An asymmetric Michael addition of α,α-disubstituted aldehydes to maleimides leading to a one-pot enantioselective synthesis of lactones catalyzed by amino acids

Article abstract of DOI:10.1021/ol4008662

A cheap and fast construction of both enantiomers of substituted succinimides is reported. α- or β-amino acids, such as β-phenylalanine and α-tert-butyl aspartate, were found to be efficient organocatalysts for the reaction between α,α-disubstituted aldeh

Full text of DOI:10.1021/ol4008662

ORGANIC
LETTERS
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Vol. XX, No. XX
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An Asymmetric Michael Addition
of r,r-Disubstituted Aldehydes to
Maleimides Leading to a One-Pot
Enantioselective Synthesis
of Lactones Catalyzed by Amino Acids
Christoforos G. Kokotos*
Laboratory of Organic Chemistry, Department of Chemistry, University of Athens,
Panepistimiopolis 15771, Athens, Greece
ckokotos@chem.uoa.gr
Received March 29, 2013
ABSTRACT
A cheap and fast construction of both enantiomers of substituted succinimides is reported. R- or β-amino acids, such as β-phenylalanine and
R-tert-butyl aspartate, were found to be efficient organocatalysts for the reaction between R,R-disubstituted aldehydes and maleimides. Products
containing contiguous quaternary-tertiary stereogenic centers are obtained in high to quantitative yields and excellent selectivities utilizing low
catalyst loadings (0.5À3.5%). Finally, a one-pot efficient asymmetric synthesis of lactones is described.
The second decade of the 21st century has witnessed
many milestones and breakthroughs in the field of asym-
metric catalysis. In particular, the emerging field of Organ-
ocatalysis, which was ignored for many years, has
undergone a rebirth,1 often providing complex catalyst
architectures that efficiently promote useful transforma-
tions.2 An alternative approach taking advantage of the
diversity of commercially available amino acids has been
less thoroughly explored. Proline and its derivatives have
long been utilized in this regard; more recently other amino
acids and their derivatives have emerged as potential
catalysts.2c,3 Although most of these studies involve en-
amine intermediates,2c the nature and role of the side chain
(4) For selected examples, see: (a) Bartoli, G.; Bosco, M.; Carlone,
A.; Cavalli, A.; Locatelli, M.; Mazzanti, A.; Ricci, P.; Sambri, L.;
Melchiorre, P. Angew. Chem., Int. Ed. 2006, 45, 4966. (b) Jiang, Z.;
Pan, Y.; Zhao, Y.; Ma, T.; Lee, R.; Yang, Y.; Huang, K. W.; Wong,
M. W.; Tan, C. H. Angew. Chem., Int. Ed. 2009, 48, 3627. (c) Alba, A.-N.
R.; Valero, C.; Calbet, T.; Font-Bardia, M.; Moyano, A.; Rios, R.
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(1) (a) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc.
2000, 122, 2395. (b) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2000, 122, 4243.
(5) (a) Ahmed, S. Drug Discovery 1996, 14, 77. (b) Ballini, R.; Bosica,
G.; Cioci, G.; Fiorini, D.; Petrini, M. Tetrahedron 2003, 59, 3603.
(6) (a) Zhao, G.-X.; Xu, Y.-M.; Sunden, H.; Eriksson, L.; Sayah, M.;
Cordova, A. Chem. Commun. 2007, 43, 734. (b) Xue, F.; Liu, L.; Zhang,
S.-L.; Duan, W.-H.; Wang, W. Chem.;Eur. J. 2010, 16, 7979. (c) Yu, F.;
Jin, Z.; Huang, H.; Ye, T.; Liang, X.; Ye, J. Org. Biomol. Chem. 2010, 8,
4767. (d) Bai, J.-F.; Peng, L.; Wang, L.-L.; Wang, L.-X.; Xu, X.-Y.
