Highly enantioselective organocatalytic conjugate addition of malonates to acyclic α,β-unsaturated enones

Article abstract of DOI:10.1002/anie.200390182

An imidazolidine easily prepared from phenylalanine is the catalyst for the highly enantioselective Michael addition shown. A great diversity of α,β-unsaturated enones was transformed with excellent enantioselectivities. The scope of the reaction is furth

Full text of DOI:10.1002/anie.200390182

Angewandte
Chemie
[13] a) L. B. Groenendaal, F. Jonas, D. Freitag, H. Pielartzik, J. R.
Experimental Section
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DBEDOT was obtained according to ref. [14] with 76% yield: m.p.
968C; 1H NMR (500 MHz, CDCl3, 258C, TMS): d = 4.27 ppm (s, 4H);
13C NMR (125 MHz, CDCl3, 258C, TMS): d = 139.6, 85.4, 64.9 ppm;
CP-MAS 13C NMR (75 MHz, solid state, 258C, TMS): d = 140.3, 84.6,
65.1 ppm; MS (70 eV): m/z (%): 302 (55) [M+], 300 (100), 298 (55);
elemental analysis: found: C 23.79, H 1.28, Br 53.00, S 10.86; calcd for
C6H4Br2O2S: C 24.02, H 1.34, Br 53.27, S 10.69.
[14] DBEDOT was first reported by Reynolds et al.: G. A. Sotzing,
J. R. Reynolds, P. J. Steel, Chem. Mater. 1996, 8, 882. It was used
for a Ni0-mediated coupling in solution to give oligo-EDOT: F.
Tran-Van, S. Garreau, G. Louarn, G. Froyer, C. Chevrot, J.
Mater. Chem. 2001, 11, 1378.
[15] In-situ ESR monitoring of the polymerization at 658C showed
the development of a symmetric ESR signal (g = 2.006), which
reached a maximum after 4 h (corresponding to the formation of
a polaron) and then gradually decreased to 65% of the
maximum intensity (and changed shape, as a result of bipolaron
formation).[16,17]
[16] H. Meng, F. Wudl, G. Z. Pan, W. Yu, W. Dong, S. Brown,
unpublished results.
[17] A. O. Patil, A. J. Heeger, F. Wudl, Chem. Rev. 1988, 88, 183.
[18] 2,5-Dichoro-3,4-ethylenedioxythiophene, the intermolecular
PEDOT: In a typical experiment, DBEDOT (0.01 2 g) was
incubated at 608C for 24 h and dried in vacuum (0.1 mbar) at room
temperature to give black crystals of bromine-doped PEDOT;
elemental analysis: found: C 28.87, H 1.65, Br 38.42, S 12.90; calcd
for C6H4Br1.2O2S(H2O)0.6: C 28.01, H 3.50, Br 38.73, S 12.45.
The well-ground material was additionally dried in vacuum
(0.1 mbar) at 1508C overnight, then stirred with hydrazine hydrate
(50% aqueous solution, in MeCN) overnight, filtered, and washed
with neat MeCN. Vacuum drying afforded a nearly fully dedoped
PEDOT; elemental analysis: found: C 46.84, H 2.42, N ~ 2, Br 0.42, S
19.04; calcd for C6H4O2Br0.01S(NH2NH2¥3H2O)0.12: C 47.63, H 3.44, N
2.22, Br 0.53, S 21.19. CP-MAS 13C NMR (75 MHz, solid state, 258C,
TMS): dc = 136.5, 108.7, 64.9 ppm; IR (KBr): n˜ = 1650, 1431, 1358,
À
Cl Cl distance of which (3.58 ä) is larger than the double
vdW radius of chlorine (3.4 ä), does not polymerize under these
conditions.
1203, 1066, 984, 918, 832, 690 cmÀ1
.
[19] F. Zhang, M. Johansson, M. R. Andersson, J. C. Hummelen, O.
Ingan‰s, Adv. Mater. 2002, 14, 662.
Received: September 24, 2002 [Z50225]
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New York, 1998.
Asymmetric Michael Addition
Highly Enantioselective Organocatalytic
Conjugate Addition of Malonates to
Acyclic a,b-Unsaturated Enones**
[3] G. Yu, J. Gao, J. C. Hummelen, F. Wudl, A. J. Heeger, Science
1995, 270, 1789.
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Nature 1990, 347, 539.
Nis Halland, Pompiliu S. Aburel, and
Karl Anker J˘rgensen*
Even though the first reports of enantioselective organo-
catalysis by Wiechert et al. and Hajos and Parrish appeared
almost three decades ago,[1] the field of asymmetric catalysis
has been dominated by metal catalysis. It is only recently that
asymmetric organocatalysis has received renewed attention
and become the focus of intense research efforts.[2] This is
primarily due to the operational simplicity, the cheap
catalysts, and the obvious industrial applications.
