiomers of a chiral ligand, sometimes one of 3a wasconverted to 2-amino-4-phenylbutyric ethyl
the enantiomersof a chiral ligand may not be readily ester hydrochloride 12 (Scheme 1). The (S) configura-
To determine the absolute configuration, product
Adv. Synth. Catal. 2007, 349, 2375 – 2379
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2377

Zhihui Shao et al.
UPDATES
Table 5. Cu-catalyzed addition aromatic alkynesto a-imino
ester 1.[a]
ExperimentalSection
TypicalProcedure for Catayl tic Asymmetric
Alkynylation of a-Imino Ester 1
Pybox 8 (9.2 mg, 0.025 mmol) and CuOTf·0.5C6H6 (6.3 mg,
0.025 mmol) were added to a dried 5-mL reaction flask con-
taining a magnetic stirring bar. CH2Cl2 (0.5 mL) wasadded,
and the mixture wastsirred at room temperature for 1 h.
Entry
2 (Ar)
Yield [%][b]
ee [%][c]
Then a-imino ester
1 (52 mg, 0.25 mmol) in CH2Cl2
(0.5 mL) and alkyne (0.5 mmol) were sequentially added
under vigorous stirring. The resulting solution was stirred at
room temperature until TLC monitored the completion of
the reaction. The mixture was then passed through a short
plug of silica gel that was subsequently washed with ether.
The combined solution was concentrated under vacuum.
The purification of the residue by flash silica gel column
chromatography yielded the corresponding alkynylation
product. The enantiomeric excess of the product was deter-
mined by chiral HPLC analysis.
1
2
3
4
5
Ph
Ph
80 (3a)
74 (3a)
65 (3b)
80 (3c)
86 (3d)
70
73[d]
67
4-MeO-C6H4
4-Me-C6H4
4-Br-C6H4
74[e]
69[f]
[a]
All the reactionswere carried out in a 0.25-mmol csale
of 1 using 2 equivs. of aromatic alkynes 2 in 1.0 mL
DCM with 10 mol% catalyst.
Isolated yield.
[b]
[c]
Determined by chiral HPLC using a Chiralpak AD-H
column except entry 4.
08C, 48 h.
Determined by chiral HPLC using a Chiralcel OD-H
[d]
[e]
Acknowledgements
column.
08C, 24 h.
[f]
We thank the Hong Kong Research Grants Council (PolyU
5002/05P), 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.
References
[1] G. C. Barrett, Chemistry and Biochemistry of the
Amino Acids, Chapman and Hall, London, 1985.
[2] R. M. Williams, Synthesis of Optically Active a-Amino
Acids, Pergamon Press, Oxford, 1989.
Scheme 1. Determination of the absolute configuration of
3a.
[3] R. O. Duthaler, Tetrahedron 1994, 50, 1539–1650.
[4] L. S. Hegedus, Acc. Chem. Res. 1995, 28, 299–305.
[5] J. W. Chin, T. A. Cropp, J. C. Anderson, M. Mukherji,
Z. Zhang, P. G. Schultz, Science 2003, 301, 964–967.
[6] L. Wang, P. G. Schultz, Angew. Chem. Int. Ed. 2004,
44, 34–66.
[7] S. A. Abdulganeeva, K. B. Erzhanov, Russ. Chem. Rev.
1991, 60, 676–688.
[8] R. R. Rando, Methods in Enzymology, Academic Press,
tion was established by comparison of the optical ro-
tation of 12 with the previously reported value of this
compound.[15]
In conclusion, we have carried out the first catalytic
asymmetric alkynylation of an a-imino ester with aryl-
acetylenesuinsg a commercially available chiral
ligand 8. There are several features to this enantiose-
lective alkynylation: (1) the experimental procedure
is convenient and simple, and the use of additives can
be avoided; (2) two enantiomersof the desired prod-
uct can be prepared in almost the same enantiomeric
excess with the same chiral ligand simply by adjusting
the ligand-to-metal ratio. The rich chemistry of the al-
kynyl functionality and the aromatic functionality
makes the present method a powerful and versatile
approach to a wide range of optically active a-amino
acid derivatives. A study aiming at elucidating the re-
action mechanism and improving the enantioselectivi-
ty isin progres.
New York, San Francisco, London, 1977.
[9] For a review, see: L. Zani, C. Bolm, Chem. Commun.
2006, 4263–4275; for excellent examples, see: a) C.-M.
Wei, C.-J. Li, J. Am. Chem. Soc. 2002, 124, 5638–5639;
b) C. Koradin, K. Polborn, P. Knochel, Angew. Chem.
Int. Ed. 2002, 41, 2535–2538; c) N. Gommermann, C.
Koradin, K. Polborn, P. Knochel, Angew. Chem. Int.
Ed. 2003, 42, 5763–5766; d) T. F. Knopfel, P. Aschwan-
den, T. Ichikawa, T. Watanabe, E. M. Carreira, Angew.
Chem. Int. Ed. 2004, 42, 5971–5973; e) C.-M. Wei, J. T.
Mague, C.-J. Li, Proc. Natl. Acad. Sci. USA, 2004, 101,
5749–5754; f) R. Dodda, C.-G. Zhao, Org. Lett. 2007,
9, 165–167.
[10] J.-X. Ji, T. T.-L. Au-Yeung, J. Wu, C.-W. Yip, A. S. C.
Chan, Adv. Synth. Catal. 2004, 346, 42–44.
2378
asc.wiley-vch.de
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 2375 – 2379

Unprecedented Effectsof Additivesand Ligand-to-Metal Ratio on the Enantiofacial Selection
UPDATES
[11] J.-X. Ji, J. Wu, A. S. C. Chan, Proc. Natl. Acad. Sci.
USA 2005, 102, 11196–11200.
[14] A. K. Ghosh, P. Mathivanan, J. Cappiello, Tetrahedron:
Asymmetry 1998, 9, 1–45.
[12] D. A. Evans, M. C. Kozlowski, J. A. Murry, C. S.
Burgey, K. R. Campos, B. T. Connell, R. J. Staples, J.
Am. Chem. Soc. 1999, 121, 669–685.
[15] W.-Q. Lin, Z. He, Y. Jing, X. Cui, H. Liu, A.-Q. Mi,
Tetrahedron: Asymmetry 2001, 12, 1583–1587, and ref-
erence cited therein.
[13] F. Fache, E. Schulz, M. L. Tommasino, M. Lemaire,
Chem. Rev. 2000, 100, 2159–2232.
Adv. Synth. Catal. 2007, 349, 2375 – 2379
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2379