Organocatalytic asymmetric "anti-Michael" reaction of β-ketoesters

Article abstract of DOI:10.1039/b710393j

The first organocatalytic "anti-Michael" reaction of cyclic-β-ketoesters to unsaturated double bonds is described in a highly asymmetric version leading to the synthesis of α,α′- disubstituted branched double bonds as optically active Baylis-Hillman-like adducts. The Royal Society of Chemistry.

Full text of DOI:10.1039/b710393j

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Organocatalytic asymmetric ‘‘anti-Michael’’ reaction of b-ketoesters{
Jose´ Alema´n, Efra´ım Reyes, Bo Richter, Jacob Overgaard and Karl Anker Jørgensen*
Received (in Cambridge, UK) 9th July 2007, Accepted 7th August 2007
First published as an Advance Article on the web 16th August 2007
DOI: 10.1039/b710393j
The first organocatalytic ‘‘anti-Michael’’ reaction of cyclic-
b-ketoesters to unsaturated double bonds is described in a
highly asymmetric version leading to the synthesis of a,a9-di-
substituted branched double bonds as optically active Baylis–
Hillman-like adducts.
The conjugate addition of nucleophilic species to a,b-unsaturated
systems is a fundamental reaction in organic chemistry.1 One of
the most important carbon-carbon bond forming reactions in this
field is the Michael reaction2 – the 1,4-addition. For the
performance of a Michael reaction leading to optically active
products having an unsaturated functionality several strategies can
be applied (left equation, Scheme 1). Two main strategies are the
addition of b-ketoesters to triple bonds, leading to products as a
mixture of Z/E Michael-addition products3 or the addition/
elimination of b-ketoesters to b-haloacrylate esters, where complete
control of the double-bond geometry and good enantioselectivies
are found.4a
Scheme 2 The sulfone moiety as a directing and leaving group for the
anti-Michael product or a-addition.
We started our investigation by the addition of the indanone
b-ketoester derivative 1a to the sulfone 2,6c using cinchona
alkaloids7 as the catalysts under various reaction conditions. It
turned out, that the application of the cinchona alkaloids as
quaternary ammonium salts 3a, 3a9 and 3b9 under phase-transfer
catalytic (PTC) conditions, in the presence of aq. NaOH (10 wt%)
as the base provided the desired anti-Michael reaction. In Table 1
some representative results are shown.
Table 1 Screening and optimization conditions for the addition of
indanones 1a,b to sulfone 2a
In some cases, the addition to the carbonyl compound can take
place as an anti- or contra-Michael reaction (right equation,
Scheme 1).5 This reaction can be achieved by different methodo-
logies, such as alkynoates redirected by phosphine base modifica-
tion, addition at the a-position of Michael acceptors catalyzed by
palladium complexes, or by controlling the selectivity of the
Michael reaction with organometallic reagents.
We considered the possibility of developing an organocatalytic
asymmetric version of the anti-Michael reaction by using
b-ketoesters as nucleophiles and as the electrophiles, alkenes
having both an electron-withdrawing substituent and a directing
group (DG in Scheme 1). For the latter reagent, we decided to use
a sulfone, which also acts as a leaving group6 in a one-pot reaction
(intermediate not isolated). Thus, it will allow the synthesis of
optically active anti-Michael- or a-addition-Baylis–Hillman-like
adducts (Scheme 2).
Catalyst
Entry (mol%) Solvent
Base (wt%)b
T/uC eec (%)
1d
2d
3e
3a (6)
3b9 (6)
3a (6)
3a (6)
3a (6)
3a (3)
3a (6)
3a (6)
3a (6)
3a (6)
3a (6)
3a (6)
Tol–CHCl3 (7 : 1) Cs2CO3 (33%) 220 76
Tol–CHCl3 (7 : 1) Cs2CO3 (33%) 220 244
Tol–CHCl3 (7 : 1) Cs2CO3 (66%) 220
Tol–CHCl3 (7 : 1) NaOH (10%) 220
Tol–CHCl3 (7 : 1) K3PO4 (50%) 4
Tol–CHCl3 (7 : 1) Cs2CO3 (33%) 220
Tol–CHCl3 (7 : 1) K2CO3 (33%) 220
86
20
28
70
70
55
86
72
83
75
4e
5e
6e
7e
f
8e
o-Xylene–CHCl3
CHCl3
CH2Cl2
Toluene
o-Xylene
Cs2CO3 (66%) 220
Cs2CO3 (66%) 220
Cs2CO3 (66%) 220
Cs2CO3 (66%) 220
Cs2CO3 (66%) 220
9e
10e
11e
12e
a
Scheme 1 Two different approaches for the synthesis of a- and
b-Michael addition products.
