Origin of the enantioselectivity in organocatalytic michael additions of β-ketoamides to α,β-unsaturated carbonyls: A combined experimental, spectroscopic and theoretical study

Article abstract of DOI:10.1002/chem.201404481

The organocatalytic enantioselective conjugate addition of secondary β-ketoamides to α,β -unsaturated carbonyl compounds is reported. Use of bifunctional Takemoto's thiourea catalyst allows enantiocontrol of the reaction leading either to simple Michael a

Full text of DOI:10.1002/chem.201404481

DOI: 10.1002/chem.201404481
Full Paper
&
Organocatalysis |Hot Paper|
Origin of the Enantioselectivity in Organocatalytic Michael
Additions of b-Ketoamides to a,b-Unsaturated Carbonyls: A
Combined Experimental, Spectroscopic and Theoretical Study
Adrien Quintard,[a] Diana Cheshmedzhieva,[b, e] Maria del Mar Sanchez Duque,[a]
Anouk Gaudel-Siri,[b] Jean-Valꢀre Naubron,[c] Yves Gꢁnisson,[d] Jean-Christophe Plaquevent,[d]
Xavier Bugaut,[a] Jean Rodriguez,*[a] and Thierry Constantieux*[a]
Abstract: The organocatalytic enantioselective conjugate ad-
dition of secondary b-ketoamides to a,b-unsaturated car-
bonyl compounds is reported. Use of bifunctional Takemo-
to’s thiourea catalyst allows enantiocontrol of the reaction
leading either to simple Michael adducts or spirocyclic ami-
nals in up to 99% ee. The origin of the enantioselectivity has
been rationalised based on combined DFT calculations and
kinetic analysis. This study provides a deeper understanding
of the reaction mechanism, which involves a predominant
role of the secondary amide proton, and clarifies the com-
plex interactions occurring between substrates and the cata-
lyst.
Introduction
tive formation of carbon–carbon or carbon–heteroatom bonds,
and is being increasingly applied in multiple bond-forming
transformations[3] such as one-pot,[4] domino[5] and multicom-
ponent procedures,[6] including in the total synthesis of com-
plex molecules.[7] Current developments mainly focus on the
design of new catalysts and the identification of new modes of
activation for the discovery of original reactivities. However, to
convert these scientific advances into synthetically useful or-
ganic transformations, especially for the implementation of an
academic process to industry,[8] a clear understanding of the
mechanism of a new organocatalysed reaction is fundamental
and will help to define its scope and limitations.[9] In this sense,
recent significant advances have blossomed from experimental
investigations combined with computational explorations,[10]
resulting in an enrichment of the modern toolbox of asymmet-
ric synthesis with environmentally-friendly methods.
Recent years have witnessed an explosive growth in the field
of asymmetric organocatalysis, which is now considered as
one of the three pillars of enantioselective synthesis, together
with biocatalysis and organometallic catalysis.[1] Compared to
these last two well-established modes of activation, organocat-
alysis can deliver complementary or orthogonal selectivities.
Although still in its adolescence,[2] this hot research topic has
already demonstrated its high potential for the enantioselec-
[a] Dr. A. Quintard, Dr. M. M. Sanchez Duque, Dr. X. Bugaut, Prof. J. Rodriguez,
Prof. T. Constantieux
Aix Marseille Universitꢀ
Centrale Marseille
CNRS, iSm2 UMR 7313
13397, Marseille (France).
Fax: (+33)491-289-187
E-mail: jean.rodriguez@univ-amu.fr
thierry.constantieux@univ-amu.fr
In the context of our ongoing efforts in the development of
domino and multicomponent reactions from 1,2- and 1,3-dicar-
bonyl derivatives to reach polyfunctionalised heterocycles in
a regio- and/or stereoselective manner,[11,12] we recently turned
our attention to the use of 1,3-ketoamides as substrates.[13]
Compared with the corresponding intensively studied 1,2- and
1,3-ketoesters, these pronucleophiles have received considera-
bly less attention in such processes. Nevertheless, they possess
an additional aza-nucleophilic function that can be used to
tune their reactivity and is of great synthetic value for subse-
quent derivatisation reactions or domino cascades.[14] As an il-
lustration of this high but still unexplored synthetic potential,
we pioneered in 2005 the use of b-ketoamides in multicompo-
nent reactions by reporting a molecular sieves-promoted dia-
stereoselective three-component reaction that leads to original
bicyclic compounds with a 2,6-DABCO (diazabicyclo[2.2.2]-
octane) type core.[15] In this Michael addition-initiated se-
[b] Dr. D. Cheshmedzhieva, Dr. A. Gaudel-Siri
Aix Marseille Universitꢀ - CNRS
Institut de Chimie Radicalaire (UMR-7273)
Marseille (France).
[c] Dr. J.-V. Naubron
Spectropole - Aix Marseille Universitꢀ
13397, Marseille (France).
[d] Dr. Y. Gꢀnisson, Dr. J.-C. Plaquevent
Universitꢀ Paul Sabatier - Toulouse III, CNRS
UMR 5068 LSPCMIB
Toulouse (France).
[e] Dr. D. Cheshmedzhieva
Present address : Faculty of Chemistry and Pharmacy
University of Sofia
1164 Sofia (Bulgaria).
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201404481.
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quence, the b-ketoamide acts as a dual C,N bis-nucleophile.
However, when we turned our attention to the development
of an organocatalysed enantioselective version of this reac-
tion,[16] we realised that the activation of simple b-ketoamides
by small chiral organic molecules had not been previously re-
ported. This fact prompted us to develop our own methodolo-
gy for the organocatalysed enantioselective Michael addition
of b-ketoamides to enals and enones. Thus, in a preliminary
communication,[17] we identified bifunctional tertiary amine-
thiourea derivatives as excellent catalysts for the activation of
secondary a-substituted-b-ketoamides18 leading enantioselec-
tively to Michael adducts containing an all-carbon quaternary
stereogenic centre (Figure 1).[19] These products constitute val-
uable synthetic platforms from which to access more complex
chiral building blocks by cascade sequences or post-functional-
isation. Moreover, this study highlighted a crucial role played
by the hydrogen atom of the amide moiety, allowing us to dis-
close an unprecedented activation mode for these pronucleo-
philes.
the activation of the pronucleophile by an organocatalyst, but
on the activation of the electrophile through the formation of
an iminium intermediate by reaction with chiral secondary
amines.[20] In all cases, the corresponding adducts evolve
through the formation of a cyclic hemiaminal. To avoid this
type of cascade reaction, that is, to stop the reaction at the
formation of the adduct, and to control its enantioselective for-
mation, we decided first to focus on the conjugate addition of
a-substituted b-ketoamides to a,b-unsaturated ketones. Thus,
we started our study by exploring the application of structural-
ly different catalysts in the addition of b-ketoamide 1a[21] to
methyl vinyl ketone (2) (Scheme 1).[22] At the outset, as de-
Scheme 1. Iminium catalysts screening in the organocatalytic conjugate ad-
dition of 1a to 2.
Figure 1. Interest and challenges associated with the asymmetric Michael
addition of b-ketoamides to a,b-unsaturated carbonyls.
scribed for the organocatalytic conjugate addition of b-ami-
doesters to enals, we tested a strategy based on simple activa-
tion of the electrophile through potential iminium ion forma-
tion. Unfortunately, by using secondary amine catalysts 3a or
3a’, almost no reaction was observed. Alternatively, the use of
primary amines 3b and 3b’, which are known to be good cata-
lysts for the activation of unsaturated ketones,[23] only provided
the Michael adduct with moderate levels of enantiocontrol (28
and 32% ee) and at low reaction rate.
