Expanding the scope of the direct regiospecific asymmetric aldol reaction to enones and dienones catalyzed by a BINOL-derived bronsted acid

Article abstract of DOI:10.1002/ejoc.201101282

Chiral phosphoric acid (R)-1a has been shown to be an efficient Bronsted acid catalyst for the useful asymmetric synthesis of various acyclic and endo-and exocyclic β-hydroxyenones through a regiospecific aldol reaction between α,β-unsaturated ketones and ethyl glyoxalate. Moreover, two unprecedented examples involving sensitive dienones are reported.

Full text of DOI:10.1002/ejoc.201101282

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201101282
Expanding the Scope of the Direct Regiospecific Asymmetric Aldol Reaction to
Enones and Dienones Catalyzed by a BINOL-Derived Brønsted Acid
Joydeb Das,[a] Fabien Le Cavelier,[a] Jacques Rouden,[a] and Jérôme Blanchet*[a]
Keywords: Organocatalysis / Aldol reactions / Brønsted acids / Enones / Asymmetric synthesis
Chiral phosphoric acid (R)-1a has been shown to be an ef-
ficient Brønsted acid catalyst for the useful asymmetric syn-
unsaturated ketones and ethyl glyoxalate. Moreover, two un-
precedented examples involving sensitive dienones are re-
thesis of various acyclic and endo- and exocyclic β-hydroxy- ported.
enones through a regiospecific aldol reaction between α,β-
catalysts bearing primary or secondary amino groups are
Introduction
able to catalyze the direct aldol reaction more or less by
using the same mode of nucleophilic activation, via an en-
amine intermediate. However, despite its synthetic poten-
tial, enamine catalysis does not operate properly with sev-
eral types of ketones.
On the basis of this observation and the long history of
the aldol reaction, we recently developed the first direct
Brønsted acid organocatalyzed aldol reaction[9] by using
BINOL-derived phosphoric acid 1a[10] prepared conve-
niently in only four steps from (R)-BINOL according to an
improved methodology developed in our laboratory.[11] We
focused our attention mostly on compounds that have not
been described in amino-catalyzed aldol reactions. In this
respect, only two simple enones (2-cyclohexenone or 3-
penten-2-one) were tested.
Before our work, only two reports have described the di-
rect asymmetric aldol reaction of enones catalyzed by zinc
or rhodium complexes with good selectivities but variable
yields.[12] However, the main limitation of these previous
reports is the limited number of enones used. For example,
Trost used only methyl vinyl ketone in his report, whereas
Nishiyama has shown that only cyclic enones were suitable
substrates for their metal-catalyzed direct aldol (Scheme 1).
Since then a recent publication described the αЈ position
activation of enones by deprotonation with the use of cin-
chona alkaloid derivatives (two enones tested).[13] There-
fore, expanding the scope of this largely unexplored reac-
tion is highly valuable, especially regarding the enone part-
ner, as the resulting hydroxy enones are useful synthetic in-
termediates due to their highly functionalized nature.[14]
The objective was to expand the reaction to a wide variety
of compounds including unstable enones carrying an acid-
sensitive moiety to show the full potential of our methodol-
ogy.
The aldol reaction is a venerable chemical transforma-
tion that is still stimulating intense research despite a very
long history. This useful reaction, carried out under acidic
or basic conditions, enables the rapid formation of β-hy-
droxy ketones or aldehydes with potentially two new
stereocenters. Control of their relative and absolute stereo-
chemistries has focused the attention of chemists for the last
40 years.[1] This has been achieved by using chiral auxilia-
ries and stoichiometric or catalytic amounts of enantiopure
organometallic complexes and organocatalysts.[2] Nowa-
days, one of the current challenges is to carry out the aldol
reaction in a direct catalytic diastereo- and enantioselective
manner.[3] The direct use of a simple carbonyl nucleophile
for this reaction is relevant if one considers the instability
and tedious handling of silyl enol ethers required for Mu-
kaiyama aldol reactions[4] and because of an increasing de-
mand for environmentally benign processes. The direct
asymmetric aldol reaction has been achieved early on by
using enzymes as catalysts with, however, a limited sub-
strate scope.[5] Other important contributions include the
use of bifunctional chiral metal complexes for the catalysis
of direct aldol reactions.[6] In the last decade, since the semi-
nal publication of List, Lerner, and Barbas,[7] organocata-
lysis and in particular aminocatalysis has solved this prob-
lem partially.[8] Indeed, proline and all subsequent organo-
[a] Laboratoire de Chimie Moléculaire et Thio-organique,
ENSICAEN, Université de Caen,
UMR CNRS 6507, INC3M FR 3038
6 boulevard du Maréchal Juin, 14050 Caen, France
Fax: +33-2-31452877
E-mail: jerome.blanchet@ensicaen.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101282.
