Enantioselective aza-Michael addition of imides by using an integrated strategy involving the synthesis of a family of multifunctional catalysts, usage of multiple catalysis, and rational design of experiment

Article abstract of DOI:10.1002/chem.201301493

A challenging asymmetric reaction (aza-Michael addition of imides to enones) has been optimized through an integrated approach involving the synthesis of a family of organocatalysts, multiple catalysis (usage of additives), and finally with rational explo

Full text of DOI:10.1002/chem.201301493

FULL PAPER
DOI: 10.1002/chem.201301493
Enantioselective Aza-Michael Addition of Imides by Using an Integrated
Strategy Involving the Synthesis of a Family of Multifunctional Catalysts,
Usage of Multiple Catalysis, and Rational Design of Experiment
Mattia Silvi,[a] Polyssena Renzi,[a] Deborah Rosato,[a] Cristiana Margarita,[a]
Alessio Vecchioni,[a] Ivan Bordacchini,[a] Diego Morra,[a] Alessandro Nicolosi,[a]
Riccardo Cari,[a] Fabio Sciubba,[a] Daniele M. Scarpino Schietroma,[a] and
Marco Bella*[a, b]
Abstract: A challenging asymmetric reaction (aza-Michael addition of imides to
enones) has been optimized through an integrated approach involving the synthe-
sis of a family of organocatalysts, multiple catalysis (usage of additives), and finally
with rational exploration of the chemical space by the application of the experi-
ment design.
Keywords: asymmetric catalysis
aza-Michael reaction enones
imides · synthetic methods
·
·
·
Introduction
but rather a specific example lacking an effective solution.
Our objective was to mimic the complexity of issues encoun-
tered in process chemistry, in which the goal is not to have a
transformation with broad scope, but to find the best possi-
ble solution for a specific problem.
Despite the enormous advancements in chiral non-racemic
compounds preparation,[1] effective solutions have only been
found for a fraction of the known asymmetric transforma-
tions. One of the most common approaches pursued to
study a new asymmetric reaction with a single catalyst con-
sists in the use of an “enzyme-like” bi- or multifunctional
catalyst.[2] In the last few years, another strategy, multiple or
cooperative catalysis, also gathered pace. Combinations of
non-covalently bound organocatalysts, metal catalysts, bioca-
talysts, and hybrid systems became increasingly popular to
discover new reactivity or to greatly expand the scope of
known transformations.[3]
Our aim was to develop a sound integrated methodologi-
cal approach to optimize “orphan” transformations for
which a highly performing catalytic system has not yet been
disclosed. In particular, to consider the several variables af-
fecting the outcome of a reaction mediated by using multi-
ple catalysis, a more rational approach with respect to
simply trial-and-error was required. To test the validity of
our strategy, we did not choose a known simplified model,
Results and Discussion
The subject we chose for our study, the addition of imides to
enones, is a challenging transformation. Despite the addition
reaction of aromatic heterocycles to ketones and aldehydes
proceeds in good yield, imides such as succinimide[4a] or the
“nitrogen atom synthetic equivalent” non-substituted phtha-
limide[4b,c] have only been added to unsaturated aldehydes,
by means of iminium ion activation.[4d–h] Enones are less
prone to form an iminium ion. To extend the addition of
imides to the latter compounds is not straightforward and,
to the best of our knowledge, this reaction has not yet been
reported. The issues to tackle are: 1) Reactivity: imides are
weak nucleophiles and simply cyclic enones are not activat-
ed enough. 2) Stereoselectivity: the Michael reaction of
imides is reversible and the resulting adducts are not config-
urationally stable. As expected, treating succinimide 1a with
2-cyclohexen-1-one 2a no product was isolated, with or
[a] M. Silvi,+ P. Renzi,+ D. Rosato, C. Margarita, A. Vecchioni,
I. Bordacchini, D. Morra, A. Nicolosi, R. Cari, Dr. F. Sciubba,
Dr. D. M. Scarpino Schietroma, Dr. M. Bella
without catalyst (quinine
I or other amines tested,
Scheme 1). In contrast, when the especially activated elec-
trophile 2-ethoxycarbonyl 2-cyclohexen-1-one (2b)[5] was
employed in the reaction catalyzed by quinine I, Michael
adduct 3a was obtained, albeit in a low amount. (Scheme 1)
To find the best performing catalysts, we screened structures
II–IV analyzing the crude reaction mixture by HPLC.