The aim of this article is to shed light on the unique role of
the hydrogen atom of the amide in determining both the reac-
tivity and the enantiocontrol in Michael addition reactions of
secondary b-ketoamides to enones and enals. Based on the X-
ray determination of the absolute configuration of the newly
created all-carbon quaternary centre, combined with a kinetic
study and a detailed theoretical investigation, a mechanism is
proposed that correlates with the observed enantioselectivi-
ties, arising from the predominant role of the secondary amide
proton, and the complex interactions occurring between sub-
strates and the catalyst. With this rational in hand, the scope
of the conjugate addition and some synthetically useful post-
functionalisation reactions of the adducts are also presented.
These disappointing results showed that simple activation of
the electrophile was insufficient in the case of b-ketoamides to
promote both good reactivity and enantiocontrol, but strongly
suggested that bifunctional entities might be appropriate cata-
lysts for our purpose. Indeed, literature studies on proton ex-
changes indicated that NH-containing b-ketoamides can be in
equilibrium with their imidic acid form (Scheme 2).[24]
Results and Discussion
Optimisation and scope
When we started our study, the organocatalysed activation of
b-ketoamides toward nucleophilic addition was unknown.
However, in parallel to our investigations, some efficient asym-
metric cascade reactions involving Michael addition of related
b-amidoesters to a,b-unsaturated aldehydes were re-
ported.[17b–h] In these studies, the strategy was based not on
Scheme 2. Specific behaviour of b-ketoamides and potential activation.
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This particular behaviour with an apparent acidic proton, in-
dicated a potential for applying bifunctional thiourea-based
catalysts.[19d,25] Notably, this unexplored acid imidic form should
increase the reactivity of the starting material by favouring the
equilibrium toward a more reactive enol/enolate with the aid
of an appropriate catalyst. The bifunctional character of the
catalyst should also activate the acceptor, leading to a highly
defined transition state and thus achieving good enantiocon-
trol. To validate this hypothesis, different bifunctional organo-
catalysts were screened in the test reaction (Scheme 3).
Table 1. Screening of conditions for the organocatalytic conjugate addi-
tion of 1a to MVK 2.[a]
Entry
3g
[equiv]
Solvent
t
[h]
T
[8C]
ee
[%][b]
1
2
3
4
5
6
7
0.1
0.1
0.1
0.1
0.1
0.1
0.05
toluene
CH2Cl2
H2O
toluene
CH2Cl2
toluene
toluene
72
48
96
40
72
40
48
RT
RT
RT
0
0
50
RT
87
86
11
83
82
70
79
[a] A solution of 1a (1 equiv), 2 (2 equiv), and catalyst 3g (10 mol%) in
toluene (0.05m) was stirred until full conversion. [b] Determined by HPLC
analysis on a chiral stationary phase.
dramatically reduced the enantioselectivity (11% ee; entry 3),
supporting the proposed mode of activation. Finally, either
changing the temperature (entries 4–6) or decreasing the cata-
lyst loading to 5 mol% (entry 7) were also detrimental to the
enantioselectivity.
Based on the postulated mechanistic importance of the
amide proton on the reactivity of the b-ketoamide, we won-
dered whether a slight modification on the nitrogen substitu-
ent would impact the reaction profile. By appropriately design-
ing the Michael donor, it should thus be possible to modulate
both reactivity and enantiocontrol by favouring the H-bonding
character of the donor (b-ketoamide). When a phenyl group is
present on the nitrogen, modifying the steric bulk by including
ortho-substituents on the ring hampered the reaction and re-
duced the stereoselectivity (Table 2, entries 1 and 2). Substrates
bearing an N-substituent with extended aromatic system per-
formed efficiently (Table 2, entries 3–5). Highly sterically de-
manding substrate 1b significantly decreased the ee to 79%
(entry 2), suggesting a possible repulsion with the catalyst. In
contrast, 1-naphthyl or 1-anthracenyl substituent 1c or 1e
were tolerated well, leading to the products in 91 and 90% ee,
respectively (entries 3 and 5). Quite surprisingly, 2-naphthyl b-
ketoamide 1d gave slightly reduced levels of enantiocontrol
(82% ee, entry 4). Alternatively, when placing a benzylic chain
on the nitrogen, a dramatic drop in both reactivity and enan-
tioselectivity was observed (46% ee, entries 6–7) whereas the
inclusion of a tert-butyl group completely inhibited the reac-
tion (entry 8). At first glance, these results suggested that a pos-
sible p-stacking was involved between the aromatic substitu-
ent on the nitrogen and that of the catalyst. To investigate this
first hypothesis, the electronic nature of the substituent on the
aromatic ring was then modulated (Table 3).
Scheme 3. Selected bifunctional catalysts screening in the organocatalytic
conjugate addition of 1a to MVK 2.
It rapidly became clear that the presence on the catalyst of
a tertiary amine together with at least one acidic hydrogen
atom was beneficial for both reactivity and enantiocontrol,
confirming our dual activation hypothesis. As a result of this
dual activation, cinchona derivatives 3c and 3d, possessing
both tertiary amines and free OH, led to excellent reactivity
(full conversion in 24 h) and promising levels of enantiocontrol
(44–73% ee).[26] Inserting a thiourea in catalyst 3 f slightly in-
creased the enantioselectivity to 80% ee, whereas the
squaramide catalyst 3e, totally shut down the reactivity. Finally,
the best result was obtained by applying the Takemoto thio-
urea catalyst (R,R)-TUC 3g,[26c] leading to the creation of the
quaternary stereogenic centre with full conversion and 87% ee.
Attempts to improve these preliminary results were then un-
dertaken by optimising the reaction conditions. These efforts
are summarised in Table 1. Unfortunately, although good reac-
tivity was obtained in all cases, deviations from the original
conditions (entry 1, 10 mol% 3g, toluene, RT) led to a decrease
in the enantioselectivity. It must be pointed out that the pres-
ence of water, which is a solvent that can potentially limit H-
bonding interactions between the catalyst and the substrates,
As expected, modification of the R group strongly impacted
the enantioselectivity (54–99% ee). Unfortunately, attempts to
favour possible p-stacking by the introduction of an electron-
rich aromatic ring (entries 2–5), did not lead to any improve-
ment in the enantioselectivity (65–83% ee) and, as expected,
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the inclusion of a substituent in the sterically demanding
ortho-position worsened the situation (entry 4). These results
suggested that a p-stacking of this group with the catalyst was
not the most important factor controlling the enantioselectivi-
ty. Placing an inductively attractive substituent in the para po-
sition had a moderate impact on the enantiocontrol (entries 5
and 6), whereas the mesomeric attractive para-nitro substitu-
ent, impressively increased the ee to 97% with compound 4p
(entry 8). Finally, increasing the steric demand by the introduc-
tion of a second group on the aromatic ring dramatically re-
duced the selectivity (54–82% ee; entries 9 and 10). Even
though these variations could be the result of several parame-
ters, the best enantioselectivity, found for 4p, might be due to
the higher acidity of the proton in the starting b-ketoamide. To
verify this second hypothesis, we studied the influence of
other electron-withdrawing groups on the nitrogen atom
(Table 4).