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Expanding the Scope of Direct Regiospecific Asymmetric Aldol Reactions
Scheme 1. Previous direct asymmetric aldol reactions with enones.
Results and Discussion
Initially, on the basis of the promising results obtained
previously with phosphoric acid 1a, we reconsidered the re-
action parameters to define the best conditions compatible
with the acid-sensitive enones by using (E)-4-phenylbut-3-
en-2-one (3a) as a model substrate with ethyl glyoxalate.[15]
Stoichiometry of the reagents, amount of catalyst, concen-
tration, and temperature were the main parameters evalu-
ated in the first part of this work. The main guidelines to
optimize the reaction conditions were to avoid the use of
an excess amount of the ketone, as is often done in organo-
catalysis, and to keep the amount of catalyst as low as pos-
sible while retaining good product selectivity and reaction
rate. Initial screening of the catalysts identified (R)-1a as
the most promising in terms of reactivity and selectivity:
experiments have shown that with 5 mol-% catalyst, (R)-1a
delivered 63%ee, whereas more sterically hindered (R)-1d
led to only 50%ee; (R)-1b and (R)-1c gave even lower selec-
tivities (Scheme 2). Surprisingly, spirobiindane-derived
phosphoric acids, which have shown great promise for other
enantioselective reactions,[16] led to lower selectivities. Un-
der similar conditions, (R)-2a afforded 61%ee and (R)-2b
only 52%ee.[17] Therefore, catalyst (R)-1a was selected for
the optimization of the reaction conditions.
Scheme 2. Catalysts screened in this study.
Table 1. Optimization of the aldol reaction involving (E)-4-phen-
ylbut-3-en-2-one.
A test reaction using an excess amount of ketone 3a at
room temperature in the absence of acid yielded a trace
amount of product 4a, whereas with (R)-1a (5 mol-%), a
67% yield of 4a was isolated, attesting the importance of
the catalyst for the reaction (Table 1, Entries 1 & 2). In our
previous report, a ketone/glyoxalate ratio of 10:1 was opti-
mized to maintain high reactivity and selectivity.[9] How-
ever, decreasing the amount of ketone was considered nec-
essary to make the chemistry more appealing in the case of
a valuable ketone substrate. Consequently, we investigated
the impact of various ketone/glyoxalate ratios on the yield
and selectivity of the reaction. When an equimolar ratio
of both substrates was used the reaction became sluggish,
affording a low 46% yield (Table 1, Entry 4). More interest-
Entry
(R)-1
Ratio
Time
[d]
Yield
[%][a]
ee
[mol-%] 3/glyoxalate
[%][b]
1
2
3
4
5
6
7
8
0
5
5
5
5
5
4
2
1
0.5
2
10
1
10:1
10:1
2:1
1:1
1:2
1:5
1:2
1:2
1:2
1:2
1:2
1:2
1:2
4
4
5
5
5
2
2
2
4
1
5
5
14
2
–
61
63
63
64
66
67
73
46
70
78
64
50
53
42
73
79
70
68[c]
67[c]
62
9
10
11
12
13
58[d]
63
71[e]
75[e]
[a] Isolated product. [b] Determined by chiral HPLC. [c] Concen-
ingly, the use of an excess amount of inexpensive ethyl gly- tration 1 m. [d] Run at 45 °C. [e] Run at 0 °C.
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J. Das, F. Le Cavelier, J. Rouden, J. Blanchet
SHORT COMMUNICATION
oxalate led to improved reaction rates (Table 1, Entries 5 enantioselectivity was noticed (Table 1, Entry 10). Regard-
and 6). The use of a fivefold excess gave slightly higher yield ing the various results obtained with 5, 4, 2, 1, and 0.5 mol-
and selectivity, and a twofold excess was retained to sim- %, a catalyst loading of 2 mol-% was retained as a good
plify the purification process and to maintain an atom compromise between yield and selectivity (Table 1, compare
economic process. Next we probed the minimal amount of Entries 6–10).
catalyst necessary. Although 0.5 mol-% of (R)-1a was found
In parallel we observed a moderate effect of dilution:
to be still effective at 45 °C, a significant erosion of the more diluted reactions afforded slightly higher selectivities
at the expenses of yields (Table 1, compare Entries 5/7 and
8/11). Thus, a 1 m concentration was selected and the reac-
tion time was increased (5 days) to preserve the high con-
Table 2. Aldol reactions with enones and ynone derivatives.
version of ketone 3. Finally, the reaction conducted at 0 °C
afforded higher selectivity but led to an unacceptable long
reaction time of 14 d (Table 1, Entry 13) with a low catalyst
loading. Noteworthy, no elimination product was observed
during the optimization process even at higher temperature,
witnessing the very mild conditions of the reaction. A pos-
sible intramolecular acid-catalyzed oxa-Michael reaction
was not detected either,[17] probably due to the low nucleo-
philic character of the hydroxy group adjacent to an ester
in aldol products 4.