Tetrahedron 2010, 66, 8928. (e) Miura, T.; Nishida, S.; Masuda, A.;
Tada, N.; Itoh, A. Tetrahedron Lett. 2011, 52, 4158. (f) Miura, T.;
Masuda, A.; Ina, M.; Nakashima, K.; Nishida, S.; Tada, N.; Itoh, A.
Tetrahedron: Asymmetry 2011, 22, 1605. (g) Ma, Z.-W.; Liu, Y.-X.; Li,
P.-L.; Ren, H.; Zhu, Y.; Tao, J.-C. Tetrahedron: Asymmetry 2011, 22,
1740. (h) Nugent, T. C.; Sadiq, A.; Bibi, A.; Heine, T.; Zeonjuk, L. L.;
Vankova, N.; Bassil, B. S. Chem.;Eur. J. 2012, 18, 4088.
(2) For books, see: (a) Berkessel, A.; Groger, H. Asymmetric
Organocatalysis À From Biomimetic Concepts to Powerful Methods for
Asymmetric Synthesis; Berkessel, A., Groger, H., Eds.; Wiley-VCH:
Weinheim, 2005. (b) Dalko, P. I. Enantioselective Organocatalysis Reactions
and Experimental Procedure; Dalko, P. I., Ed.; Wiley-VCH: Weinheim, 2007.
For selected reviews, see: (c) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B.
Chem. Rev. 2007, 107, 5471. (d) Doyle, A. G.; Jacobsen, E. N. Chem. Rev.
2007, 107, 5713. (e) MacMillan, D. W. C. Nature 2008, 455, 304.
(3) For reviews, see: (a) Colby Davie, E. A.; Mennen, S. M.; Miller,
S. J. Chem. Rev. 2007, 107, 5759. Chai, Z.; Zhao, G. Catal. Sci. Technol.
2012, 2, 29.
r
10.1021/ol4008662
XXXX American Chemical Society

(R)-amino acids are commercially available, since they are
expensive relative to (S)-amino acids, our design uses
(S)-amino acid derivatives to gain access in both series of
enantiomers as highlighted in Figure 1. Building on
Nugent’s contribution6h and our own experience,10 the
primary amine of an R-amino acid activates the aldehyde
via enamine formation. A synclinical addition to the
electrophile for the CÀC forming reaction occurs, which
is directed by metal complexation leading to one enantio-
mer of the product (Figure 1, intermediate I). Herein, the
approach of the electrophile is controlled by the electro-
static interactions with the catalyst, while the amino acid
side chain can contribute in the enantioselectivity by
blocking the front face. Utilizing an (S)-R-amino acid with
its carboxylic group blocked by a bulky tert-butyl ester and
by having a free carboxylic group in the amino acid side
chain (e.g., R-tert-butyl aspartate, R-tert-butyl glutamate),
the facial control of the reaction can be switched by
adopting intermediate II (Figure 1). The nucleophile acti-
vation occurs in a similar manner; however, the electro-
phile is guided from the front face, instead of the back face,
through a similar complexation with the free carboxylic
group of the side chain. Finally, β-amino acids, such as
β-phenylalanine,11,12 are expected to behave similarly to
Scheme 1. Known Organocatalysts for the Michael Reaction
between Isobutyraldehyde and Maleimide
of the amino acid seems to have been overlooked. Among
Michael additions, the addition to maleimides represents
an attractive transformation,4 since substituted succini-
mides are valuable synthetic targets and precursors of
biologically interesting substances.5 The use of R-branched
aldehydes as nucleophilic partners in the reaction with
maleimides is scarcely documented,6 a reaction that leads
to the formation of quaternary centers.7 As a model, the
reaction between isobutyraldehyde (1a) and N-phenyl
maleimide (2a) was chosen (Scheme 1). Cordova et al.
