Enantioselective catalysis of ketoester-ene reaction of silyl enol ether to construct quaternary carbons by chiral dicationic palladium(II) complexes

Article abstract of DOI:10.1021/ja076539f

Dicationic SEGPHOS-Pd complex-catalyzed ketoester-ene reaction with silyl enol ether can be achieved to produce an ene product with a quaternary carbon center in high yield and enantioselectivity. Even lower catalyst loading (up to 0.01 mol%) can be perfo

Full text of DOI:10.1021/ja076539f

Published on Web 10/06/2007
Enantioselective Catalysis of Ketoester-ene Reaction of Silyl Enol Ether to
Construct Quaternary Carbons by Chiral Dicationic Palladium(II) Complexes
Koichi Mikami,* Yuji Kawakami, Katsuhiro Akiyama, and Kohsuke Aikawa
Department of Applied Chemistry Tokyo Institute of Technology, Tokyo 152-8552, Japan
Received August 30, 2007; E-mail: mikami.k.ab@m.titech.ac.jp
Table 1. Enantioselective Ketoester-ene Reaction with Silyl Enol
Ether 1 and Ethyl Pyruvate 2a by Chiral Dication Pd Catalysts
Development of synthetic methods for optically active and highly
functionalized silyl enol ethers are in great demand in organic
synthesis.1 Since the optically active â-hydroxy silyl enol ethers
are valuable as chiral building blocks for many bioactive com-
pounds,2 an asymmetric carbonyl-ene reaction with silyl enol ether
is one of the most efficient synthetic methods. The problems
associated in this reaction, however, are the decomposition of silyl
enol ethers under the Lewis acid conditions and competition with
the Mukaiyama aldol reaction.3,4 There are only two types of
asymmetric carbonyl-ene reactions using silyl enol ether as an ene
substrate. We have reported a BINOL-derivated chiral Ti complex-
catalyzed asymmetric glyoxylate-ene reaction of trimethylsilyl enol
ether to give chiral â-hydroxy silyl enol ether (ene-type) products
in high yield and enantioselectivity instead of secondary â-hydroxy
ketone (Mukaiyama aldol-type product).5 Recently, Jacobsen has
also reported a chiral Cr complex-catalyzed ene reaction between
aldehyde and trimethylsilyl enol ether to give the ene-type product
in an excellent yield with enantioselectivity.6 These reactions
produce silyl enol ethers, however, with the chiral tertiary carbon
centers. There is so far no report on silyl enol ether to afford
quaternary carbon centers.7 Herein we report a chiral dicationic Pd
complex-catalyzed asymmetric ketoester-ene reaction of silyl enol
ether, which constructs an optically active â-hydroxy silyl enol ether
with a quaternary carbon center.8-10
entry
PP*-ligand
yield (%)a
ee (%)b
1
2
3
4
5
6
7
8
(R,R)-DUPHOS
(S,S)-BDPP
(S)-QUINAP
(S)-BINAP
(S)-tol-BINAP
(S)-xylyl-BINAP
(S)-SYNPHOS
(S)-SEGPHOS
68
52
9
77
62
47
79
96
5c
75c
76c
92
95
61
92
93
a Isolated yield. b Enantiopurity was determinded by HPLC analysis after
desilylation to â-hydroxyketone 4a. c Opposite configuration.
The asymmetric ketoester-ene reaction was first investigated with
acetone silyl enol ether 1 bearing TIPS group and ethyl pyruvate
2a (Table 1). The active dicationic Pd catalyst as Lewis acid was
in situ generated from 5 mol % of chiral PP*-PdCl2 complex and
11 mol % of AgSbF6 in dichloromethane.8a (S)-BINAP-PdCl2
bearing C2 symmetric binaphthyl-backbone gave ene-type product
3a in 77% yield and 92% ee without aldol-type product (entries
1-3 vs 4).11 While the use of (S)-tol-BINAP increased the
enantioselectivity up to 95% ee, the yield was decreased by
decomposition of 1 (entry 5). The sterically more demanding (S)-
xylyl-BINAP-PdCl2 gave lower yield and enantioselectivity (entry
6). (S)-SEGPHOS12 was found to be the most effective to give 3a
with 93% ee in 96% yield without decomposition of 1 (entry 8).13
Several Si groups in 1 were further examined by (S)-SEGPHOS-
PdCl2 under the same conditions (Scheme 1). The less hindered
TMS enol ether yielded only aldol product 4a bearing the same
absolute configuration (46%, 80% ee).14 The use of TBDMS
decreased the enatioselectivity of the ene product. In addition, the
sterically more hindered TBDPS gave ene product 3a in higher
enantioselectivity (96% ee), but the reactivity of TBDPS ether
significantly decreased.