[5] a) J. A. Rogers, Z. Bao, K. Baldwin, A. Dodabalapur, B. Crone,
V. R. Raju, V. Kuck, H. Katz, K. Amundson, J. Ewing, P. Drzaic,
Proc. Natl. Acad. Sci. USA 2001, 98, 4817; b) H. Sirringhaus, T.
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Brabec, N. S. Sariciftci, J. C. Hummelen, Adv. Funct. Mater.2001,
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Recently, a number of reports on organocatalytic trans-
formations has appeared covering a wide range of reactions
including Diels Alder reactions,[3] aldol reactions,[4] Mannich
[*] K. A. J˘rgensen, N. Halland, P. S. Aburel
Danish National Research Foundation:Center for Catalysis
Department of Chemistry
Aarhus University
8000 Aarhus C (Denmark)
Fax:( +45)86196199
E-mail:kaj@chem.au.dk
[**] This work was supported by a grant from The Danish National
Research Foundation. We are grateful to Dr. R. G. Hazell for X-ray
crystallographic analysis.
[12] Handbook of Organic Conductive Molecules and Polymers,
Vol. 2 (Ed.: H. S. Nalwa), Wiley, New York, 1997.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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reactions,[5] 1,3-dipolar cycloadditions,[6] a amination,[7] syn-
thesis of electron-rich benzene systems,[8] Robinson annula-
tion,[9] Michael reaction,[10] Strecker reaction,[11] and others.[12]
Although impressive results have been achieved in many
organocatalytic asymmetric reactions, reports on enantiose-
lective Michael addition reactions with excellent enantiose-
lectivities (> 90% ee) have until recently[10l] been limited to
cyclic substrates[10e] or reactions with very low yields.[10f]
Herein we report the first enantioselective Michael
addition of malonates to acyclic enones in excellent yields
and enantioselectivities using an imidazolidine catalyst easily
prepared from phenylalanine.[13] The potential of this new
It turned out that the ester functionality has a large
influence on the yield and enantioselective induction. The use
of dimethyl malonate (3a) afforded only 73% ee (Table 1,
entry 1), which is substantially lower than the 91% ee
obtained in the initial test reaction with 3b (Table 1, entry 2).
For the sterically more hindered malonates 3c, 3d, and 3i, the
reaction rate was decreased considerably and only low yields
were obtained (Table 1, entries 3, 4, 9). The reactions of the
medium-sized malonates 3e h all proceeded with excellent
yields and enantioselectivities. For example, dibenzyl malo-
nate (3 f) afforded the Michael adduct in 93% yield and
higher than 99% ee (Table 1, entry 6). Unfortunately the
diastereoselectivities with the nonsymmetrical malonates
3g,h were rather low (Table 1, entries 7, 8) as almost equal
amounts of the isomers at the a-carbon atom were formed.
This has been observed previously in amine-catalyzed Mi-
chael additions of nitroalkanes to enones.[10b,13]
À
catalytic enantioselective C C bond-forming reaction is
demonstrated by an easy synthetic route to optically active
d ketoesters after a simple decarboxylation procedure and the
formation of optically active tetrahydroquinolines
(Scheme 1). This organocatalytic approach compares favor-
To further explore the scope of the reaction, a series of
a,b-unsaturated enones 2a o were reacted with dibenzyl
malonate (3 f) in the presence of 10 mol% of catalyst 1
[Eq. (2)]. The results are presented in Table 2. The aromatic
Scheme 1. Enantioselective Michael addition of malonates to acyclic
enones.
ably to Lewis acid catalyzed[14] and indirect Lewis acid
catalyzed[15] Michael additions to acyclic substrates in terms of
ease of handling, yields, and enantioselectivities.
The imidazolidine catalyst 1 is
an efficient catalyst for the Michael
addition of malonate nucleophiles
to a,b-unsaturated enones
Table 1: Enantioselective Michael addition of malonates 3a-i to benzylideneacetone (2a) catalyzed by 1
[Eq. (1)].[a]
Entry
Malonate
R
R’
t [h]
d.r.
Yield of 4 [%][b]
ee [%][c]
[Eq. (1)], and a test reaction of
benzylideneacetone (2a) with di-
ethyl malonate (3b) and 10 mol%
of catalyst 1 yielded the Michael
adduct 4b in high yield and 91% ee
(Table 1, entry 2). A series of mal-
onates were tested as it is known
that the ester group has a large
effect on the asymmetric induction
of the reaction.[10a] The results of the
screening of malonates 3a i in the
reaction with 2a in the presence of
10 mol% of 1 are presented in
Table 1.