demonstrated first the reaction between aldehydes and
maleimides, but R-branched aldehydes led to low yields
and enantioselectivities.6a Primary amine thioureas can
catalyze this reaction (5À10 mol % catalyst loading).6bÀg
Finally, Nugent et al. utilized 5 mol % tert-butyl ether of
threonine for the same transformation.6h
Our design plan was to identify an amino acid based
catalyst that is commercially available and could afford
better catalytic activities primarily allowing for a decreased
catalyst loading. Often, both enantiomers of a chiral
compound are required in the pharmaceutical industry
or organic synthesis.8 Unfortunately, the efficient prepara-
tion of both enantiomers is usually a daunting task, and to
untangle this problem, diastereoselective catalytic motifs
are employed.6g,9 Although the simplest solution would be
the use of the other enantiomer of the catalyst, this is either
not readily available or fairly expensive. Thus, although
(7) (a) Christoffers, J.; Baro, A. Quaternary Stereocenters: Challenges
and Solutions for Organic Synthesis; Christoffers, J., Baro, A., Eds.;
Wiley-VCH: Weinheim, 2005. For selected organocatalytic studies on the
formation of quaternary centers from R-branched aldehydes, see: (b) Mase,
N.; Tanaka, F.; Barabas, C. F., III. Angew. Chem., Int. Ed. 2004, 43, 2420. (c)
Chowdari, N. S.; Barbas, C. F., III. Org. Lett. 2004, 6, 2507. (d) Mase,
N.; Thayumanavan, R.; Tanaka, F.; Barbas, C. F., III. Org. Lett. 2004,
6, 2527. (e) Chowdari, N. S.; Barbas, C. F., III. Org. Lett. 2005, 7, 867. (f)
Brown, A. R.; Kuo, W.-H.; Jacobsen, E. N. J. Am. Chem. Soc. 2010, 132,
9286.
Figure 1. Proposed activation and reaction intermediates.
(8) For reviews, see: (a) Burke, M. D.; Schreiber, S. L. Angew. Chem.,
Int. Ed. 2004, 43, 46. (b) Zanoni, G.; Castronovo, F.; Franzini, M.;
Vidari, G.; Gianini, E. Chem. Soc. Rev. 2003, 32, 115.
(9) (a) Jiang, X.-X.; Zhang, Y.-F.; Chan, A. S. C.; Wang, R. Org.
Lett. 2009, 11, 153. (b) Chen, J.-R.; Cao, Y.-J.; Zou, Y.-Q.; Tan, F.; Fu,
L.; Zhu, X.-Y.; Xiao, W.-J. Org. Biomol. Chem. 2010, 8, 1275. (c) Chen,
J.-R.; Zou, Y.-Q.; Fu, L.; Ren, F.; Tan, F.; Xiao, W.-J. Tetrahedron
2010, 66, 5367.
R-amino acids through the slightly varied intermediate III
(Figure 1). To test our hypothesis, a variety of amino acids
and their derivatives were tested.11 After catalyst optimiza-
tion, tert-Leu, Phe, β-Phe, and Trp were identified as the
best catalysts (see Supporting Information (SI)). However,
(10) (a) Kokotos, C. G.; Kokotos, G. Adv. Synth. Catal. 2009, 351,
1355. (b) Kokotos, C. G.; Limnios, D.; Triggidou, D.; Trifonidou, M.;
Kokotos, G. Org. Biomol. Chem. 2011, 9, 3386. (c) Kokotos, C. G.
J. Org. Chem. 2012, 77, 1131. (d) Tsakos, M.; Kokotos, C. G.; Kokotos,
G. Adv. Synth. Catal. 2012, 354, 740. (e) Tsakos, M.; Elsegood, M. R. J.;
Kokotos, C. G. Chem. Commun. 2013, 49, 2219.
(11) For a detailed report on catalyst screening, optimization condi-
tions, and the choice of β-phenylalanine and R-tert-butyl aspartate as the
optimum catalysts, see SI.