The reactions of various ketoester substrates 2b-f and TIPS enol
ether 1 were examined by (S)-SEGPHOS-PdCl2 under the optimized
conditions (Table 2). Methyl pyruvate 2b produced ene product
3b quantitatively (85% ee) (entry 2). The absolute configuration
of ene product 3c from benzyl pyruvate 2c was determined to be
R (entry 3).15 The substrate 2d,e bearing CF3 and â-phenyl ethyl
groups gave high enantioselectivity (88 and 87% ee, respectively)
(entries 4, 5). Benzoylformate 2f yielded ene product 3f in higher
enantioselectivity (98% ee) (entry 6). The construction of quaternary
Scheme 1. Silyl Effects on SEGPHOS-Pd2+-Catalyzed
Ketoester-ene Reaction
a Reaction time was 24 h.
carbon center was thus succeeded with high enantioselectivity from
various ketoester substrates. Significantly, less reactive diketone
2g,h could be employed in the reaction. Dimethyl diketone 2g
afforded the corresponding desymmetrized16 product in good yield
with high enantioselectivity (entry 7). The more significant result
was obtained with unsymmetrical diketone 2h, leading to the
complete regioselectivity and enantioselsectivity (entry 8).
With these successful results in terms of catalyst activity and
enantioselectivity, we attempted to decrease the catalyst loading
(Scheme 2). Ene product 3a was quantitively obtained in 92% ee
with the less catalyst loading (0.05 mol %). Even with the smallest
9
12950
J. AM. CHEM. SOC. 2007, 129, 12950-12951
10.1021/ja076539f CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Enantioselective Ene Reaction with Various Enophiles
Co. for providing BINAP derivatives and SEGPHOS and to
Dowpharma for giving DUPHOS. This work was supported by a
Grant-in-Aid for Scientific Research on Priority Areas “Advanced
Molecular Transformations of Carbon Resources” from the Ministry
of Education, Culture, Sports, Science and Technology, Japan. This
paper is dedicated to Prof. Frederick E. Ziegler for his contribution
to synthetic organic chemistry.
Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(1) (a) Mukaiyama, T. Org. React. 1982, 28, 203. (b) Mahrwald, R. Chem.
ReV. 1999, 99, 1095. (c) Carreira, E. M. In Catalytic Asymmetric Synthesis;
Ojima, I., Ed.; Wiley-VCH: New York, 2000; Chapter 8B2. (d)
Machajewski, T. D.; Wong, C.-H.; Lerner, R. A. Angew. Chem., Int. Ed.
2000, 39, 1352. (e) Palomo, C.; Oiarbide, M.; Garcia, J. M. Chem. Soc.
ReV. 2004, 33, 65.
(2) Examples of chiral alcohols with quaternary carbon centers: (a) Harris,
G. H.; Jones, E. T. T.; Meinz, M. S.; Nallin-Omstead, M.; Helms, G. L.;
Bills, G. F.; Zink, D.; Wilson, K. E. Tetrahedron Lett. 1993, 34, 5235.
(b) Tan, L.; Chen, C.-Y.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. J.
Tetrahedron Lett. 1998, 39, 3961. (c) Oxybutynin: Senanayake, C. H.;
Fang, K.; Grover, P.; Bakale, R. P.; Vandenbossche, C. P.; Wald, S. A.
Tetrahedron Lett. 1999, 40, 819.
a Reaction time was 18 h. b Isolated yield. c Enantiopurity was determined
by HPLC analysis after desilylation to â-hydroxyketone 4. d Enantiopurity
was determined by GC analysis after desilylation to â-hydroxyketone 4.
Scheme 2. Low Catalyst Loading of SEGPHOS-Pd Complex
(3) Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973, 2, 1011.
(4) Examples of asymmetric Mukaiyama-aldol reactions. (a) Carreira, E. M.;
Singer, R. A.; Lee, W. J. Am. Chem. Soc. 1994, 116, 8837. (b) Evans, D.
A.; Murry, J. A.; Kozlowski, M. C. J. Am. Chem. Soc. 1996, 118, 5814.
(c) Ferraris, D.; Young, B.; Dudding, T.; Lectka, T. J. Am. Chem. Soc.
1998, 120, 4548. (d) Langner, M.; Bolm, C. Angew. Chem., Int. Ed. 2004,
43, 5984.
(5) (a) Mikami, K.; Matsukawa, S. J. Am. Chem. Soc. 1993, 115, 7039. (b)
Mikami, K.; Matsukawa, S. J. Am. Chem. Soc. 1994, 116, 4077.
(6) (a) Ruck, R. T.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 2882. (b)
Ruck, R. T.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2003, 42, 4771.
(7) Reviews on the construction of quaternary carbon centers: (a) Martin, S.
F. Tetrahedron 1980, 36, 419. (b) Fuji, K. Chem. ReV. 1993, 93, 2037.
(c) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37,
388. (d) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5363. (e) Trost, B. M.; Jiang, C. Synthesis 2006, 369.
(8) We have reported Pd-catalyzed asymmetric ene reactions. (a) Aikawa,
K.; Kainuma, S.; Hatano, M.; Mikami, K. Tetrahedron Lett. 2004, 45,
183. (b) Hao, J.; Hatano, M.; Mikami, K. Org. Lett. 2000, 2, 4059.