b
All the reactions were performed in 0.10 mmol scale (0.15 M). In
all the cases after the consumption of the starting material 0.1 mL of
NaOH was added for 1 h to eliminate the sulfone anion (except in
Danish National Research Foundation: Center for Catalysis,
Department of Chemistry, Aarhus University, DK-8000, Aarhus C,
Denmark. E-mail: kaj@chem.au.dk; Fax: 45 8619 6199;
Tel: 45 8942 3910
{ Electronic supplementary information (ESI) available: Experimental
section. See DOI: 10.1039/b710393j
c
entries 4 and 5). The enantiomeric excess was determined by HPLC
using a chiral stationary phase. Indanone 1a was used for this
d
e
entry. Indanone 1b was used for this entry. 7 : 1.
f
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Table 2 Scope of the addition of b-ketoesters 1b–f to the sulfone 2aa
We found that the use of the indanone 1a and catalyst 3a gave
good results after few hours, obtaining the anti-Michael product 4a
with 76% ee (Table 1, entry 1). Changing the catalyst from 3a to
3b9 led to a decrease in enantioselectivity of 4a to 44% ee (entry 2).
When the ester moiety in the b-ketoester was changed from Me
(1a) to t-Bu (1b), it was observed that the elimination of the sulfone
from the intermediate to give the final product was more sluggish
compared to the methyl b-ketoester. In this case, it was necessary
to add aq. NaOH (10%) to eliminate the sulfone counterpart after
the enantioselective addition step performed with Cs2CO3 as an
external base. Thus, the reaction of indanone 1b led to an
improvement of the enantiomeric excess of the anti-Michael
product 4b to be 86% ee (entry 3). Using aq. NaOH (10%) as sole
base gave 4b directly; however, due to the background reaction
poor enantioselectivity was obtained (entry 4). Weaker bases, such
as K3PO4, allowed also the isolation of 4b with better enantio-
selectivity even at room temperature (entry 5). It was also noted
that lowering the concentrations of the catalyst, as well as
changing the base to K2CO3, decreased the enantioselectivity when
the reaction was performed at 220 uC (entries 6, 7). In addition,
performing the reaction in solvents such as o-xylene–CHCl3 (7 : 1),
CH2Cl2 or o-xylene gave enantioselectivities in the range of 55–
83% ee (entries 8, 10, 11), whereas in CHCl3 and toluene the
enantioselectivity was 83–86% ee (see entries 3, 9, 11).
Yieldb eec
(%) (%)
Entry 1 Base, T/uC
1b Cs2CO3 66%, 220
Product 4
1
2
3
4
5
4b – 90 86
1c Cs2CO3 66%, 220
1d Cs2CO3 66%, 220
1e Cs2CO3 66%, 220
1f K3PO4 50%, +4
4c – 89 94
ent-4c
– 88c 66d
4d – 85 79
4e – 80 88
4f – 76 66
4g – 80 68e
With the reaction conditions developed, a number of different
nucleophiles were tested with (E)-3-(phenylsulfonyl)acrylonitrile 2
in the presence of catalyst 3a (6 mol%) (Table 2). The reaction of
the indanone derivatives 1b–e proceeded in all the cases with good
yields and enantioselectivies of up to 94% ee (entries 1–4). The
dimethoxy indanone derivative 1c (entry 2) gave the highest
enantioselectivity, 94% ee, while for the chloro indanone 1d the
enantioselectivity was 79% ee (entry 3). Alternatively, by using the
indanone derivative with only one methoxy group an enantio-
selectivity of 88% ee was observed (entry 4).
6
7
8
9
a
1g Cs2CO3 66%, +4
1h K3PO4 50%, 220
1i K3PO4 50%, +4
1j K3PO4 50%, +4
(.99)f
4h – 52 63
4i – 60 60
4j – 42 63
A decrease in the asymmetric induction was noted when the
adjacent aromatic group was removed. Thus, for the tert-butyl
derivative 1f, the enantioselectivity was reduced to be 66% ee;
however, the good yield was maintained (entry 5). The reaction of
the functionalized tetralone 1g leads to an enantiomeric excess of
68% ee, which was increased to .99% ee by recrystallization (entry
6). Remarkably, the anti-Michael reaction also proceeded well for
other non-phenyl-fused b-ketoesters 1h and 1i (entries 7, 8)
observing moderate enantioselectivities (63 and 60% ee, respec-
tively). In addition, this reaction could be achieved with the
seven-membered ring b-ketoester derivative 1j giving similar
enantioselectivity and moderate yield (entry 9), demonstrating in
this manner, that the anti-Michael reaction could be performed
with five-, six- and seven-membered rings.
In all the cases after the consumption of the starting material
0.2 mL of NaOH was added for 1 h at rt to eliminate the sulfone
b
c
anion. Isolated yield. The enantiomeric excess was determined by
HPLC using chiral stationary phase or by GC (see ESI).