Table 2. Effect of the nature of the nitrogen substituent on substrates
1.[a]
,
Entry
R
4
t
[h]
Yield
[%][b]
ee
[%][c]
1
2
4a
4b
72
>99
87
79
72
48
70
3
4
4c
90
95
91
82
Benzoyl substituents were found to strongly enhance the re-
activity of the substrates, resulting in fast transformations even
at ꢀ108C (entries 1–3). Under these conditions, full conversion
was observed in 5 min to 24 h, without any notable difference
in the enantioselectivity (85–86% ee). Alternatively, insertion of
methyl- or p-anisyl-sulfonyl groups did not produce a notable
increase of the reactivity and conserved the same level of
enantiocontrol (entries 4 and 5). To our delight, tosylamide 1x,
provided the Michael adduct in a perfect 99% ee and 88%
yield, validating our hypothesis (entry 6). This result indicates
4d
72
5
6
4e
4 f
96
48
98
26
90
46
7
8
4g
4h
168
168
73
0
46
–
Table 4. Effect of the nature of the nitrogen substituent on substrates
1.[a]
[a] A solution of 1 (1 equiv), MVK 2 (2 equiv), and catalyst (10 mol%) in
toluene (0.05m) was stirred until full conversion. [b] Isolated after silica
gel column chromatography. [c] Determined by HPLC analysis on a chiral
stationary phase.
Entry
R
T
[8C]
4
t
[h]
Yield
[%][b]
ee
[%][c]
Table 3. Effect of the electronic nature of the nitrogen substituent on
substrates 1.[a]
1
2
RT
4s
5 min
94
86
85
85
ꢀ108C 4t
20
Entry
R
4
t
[h]
Yield
[%][b]
ee
[%][c]
3
ꢀ108C 4u
ꢀ108C 4v
24
99
86
1
2
3
4
5
6
7
8
9
10
p-MeOC6H4
m-MeOC6H4
o-MeOC6H4
m,m’-(MeO)2C6H3
p-FC6H4
p-(CF3)C6H4
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
40
48
72
20
96
96
24
72
48
48
98
64
75
nd
82
87
96
62
87
81
83
83
65
82
80
82
78
97
54
82
4
5
120
72
94
40
85
89
RT
RT
4w
4x
p-(CN)C6H4
p-(NO2)C6H4
m,m’-(CF3)2C6H3
m,m’-(NO2)2C6H3
6
72
88
99
[a] A solution of 1 (1 equiv), MVK 2 (2 equiv), and catalyst (10 mol%) in
toluene (0.05m) was stirred until full conversion. [b] Isolated after silica
gel column chromatography. [c] Determined by HPLC analysis on a chiral
stationary phase.
[a] A solution of 1 (1 equiv), MVK 2 (2 equiv), and catalyst (10 mol%) in
toluene (0.05m) was stirred until full conversion. [b] Isolated after silica
gel column chromatography. [c] Determined by HPLC analysis on a chiral
stationary phase.
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the crucial importance of the secondary amide proton on the
enantioselectivity of the reaction. To confirm this role, we
tested two substrates 1y and 1z, possessing a tertiary amide
motif (Scheme 4). In full agreement with our expectation, abso-
lutely no reaction was observed in either case, highlighting the
crucial role of the secondary amide proton for the substrate
activation.[27]
With this accumulated knowledge on the role of the amide
substituent, we then decided to investigate the scope of this
process by focusing on the partner structures. First modifica-
tions were performed on the Michael acceptor (enones,
Scheme 5). Besides methyl vinyl ketone (MVK; 2), the parent
ethyl vinyl ketone was also well tolerated, leading to Michael
adducts 5a–d in 84–93% ee. Phenyl vinyl ketone also reacted
well with the b-ketoamide 1x, giving adduct 5e in 98% yield,
albeit with decreased enantiocontrol (73% ee). Finally, increas-
ing the substitution at the b-position of the enone considera-
bly decreased the stereoselectivity, and 5 f was obtained with
a 3:1 d.r. and 14% ee, indicating a poor tolerance for this type
of compound.[28]
Concerning the Michael donor, various b-ketoamides could
also be efficiently applied in this transformation (Scheme 5).
Totally different backbones were well tolerated in this process:
Various cyclic five- and six-membered b-ketoamides could be
applied, generating structurally diverse compounds 5g–k in
usually good enantioselectivities (85–99% ee). In the case of
5g–i, difficulties in preparing the starting N-tosylamides forced
us to use the parent N-phenyl or N-naphthyl substrates, how-
ever preserving a good level of enantioselectivity (85–91% ee).
In contrast, with an acyclic b-ketoamide, both reactivity and
stereocontrol were considerably decreased (5l; 17% yield,
65% ee). This suggests that a greater level of rotational free-
dom is not tolerated on the b-ketoamide and that conforma-
tional rigidity is a prerequisite for better efficiency.
Scheme 4. Michael addition in the presence of a tertiary amide.
Mechanistic study and determination of the activation
mode
Experimental Study
Having pointed out the broad substrate scope of this new
transformation, we then focused on its particular mechanism.
Notably, given the bifunctional character of the catalyst and
the unusual structure of the Michael donor, the question of
the possible interactions and activation modes occurring
during the process remains open.
At first, to better understand this transformation, the abso-
lute configurations of the obtained products were determined.
As previously reported in our preliminary communication,[17a]
single-crystal X-ray analysis of 4p indicated an R absolute con-
figuration on the Michael adduct. VCD spectroscopy was also
used to determine the absolute configurations of 4p, 4x and
4c. Thus, based on the vibrational excitonic coupling model
proposed by Taniguchi et al.,[29] we have confirmed the abso-
lute configuration R of 4p and established that 4x[17a] and 4c
are also R enantiomers.[30] A complete study of the VCD analy-
ses will be published later in full details.
To shed light on the potential activation mode of the sub-
strate with the catalyst, we undertook several other mechanis-
tic experiments. First we investigated the change in the NMR
spectra recorded with a stoichiometric mixture of starting b-ke-
toamide 1x and catalyst 3g (Figure 2). A clear and instantane-
ous modification was observed in CD3CN whereas several days
were required in [D8]-toluene (see the Supporting Information).
First, the persistence of a triplet for proton 2 at 2.95 ppm
Scheme 5. Scope of acceptors and donors in the enantioselective Michael
addition.
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not lead to any evolution, sug-
gesting a poor reaction reversi-
bility.
To identify the potential inhib-
ition pathway and the kinetically
significant steps in this transfor-
mation, the order in each com-
ponent was determined by inde-
pendently varying their respec-
tive concentration. Given the re-
action profile, the initial rate was
chosen at 60 min and conver-
sions were determined by
1H NMR spectroscopic analysis
after acidic treatment of the mix-
ture; the results are summarised
in Figure 4. As expected, a posi-
tive rate order was observed for
both MVK and the catalyst (Fig-
ure 4a,c). In contrast, a zero rate
order was observed for the b-ke-
toamide (Figure 4b).[31] Finally,
increasing the initial concentra-
tion in final Michael adduct,
clearly reduced the initial reac-
tion rate (Figure 4d). The ab-
sence of a significant primary ki-
netic isotopic effect (KH/D =1.15)
when starting from >80% deu-
terated b-ketoamide is also con-
sistent with a rapid deprotona-
tion leading to the active form
(Scheme 6).
Figure 2. 1 H NMR spectroscopic study of a mixture of b-ketoamide 1x and 3g in CD3CN. (Top) b-ketoamide 1x;
(centre) 1:1 mixture; (bottom) 3g.
(Figure 2, centre) indicates that the enol form of the substrate
was not present. Consistent with this finding, a strong down-
Theoretical study
field shift operating on proton 1’ (D=0.5 ppm) together with
a strong downfield shift on protons 7’ of the dimethyl amino
substituent of the catalyst (D=0.7 ppm) indicates the presence
of a hydrogen bond. Finally, it must be pointed out that aro-
matic protons 8 and 9, and protons 10’ and 12’ from the sub-
strate and catalyst, respectively, are also significantly shifted,
indicating a probable interaction between these two groups.
