Enantioselective Michael additions to α,β-unsaturated imides catalyzed by a salen-al complex

Article abstract of DOI:10.1021/ja037177o

(Salen)aluminum complex 1b is an efficient catalyst for the conjugate addition of di- and trisubstituted nitriles to a wide range of acyclic alkyl- and aryl-substituted α,β-unsaturated imides. This new methodology provides access to multifunctional compounds that previously have not been readily accessible in enantioenriched form. Synthetic applications of these products include the preparation of enantiomerically enriched piperidines, as exemplified by an expedient asymmetric catalytic synthesis of (-)-paroxetine. Copyright

Full text of DOI:10.1021/ja037177o

Published on Web 08/23/2003
Enantioselective Michael Additions to r,â-Unsaturated Imides Catalyzed by a
Salen-Al Complex
Mark S. Taylor and Eric N. Jacobsen*
Department of Chemistry and Chemical Biology, HarVard UniVersity, 12 Oxford Street,
Cambridge, Massachusetts 02138
Received July 9, 2003; E-mail: jacobsen@chemistry.harvard.edu
Table 1. Conjugate Addition of Malononitrile and Methyl
Cyanoacetate to Imides 2a-g
The conjugate addition of carbon-based nucleophiles to R,â-
unsaturated carbonyl compounds is one of the classical methods
for C-C bond construction, and the development of asymmetric
catalytic versions of this type of transformation has been the subject
of intensive research over the past several years.1 An attractive
approach to this problem involves the generation of nucleophilic
species by in situ deprotonation of acidic hydrocarbons. In principle,
direct Michael additions with such nucleophiles may form the basis
for operationally simple, atom economical, and functional group-
tolerant methods. Although substantial progress has been realized
in the development of asymmetric Michael addition reactions, the
nucleophiles employed generally have been limited to â-dicarbonyl
compounds2 and nitroalkanes.3 Furthermore, general methods for
addition to unsaturated carboxylic acid derivatives have not yet been
developed. Expanding the scope of the asymmetric Michael reaction
product
R
EWG
CN
CN
CN
CN
CN
CN
CN
CO2CH3
CO2CH3
CO2CH3
CO2CH3
CO2CH3
CO2CH3
time
yield (%)a
ee (%)b
with respect to both the electrophile and the nucleophile would
represent an important advance. Herein, we report highly enantio-
selective conjugate additions of electron-deficient nitrile derivatives
to acyclic R,â-unsaturated imides catalyzed by a chiral (salen)-
aluminum complex. The scope of useful nucleophiles includes
trisubstituted nitriles, allowing diastereo- and enantioselective access
to carbon- and heteroatom-substituted quaternary stereocenters.
Aluminum salen complexes have been identified recently as
effective catalysts for asymmetric conjugate addition reactions.4 A
screen of acidic hydrocarbons as potential nucleophiles5 revealed
that µ-oxo dimer 16 catalyzes the addition of malononitrile and
methyl cyanoacetate to imides 2 with high enantioselectivity and
in the absence of Bro¨nsted base (Table 1). The scope of the reaction
proved to be quite broad with respect to â-substitution on the
electrophile: alkyl groups with widely varying steric properties,
as well as aryl groups (with the exception of electron-rich
derivatives such as p-methoxyphenyl, for which the malononitrile
addition product was obtained in only 44% ee), were tolerated. The
use of nonpolar solvents led to increased enantioselectivity, with
cyclohexane affording optimal results. This improvement was
accompanied by decreases in reaction rate; however, useful
reactivity could be restored by the addition of tert-butyl alcohol
(1.2 equiv relative to substrate).7 The absolute configuration of
adducts 3 and 4 prepared using (S,S)-1 is consistent with earlier
observations in conjugate additions of azide and cyanide.4a,b
Although the conjugate addition of methyl cyanoacetate generates
two stereocenters, the R-cyano ester stereocenter is readily epimer-
izable, and the adducts were obtained as roughly 1:1 mixtures of
diastereomers. The use of substituted cyanoacetate derivatives offers
the possibility of generating a configurationally stable quaternary
stereocenter under kinetic control.8 Upon screening such nucleo-
philes, we found that methyl phenylcyanoacetate added to imide
2e to afford adduct 5a with 14:1 diastereoselectivity and 97%
enantiomeric excess (Table 2).
