Angewandte
Chemie
DOI: 10.1002/anie.201201060
Homogeneous Catalysis
Enantioselective 5-endo-dig Carbocyclization of b-Ketoesters with
Internal Alkynes Employing a Four-Component Catalyst System**
Satoru Suzuki, Etsuko Tokunaga, Dhande Sudhakar Reddy, Takashi Matsumoto, Motoo Shiro,
and Norio Shibata*
The Conia-ene reaction of acetylenic b-dicarbonyl com-
pounds represents one of the most direct methods for the
formation of carbocycles,[1] and is particularly attractive for
the preparation of cyclopentane derivatives. Although the
classical method of the Conia-ene reaction has some limi-
tations in its application because of the harsh experimental
conditions[1,2] such as high temperature, strong base, strong
acid, or photochemical activation, recent advances in the use
Scheme 1. Enantioselective carbocyclization. a) 5-Exo-dig cyclization of
of transition-metal catalysis[3] and organocatalysis[4] have
b-dicarbonyl compounds with terminal alkynes (known). b) The 5-endo-
dig cyclization of b-dicarbonyl compounds with internal alkynes
(challenge).
dramatically expanded the diversity of this reaction. In
2005, the first enantioselective intramolecular Conia-ene
reaction of b-ketoesters was reported by Toste and co-
workers using
a
palladium(II)/ytterbium(III) catalyst
system.[5] This work brought the enantioselective Conia-ene
reaction to the attention of a number of organic chemists
worldwide, and two more methods have since appeared.[6]
However, all the enantioselective methods are limited to the
5-exo-dig cyclization of b-dicarbonyl compounds with termi-
nal alkynes. An endocyclic variant of the Conia-ene reaction,
that is, 5-endo-dig cyclization of b-dicarbonyl compounds with
internal alkynes, is still a challenge (Scheme 1), although the
transition-metal-catalyzed 5-endo-dig addition of heteroatom
nucleophiles to internal alkynes are common.[7]
In 2004, Toste and co-workers achieved a rare example of
the gold(I)-catalyzed 5-endo-dig carbocyclization of 1,3-
dicarbonyl compounds with internal alkynes to provide
cyclopentene adducts in high yields.[8] They surveyed several
cationic group 11 metal triflates including copper(I) and
silver(I) triflates as catalysts for the cyclization of b-ketoesters
with internal alkynyl substituents, but only triphenylphos-
phine/gold(I) triflate gave the desired cyclization products.
The gold(I)-catalyzed 5-endo-dig carbocyclization reported
by Toste and co-workers is amenable to a wide range of b-
ketoesters having an alkynyl unit, however, the corresponding
asymmetric variants are difficult and give racemic products.[5]
Meanwhile, we have been engaged for several years in the
development of enantioselective a-functionalization of b-
dicarbonyl compounds as represented by enantioselective
fluorination and hydroxylation reactions using nickel(II),
zinc(II), or copper(II) complexes with a chiral 4,6-dibenzo-
furandiyl-2,2’-bis(4-phenyloxazoline) (DBFOX-Ph) or a 2,2’-
isopropylidinebis(4-phenyl-2-oxazoline) (Box-Ph) ligand.[9,10]
As a part of this research program for the metal-catalyzed
enantioselective functionalization of 1,3-dicarbonyls, we
started to investigate the enantioselective 5-endo-dig cycliza-
tion of b-dicarbonyl compounds with internal alkynes. Before
the completion of our work, a single example of an
enantioselective 5-endo-dig cyclization of a substrate bearing
an internal alkyne was reported (65% yield with 52% ee) in
a paper focusing on an asymmetric exocyclic Conia-ene
reaction of b-dicarbonyl compounds using a La/Ag hetero-
bimetallic catalyst.[6b] On the basis of the work by Toste and
co-workers, Sanz and co-workers recently devised an enan-
tioselective 5-endo-dig gold(I)-catalyzed cycloisomerization
of o-(alkynyl)styrenes,[6c] however, their achievement could
not be applied for the target enantioselctive endocyclic
variant of the Conia-ene reaction using 1,3-dicarbonyl com-
pounds. Just before the submission of this manuscript, the
group of Toste achieved a unique enantioselective transition-
metal-catalyzed cyclization of use of silyloxyenyens, and not
b-ketoesters, using chiral phosphine ligands.[11] We report
herein the first achievement of a 5-endo-dig cyclization of b-
dicarbonyl compounds having internal alkynes by employing
the four-component system Box-Ph/ZnII/Yb(OTf)3/HFIP
(HFIP = hexafluoroisopropyl alcohol) to deliver products in
high yields and with enantioselectivities of up to 98% ee.
We envisioned that novel catalytic access to enantio-
selective 5-endo-dig cyclization of b-dicarbonyl compounds
with internal alkynes 1 should be feasible by the proper
[*] S. Suzuki, E. Tokunaga, D. S. Reddy, Prof. N. Shibata
Department of Frontier Materials, Graduate School of Engineering,
Nagoya Institute of Technology
Gokiso, Showa-ku, Nagoya 466-8555 (Japan)
E-mail: nozshiba@nitech.ac.jp
T. Matsumoto, Dr. M. Shiro
Rigaku Corporation
3-9-12 Mastubara-cho, Akishima Tokyo 196-8666 (Japan)
[**] This study was financially supported in part by Grants-in-Aid for
Scientific Research (21390030, 22106515, Project No. 2105:
Organic Synthesis Based on Reaction Integration). We also thank
TOSOH F-TECH INC., and the Asahi Glass Foundation for support
in part. E.T. acknowledges Grants-in-Aid for Scientific Research for
financial support (23915014).
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2012, 51, 4131 –4135
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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