Although we cannot draw direct conclusions for the structure,
this simple NMR experiment clearly indicates the presence of
a relatively strong interaction between the catalyst 3g and
b-ketoamide 1x.
With these experimental data in hand, we then attempted to
complete the study with a detailed computational investiga-
With these preliminary NMR experiments, we then decided
to undertake a kinetic analysis of the described transformation.
First, the reaction profile was determined by following the con-
version by 1H NMR spectroscopic analysis in [D8]-toluene
(Figure 3). The obtained curve indicates a fast initial rate with-
out any induction period. The decrease in reactivity observed
after a relatively short period of time is characteristic of either
catalyst decomposition or inhibition by the product, but can
also be attributed to the reversibility of the reaction. However,
mixing back the Michael adduct with 10 mol% of catalyst did
Figure 3. Kinetic profile of the reaction at 168C.
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substrates showed that the most stable form in all the substi-
tuted b-ketoamides is the keto form. The difference between
the keto and enol forms is in the range of 0.5–3.0 kcalmolꢀ1
depending on the substitution of the nitrogen atom (for 1a,
1c, 1i, 1k, 1p and 1x). The imidic acid form is very unstable in
comparison to the keto form. For the tosyl substituted b-keto-
amide 1x (Figure 5), the imidic acid form Ax is 9.03 kcalmolꢀ1
Figure 5. The HOMO orbitals for keto form 1x, imidic acid form Ax and enol
form Bx.
higher in energy. Both Ax and Bx have an intramolecular H-
bond, but the observed relative higher stability of Bx can be
attributed to the extension of conjugation. The HOMO orbitals
in amide, enol and imidic acid forms are represented in
Figure 5.
Figure 4. Initial rate dependence on the concentration of the different com-
ponents: a) [enone], b) [b-ketoamide], c) [catalyst], d) [product].
Reaction mechanism: With these preliminary indications on
the b-ketoamide behaviour, a detailed study on the reaction
mechanism has been carried out. The computations have been
performed with the hybrid meta-GGA DFT functional M06-
2X,34 with the 6-31G(d) basis set. The functional was chosen
based on a model calibration carried out for the prediction of
keto-enol tautomeric equilibrium and literature data.[34,35] Full
geometry optimisations in toluene were carried out for all the
stationary points along the reaction path by using IEFPCM for-
malism.[36] There was no significant difference found between
the transition-state structures in the gas phase and in solvent.
Vibrational frequencies were calculated at the same level to
determine the nature of the located stationary points; zero
point energies and thermodynamic data were calculated by
using the specified scaling factor (0.947).[37] All transition-state
geometries were confirmed by intrinsic reaction coordinate
(IRC) calculations. Stabilisation energies of the complexes in all
stationary points are BSSE-corrected (Figure 6).
Scheme 6. Deuterium kinetic isotope effect experiment.
tion. We anticipated that the calculations would help to clarify
the mechanism mainly by improving our understanding of the
interactions present with the bifunctional catalyst.
Tautomeric equilibrium: Computational calculations on the
nature of the starting b-ketoamide have been performed with
the hybrid meta-GGA DFT functional M06-2X[32] with the 6-31+
G(d,p) basis set implemented in Gaussian 09.[33] Vibrational fre-
quencies were calculated at the same level to determine the
nature of the located stationary points; zero point energies
and thermodynamic data were calculated by using the speci-
fied scaling factor (0.940).[34] The theoretical calculations on the
To analyse the proposed transformations, we focused on
three distinct parts, namely deprotonation of the b-ketoamide,
the CꢀC bond-formation event and liberation of the catalyst.
The reaction mechanism was studied for the tosyl substituted
b-ketoamide 1x, which shows the highest ee values in the
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Figure 6. Relative Gibbs free energies (in kcalmolꢀ1) along the reaction coordinate.
studied series (Figure 6). The first stage of the reaction is the
deprotonation of the substrate and the formation of the
nucleophile (TS1). Two possible paths for the production of
the reactive enolate form have been studied. Between the two
acidic hydrogen atoms present on 1x, the more acidic is the
methine proton (pKa =7.1 vs. 15.4 for the NH). Even though
the CH is more acidic, the energy barrier for the direct NH de-
protonation (Table 5) by 3g is much lower than for CH depro-
quired a proton transfer event that was higher in energy.[38]
Based on these calculations and on the experimental observa-
tion of a fast deprotonation, it seems that the most probable
path involves abstraction of the amide hydrogen of 1x by the
organocatalyst 3g. This leads reversibly to an off-cycle unreac-
tive form.
For the reaction to proceed forward, equilibrium back to the
starting b-ketoamide and subsequent enolate methine hydro-
gen abstraction would be the preferred path (Figure 6). Subse-
quent coordination of the MVK to the amide hydrogen leads
to the direct formation of the most stable enolate intermediate
(Figure 6; DG=14.4 kcalmolꢀ1).
¼
tonation (Table 5, DG =16.7 kcalmolꢀ1). The relatively low
energy barrier observed for the direct NH deprotonation
¼
(Table 5, DG =1.1 kcalmolꢀ1) is in complete agreement with
the fast deprotonation observed by 1H NMR spectroscopic
analysis, mixing ketoamide and TUC only. The deprotonation
of the amide hydrogen is an equilibrium process with a low
barrier for the forward and reverse reaction. Even though the
energy barrier is lower for the N deprotonation, it does not
lead directly to a reactive form. Indeed, from this N-deproton-
ated intermediate, the possibility for an intramolecular hydro-
gen transfer and formation of the reactive enolate form were
studied. All the obtained paths were very high in energy (>
46 kcalmolꢀ1), disfavouring such a process.[38] Finally, direct
enolate formation from the corresponding enol form also re-
The second stage of the reaction is nucleophilic addition to
the MVK, creating the new stereogenic centre (CꢀC bond-
forming event, TS2). First, it should be noted that the CꢀC
bond-forming step is not thermodynamically favoured because
the resulting intermediate lies higher in energy than the terna-
ry complex deprotonated b-ketoamide-protonated catalyst-
MVK (DDG=3.9 kcalmolꢀ1). Various addition possibilities lead-
ing to the formation of R and S products have been studied.
The transition states differ in the enolate coordination to the
catalyst and/or the approaching site of the ketone.[38] As al-
ready described by Pꢃpai,[39] coordination of the b-ketoamide
to the thiourea part of the Takemoto catalyst is energetically
preferred, with a lower energy barrier for this CꢀC bond forma-
tion of 18.2 kcalmolꢀ1 (DG=32.6 kcalmolꢀ1). In the most fav-
oured transition states, the b-ketoamide (pronucleophile) has
an orientation that is perpendicular with the thiourea
(Figure 7). Gratifyingly, the structure leading to the formation
Table 5. Energy barriers for the b-ketoamide 1x deprotonation.
¼
DG [kcalmolꢀ1
]
deprotonation from C*
deprotonation from N*
16.7
1.1
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¼
vation energy of DG =14.5 kcalmolꢀ1 (TS3–TS4; Figure 6).
The ease of proton transfer from the amide to the enolate,
combined with the high stability of the resulting intermediate
probably helps to displace the equilibrium of the thermody-
namically unfavourable CꢀC bond-formation step. This phe-
nomenon probably explains the experimental observation that
the acidity of the amide proton is crucial for the success of the
reaction. What is also notable here is that the deprotonated
amide–ammonium complex is thermodynamically more stable
than the separated products (DDG=4.6 kcalmolꢀ1; Figure 6),
in complete agreement with the experimentally observed in-
hibition of the catalyst by the product. With both energy dia-
gram and experimental study in hand, a complete catalytic
mechanism can be drawn for the conjugate addition
(Scheme 7).