(12) For β-amino acids as catalysts for Mannich reactions, see:
Dziedzic, P.; Cordova, A. Tetrahedron: Asymmetry 2007, 18, 1033.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Various Amino Acids As Catalysts in the Michael
Addition of Isobutyraldehyde to N-Phenyl Maleimide
Table 2. Substrate Scope of the Michael Addition
a NMR yield; isolated yield in parentheses. b The ee was determined
by chiral HPLC. c No KOH was added. d Reaction time: 48 h, 98% yield.
e Reaction time: 72 h. f Ratio of aldehyde/maleimide 5:1.
with a 2 mol % catalyst loading, only Phe and β-Phe
afforded a quantitative conversion to the product (entries
1, 3, 4, Table 1). In the absence of KOH, no reaction
occurred (entry 2, Table 1). A further decrease in the
catalyst loading could be achieved; however, for quantita-
tive conversion to the product, the additive had to be
changed (entries 5À7, Table 1). Thus, the desired product
could be isolated in 96% yield and >99% ee. Decreasing
the catalyst loading led to lower conversions that required
prolonged reaction times to get to completion (entry 8,
Table 1). Finally, after experimentation,11 R-tert-butyl
aspartate was identified as the optimum catalyst to lead
to the other enantiomer (entries 9À11, Table 1).
a Conditions A: β-Phe (1 mol %), Cs2CO3 (1 mol %), maleimide
(0.40 mmol), CH2Cl2 (1 mL), aldehyde (0.44 mmol), 24 h, rt. Conditions B:
H-Asp-Ot-Bu (3.5 mol %), KOH (3.5 mol %), maleimide (0.40 mmol),
CH2Cl2 (1 mL), aldehyde (2.00 mmol), 24 h, rt. b Isolated yield. c The dr
was determined by 1H NMR. d The ee was determined by chiral HPLC;
ee of the minor diastereomer in parentheses. e 2 mol % catalyst. f Reac-
tion time: 48 h. g 5 mol % catalyst. h 20 mol % catalyst. i Reaction time:
72 h. j 10 mol % catalyst.
Then, the substrate scope was evaluated (Table 2).
N-Substituted maleimides were well tolerated (entries 1À12,
Table 2). Both electron-donating and -withdrawing sub-
stituted aromatics on the maleimide are well tolerated
(entries 3À6, Table 2). In the change to alkyl-substituted
maleimides, benzyl maleimide was observed to perform
similarly to aryl maleimides, while, for N-aliphatic mal-
eimides, only for the preparation of the opposite enantio-
mer, a higher catalyst loading was required for high yields
(entries 7À12, Table 2). A variety of aldehydes were also
utilized successfully (entries 13À28, Table 2). For symme-
trical R,R-disusbstituted aldehydes, high yields and selec-
tivities were observed although a longer reaction time was
required (entries 13À18, Table 2). Cyclic carboxyalde-
hydes performed equally well (entries 13À16, Table 2).
When cyclopropyl carboxyaldehyde was used, only start-
ing material was recovered. When the steric bulkiness of
the substituents of the aldehyde was increased from
methyl to ethyl, the reaction became more difficult and
a higher catalyst loading was required (entries 17À18,
Table 2). Next, a variety of nonsymmetrical aldehydes
were utilized, since in this manner the formation of two
contiguous (quaternary-tertiary) stereogenic centers will
be possible (entries 19À24, Table 2). In all cases, higher
catalyst loadings were required to achieve acceptable
yields and selectivities. In the case of aryl, alkyl substi-
tuted aldehydes, a 9:1 dr was observed; unfortunately, the
aspartate catalyst provided a decreased ee (72% ee)
(entries 19À20, Table 2). To explore the limits of this
protocol, propyl-methyl aldehyde was utilized (entries
21À22, Table 2). β-Phe afforded the product in high yield,
with a 3:1 dr and excellent ee; unfortunately the aspartate
led to low selectivities. The results improved slightly when
a small and a larger aliphatic substituent were employed
Org. Lett., Vol. XX, No. XX, XXXX
C

on the aldehyde (entries 23À24, Table 2). Although the
yield and the dr remained at similar levels, the ee was
profoundly improved. In the case of model I of Figure 1, it
seems that when a bulky aryl moiety is utilized, it is placed
in the position of R2, while the smaller methyl group
prefers to occupy the position of R1, leading to high
selectivities. When moieties of similar bulkiness, such as
methyl and n-propyl, are utilized, both can be placed in
both positions. This distribution in both positions lead to
low levels of selectivities. However, when one of the groups
utilized is bulkier than the other, the adoption of the
R1/R2 positions in the model resembles more the aryl/
alkyl case leading back to higher selectivities. Finally,
linear aldehydes, heptanal and propanal, were utilized
(entries25À28, Table 2). In both cases, a 1:1 dr was observed;
however, the ee’s remained excellent. In order to prove the
validity of our initial design plan, NMR, IR, and MS
experiments were performed, which support the formation
of an enamine intermediate and the formation of the product
having the catalyst on (for details, see SI).