Having set the optimized parameters, the scope of the
reaction was explored to broaden the utility of the organo-
catalyzed aldol reaction (Table 2). Methyl vinyl ketones β-
substituted by an aryl or heteroaryl moiety behaved simi-
larly, regardless of the electronic nature of the aromatic sub-
stituents (Table 2, products 4a–h). Interestingly, acid-sensi-
tive furan and thiophene β-substituted vinyl ketones 3f and
3g afforded 4f and 4g in 67 and 71% yield, respectively.
When cyclic enones were used, the regioselective adduct
corresponding again to the αЈ-aldol reaction (no reaction
on the γ position is detected) was obtained in 66–80% yield
with higher enantioselectivities for the exocyclic enones ad-
ducts 4j and 4k but with no diastereoselectivity (Table 2).
Methyl vinyl ketones αЈ-substituted by a methyl reacted
slowly and led to 4l in a moderate 48% yield, probably due
to a hindered enol intermediate.
Intrigued by the unique reactivity of catalyst (R)-1a we
decided to test dienones. Such substrates are unexplored in
aldol reactions, probably because of their limited stability
under either basic or acidic conditions. Considering those
substrates as a good challenge for our mild reaction condi-
tions, we submitted ketones 5a and 5b to the same condi-
tions as defined previously, that is, a twofold excess of ethyl
Table 3. Aldol reactions with dienones derivatives.
[a] Isolated yields. [b] Determined by chiral HPLC. [c] Run at
10 °C.
[a] Isolated yields. [b] Determined by chiral HPLC.
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Expanding the Scope of Direct Regiospecific Asymmetric Aldol Reactions
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Michael compound was detected.[18] The observed enantio-
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earlier, but to the best of our knowledge those results are
the first examples of asymmetric direct aldol reactions in-
volving dienones.
[5]
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In conclusion, we have extended the direct asymmetric
aldol reaction catalyzed by Brønsted acids to challenging
enones that have never been used. The very mild conditions
notably optimized for this study are compatible with a large
variety of enones, including acyclic and endo- or exocyclic
enones, and dienones. Moreover, the results presented above
were obtained by using low catalyst loadings and reason-
able stoichiometries of the reagents, which make this chem-
istry very practical for synthetic applications and compati-
ble with atom-efficient processes. We believe this reaction
could serve as a benchmark for the development of new
chiral acid catalysts owing to the chemical challenge offered
by the substrates involved. In its current state, the reaction
should be quite useful due to the complex molecular struc-
tures obtained in a straightforward manner and is a an im-
portant step forward complementing aminocatalysis in the
field of organocatalyzed aldol reactions.
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[15] Other aldehydes were tested in our previous report. However,
lower yields were obtained. Accordingly, these were not tested
in this study.
Experimental Section
Representative Procedure for the Acid-Catalyzed Aldol Reaction: A
glass tube equipped with a septum was charged with ketone 3a
(59 mg, 0.4 mmol), catalyst (R)-1a (5 mg, 0.008 mmol, 2 mol-%),
and a solution of ethyl glyoxylate in toluene (50% w/w, 164 mg,
0.8 mmol). The reaction was stirred for 120 h at room temperature
and deposed on silica. Column chromatography of the crude mix-
ture (cyclohexane/EtOAc, 7:3 to 6:4) yielded 4a (72 mg, 72% yield,
66%ee) as a colorless solid.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and characterization of the products.
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Y.-X. Liao, J. Ng, Q.-S. Hu, J. Org. Chem. 2011, 76, 4125–4131.
[17] The synthesis of 1e and 1f are parts of the PhD thesis of G.
Pousse (Ph.D. Thesis, University of Caen-Basse Normandie,
2010) and will be reported in due course.
[18] For selected examples of acid-mediated intramolecular oxa-
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Acknowledgments
We gratefully acknowledge the Agence Nationale de la Recherche
“MESORCAT” for a fellowship to J. D. (CP2D program), the Cen-
tre National de la Recherche Scientifique (CNRS), the Ministère
de l’Enseignement Supérieur et de la Recherche, the Région Basse-
Normandie, and the European Union (FEDER funding) for finan-
cial support.
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Received: September 1, 2011
Published Online: October 14, 2011
1632.
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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