Cysteine-derived organocatalyst in a highly enantioselective intramolecular Michael reaction

Article abstract of DOI:10.1021/ja055740s

Asymmetric intramolecular Michael reaction catalyzed by an organocatalyst derived from cysteine has been developed for the synthesis of chiral bicyclo[4.3.0]nonene and cis-disubstituted cyclopentane skeletons with a creation of three or two contiguous chiral centers in good yield with high diastereo- and excellent enantioselectivities. Copyright

Full text of DOI:10.1021/ja055740s

Published on Web 10/26/2005
Cysteine-Derived Organocatalyst in a Highly Enantioselective Intramolecular
Michael Reaction
Yujiro Hayashi,* Hiroaki Gotoh, Tomohiro Tamura, Hirofumi Yamaguchi, Ryouhei Masui, and
Mitsuru Shoji
Department of Industrial Chemistry, Faculty of Engineering, Tokyo UniVersity of Science, Kagurazaka, Shinjuku-ku,
Tokyo 162-8601, Japan
Received August 22, 2005; E-mail: hayashi@ci.kagu.tus.ac.jp
Table 1. Effect of Catalyst on Asymmetric Intramolecular Michael
The Michael reaction is an important carbon-carbon bond
Reaction of 1a (R ) PhCH2)a
forming reaction for which the catalytic asymmetric version using
metal carbanions has been developed with great success.1 In recent
years, the organocatalyst-mediated Michael reaction has undergone
rapid development, and excellent results have been reported for
intermolecular reactions.2 To attain high enantioselectivity, the
design of the organocatalyst is crucial, and we have developed
diphenylprolinol silyl ether as an efficient catalyst for the Michael
reaction of aldehydes and nitroalkenes.3 Only one excellent report
has described the enantioselective, intramolecular, catalytic Michael
reaction, an important method for the preparation of chiral, cyclic
carbon skeletons from acyclic precursors, in which List and Fonseca
reported the synthesis of chiral trans-disubstituted cyclopentanes
from formyl enones.4
The bicyclo[4.3.0]nonene carbon skeleton is found in several
natural products, such as the elinacines,5 axanes,6 and scabronines,7
and its asymmetric construction is a synthetic challenge. This
a Unless otherwise shown, reactions were conducted with 10 mol % of
skeleton could be synthesized from an achiral precursor, 4-substituted-
catalyst in CH3CN at 0 °C. b Yield of isolated products of 2 and 3.
c Determined by 1H NMR (400 MHz). d Determined by HPLC using a
Chiralpak AS-H column. e A 20 mol % of the catalyst was employed.f A
5 mol % of the catalyst was employed.
4-(3-formylpropyl)cyclohexa-2,5-dien-1-one (1), via asymmetric
intramolecular Michael reaction with creation of three contiguous
chiral centers in a single step, if selective reaction of one of the
two enantiotopic π-bonds of 1 can be achieved (eq 1).
Table 2. Asymmetric Intramolecular Michael Reaction of 1a
The achiral 1a possessing a benzyl group at the 4-position was
selected as a model and was prepared from 3-ethoxycyclohex-2-
en-1-one in six steps.8 When 1a was treated with a catalytic amount
of L-proline, the reaction was slow, affording 2a in low yield and
11% ee (Table 1, entry 1). Low enantiomeric excess was obtained
in the case of MacMillan’s catalyst 5,2c,4a while prolinol silyl ether,
which is an effective catalyst in our aldehyde-nitroalkene Michael
reaction,3 gave good yield and moderate enantiomeric excess. After
screening various organocatalysts, the trifluoroacetic acid salt9 of
cysteine-derived amine 7 was found to be the catalyst of choice,
affording 2a in good yield with high diastereo- and excellent
enantioselectivity. Moreover, the catalyst loading can be reduced
to 5 mol %, without compromising the enantioselectivity. It should
be noted that the activity of catalyst 7 is much higher than that of
MacMillan’s catalyst 5 under the present reaction conditions. The
reaction using 7 was complete within 3 h, while the reaction using
5 had not finished even after 24 h.10
a The reactions were conducted with 10 mol % of catalyst 7 in CH3CN
at 0 °C for 3-5 h. b Yield of isolated products of 2 and 3. c Determined by
1H NMR (400 MHz). d Determined by HPLC using a chiral column.
skeleton in good yield with high diastereo- and excellent enantio-
selectivity.
Next, the catalyst 7 was applied to the reaction of formyl enones
8 for the synthesis of chiral, disubstituted cyclopentane derivatives
9 via intramolecular Michael reaction (eq 2). When 8a was treated
with 10 mol % of 7 at 0 °C, the reaction proceeded smoothly,
affording the cis-isomer diastereo- and enantioselectively. Note-
worthy is the selectiVe formation of the cis-isomer, which is opposite
The generality of the present intramolecular Michael reaction
was investigated, with the results summarized in Table 2. Not only
benzyl but also alkyl groups, such as methyl and butyl, are tolerated
in the 4-position. Other synthetically useful substituents, such as
the allyl group, are also suitable, affording the bicyclo[4.3.0]nonene
9