Direct abstraction of the amide proton is fast and reversible
(off cycle). Deprotonation from the acidic CH gives a productive
ammonium enolate that can then add to MVK. This rate-deter-
mining step is highly enantioselective and gives the R adduct
with 99% ee. Subsequent intramolecular proton transfer from
the amide to the enolate leads to the thermodynamic ammo-
nium salt intermediate, from which the liberation of the cata-
lyst occurs by protonation of the amide anion. Given this
mechanism, it appears that the thermodynamically demanding
liberation of the catalyst can be a limitation of this reaction.
We surmised that the formation of a cyclic hemiaminal inter-
Figure 7. Optimised geometries for the preferred transition-state structures
calculated for the CꢀC bond formation.
of the R adducts (Figure 7; TS2-a-R) is lower in energy by
2.9 kcalmolꢀ1 over the structure leading to the formation of
the S adducts (Figure 7; TS2-a-S). This is in complete agreement
with the experimentally observed 99% ee at room temperature
using 3g. It must be pointed out that these transition-state
structures are very ordered. A network of hydrogen bonds be-
tween the catalyst and the substrate stabilises the transition
state. Additional stabilisation is gained due to the p-stacking
between the aromatic rings. The thiourea NꢀH bonds position
the enolate CꢀO bonds with the help of a network of hydro-
gen bonds. At this stage, the enolate generated during the
CꢀC bond formation must be reprotonated. Direct abstraction
of the proton of the catalyst by the enolate has a barrier of
11.8 kcalmolꢀ1 (TS’3; Figure 6). Alternatively, a relay by prior
abstraction of the amide proton by the enolate followed by
a proton transfer from the ammonium to the amide is a greatly
favoured pathway: the first of these steps is nearly barrierless
(0.4 kcalmolꢀ1), whereas the second step has reasonable acti-
Figure 8. Gibbs free energies (kcalmolꢀ1) for the formation of the hemiami-
nal for a) MVK adduct with 1x, or b) acrolein adduct with 1x.
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favour the catalyst turnover by
pushing the formation of spiro-
hemiaminals 8 (Scheme 8). Given
the prevalence of this spiro skel-
eton in natural products and the
challenge associated with its
synthesis, a modular enantiose-
lective access would be of high
synthetic interest. Gratifyingly,
when the addition of various b-
ketoamides to acrolein was per-
formed at low temperature
(ꢀ358C), exclusive formation of
the expected spiro compounds
8 was observed (Scheme 9). As
expected, the reaction was
much faster than in the case of
MVK, probably due to easier cat-
alyst liberation, and full conver-
sion was observed after 24–48 h
even at this low temperature. To
simplify isolation and to deter-
mine the enantioselectivity of
the reactions, spiro compounds
8 were directly derivatised to
the corresponding enantioen-
riched glutarimides 9 or dihydro-
pyridones 10 by oxidation or de-
hydration, respectively. Moderate
to good enantiocontrol (52–
98% ee) was observed, depend-
ing on the nature of the R sub-
stituent present on the nitrogen
atom. As already indicated in
our preliminary study,[17a] the
enantiopurities of compounds 8
were not determined because of
their instability under HPLC con-
Scheme 7. Detailed catalytic cycle of the conjugate addition of substituted b-ketoamides to MVK catalysed by 3g.
mediate, by intramolecular addition of the amide to the elec-
trophilic carbonyl, should displace the equilibrium toward cata-
lyst release (Figure 8). Calculations performed on the MVK
adduct with 1x confirmed that this cyclisation is kinetically de-
ditions, but we may assume that oxidised compounds 9 and
their precursors 8 have the same enantiomeric excess. Howev-
er, the partial racemisation observed upon dehydration (9x vs.
10x, for example) may be due to the formation of an iminium
intermediate under acidic conditions, for which a racemisation
pathway through a retro-Michael and uncatalysed intramolecu-
lar Michael addition sequence can be envisioned.[40] Although
both heterocyclic scaffolds are important structural motives
that are found in many bioactive natural products,[41,42] to our
¼
manding (DG =16.1 kcalmolꢀ1; Figure 8a) and thermodynam-
ically disfavoured in the case of ketones (DDG=4.8 kcalmolꢀ1
;
Figure 8a). In contrast, calculations performed on the corre-
sponding acrolein adduct indicate a kinetically affordable
¼
(DG =7.1 kcalmolꢀ1; Figure 8b) and thermodynamically fav-
oured process (DDG=ꢀ7.3 kcalmolꢀ1; Figure 8b). This intra-
molecular trapping strategy, already applied for the addition of
unsubstituted b-ketoamide should help liberate the catalyst
and possibly increase the reaction rate.[18]
Michael addition to a,b-unsaturated aldehydes
With this clear understanding of the complete reaction mecha-
nism and in particular of catalyst liberation, we considered
ways to take advantage of the intrinsic aldehyde reactivity to
Scheme 8. Proposed spirocyclisation of the Michael adducts with acrolein.
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level of substitution on the acceptor by using methacrolein 12
considerably decreased the reaction rate (6 days for full con-
version).[45] Despite this limitation, excellent stereocontrol was
obtained in this reaction, giving rise to the major diastereomer
of glutarimide 14 in a 5.6:1 ratio and 94% ee after oxidation of
the corresponding hemiaminal 13.
With this straightforward access to different spiro structures,
and given the potential of such scaffold in natural product syn-
thesis, different derivatisation reactions were then undertaken
with the ultimate goal of maintaining the stereointegrity of
the generated stereocentres. Thus, starting from the isolated
spiro compound 8x, diverse post-functionalisation reactions
could be successfully performed with good retention of the
stereochemical information (Scheme 12).[46] The corresponding
Scheme 9. Spirocyclisation by Michael addition of b-ketoamides to acrolein.
knowledge there is only one report on the direct enantioselec-
tive synthesis of glutarimides.[43] It must be pointed out that
compound 10c is formed as a 1:0.8 mixture of two atro-
poisomers that could not be separated. HPLC analysis indicat-
ed a rotation energy barrier of 23 kcalmolꢀ1 [44]
.
By using acyclic b-ketoamide 1’, unexpectedly, the formation
of the transient hemiaminal was followed by a hemiacetalisa-
tion, leading to the stable bicyclic compound 11 as a mixture
of two diastereomers in a 1.5:1 ratio (Scheme 10). This reactivi-
ty must be due to a better freedom of the acyclic species, al-
lowing the second cyclisation to occur. It is interesting to note
that even though an acyclic b-ketoamide was used, a promising
80% ee was obtained for the major diastereomer.
Finally, substitution on the a,b-unsaturated aldehyde was
then tested in this spirocyclisation (Scheme 11). Increasing the
Scheme 12. Post-functionalisation reactions of spirocyclic compound 8x.
glutarimide 9x, dihydropyridone 10x and 2-piperidone 15
could be obtained in 90–98% ee by using a range of oxida-
tion/reduction methods. Finally, direct one-pot Lewis acid
N-acyliminium formation and subsequent trapping with allyl
trimethylsilane allowed the efficient introduction of another
functional group in structure 16 with 80% ee and 1.5:1 d.r. on
the newly formed stereocentre.
Scheme 10. Double cyclisation with acyclic b-ketoamide 1l and acrolein.
Conclusions
An asymmetric catalysed Michael addition of a-substituted b-
ketoamides to various unsaturated carbonyl compounds has
been developed. A complete and detailed mechanistic study
has allowed us to demonstrate for the first time the unique
role of the hydrogen atom of the amide in controlling both
the reactivity and the enantioselectivity. With the accumulated
Scheme 11. Michael addition to methacrolein catalysed by (R,R)-TUC.
