Asymmetric conjugate addition of silyl enol ethers catalyzed by tethered bis(8-quinolinolato) aluminum complexes

Article abstract of DOI:10.1021/ja0668320

New chiral tethered bis(8-quinolinolato) (TBOx) aluminum(III) complexes effectively catalyze the highly enantioselective Mukaiyama-Michael reaction of silyl enol ethers, including tetrasubstituted enolates that give rise to enantioenriched α-carbonyl all-

Full text of DOI:10.1021/ja0668320

Published on Web 01/05/2007
Asymmetric Conjugate Addition of Silyl Enol Ethers Catalyzed by Tethered
Bis(8-quinolinolato) Aluminum Complexes
Norito Takenaka,† Joshua P. Abell, and Hisashi Yamamoto*
Department of Chemistry, The UniVersity of Chicago, 5735 South Ellis AVenue, Chicago, Illinois 60637
Received September 21, 2006; E-mail: yamamoto@uchicago.edu
Table 1. (TBOx)AlX Catalyzed Mukaiyama-Michael Reaction
The Lewis acid-promoted conjugate addition of silylketene
acetals and silyl enol ethers to R,â-unsaturated carbonyl derivatives,
the Mukaiyama-Michael (MM) reaction,1 is an attractive alternative
to the conventional metalloenolate process owing to a mild reaction
condition and frequently superior regioselection (1,4- in preference
to 1,2-addition).2 Catalytic asymmetric variants of this process have
received extensive attention and continue to be powerful carbon-
carbon bond forming reactions since these methods provide
synthetically useful enantioenriched 1,5-dicarbonyl synthons.3,4
Whereas various catalysts developed for the MM reaction have
centered on the use of silylketene acetals, silyl enol ethers3g-j,s,4a,c
have received relatively little attention in the context of asymmetric
catalysis. This deficiency in the aforementioned reaction may arise,
in part, from the decreased nucleophilicity of silyl enol ethers in
comparison to that of silylketene acetals. It is described herein that
a new chiral tethered bis(8-quinolinolato) (TBOx) aluminum(III)
complex effectively catalyzed the highly enantioselective MM
reaction of silyl enol ethers, including tetrasubstituted enolates that
provided access to enantiomerically enriched all-carbon quaternary
centers.5,6
entry
X
R
R
′
time (h)
yield (%)
ee (%)
1
2
3
CI
TfO
Ph
Ph
Ph
Ph
p-BrPh
p-BrPh
Cy
Cy
i-Pr
i-Pr
Me
Me
Me
Ph
Me
Ph
Me
Ph
Me
Ph
36
24
12
12
12
12
12
12
12
12
trace
70
77
86
83
76
77
69
70
66
N/Da
98
97
96
98
98
99
98
98
SbF6
SbF6
SbF6
SbF6
SbF6
SbF6
SbF6
SbF6
4
5b
6b
7b
8b
9
10b
98
On the basis of promising stereoselectivity displayed by an
enantiopure TBOx ligand recently developed in our laboratory for
the catalytic asymmetric pinacol coupling reaction,7 the possible
utility of this ligand in the enantioselective conjugate addition
reaction was explored.8 After brief screening of metal salts, TBOxH
was found to react cleanly with diethylaluminum chloride and
provided the corresponding aluminum chloride complex. While this
aluminum chloride complex (Table 1, entry 1) was not catalytically
active, activation by AgOTf or AgSbF6 provided a highly reactive
species, presumably the cationic aluminum complex9 (entries 2 and
3).10 Although the rate of the reaction catalyzed by (TBOx)AlOTf
was noticeably slower than that of the reaction catalyzed by the
corresponding hexafluoroantimonate complex, both catalysts were
highly enantioselective. Even the encumbering phenyl substituent
on a Michael acceptor did not adversely affect the yield or
enantioselectivity (entry 4). The same trend was observed for a
range of silyl enol ethers (entries 5-10).
a Not determined. b The absolute configuration was not determined.
Table 2. Syntheses of Enantio-Enriched All-Carbon Quaternary
Stereocenters
Having successfully developed an effective catalyst for the
conjugate addition of simple silyl enol ethers, the possibility of
using sterically demanding tetrasubstituted enolates was investi-
gated. The latter Michael donors would give rise to enantioenriched
carbonyl products bearing R-quaternary stereocenters, whose
preparation by catalytic means remains largely an unsolved, albeit
highly important, problem.5,6 To our delight, a range of tetrasub-
stituted trimethylsilyl enol ethers underwent the MM reaction and
formed all-carbon quaternary stereocenters with high enantiose-
lectivities (Table 2).11 Diastereoselectivities and yields varied from
moderate to high ranges.12 Interestingly, triethoxy silyl enol ethers13
(entries 2 and 7) were found to be more reactive than corresponding
a Values are the ee of a major diastereomer. Those of minor isomers
were 50, 83, 81, 58, N/D, 79, and 72%, respectively.
trimethyl silyl enol ethers (entries 1 and 6). The former nucleophiles
underwent smooth conjugate addition reaction at 0 °C, leading to
increased diastereoselectivities. To our knowledge, the present
† Present address: Department of Chemistry, University of Miami, Coral Gables,
Florida 33124-0431.
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C O M M U N I C A T I O N S
method represents the only catalytic asymmetric MM reaction that
provides access to enantioenriched R-carbonyl all-carbon-substituted
quaternary stereocenters.
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Evans et al. reported that pybox-scandium(III) triflate complexes
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phosphonates with excellent yields and enantioselectivities (indole
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interest to us whether our catalyst was also capable of promoting
the above reaction since the indole skeleton is an important
substructure in both natural products and therapeutic agents15b (eq
1). N-Benzylindole readily reacted with both crotonyl (83% yield,
95% ee) and cinnamoyl (85% yield, 98% ee) phosphonates.16 It is
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duction of the present MM reaction (Table 1) is provided in Figure
1.17 The direct product, silyl enol phosphonate, was obtained as a
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1
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ing interactions. The absolute stereochemistry observed in the indole
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(11) Relative stereochemistry of the major diastereomer (entry 4) was
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(12) TMS enol ether of isopropyl phenyl ketone reacted very sluggishly (35%
yield).
Figure 1. Model of [Al(TBOx)(crotonylphosphonate)]+ complex.
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AlSbF6 proved to be a highly enantioselective catalyst for the
Mukaiyama-Michael reaction of simple silyl enol ethers, as well
as tetrasubstituted silyl enol ethers that gave rise to enantioenriched
R-carbonyl all-carbon-substituted quaternary stereocenters. This
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reported for the indole Friedel-Crafts alkylation reaction.
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Acknowledgment. Support of this research was provided by
the National Science Foundation (Grant CHE-0412060). We thank
Dr. Ian M. Steel for the X-ray structure determination.
(16) The absolute configuration was not determined for R′ ) Ph.
(17) [Al(TBOx)(crotonylphosphonate)]+ is expected to be cis-â-configured
octahedral complex by analogy (see refs 7 and 9).
(18) Karaman, R.; Goldblum, A.; Breuer, E. J. Chem. Soc., Perkin Trans. 1
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Supporting Information Available: Experimental procedures,
spectral data for all new compounds, and crystallographic data; X-ray
crystallographic file in CIF format. This material is available free of
charge via the Internet at http://pubs.acs.org.
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