Enantioselective Conjugate Silyl Additions to a,b-Unsaturated Aldehydes
setting up the lab and Dr. Pawel Dziedzic for running the
HR-MS analysis.
In summary, we have shown that it is possible to
merge the catalytic cycles of transition metal-cata-
lyzed nucleophilic activation and amine-catalyzed imi-
nium activation to achieve enantioselective bond for-
mation. This concept was exemplified by the first
report of an enantioselective b-silyl addition to a,b-
unsaturated aldehydes using simple and commercially
available Cu salts and chiral amines to give the corre-
sponding b-silyl aldehydes in up to 97:3 er. The prod-
ucts can be efficiently converted to protected 1,3-diols
and b-functionalized esters. It is also noteworthy that
a quaternary stereocenter can be generated by this
co-catalytic transformation. Furthermore, DFT calcu-
lations have been used to investigate the reaction
mechanism. The reaction is shown to proceed through
a nucleophilic attack of the silyl moiety from a
PhMe2SiCuL species on the iminium intermediate.
The origin of the enantioselectivity has been shown to
be the steric repulsion between the nucleophile and
the bulky group of the organocatalyst. Future studies
will involve investigating the possibilities of develop-
ing more efficient chiral amine catalysts and the em-
ployment of other nucleophiles based on the concept
presented herein.
References
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Experimental Section
Representative Procedure for Iminium-Cu-Catalytic
Enantioselective Conjugate Silyl Additions
[6] For the use of 1 as the reagent in Cu-catalyzed ECA,
see: a) K. S. Lee, A. H. Hoveyda, J. Am. Chem. Soc.
2010, 132, 2898; b) A. H. Hoveyda, personal communi-
cation.
A 6-mL oven-dried vial with a magnetic stir bar was charged
with KO-t-Bu (1.0 mg, 8.75 mmol, 5 mol%) and CuCl
(2.0 mg, 17.5 mmol, 10 mol%). The vial was sealed and
purged with a stream of N2 before CH2Cl2 (875 mL) was
added. The solution was allowed to stir for one hour at
228C under an N2 atmosphere. The resulting solution was
[7] For catalytic methods giving racemic b-silyl carbonyls,
see: a) B. H. Lipshutz, J. A. Scalfani, T. Takanami, J.
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charged with PhMe2Si
1.0 equiv.). In a separate oven-dried vial (6ꢄ1 cm), alde-
hydes (0.350 mmol, 2.0 equiv.) and the catalyst 5a
A
1
(48.0 mL, 0.175 mmol,
2
(14.2 mg, 43.8 mmol, 25 mol%) were dissolved in CH2Cl2
(875 mL) with para-nitrobenzoic acid (3.0 mg, 17.5 mmol,
10 mol%) under N2, and then transferred by syringe to the
solution of KO-t-Bu and CuCl (final substrate concentra-
tion=0.1M). The resulting mixture was allowed to stir for
4 h at 228C. Next, the resulting brown reaction mixture was
directly loaded upon a silica gel column and immediate
chromatography (hexane:EtOAc-mixtures) furnished the b-
silyl aldehyde products 3.
[8] I. Fleming, Science of Synthesis, Thieme, Stuttgart, Ger-
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1986; Angew. Chem. Int. Ed. 2006, 45, 1952.
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Kirsch, Angew. Chem. 2008, 120, 5787; Angew. Chem.
Int. Ed. 2008, 47, 5703; b) Z. Shao, H. Zhang, Chem.
Soc. Rev. 2009, 38, 2745, and references cited therein.
For an example of merging of transition metal cata-
lyzed electrophile acitivation with asymmetric amine-
catalyzed iminium, enamine activation, see: c) G.-L.
Zhao, F. Ullah, L. Deiana, S. Lin, Q. Zhang, J. Sun, I.
Ibrahem, P. Dziedzic, A. Cꢀrdova, Chem. Eur. J. 2010,
Acknowledgements
Financial support was provided by Mid Sweden University
and The Swedish National Research Council (V.R.). I I. is
grateful for repatriation funding from VR. S. S. thanks the
Wenner-Gren Foundations for a postdoctoral fellowship. We
are most grateful to Prof. Amir H. Hoveyda for valuable dis-
cussions. We are also grateful to Hꢀkan Norberg for help in
Adv. Synth. Catal. 2011, 353, 245 – 252
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
251