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detailed knowledge of the reaction process, a large panel of
attractive structurally different skeletons possessing a quaterna-
ry stereogenic centre have been obtained with usually high
levels of enantiocontrol (up to 99% ee). Additional reactions
were successfully designed leading to original spiro hemiami-
nals by taking advantage of the reactivity of the Michael ad-
ducts with acroleins. The utility of the obtained scaffolds was
further demonstrated by several post-functionalisation reac-
tions leading to valuable enantioenriched glutarimides and
pyridones.
Keywords: density functional calculations · enantioselectivity ·
Michael addition · organocatalysis · reaction mechanisms
[1] For some recent selected reviews on asymmetric organocatalysis, see:
a) A. G. Doyle, E. N. Jacobsen, Chem. Rev. 2007, 107, 5713; b) S. Mukher-
jee, J. W. Yang, S. Hoffmann, B. List, Chem. Rev. 2007, 107, 5471; c) S.
Bertelsen, K. A. Jørgensen, Chem. Soc. Rev. 2009, 38, 2178; d) M. Bella, T.
Gasperi, Synthesis 2009, 1583; e) R. C. Wende, P. R. Schreiner, Green
Chem. 2012, 14, 1821; f) L. Bernardi, M. Fochi, M. C. Franchini, A. Ricci,
Org. Biomol. Chem. 2012, 10, 2911.
[2] A. Dondoni, A. Massi, Angew. Chem. Int. Ed. 2008, 47, 4638; Angew.
Chem. 2008, 120, 4716.
Given the reaction efficiency, simple protocols, wide scope
and detailed mechanistic understanding, we are convinced
that this study will serve as a stepping stone for the develop-
ment of related transformations and should readily find appli-
cations in drug and natural products synthesis.
[3] For a recent concept article from our group, see: a) D. Bonne, T. Con-
stantieux, Y. Coquerel, J. Rodriguez, Chem. Eur. J. 2013, 19, 2218. See
also: b) N. J. Green, M. S. Sherburn, Aust. J. Chem. 2013, 66, 267.
[4] L. Albrecht, K. Jiang, K. A. Jørgensen, Angew. Chem. Int. Ed. 2011, 50,
8492; Angew. Chem. 2011, 123, 8642.
[5] H. Pellissier, Adv. Synth. Catal. 2012, 354, 237.
[6] For selected recent reviews, see: a) J. Yu, F. Shi, L.-Z. Gong, Acc. Chem.
Res. 2011, 44, 1156; b) A. Moyano, R. Rios, Chem. Rev. 2011, 111, 4703;
c) C. M. Marson, Chem. Soc. Rev. 2012, 41, 7712; d) C. de Graaff, E. Ruijt-
er, R. V. A. Orru, Chem. Soc. Rev. 2012, 41, 3969; e) S. S. van Berkel,
B. G. M. Bçgels, M. A. Wijdeven, B. Westermann, F. P. J. T. Rutjes, Eur. J.
Org. Chem. 2012, 3543.
[7] For selected reviews on the application of asymmetric organocatalysis
to total synthesis, see: a) R. M. de Figueiredo, M. Christmann, Eur. J. Org.
chem. 2007, 2575; b) E. Marquꢁs-Lꢄpez, R. P. Herrera, M. Christmann,
Nat. Prod. Rep. 2010, 27, 1138; c) C. Grondal, M. Jeanty, D. Enders,
Nature Chem. 2010, 2, 167.
[8] For an interesting recent highlight on the necessary factors for the ap-
plication of an academic reaction to industry, see: T. W. J. Cooper, I. B.
Campbell, S. J. F. MacDonald, Angew. Chem. Int. Ed. 2010, 49, 8082;
Angew. Chem. 2010, 122, 8258.
[9] For a recent review dealing with mechanistic studies in aminocatalysis,
see: N. Nielsen, D. Worgull, T. Zweifel, B. Gschwend, S. Bertelsen, K. A.
Jørgensen, Chem. Commun. 2011, 47, 632.
Experimental Section
General procedure for the enantioselective organocatalytic
Michael addition of b-ketoamides to enones: a,b-Unsaturated
ketone 2 (0.4 mmol, 2.0 equiv) was added at RT to a stirred solu-
tion of b-ketoamide 1 (0.2 mmol, 1.0 equiv) and R,R-TUC 3g
(0.02 mmol, 0.1 equiv) in anhydrous toluene (4 mL). The progress
of the reaction was monitored by TLC analysis. Upon full conver-
sion, the reaction mixture was concentrated in vacuo and the
product was purified by flash column chromatography on silica gel
(EtOAc/petroleum ether) to afford the desired Michael adduct. The
enantiomeric excess was determined by HPLC analysis on a chiral
stationary phase.
Representative description of product (4a): By following the gen-
eral procedure, 4a (99% yield) was afforded as a white solid; m.p.
66.2–69.38C; HPLC: ee=87% (Chiralpak AD-H; hexane/ethanol=
90/10; flow rate=1.0 mLminꢀ1; l=254 nm): tR =25.45 (major),
35.60 min (minor); [a]D30 =ꢀ60.97 (c=1.23 in CHCl3); Rf =0.13
(EtOAc/PE, 1:4); 1H NMR (400 MHz, CDCl3): d=8.71 (brs, 1H; NH),
7.53 (d, J=7.7 Hz, 2H; H-8), 7.33 (t, J=7.7 Hz, 2H; H-9), 7.11 (t, J=
7.7 Hz, 1H; H-10), 2.70–2.60 (m, 1H; H-6), 2.52 (t, J=7.7 Hz, 2H;
H-12), 2.49–2.35 (m, 2H; H-4), 2.17–2.09 (m, 1H; H-6’), 2.12 (s, 3H;
H-14), 2.02–1.89 ppm (m, 4H; H-5,11); 13C NMR (75 MHz, CDCl3):
d=220.56 (C3), 206.91 (C13), 167.09 (C1), 137.53 (C7), 128.96 (2CH),
124.42 (CH10), 119.75 (2CH), 59.86 (C2), 38.69 (CH2(4)), 38.46
(CH2(12)), 31.54 (CH2(6)), 30.31 (CH2(11)), 30.04 (CH3(14)), 18.63 ppm
(CH2(5)); HRMS (ESI): m/z calcd for [C16H19NO3+H]+: 274.1438;
found: 274.1434.
[10] P. H.-Y. Cheong, C. Y. Legault, J. M. Um, N. Celebi-OlÅꢅm, K. N. Houk,
Chem. Rev. 2011, 111, 5042.
[11] For some recent reviews from our group, see: a) D. Bonne, Y. Coquerel,
T. Constantieux, J. Rodriguez, Tetrahedron: Asymmetry 2010, 21, 1085;
b) N. Isambert, M. M. Sanchez Duque, J.-C. Plaquevent, Y. Gꢁnisson, J.
Rodriguez, T. Constantieux, Chem. Soc. Rev. 2011, 40, 1347; c) D. Bonne,
T. Constantieux, Y. Coquerel, J. Rodriguez, Org. Biomol. Chem. 2012, 10,
3969; d) S. Goudedranche, W. Raimondi, X. Bugaut, T. Constantieux, D.
Bonne, J. Rodriguez, Synthesis 2013, 45, 1909; e) X. Bugaut, D. Bonne, Y.
Coquerel, J. Rodriguez, T. Constantieux, Curr. Org. Chem. 2013, 17, 1920.