Department of Chemistry, “Sapienza” University of Roma
P.le Aldo Moro 5, 00185 Roma (Italy)
[b] Dr. M. Bella
Istituto di Chimica Biomolecolare del CNR
P.le Aldo Moro 5, 00185 Roma (Italy)
E-mail: Marco.Bella@uiniroma1.it
[+] These authors contributed equally to this work.
Privileged thiourea catalyst II, which since its introduction
in 2005 has been successfully employed in a vast number of
stereoselective reactions,[6] afforded moderate enantioselec-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201301493.
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al trifunctional amino acid-thio-
urea catalysts (IIIa–h)[8] per-
forming with comparable con-
version, gave higher enantiose-
lectivities (up to 77% ee em-
ploying catalysts IIIb or IIIe)
with respect to catalyst II.
We then designed our own
family of “tunable” catalysts
(IVa–i). These structures pres-
ent the key thiourea moiety
flanked by two chiral units.
Some of compounds III or IV
lacking the 3,5-bis(trifluoro-
methyl) group[9] were less
active as catalysts with respect
to structures such as II or III.
Gratifying, quinine- and cincho-
nidine-derived catalysts IVg
and IVh afforded the highest
enantioselectivity for this spe-
cific transformation (Scheme 1
and Table 1, entry 2, 83% ee
and entry 3, 85% ee for com-
pound 4a). However, the yield
of the isolated product after re-
duction was not optimal.
We then investigated the
effect of additives on the reac-
tion
enantioselectivity.
We
found that inorganic Lewis
acids (Table 1, entries 4–6) and
the organic acid camphorsul-
fonic acid [(+)-CSA][10] were
beneficial in terms of increasing
the reaction enantioselectivity.
We also tested the reaction
with different amount of the
additive (+)-CSA, (Table 1, en-
tries 7–11) and found its opti-
mal ratio with respect to cata-
lyst IVh (20 mol% catalyst
IVh,
10 mol%
(+)-CSA,
Table 1, entry 9). When we at-
tempted to determine the con-
ditions leading to the highest
reaction yield we faced a new
Scheme 1. Screening of catalysts for the asymmetric addition of succinimide 1a to enones 2a and b. The values
in brackets refer to conversion, enantiomeric excess, and reaction time for Michael adduct 3a. Negative ee
values indicate the formation of the opposite enantiomer with respect to the one shown. For absolute and rela-
tive stereochemical determination of compound 4a, see the Supporting Information.
challenge.
Longer
reaction
times lead to a higher yield of
tivity [70% enantiomeric excess (ee)]. As was anticipated,
compound 3a was both chemically and configurationally un-
stable, so to determine the yield and reaction enantioselec-
tivity, the reaction mixture obtained employing catalyst II
was treated with NaBH4 and product 4a bearing two addi-
tional stereocenters, was obtained as single isolated (major)
stereoisomer with 70% ee and in 62% yield (Table 1,
entry 1, and the Supporting Information).[7] A class of sever-
the isolated product, but because of the in situ racemization
of intermediate 3a, longer reaction times were also associat-
ed with a lower enantiomeric excess. Chemical transforma-
tions in which the enantiomeric excess of the products
changes during reaction time are not uncommon, for exam-
ple, in kinetic resolution. We foresaw that tackling this prob-
lem with a rational approach could not only have been ben-
eficial to our specific study, but could serve as a proof-of-
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Enantioselective Aza-Michael Addition
FULL PAPER
Table 1. Screening of conditions for the one-pot addition of succinimide 1a to enones
2b and in situ reduction to afford alcohol 4a (Scheme 1).
lyze were: 1) the presence or absence of the addi-
tive [PdACTHNURGTNEUNG(OAc)2] in addition to (+)-CSA, (discrete
Entry[a]
Cat.