(9) Cu-catalyzed asymmetric ketoester-ene reactions. (a) Evans, D. A.; Tregay,
S. W.; Burgey, C. S.; Paras, N. A.; Vojkovsky, T. J. Am. Chem. Soc.
2000, 122, 7936. Sc-catalyzed asymmetric carbonyl-ene reactions. (b)
Evans, D. A.; Wu, J. J. Am. Chem. Soc. 2005, 127, 8006.
Scheme 3. Hetero Two-Directional Reaction by BINOL/Ti(OiPr)4
Catalyst
(10) Catalytic asymmetric reactions by using ketoester. (a) Dimauro, E. F.;
Kozlowski, M. C. J. Am. Chem. Soc. 2002, 124, 12668. (b) Jiang, B.;
Chen, Z.; Tang, X. Org. Lett. 2002, 4, 3451. (c) Funabashi, K.; Jachmann,
M.; Kanai, M.; Shibasaki J. Am. Chem. Soc. 2002, 124, 12668.
(11) Whether AgCl was filtered or not, the condition of 10 mol % AgSbF6 to
5 mol % Pd complex gave almost the same result. We had confirmed
that AgSbF6 did not catalyze the reaction. Therefore, there is no
participation of silver salt in this reaction.
(12) Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo, N.; Miura, T.;
Kumobayashi, H. AdV. Synth. Catal. 2001, 343, 264.
(13) The use of 2-(triisopropyl)siloxy-1-butene instead of 1 gave the ene product
in 91% yield, E/Z ) 7/3, 85% ee (enantiopurity was determined after
desilylation of E- and Z-isomer mixture).
(14) Sodeoka and Shibasaki reported Pd-catalyzed asymmetric aldol reaction
via Pd enolate. The aldol product would be obtained via Pd enolate. (a)
Sodeoka, M.; Ohrai, K.; Shibasaki, M. J. Org. Chem. 1995, 60, 2648. (b)
Hamashima, Y.; Sodeoka, M. Chem. Rec. 2004, 4, 231.
(15) The absolute configuration was determined in comparison of the value of
optical rotation. Evans, D. A.; Kozlowski, M. C.; Burgey, C. S.;
MacMillan, D. W. C. J. Am. Chem. Soc. 1997, 119, 7893.
(16) (a) Willis, M. C. J. Chem. Soc., Perkin Trans. 1 1999, 1765. (b) Mikami,
K.; Yoshida, A. J. Syn. Org. Chem. Jpn. 2002, 60, 732. (c) Rovis, T. In
New Frontiers in Asymmetric Catalysis; Mikami, K., Lautens, M., Eds.;
Wiley: New York, 2007; Chapter 10.
(17) Reviews on tandem (domino) reactions: (a) Ziegler, F. E. In Compre-
hensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon:
New York, 1991; Vol. 6, p. 875. (b) Tietze, L. F. Chem. ReV. 1996, 96,
115. Wender, P. A., Ed. Chem. ReV. 1996, 96 (thematic issue). (c) Nakai,
T.; Mikami, K. Kagaku no Ryoiki 1982, 36, 661; Chem. Abstr. 1982, 96,
16001.
substrate/catalyst ratio, namely S/C 10,000 at 0 °C, the high yield
and enantioselectivity could be obtained.
Next, our attention was focused on heterocombination of ene
reaction sequence17 with 3a (92% ee R) by using chiral BINOL-Ti
catalyst (Scheme 3).18 In the presence of 10 mol % (S)-BINOL/
Ti(OiPr)4, the reaction with ethyl glyoxylate 5 afforded the mixture
of ene,18 Friedel-Crafts,19 and aldol products.20 However, diol (R)/
(S)-6 bearing both quaternary and tertiary carbon centers was ob-
tained in 67% yield and >99% ee (92% diastereoselectivity) after
desilylation by TBAF. In contrast, the treatment with (R)-BINOL-
Ti catalyst led to the diol (R)/(R)-6 in 61% yield and 97% ee (dr )
91/9).
In summary, we have succeeded in dicationic SEGPHOS-Pd
complex-catalyzed ketoester-ene reaction, which constructs highly
optically active â-hydroxy silyl enol ether with quaternary carbon
center. We have also succeeded in lowering the catalyst loading
up to 0.01 mol % without significant decrease in the yield and
enantioselectivity. This low catalyst loading will open the door to
industrial applications of the present chiral Lewis acid catalysis.
Further investigations on engineered Lewis acid catalysis of tandem
reactions are currently in progress.
(18) Homo two-directional glyoxylate-ene reaction: Mikami, K.; Matsukawa,
S.; Nagashima, M.; Funabashi, H.; Morishima, H. Tetrahedron Lett. 1997,
38, 579.
(19) Ishii, A.; Kojima, J.; Mikami, K. Org. Lett. 1999, 1, 2013.
(20) These three products were incompletely separated by silica-gel chroma-
tography and transformed into 6 with TBAF.
Acknowledgment. We are grateful to Prof. John M. Brown for
providing QUINAP. We are also grateful to Takasago International
JA076539F
9
J. AM. CHEM. SOC. VOL. 129, NO. 43, 2007 12951