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3 f
3g
3h
3i
Me
Et
Me
Et
iPr
tBu
allyl
Bn
Me
Et
120
120
210
210
150
150
150
150
150
66
73
26
<5
92
93
92
90
<10
73
91
71
nd
89
>99
98/97
90[d]
nd
iPr
tBu
allyl
Bn
Bn
Bn
Et
1:1.5
1:1
1:1.3
tBu
[a] Experimental conditions: 2a (0.5 mmol) and 1 (0.05 mmol) were added to 3 (1.0 mL) and the
reaction mixture was stirred at ambient temperature for the time indicated in the table. [b] Unoptimized
yields determined by GC. [c] Determined by chiral stationary-phase HPLC, see Supporting Information;
nd:not determined. [d] Determined by chiral stationary-phase HPLC after decarboxylation, see
Supporting Information.
662
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Table 2: Enantioselective Michael addition of dibenzyl malonate (3 f) to 2a o catalyzed by 1 [Eq. (2)].[a]
Entry
Enone
Product
t [h] Yield [%][b]
ee [%][c]
Entry
Enone
Product
t [h] Yield [%][b]
ee [%][c]
1
165
86
99
9
165
165
75
95
92
88
165
165
99
74
90
93[d]
10
2
3
4
5
6
7
8
165
165
165
150
170
150
75
75
84
87
58
75
98
93
89[e]
86
77
92
11
12
13
14
15
16
250
170
150
250
170
288
61
33
78
66
2
91[f]
84
83
95[f]
94
59
59[e]
[a] Experimental conditions:Enone 2 (0.5 mmol) and 1 (0.05 mmol) were added to 3 f (1.0 mL) and the reaction mixture was stirred at ambient temperature for
the time indicated in the table. [b] Yields after flash chromatography. [c] Determined by chiral stationary-phase HPLC, see Supporting Information. [d] Performed
at 108C. [e] Performed at 08C. [f] Performed by using 20 mol% of catalyst.
enones 2a f reacted very well with 3 f and the Michael
adducts 4 f,j n were all formed in high yields and enantiose-
lectivities (Table 2, entries 1 6). Both electron-withdrawing
(NO2, Cl) and -donating substituents (OH) can be introduced
on the aromatic ring without compromising the yield or
enantioselectivity of the reaction (Table 2, entries 3 6). The
only exception to the generally high yields and enantioselec-
tivities with aromatic enones was the N,N-dimethylaniline
derivative 2g (58% 4o with 77% ee, Table 2, entry 7). The
heteroaromatic enones 2h j were also successfully used in
this Michael reaction (Table 2, entries 8 10). The alkyl-
substituted enones 2k,l were found to react quite slowly
and with lower yields even when longer reaction times and
higher catalyst loadings were employed (Table 2, entry 11),
however high enantioselectivities were still obtained (Table 2,
entries 11, 12).
It should be noted that no by-products were observed in
any of the reactions, that the yields for the slowly reacting
substrates 2k,l,n,o are a consequence of the reaction time,
and that higher yields could be obtained at longer reaction
times. Higher yields[16] could also be achieved at elevated
reaction temperatures, but generally accompanied by slightly
decreased enantioselectivies: for instance, compound 4v was
formed in 82% yield and 87% ee at 608C (10 mol% of 1 and
shorter reaction time). For the sterically more hindered
enones 2n,o, the reaction rate was decreased and lower yields
resulted. This seems to be an effect of the added steric bulk on
the ketone, hindering the catalyst approach, and thus slowing
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down the reaction rate. The reduced reac-
tion rate did not affect the asymmetric
induction (Table 2, entries 14, 15). An
ester-substituted enone, 2p, was also test-
ed; the Michael adduct 4x was formed,
although in moderate yield and enantiose-
lectivity (Table 2, entry 16).
The absolute configuration of the Mi-
chael adduct 4k was determined to be R.[17]
This is in complete agreement with an
iminium ion intermediate 5 (Figure 1),[18]
Scheme 2. Synthesis of an optically active tetrahydroquinoline from 4n.
obtained from activation of enone 2a by the chiral catalyst.
The Re face of the enone in this intermediate is shielded by
the benzyl group of the chiral catalyst allowing the malonate
to approach the open Si face of the enone as outlined in
Figure 1.
by the synthesis of optically active d ketoesters and tetrahy-
droquinolines.
Received: October 10, 2002 [Z50341]
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Figure 1. PM3-minimized structure and formula of the proposed imini-
um ion intermediate 5.
The Michael adducts 4 could easily undergo a simple one-
pot decarboxylation transesterification procedure to give the
corresponding optically active d ketoesters 6 as shown in
Equation (3) for Michael adduct 4 f which is decarboxylated
in 67% yield (unoptimized) and without detectable loss of
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Michael adduct 4n could be used for a facile synthesis of
the biologically interesting optically active tetrahydroquino-
line 7 (Scheme 2).[19] The transformation of dibenzyl ester 4n
into the corresponding dimethyl ester 4y was followed by
reductive amination giving tetrahydroquinoline 7 as a single
diastereomer in 78% yield and without loss of otical purity.