[12] Selected recent contributions from our group: a) W. Raimondi, D. Dau-
zonne, T. Constantieux, D. Bonne, J. Rodriguez, Eur. J. Org. Chem. 2012,
6119; b) W. Raimondi, O. Baslꢁ, T. Constantieux, D. Bonne, J. Rodriguez,
Adv. Synth. Catal. 2012, 354, 563; c) A. Quintard, T. Constantieux, J. Ro-
driguez, Angew. Chem. Int. Ed. 2013, 52, 12883; Angew. Chem. 2013,
125, 13121.
[13] Selected recent contributions from our group: a) C. Allais, O. Baslꢁ, J.-M.
Grassot, M. Fontaine, S. Anguille, J. Rodriguez, T. Constantieux, Adv.
Synth. Catal. 2012, 354, 2084; b) D. Mailhol, M. M. Sanchez Duque, W.
Raimondi, D. Bonne, T. Constantieux, Y. Coquerel, J. Rodriguez, Adv.
Synth. Catal. 2012, 354, 3523; c) W. Raimondi, M. M. Sanchez Duque, S.
Goudedranche, A. Quintard, T. Constantieux, X. Bugaut, D. Bonne, J. Ro-
driguez, Synthesis 2013, 45, 1659; d) S. Goudedranche, X. Bugaut, T.
Constantieux, D. Bonne, J. Rodriguez, Chem. Eur. J. 2014, 20, 410.
[14] For pioneering racemic cascade reaction from b-amidoesters, see:
a) A. W. Pilling, J. Boehmer, D. J. Dixon, Angew. Chem. Int. Ed. 2007, 46,
5428; Angew. Chem. 2007, 119, 5524; b) A. W. Pilling, J. Bçhmer, D. J.
Dixon, Chem. Commun. 2008, 832; c) K. M. Bogle, D. J. Hirst, D. J. Dixon,
Org. Lett. 2010, 12, 1252.
Acknowledgements
The Agence Nationale pour la Recherche (ANR-07-CP2D-06 and
ANR-11-BS07-0014), the COST ORCA (CM0905), the Centre Na-
tional de la Recherche Scientifique (CNRS) and the Aix-Marseille
Universitꢁ are gratefully acknowledged for financial support.
We also thank Dr. N. Vanthuyne and M. Jean (ee measure-
ments) and Dr. M. Giorgi (X-ray diffraction analysis). This work
was supported by the computing facilities of the CRCMM,
“Centre Rꢁgional de Compꢁtences en Modꢁlisation Molꢁculaire
de Marseille”.
[15] a) F. Liꢁby-Muller, T. Constantieux, J. Rodriguez, J. Am. Chem. Soc. 2005,
127, 17176; See also: b) Z. El Asri, Y. Gꢁnisson, F. Guillen, O. Baslꢁ, N.
Isambert, M. M. Sanchez Duque, S. Ladeira, J. Rodriguez, T. Constan-
tieux, J.-C. Plaquevent, Green Chem. 2011, 13, 2549.
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[16] We recently succeeded in the development of the enantioselective ver-
sion of this reaction, see: M. M. Sanchez Duque, O. Baslꢁ, Y. Gꢁnisson, J.-
C. Plaquevent, X. Bugaut, T. Constantieux, J. Rodriguez, Angew. Chem.
Int. Ed. 2013, 52, 14143; Angew. Chem. 2013, 125, 14393.
[31] The low correlation observed on this slope (R2 =0.095) is not significant
and the measured differences (less than 0.001m on the product
formed) are within the experimental error. See the Supporting Informa-
tion for details.
[17] For our preliminary report on this Michael addition, see: a) M. M. San-
chez Duque, O. Baslꢁ, N. Isambert, A. Gaudel-Siri, Y. Genisson, J.-C. Pla-
quevent, J. Rodriguez, T. Constantieux, Org. Lett. 2011, 13, 3296; During
our investigations involving simple b-ketoamides, some work on the ac-
tivation of more reactive b-amidoesters by chiral organocatalysts, and
its application to enantioselective cascades have also been published,
see: b) P. Jakubec, M. Helliwell, D. J. Dixon, Org. Lett. 2008, 10, 4267;
c) P. Jakubec, D. M. Cockfield, D. J. Dixon, J. Am. Chem. Soc. 2009, 131,
16632; d) G. Valero, J. Schimer, I. Cisarova, J. Vesely, A. Moyano, R. Rios,
Tetrahedron Lett. 2009, 50, 1943; e) J. Franzꢁn, A. Fisher, Angew. Chem.
Int. Ed. 2009, 48, 787; Angew. Chem. 2009, 121, 801; f) Z. Jin, X. Wang, H.
Huang, X. Liang, J. Ye, Org. Lett. 2011, 13, 564; g) Z. Jin, F. Yu, X. Wang,
H. Huang, X. Luo, X. Liang, J. Ye, Org. Biomol. Chem. 2011, 9, 1809; h) Z.
Jin, H. Huang, W. Li, X. Luo, X. Liang, J. Ye, Adv. Synth. Catal. 2011, 353,
343.
[32] Y. Zhao, D. Truhlar, Acc. Chem. Res. 2008, 41, 157.
[33] Gaussian 09, Revision A.02, M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E.
Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B. Men-
nucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P. Hratchian,
A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M. Ehara,
K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O.
Kitao, H. Nakai, T. Vreven, J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro,
M. Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, R. Ko-
bayashi, J. Normand, K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyen-
gar, J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox, J. B.
Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann,
O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin,
K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador, J. J. Dannenberg,
S. Dapprich, A. D. Daniels, ꢇ. Farkas, J. B. Foresman, J. V. Ortiz, J. Cio-
slowski, D. J. Fox, Gaussian, Inc., Wallingford CT, 2009.
[18] More recently, proline derivatives also proved to be efficient catalysts
for the activation of b-ketoamides in conjugated addition processes,
see: a) W. Zhang, J. Bah, A. Wohlfarth, J. Franzꢁn, Chem. Eur. J. 2011, 17,
13814; b) X. Wu, Q. Liu, H. Fang, J. Chen, W. Cao, G. Zhao, Chem. Eur. J.
2012, 18, 12196.
[19] The generation of all-carbon quaternary stereocentres still constitutes
a formidable challenge because of the additional steric hindrance con-
siderations. For recent reviews highlighting works based on conjugate
addition strategies to achieve this goal, see: a) S. B. Tsogoeva, Eur. J.
Org. Chem. 2007, 1701; b) A. Erkkilꢆ, I. Majander, P. M. Pihko, Chem. Rev.
2007, 107, 5416; c) P. Melchiorre, M. Marigo, A. Carlone, G. Bartoli,
Angew. Chem. Int. Ed. 2008, 47, 6138; Angew. Chem. 2008, 120, 6232;
d) C. Palomo, M. Oiarbide, R. Lopez, Chem. Soc. Rev. 2009, 38, 632.
[20] K. L. Jensen, G. Dickmeiss, H. Jiang, L. Albrecht, K. A. Jørgensen, Acc.
Chem. Res. 2012, 45, 248.
[34] I. M. Alecu, J. Zheng, Y. Zhao, D. G. Truhlar, J. Chem. Theory Comput.
2010, 6, 2872.
[35] a) S. Steinmann, C. Corminboeuf, J. Chem. Theory Comput. 2011, 7,
3567; b) S. Ilieva, D. Cheshmedzhieva, D. Tasheva, Tetrahedron 2010, 66,
5168; c) B. Cho, C.-H. Tan, M. W. Wong, Org. Biomol. Chem. 2011, 9,
4550; d) H. Yang, M. W. Wong, Org. Biomol. Chem. 2012, 10, 3229; e) Y.-
H. Lam, K. N. Houk, U. Scheffler, R. Mahrwald, J. Am. Chem. Soc. 2012,
134, 6286.