3a
3b
3c
3d
3e
3f
3g
4a
4b
4c
4d
4e
4f
Phc
p-FC6H4
p-ClC6H4
Mec,d
n-Prc,d
i-Prc
28 h
36 h
38 h
20 h
20 h
36 h
48 h
40 h
54 h
56 h
48 h
40 h
6 d
87
88
99
89
95
91
88
98
94
99
96
88
89
90
93
92
96
97
96
97
c,j
c
t-Buc
Phe
88f
89f
89f
86f,h
90f
95f
e,g,k
p-FC6H4
p-ClC6H4
Mee
e
n-Pre
i-Pri
a Isolated yield, after chromatography, from reactions carried out on 0.50
mmol scale. Unpurified commercial solvents were used, without inert
atmosphere techniques. b Determined by chiral HPLC of the adduct, unless
noted otherwise (see Supporting Information for full details). c 1.2 equiv
of nucleophile was used. d 2.5 mol % catalyst was used. e 2.5 equiv of
nucleophile was used. f Enantiomeric excess values represent the 3R/3S ratio.
g Reaction carried out on 25 mmol scale. h Determined by chiral GC analysis
after hydrogenation and cyclization to the δ-lactam. i 5.0 equiv of nucleo-
phile was used. j Absolute configuration determined by imide methanolysis
and decyanation to 7. k Absolute configuration determined by derivitization
to (-)-paroxetine (see text).
sition, were found to be effective reacting partners in the conju-
gate addition. In addition to products bearing carbon-substituted
quaternary stereocenters, diastereomerically and enantiomerically
enriched quaternary amino nitriles were also prepared in a selective
fashion by conjugate addition of ethyl (N-benzylamino)cyanoace-
tate, followed by cyclization to the γ-lactam. X-ray crystallographic
analysis served to elucidate the relative configuration of 5b and
6d.
This new method provides access to useful building blocks for
organic synthesis (Scheme 1). Methyl cyanoacetate adducts undergo
clean demethoxycarboxylation under Krapcho conditions9 to provide
the 3-substituted 4-cyanobutyrate derivatives (7). Regioselective
cleavage of the imide functional group occurs smoothly to furnish
a variety of carboxylic acid derivatives under mild conditions;
A variety of aryl and heteroaryl cyanoacetates, as well as a num-
ber of imides bearing unbranched alkyl substitutents at the â po-
9
11204
J. AM. CHEM. SOC. 2003, 125, 11204-11205
10.1021/ja037177o CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Diastereo- and Enantioselective Conjugate Addition of
Trisubstituted Cyanoacetate Derivatives
accessible in enantioenriched form. Synthetic applications of these
products include the preparation of enantiomerically enriched
piperidines, as exemplified by an expedient asymmetric catalytic
synthesis of (-)-paroxetine. Studies are underway to expand the
scope and synthetic utility of this new reaction, as well as to glean
insight into its mechanism.
Acknowledgment. This work was supported by the NIH (GM-
43214). We are grateful to Dr. R. Staples for carrying out the X-ray
structural analyses.
product
R
R′
time
yield (%)a
ee (%)b
drc
5ad,f
5bd,f
5cd,g
5dd,g
n-Pr
n-Pr
n-Pr
n-Pr
Ph
19 h
15 h
38 h
51 h
98
96
94
79
97
98
95
95
14:1
35:1
6:1
Supporting Information Available: Complete experimental pro-
cedures, characterization data, and chiral chromatographic analyses of
racemic and enantiomerically enriched products (PDF and CIF). This
material is available free of charge via the Internet at http://pubs.acs.org.
m-CF3C6H4
p-MeOC6H4
14:1
5ed,g
5fd,f
n-Pr
Me
i-Bu
Me
n-Pr
i-Bu
Ph
2-thiophenyl
Ph
4 d
76
95
96
74
92
89
68
91
86
96
92
91
97
96
14:1
5:1
References
24 h
24 h
26 h
23 h
60 h
54 h
5gd,g
6ae,f
6be,g
6ce,g
6de,h
Ph
16:1
10:1
14:1
13:1
20:1
(1) For reviews, see: (a) Tomioka, K.; Nagaoka, Y.; Yamaguchi, M. In
ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 3, Chapters 31.1 and
31.2. (b) Krause, N.; Hoffmann-Ro¨der, A. Synthesis 2001, 171-196.