Reaction performed with the quasi-enantiomeric catalyst 3a9
a
d
e
derived from dihydrocinchonidine.
determined by X-ray analysis (see Fig. 1). After recrystallization
from hexane–AcOEt (95 : 5).
Absolute configuration
f
The absolute configuration was determined by X-ray crystal
structure analysis of compound 4g to be S of the new created
chiral center (Fig. 1).8 The observed configuration was in
agreement with previous results that we have observed in reactions
of cyclic-b-ketoesters with the same catalyst 3a.4
In order to show the potential of this new anti-Michael reaction,
we have performed some chemoselective transformations of the
optically active product 4c. Thus, acrylonitrile 4c could be reduced
under NaBH4 creating a mixture of diastereoisomers with two new
chiral centers, due to the non-chemoselective reaction,9 however,
this problem could be solved by CaCl2/NaBH4 reduction,10
Fig. 1 X-Ray crystal structure of compound 4g. Carbon: grey,
hydrogen: white, oxygen: red, nitrogen: blue.
3922 | Chem. Commun., 2007, 3921–3923
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125, 2582; (m) J. Christoffers and A. Baro, Angew. Chem., 2003, 115,
1726, (Angew. Chem., Int. Ed., 2003, 42, 1688).
2 For recent Michael reaction reviews, see: (a) Comprehensive Organic
Synthesis, ed. B. M. Trost, Pergamon, Oxford, 1991, vol. 4; (b)
P. Perlmutter, Conjugate Addition Reactions in Organic Synthesis,
Pergamon, Oxford, 1992; (c) T. Mukaiyama and S. Kobayashi, Org.
React., 1994, 46, 1 (tin enolates in Michael reaction); (d) R. D. Little,
M. R. Masjedizadeh, O. Wallquist and J. I. McLoughlin, Org. React.,
1995, 47, 315(intramolecular Michael reaction); (e) J. S. Johnson and
D. A. Evans, Acc. Chem. Res., 2000, 33, 325 (enantioselective Michael
reaction); (f) J. Christoffers, Synlett, 2001, 723 (vinylogous Michael
reaction); (g) D. Enders, K. Lu¨ttgen and A. A. Narine, Synthesis, 2007,
7, 959; (h) J. Christoffers, G. Kroipelly, A. Rosiak and M. Ro˝ssle,
Synthesis, 2007, 9, 1279.
3 For asymmetric addition of b-diketones to alkynones, see: (a) M. Bella
and K. A. Jørgensen, J. Am. Chem. Soc., 2004, 126, 5672. For addition
of a-alkyl-a-cyanoacetates to acetylenic esters with complete control of
Z and E-geometry, see: (b) X. Wang, M. Kitamura and K. Maruoka,
J. Am. Chem. Soc., 2007, 129, 1038.
4 (a) T. B. Poulsen, L. L. Bernardi, M. Bell and K. A. Jørgensen, Angew.
Chem., Int. Ed., 2006, 45, 6551; (b) T. B. Poulsen, L. Benardi, J. Alema´n,
J. Overgaard and K. A. Jørgensen, J. Am. Chem. Soc., 2007, 129, 441;
(c) L. Bernardi, J. Lo´pez-Cantarero, B. Niess and K. A. Jørgensen,
J. Am. Chem. Soc., 2007, 129, 5772.
Scheme 3 Chemoselective transformations of acrylonitrile 4c.
obtaining a complete diastereo- and chemo-selective reaction
(Scheme 3, eqn (1)).
The alkene functionality undergoes conjugate addition of
cuprate reagents;11 thus, when acrylonitrile 4c was treated with
PhMgBr/CuI, the b-functionalization of the double bond proceeds
with excellent yield and in a 3 : 1 diastereomeric ratio (Scheme 3,
eqn (2)).
5 For a recent anti- or contra-Michael review, see: E. Lewandowska,
Tetrahedron, 2007, 63, 2107, and references therein.
6 (a) N. S. Simpkins, Sulfones in Organic Synthesis, Pergamon, Oxford,
1993. For a review of sulfones as a leaving group, see: (b) C. Na´jera and
M. Yus, Tetrahedron, 1999, 55, 10547; (c) Sulfone 2 was prepared
following: C. Najera, B. Baldo and M. Yus, J. Chem. Soc., Perkin
Trans. 1, 1988, 1029.
In conclusion, the first organocatalytic enantioselective anti-
Michael reaction has been presented by using a sulfone as directing
group of the regioselectivity and as a leaving group in the same
reaction. These special properties of the sulfone have allowed the
creation of a a,a9-branched terminal double bond joined to a
quaternary center. Consequently, this very reactive double bond
could be functionalized by different nucleophiles creating in this
way new chiral centers with good diastereoselectivities.