[36] J. Tomasi, B. Mennucci, R. Cammi, Chem. Rev. 2005, 105, 2999.
[37] http://cccbdb.nist.gov/vibscalejust.asp.
[38] Full theoretical calculations can be found in the Supporting Informa-
tion.
[39] a) A. Hamza, G. Schubert, T. Soos, I. Pꢃpai, J. Am. Chem. Soc. 2006, 128,
13151; b) T. Azuma, Y. Kobayashi, K. Sakata, T. Sasamori, N. Tokitoh, Y.
Takemoto, J. Org. Chem. 2014, 79, 1805–1817. For a theoretical study
on squaramide-thiourea catalysts, see also: c) B. Kꢄtai, G. Kardos, A.
Hamza, V. Farkas, I. Pꢃpai, T. Soꢄs, Chem. Eur. J. 2014, 20, 5631.
[40] a) For a similar discussion, see Scheme 1 and its related paragraph in
ref. [16]; b) For a similar erosion of enantiomeric excess upon dehydra-
tion of a six-membered hemiaminal, see: J.-P. Wan, C. C. J. Loh, F. Pan,
D. Enders, Chem. Commun. 2012, 48, 10049.
[21] All the b-ketoamides used in this study were prepared according to our
Wolff rearrangement methodology under microwaves, see: a) M. Press-
et, Y. Coquerel, J. Rodriguez, J. Org. Chem. 2009, 74, 415; b) M; Presset,
D. Mailhol, Y. Coquerel, J. Rodriguez, Synthesis 2011, 2549.
[22] The results of a detailed screening of 34 different catalysts is provided
in the Supporting Information.
[23] P. Melchiorre, Angew. Chem. Int. Ed. 2012, 51, 9748; Angew. Chem. 2012,
124, 9886.
[41] A. Pepe, M. Pamment, Y. S. Kim, S. Lee, M-J. Lee, K. Beebe, A. Filikov, L.
Neckers, J. B. Trepel, S. V. Malhotra, J. Med. Chem. 2013, 56, 8280.
[42] For selected examples of glutarimide-containing natural products, see:
a) R. G. Powell, C. R. Smith Jr., D. Weisleder, D. A. Muthard, J. Clardy, J.
Am. Chem. Soc. 1979, 101, 2784; b) T. Kagata, S. Saito, H. Shigemori, A.
Ohsaki, H. Ishiyama, T. Kubota, J. Kobayashi, J. Nat. Prod. 2006, 69, 1517;
c) L. L. Silva, A. C. Joussef, J. Nat. Prod. 2011, 74, 1531; d) G.-B. Xu, L.-M.
Li, T. Yang, G.-L. Zhang, G.-Y. Li, Org. Lett. 2012, 14, 6052.
[43] For a recent enantioselective approach from our group, see ref. [13e].
For efficient methodologies for the construction of glutarimides in the
racemic series, see: a) H. Takaya, K. Yoshida, K. Isozaki, H. Terai, S.-I. Mur-
ahashi, Angew. Chem. Int. Ed. 2003, 42, 3302; Angew. Chem. 2003, 115,
3424; b) H.-W. Chen, R.-T. Hsu, M.-Y. Chang, N.-C. Chang, Org. Lett. 2006,
8, 3033; c) J. Zhang, M. Senthilkumar, S. C. Ghosh, S. H. Hong, Angew.
Chem. Int. Ed. 2010, 49, 6391; Angew. Chem. 2010, 122, 6535.
[44] O. Trapp, V. Schurig, J. Chromatogr. A 2001, 911, 167.
[45] When using crotonaldehyde under the same conditions, only 50% con-
version was obtained, indicating a poor tolerance for a b-substitution
on the enal.
[46] All the post-functionalisation reactions depicted in Scheme 12 were
conducted from the same batch of precursor 8x, highlighting once
again the fact that these cyclic hemiaminals can be obtained with high
enantiomeric excesses but promptly epimerise slightly under acidic
conditions.
[24] a) C. L. Perrin, T. M. Dwyer, J. Rebek Jr, R. J. Duff, J. Am. Chem. Soc. 1990,
112, 3122 and references cited herein; b) T. E. Horstmann, D. J. Guerin,
S. J. Miller, Angew. Chem. Int. Ed. 2000, 39, 3635; Angew. Chem. 2000,
112, 3781; c) M. M. Vasbinder, E. R. Jarvo, S. J. Miller, Angew. Chem. Int.
Ed. 2001, 40, 2824; Angew. Chem. 2001, 113, 2906; d) C. E. Jakobsche, G.
Peris, S. J. Miller, Angew. Chem. Int. Ed. 2008, 47, 6707; Angew. Chem.
2008, 120, 6809.
[25] For a general review, see: S. J. Connon, Chem. Commun. 2008, 2499.
[26] a) B. Vakulya, S. Varga, A. Csampai, T. Soos, Org. Lett. 2005, 7, 1967; b) H.
Li, Y. Wang, L. Tang, F. Wu, X. Liu, C. Guo, B. M. Foxman, L. Deng, Angew.
Chem. Int. Ed. 2005, 44, 105; Angew. Chem. 2005, 117, 107; c) T. Okino, Y.
Hoashi, Y. Takemoto, J. Am. Chem. Soc. 2003, 125, 12672.
[27] Such an effect was also observed in our organocatalysed addition of a-
ketoamides to nitroolefins, see: O. Baslꢁ, W. Raimondi, M. M. Sanchez
Duque, D. Bonne, T. Constantieux, J. Rodriguez, Org. Lett. 2010, 12,
5246.
[28] Neither 3-penten-2-one nor cyclohexenone reacted at all in this pro-
cess.
[29] a) T. Taniguchi, K. Monde, J. Am. Chem. Soc. 2012, 134, 3695; b) T. Asai,
T. Taniguchi, T. Yamamoto, K. Monde, Y. Oshima, Org. Lett. 2013, 15,
4320.
[30] Comparison of measured and calculated IR and VCD spectra has also
been used to establish the absolute configuration of 4p. Calculations
were performed by using DFT with the B3LYP functional and the 6–
311+G (d,p) basis set. Solvent effects (CH2Cl2) were introduced by
using the polarisable continuum model IEF-PCM combined with cavities
parameters SMD. Solutions with concentrations of 0.06 molLꢀ1 (4p, 4x)
and 0.08 molLꢀ1 (4c) in CD2Cl2 were used for measurements.
Received: July 20, 2014
Revised: September 18, 2014
Published online on && &&, 0000
Chem. Eur. J. 2014, 20, 1 – 14
www.chemeurj.org
13
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
FULL PAPER
&
Organocatalysis
A. Quintard, D. Cheshmedzhieva,
M. M. Sanchez Duque, A. Gaudel-Siri,
J.-V. Naubron, Y. Gꢀnisson,
J.-C. Plaquevent, X. Bugaut, J. Rodriguez,*
T. Constantieux*
From theory to practise: The mecha-
nism of asymmetric organocatalysed
Michael addition of b-ketoamides to
enones was studied theoretically, dem-
onstrating for the first time the unique
role of the hydrogen atom of the amide
in controlling both the reactivity and
the enantioselectivity (see scheme). Ad-
ditional reactions afforded original spiro
hemiaminals, taking advantage of the
reactivity of the Michael adducts with
acrolein. Post-functionalisation led to
valuable enantioenriched glutarimides
and pyridones.
&& – &&
Origin of the Enantioselectivity in
Organocatalytic Michael Additions of
b-Ketoamides to a,b-Unsaturated
Carbonyls: A Combined Experimental,
Spectroscopic and Theoretical Study
&
&
Chem. Eur. J. 2014, 20, 1 – 14
www.chemeurj.org
14
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!