Scheme 3. Asymmetric One-Pot Synthesis of Lactones
A variety of transformations can be performed to result
in various products. A Wittig reaction led to 4, while oxidation
followed by esterification gave 5 (Scheme 2). Reduction
utilizing NaBH4 led to lactone 6a in high yield via the
alcohol. Unfortunately, racemization occurred under the
basic reaction conditions leading to products of low en-
antiopurity (20% ee). To bypass this problem, an alter-
native route was established. The initial reduction can be
BH3 THF at À20 °C, followed by the addition of BF3 Et2O,
3
3
resulted in a smooth transformation. Substituted maleimides
can be employed without loss of ee, while other substituted
aldehydes can be employed leading to a variety of products
(6aÀf), such as spirolactone 6d in high ee’s (Scheme 3).
Aldehydes with different substituents can be employed
leading to lactones 6e,f bearing quaternary centers. How-
ever, in these cases slightly lower yields and selectivities
were obtained. In addition, the model reaction was per-
formed at a larger scale (17 mmol), leading to similar results.
In conclusion, we have demonstrated that a variety of
amino acids can be employed as catalysts for the reaction of
R,R-disubstituted aldehydes with maleimides with a low
catalyst loading. β-Phe can be used at a catalyst loading as
low as 0.5 mol % to promote the reaction in high to excellent
yields and selectivities. Furthermore, R-tert-butyl aspartate
can be used to provide the opposite enantiomer, although a
slightly higher catalyst loading was required (3.5 mol %). A
number of easy transformations were then undertaken to
highlight the utility of the product. Reduction of the product
led to lactone formation, and thus, an efficient one-pot
protocol was developed leading to a number of lactones in
high yields and selectivities. Other studies to highlight the use
of amino acids and their derivatives as chiral promoters in
organic transformations are underway in our laboratories.
performed using borane, and the addition of BF3 Et2O in
3
the reaction mixture afforded the lactone in 84% yield and
99% ee. Reductive amination afforded lactame 7, while
oxidation followed by coupling with a valine derivative
gave rise to peptidomimetic 8 (Scheme 2). Since the reduc-
tion of the aldehyde led to a lactone, a one-pot protocol to
the asymmetric synthesis of lactones could be provided
(Scheme 3). While basic conditions led to erosion of the ee
and stronger reducing agents led to an overoxidized
mixture of products, a slow reduction to the alcohol with
Scheme 2. Transformations of the Michael Addition Product 3a
Acknowledgment. The author gratefully acknowledges
the Operational Program “Education and Lifelong Learn-
ing” for financial support through the NSRF program
“ENIΣXYΣH METAΔIΔAKTOPΩN EPEYNHTΩN”
(PE 2431)” cofinanced by ESF and the Greek State.
Supporting Information Available. Experimental pro-
cedures, catalyst and conditions optimization including
NMR and HPLC data, as well as mechanistic investiga-
tions. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
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