In summary, we have developed the first highly enantio-
selective organocatalytic Michael addition of malonates to
a,b-unsaturated enones using an imidazolidine catalyst easily
prepared from phenylalanine. The reaction proceeds for a
great diversity of a,b-unsaturated enones with excellent
enantioselectivities. The scope of the reaction is demonstrated
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664
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Angewandte
Chemie
Martin, Org. Lett. 2001, 3, 2423; i) D. Enders, A. Seki, Synlett
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Structural Memory Reporters
Supramolecular Chirality: A Reporter of
Structural Memory**
Marco Ziegler, Anna V. Davis, Darren W. Johnson, and
Kenneth N. Raymond*
[13] N. Halland, R. G. Hazell, K. A. J˘rgensen, J. Org. Chem. 2002,
67, 8331.
Dedicated to Dr. Jide Xu
on the occasion of his 60th birthday
[14] For reviews of enantioselective conjugate addition reactions,
see: a) Comprehensive Asymmetric Catalysis (Eds.: E. N. Jacob-
sen, A. Pfaltz, H. Yamamoto), Springer, Berlin, 1999; b) M. P.
Sibi, S. Manyem, Tetrahedron 2000, 56, 8033; for examples of
Lewis acid catalyzed enantioselective Michael additions of 1,3-
dicarbonyl compounds to acyclic substrates, see: c) Y. Hama-
shima, D. Hotta, M. Sodeoka, J. Am. Chem. Soc. 2002, 124,
11240; d) N. End, L. Macko, M. Zehnder, A. Pfaltz, Chem. Eur.
J. 1998, 4, 818; e) J. Ji, D. M. Barnes, J. Zhang, S. A. King, S. J.
Wittenberger, H. E. Morton, J. Am. Chem. Soc. 1999, 121,
10215; f) J. Christoffers, U. Rˆ˚ler, T. Werner, Eur. J. Org.
Chem. 2000, 701.
Herein we describe a molecular structure, formed from labile
components, that exhibits structural memory. The macro-
scopic model in Figure 1 demonstrates this principle. The
wooden icosohedral puzzle retains its structure (without any
glue) despite dissociation of several pieces. These labile pieces
can be removed and replaced without disassembly of the
[15] For examples of Lewis acid catalyzed enantioselective Mukaiya-
ma Michael additions, see: a) D. A. Evans, T. Rovis, M.
Kozlowski, C. W. Downey, J. S. Tedrow, J. Am. Chem. Soc.
2000, 122, 9134; b) D. A. Evans, K. A. Scheidt, J. N. Johnston,
M. C. Willis, J. Am. Chem. Soc. 2001, 123, 4480.
[16] H2O was also tried as an additive in the reactions to affect
turnover, but it was found that the addition of 5 or 10 equiv of
H2O to the reaction mixture did not affect yield or enantiose-
lectivity.
[17] CCDC-194337 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cam-
bridge Crystallographic Data Centre, 12, Union Road, Cam-
bridge CB21EZ, UK; fax: (+ 44)1223-336-033; or deposit@
ccdc.cam.ac.uk).
[18] The calculations have been performed for the protonated
carboxylic acid form of 5.
[19] For a recent racemic synthesis of tetrahydroquinolines and their
biological activity, see R. A. Bruce, D. M. Herron, L. B. Johnson,
S. V. Kotturi, J. Org. Chem. 2001, 66, 2822, and references
therein.
Figure 1. A 3D puzzle made of labile wooden components retains its
structure despite dissociation of several pieces.
original structure. The structure itself is retained, or remem-
bered, throughout the process of component substitution. In
short, structural memory describes the substitution process
itself and not merely the starting and ending states of the
system.
Like the wooden puzzle, discrete supramolecular assem-
blies exhibit well-defined topologies, specified by the arrange-
ment and connectivity of the constituent molecular compo-
nents. If these molecular components can be substituted in a
stepwise fashion and the supramolecular structure still
persists, then there is structural memory. We describe such
structural memory–as reported by retention of chirality–in
[*] Prof. K. N. Raymond, M. Ziegler, A. V. Davis, D. W. Johnson
Department of Chemistry
University of California
Berkeley, CA 94720-1460 (USA)
Fax:( +1)510-486-5283
E-mail:raymond@socrates.berkeley.edu
[**] Coordination Number Incommensurate Cluster Formation, Part 23.
Financial support for this work was provided by NSF CHE-9709621.
We thank the Miller Foundation for a fellowship to M.Z. Part 22:
D. W. Johnson, K. N. Raymond, Inorg. Chem. 2001, 40, 5157 5161.
Angew. Chem. Int. Ed. 2003, 42, No. 6
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1433-7851/03/4206-0665 $ 20.00+.50/0
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