This work was made possible by a grant from The Danish
National Research Foundation and OChemSchool. J. A. thanks
the ‘‘Ministerio de Educacio´n y Ciencia’’ of Spain and E. R.
‘‘Eusko Jaurlaritza-Gobierno Vasco’’ for financial support (post-
doctoral fellowships).
7 For a review, see e.g.: (a) M. J. O’Donnell, in Catalytic Asymmetric
Synthesis, ed. I. Ojima, Wiley-VCH, Weinheim, 2nd edn, 2000, p. 727.
For recent examples of phase-transfer catalyzed asymmetric reactions,
see e.g.: (b) T. Kita, A. Georgieva, Y. Hashimoto, T. Nakata and
K. Nagasawa, Angew. Chem., Int. Ed., 2002, 41, 2832; (c) H.-G. Park,
B.-S. Jeong, M.-S. Yoo, J.-H. Lee, M.-K. Park, Y.-J. Lee, M.-J. Kim
and S.-S. Jew, Angew. Chem., Int. Ed., 2002, 41, 3036; (d) T. Ooi,
T. Miki, M. Taniguchi, M. Shiraishi, M. Takeuchi and K. Maruoka,
Angew. Chem., Int. Ed., 2003, 42, 3981; (e) T. Ooi, M. Kameda and
K. Maruoka, J. Am. Chem. Soc., 2003, 125, 5139; (f) A. Okada,
T. Shibuguchi, T. Ohshima, H. Masu, K. Yamaguchi and M. Shibasaki,
Angew. Chem., Int. Ed., 2005, 44, 4564; (g) F. Fini, V. Sgarzani,
D. Pettersen, R. P. Herrera, L. Bernardi and A. Ricci, Angew. Chem.,
Int. Ed., 2005, 44, 7975; (h) T. Ooi, Y. Uematsu and K. Maruoka, J. Am.
Chem. Soc., 2006, 128, 2548. For a recent review in asymmetric phase-
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Ed., 2007, 46, 4222.
Notes and references
1 (a) B. E. Rossiter and N. M. Swingle, Chem. Rev., 1992, 92, 771; (b)
K. Fuji, Chem. Rev., 1993, 93, 2037; (c) Y. Yamamoto, S. G. Pyne,
D. Schinzer, B. L. Feringa and J. F. G. A. Jansen, Methoden der
Organischen Chemie (Houben–Weyl), Weyl von Thieme, Stuttgart,
1995, vol. E21b, p. 2011; (d) E. J. Corey and A. Guzman-Perez, Angew.
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J. Leonard, E. Diez-Barra and S. Merino, Eur. J. Org. Chem., 1998,
2051, 1; (f) M. Sibi and P. S. Manyem, Tetrahedron, 2000, 56, 8033; (g)
N. Krause and A. Hoffmann-Ro˝der, Synthesis, 2001, 171; (h)
J. Christoffers and A. Mann, Angew. Chem., 2001, 113, 4725, (Angew.
Chem., Int. Ed., 2001, 40, 4591); (i) M. Shibasaki and N. Yoshikawa,
Chem. Rev., 2002, 102, 2187; (j) J. Christoffers, Chem. Eur. J., 2003, 9,
4862. Examples of stereocontrolled quaternary center formation via
conjugate addition: (k) Y. Hamashima, D. Hotta and M. Sodeoka,
J. Am. Chem. Soc., 2002, 124, 11240; (l) S. Harada, N. Kumagai,
T. Kinoshita, S. Matsunaga and M. Shibasaki, J. Am. Chem. Soc., 2003,
8 Crystal data for [4g]: C18H19NO3, M = 297.34, monoclinic, space group
˚
P21 (no. 4), a = 6.2084(2), b = 10.3461(3), c = 12.6475(3) A, V =
3
805.76(4) A , T = 150 K, Z = 2, m(Cu-Ka) = 0.674 mm
21
˚
,
9544 reflections collected, 1687 unique (Rint = 0.0329) which were used
in all calculations. Refinement on F2, final R(F) = 0.0313, Rw(F2) =
0.0778. CCDC 651317. For crystallographic data in CIF or other
electronic format see DOI: 10.1039/b710393j. For more details about the
absolute configuration see ESI{.
9 Reduction of the double bond and the ketone was observed in a
diastereoisomeric mixture (60 : 40). These compounds were most likely
epimers at the a nitrile position.
10 For reduction of cyclic b-ketoesters, see: (a) C. A. M. Fraga and
E. Barreiro, Synth. Commun., 1995, 25, 1133; (b) L. H. P. Teixeira,
E. Barreiro and C. A. M. Fraga, Synth. Commun., 1997, 27, 3241.
11 For a review of conjugate addition to a,b-unsaturated nitriles, see:
F. F. Fleming and Q. Wang, Chem. Rev., 2003, 103, 2035.
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Chem. Commun., 2007, 3921–3923 | 3923