(2) Enantioselective conjugate addition of malonates to (a) acyclic enals and
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Ed. Engl. 1993, 32, 1173-1175. Halland, N.; Aburel, P. S.; Jørgensen,
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NHBn
NHBn
NHBn
NHBn
a Isolated yield, after chromatography, from reactions carried out on 0.50
mmol scale. b Of major diastereomer, determined by chiral HPLC. c De-
termined by 1H NMR. d Reaction carried out using (R,R)-1. e Reaction
carried out using (S,S)-1. f Reaction carried out using 2.5 mol % catalyst.
g Reaction carried out using 5.0 mol % catalyst. h Reaction carried out with
10 mol % catalyst and 2.5 equiv of t-BuOH.
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Scheme 1. Regioselective Cleavage of Imides 3b and 4ba
(4) For enantioselective conjugate additions to R,â-unsaturated imides of
general structure 2, see (a) HN3: Myers, J. K.; Jacobsen, E. N. J. Am.
Chem. Soc. 1999, 121, 8959-8960. (b) HCN: Sammis, G. M.; Jacobsen,
E. N. J. Am. Chem. Soc. 2003, 125, 4442-4443. (c) thiols: Chen, Q.;
Jacobsen, E. N., manuscript in preparation. (d) salen-Red-Al-catalyzed
Michael additions to ketones have been described: Jha, S. C.; Joshi, N.
N. Tetrahedron: Asymmetry 2001, 12, 2463-2466.
(5) The screen included â-ketoesters, malonates, nitroalkanes, and sulfones;
nitrile-substituted substrates proved uniquely effective in reactions
catalyzed by 1.
(6) Catalyst 1 is a bench-stable complex prepared by partial hydrolysis of
the corresponding (salen)AlMe derivative. (a) Rutherford, D.; Atwood,
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see: (b) Dzugan, S. J.; Goedken, V. L. Inorg. Chem. 1986, 25, 2858. (c)
Gurian, P. L.; Cheatham, L. K.; Ziller, J. W.; Barron, A. R. J. Chem.
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a R ) p-FC6H4, R′ ) Me, allyl. For reagents and conditions, see
Supporting Information.
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been ascertained. However, promotion of turnover of aluminum enolate
intermediates represents a likely role. For a general discussion of the use
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Shibasaki, M. Angew. Chem., Int. Ed. 1999, 38, 1570-1577.
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carboxylic acids6a (e.g., 8), esters10 (e.g., 9a, b), Weinreb amides11
(e.g., 10), and N-benzyl amides (e.g., 11) are obtained without loss
of enantiopurity. Reduction of the nitrile group results in intramo-
lecular aminolysis, delivering the δ-lactam 12 as a 2:1 mixture of
diastereomers. Such δ-lactams are useful intermediates for the
synthesis of piperidines, ubiquitous structures in natural products
and pharmaceutically active compounds.
As an illustration of the utility of the latter methodology, paroxe-
tine (Paxil), a serotonin reuptake inhibitor used widely for the
treatment of anxiety, was prepared from 12 (R ) 4-FC6H4) in six
steps, following a synthesis developed at Sumigo Fine Chemicals.12
Starting with 2b and through the intermediacy of 4b obtained in
96% ee by recrystallization from ethanol (77% recovery), (-)-
paroxetine was obtained in a total yield of 47% over seven steps.13,14
We have demonstrated that the aluminum complex 1 is an
efficient catalyst for the conjugate addition of di- and trisubstituted
nitriles to a wide range of acyclic alkyl- and aryl-substituted R,â-
unsaturated imides. This new methodology provides access to
multifunctional compounds that, to date, have not been readily
(9) Krapcho, A. P. Synthesis 1982, 805-822, 893-913.
(10) For the Sm(OTf)3-catalyzed regioselective methanolysis of imides, see:
Evans, D. A.; Trotter, B. W.; Coleman, P. J.; Coˆte´, B.; Dias, L. C.;
Rajapakse, H. A.; Tyler, A. N. Tetrahedron 1999, 55, 8671-8726.
(11) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815-3818.
(12) The Sumigo route incorporates a racemic conjugate addition and a late
stage resolution. Sugi, K.; Itaya, N.; Katsura, T.; Igi, M.; Yamazaki, S.;
Ishibashi, T.; Yamaoka, T.; Kawada, Y.; Tagami, Y.; Otsuki, M.; Oshima,
T. Chem. Pharm. Bull. 2000, 48, 529-536.
(13) All characterization data, including optical rotation, were in agreement
with literature values (ref 12).
(14) For a prior asymmetric catalytic synthesis of paroxetine employing an
enzymatic desymmetrization as the key step, see: Yu, M.; Lantos, I.; Peng,
Z.; Yu, J.; Cacchio, T. Tetrahedron Lett. 2000, 41, 5647-5651. For other
syntheses of paroxetine, see references therein.
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