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J. AM. CHEM. SOC. 2005, 127, 16028-16029
10.1021/ja055740s CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
In summary, the naphthylamide catalyst 7 derived from cysteine
has been developed to act as an efficient organocatalyst of two
different types of asymmetric intramolecular Michael reaction. In
one, there is discrimination between two enantiotopic π-bonds, and
a bicyclo[4.3.0]nonene is formed, and, in the other, between the
enantiofaces of an R,â-enone giving cis-disubstituted cyclopentane
skeletons. These compounds, containing three and two contiguous
chiral centers, respectively, are formed in good yield with high
diastereo- and excellent enantioselectivities. There is another note-
worthy feature to this reaction: in the synthesis of the cyclopentane
skeleton, the cis-isomer is synthesized diastereo- and enantiose-
lectively, which is complementary to the intramolecular Michael
reaction using Enders’ SAMP/RAMP-hydrazone methodology,4c
and that using MacMillan’s catalyst,4a both of which afford the
trans-isomer selectively.
Table 3. Asymmetric Intramolecular Michael Reaction of 8a
Acknowledgment. This work was partially supported by a
Grand-in-Aid for Scientific Research on Priority Areas 16073219
from MEXT.
Supporting Information Available: Detailed experimental pro-
1
cedures, full characterization, copies of H, 13C NMR, and IR spectra
of all new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
a Reactions were conducted with 10 mol % of catalyst 7 in acetone at 0
°C. b Yield of isolated product. c Determined by 1H NMR (400 MHz).
d Determined by HPLC using a chiral column. e The trans-isomer was
obtained in 94% ee. f The reaction was conducted in THF at room
temperature.4a g The reaction was conducted at -20 °C.
References
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to the result obtained with MacMillan’s catalyst 5, which was
reported to give the trans-isomer stereoselectively with excellent
enantioselectivity.4a Careful examination of the cis/trans ratio at
different reaction times indicated that the cis-isomer is the kinetic
product, while the trans-isomer is thermodynamically more stable.
That is, the cis-isomer was obtained in good yield and excellent
enantioselectivity after 4 h, but this yield decreased with time, with
a concomitant increase in the trans-isomer. Both isomers are formed
with excellent enantioselectivity (entry 2). As efficient isomerization
can be realized by treatment of the isolated cis-isomer 9a with a
catalytic amount of DBU in 10 min at 0 °C, affording the trans-
isomer 10a in 90% yield without loss of optical purity (eq 3), the
present Michael reaction is a powerful method for the preparation
of both cis- and trans-isomers in synthetically useful yield with
very high optical purity. When the reaction was carried out in THF
at room temperature under List’s conditions4a using catalyst 7, the
reaction was slow, affording cyclopentanes in moderate diastereo-
meric excess and excellent enantiomeric excess after 8 h (entry 3).
The reaction is fairly general and could be used to prepare several
synthetically useful disubstituted cyclopentane and cyclopentanone
derivatives with high cis-selectivity and excellent enantioselectivity;
these results are summarized in Table 3. Both aromatic and aliphatic
R,â-enones are suitable substrates, affording almost enantiomerically
pure cyclized product.
(3) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed.
2005, 44, 4212.
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T. J. Am. Chem. Soc. 1988, 110, 958. (c) Enders, D.; Scherer, H. J.; Raabe,
G. Angew. Chem., Int. Ed. Engl. 1991, 30, 1664. (d) Hirai, Y.; Terada,
T.; Yamazaki, T.; Momose, T. J. Chem. Soc., Perkin Trans. 1 1992, 509.
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(8) See Supporting Information for details.
(9) The free amine itself scarcely promoted the reaction.
(10) The reaction of 5 in THF under List’s conditions4a is also slow.
(11) (a) Asymmetric catalytic inverse electron-demand hetero-Diels-Alder
reaction using organocatalyst: Juhl, K.; Jørgensen, K. A. Angew. Chem.,
Int. Ed. 2003, 42, 1498. (b) Stoichiometric use of chiral amine: Schreiber,
S. L.; Meyers, H. V. J. Am. Chem. Soc. 1988, 110, 5198. (c) The Lewis
acid-catalyzed enantioselective inverse-electron demand hetero-Diels-
Alder reaction: Gademann, K.; Chavez, D. E.; Jacobsen, E. N. Angew.
Chem., Int. Ed. 2002, 41, 3059 and the references therein.
R,â-Unsaturated aldehyde 8e gave different results (eq 4). When
8e was treated with 7, dihydropyran 11 was obtained quantitatively
as a single isomer. The generation of 11 indicates that a chiral
enamine is involved in the reaction,2c,4a and that possible mecha-
nisms for this transformation include not only the Michael reaction
but also the inverse-electron demand Diels-Alder reaction.11
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J. AM. CHEM. SOC. VOL. 127, NO. 46, 2005 16029