Additive
[equiv]
3a
Conv.[b] [%]
4a
Yield[c] [%]
variable, which in mathematical terms can assume
the values 0 or 1); 2) the choice of the Cinchona al-
kaloid derived catalyst (discrete variable, quinine-
based thiourea, IVg, value 1, or cinchonidine
based-thiourea IVh, value 0); 3) the catalyst load-
ing (multilevel variable, with levels 5, 10, and
20 mol%); 3) the reaction concentration (explored
by running the reaction at the multilevels 2, 2.5 and
3 mL of solvent: solution concentration: 0.225,
0.178, and 0.148m, respectively, for 75 mg
(0.446 mmol) of substrate 2b); 4) the reaction time
(multilevel variable with levels 2, 3, 5, and 9 days).
The exhaustive exploration of the pentadimen-
sional chemical space would have required (2ꢁ2ꢁ
3ꢁ3ꢁ4)=144 experiments (full factorial design),
with a considerably investment of time and chemi-
cals. The possibility to save on these important re-
sources was of course appealing, but the main fea-
ture of this strategy is that the selected experiments
are chosen through a rational process rather than in
a random way. This approach might even require
more time with respect to a trial-and-error ap-
proach, but the most significant outcome is that
data obtained are much more reliable since they
G
ee[b] [%]
ee[b] [%]
1[d]
2[d]
3[d]
4
II
None
None
None
>95
>95
>95
70
80
82
61
59
45
26
73
83
85
88
IVg
IVh
IVg
[Pd
0.04
[Pd(OAc)2]
ACHTUNGTRENNUNG(OAc)2]
5
IVh
IVh
IVh
IVh
IVh
IVh
IVh
none
T
29
31
88
85
0.04
NiCl2
0.04
(+)-(CSA)
0.04
(+)-(CSA)
0.07
(+)-(CSA)
0.1
(+)-(CSA)
0.12
(+)-(CSA)
0.15
6
7
93
85
90
91
85
rac
–
8
90
9
74
10
11
12[e]
70
<5
None
<5
–
–
[a] Reaction run employing 2b (100 mg, 0.595 mmol) and 1a (1.5 equiv) in toluene
(4 mL), with 20 mol% catalysts IVg or IVh at À208C. Reaction time: 3 days. [b] Con-
version and ee value were determined by HPLC. [c] Isolated product yield determined
after flash chromatography. [d] Reaction time of 2 days. [e] Reaction time of 12 days.
(+)-CSA=camphorsulfonic acid.
concept to develop a standard protocol for scientists dealing
with similar issues.
are the result of a logic exploration of reaction conditions
rather than “chemical intuition”. Thanks to computer-aided
experimental design (D-optimal), the rational screening was
achieved, thus running the 19 experiments depicted in
Table 2.[13a]
We chose response surface methodology (RSM). This ex-
plores the relationships between several variables and one
or more response variables.[13b] The rationale of RSM is to
employ a sequence of designed experiments to obtain an op-
timal response. Box suggests using a second-degree polyno-
mial model. Despite this model is only an approximation, it
is easy to estimate and apply, even when little is known
about the process.[13c]
Gaining insight about the mechanism of our target reac-
tion would have been a daunting task. The two diastereotop-
ic transitions states giving rise to the different enantiomers
of product 3a in 90% ee differs at RT for less than
2 kcalmolÀ1. Molecular modeling with DFT calculations
would have required input data such as a catalyst with mo-
lecular weight of about 600 Da, two non-covalently bound
additives, and the effect of the solvent, as well as other pa-
rameters. Inevitably, the approximations required to study
this model would lead to postulated intermediates that are
scarcely reliable. Any insight gained with this approach re-
sulting in a more enantioselective or higher yielding reaction
would be most likely obtained thanks to serendipity, rather
than a logical strategy. Our target was surely to optimize
this reaction, but proceeding through a rational strategy
rather than a trial-and-error approach.
For the exploration of the chemical space, we identified
some parameters that were most likely influencing the reac-
tion outcome, but whose effect was not clear from the mon-
odimensional screening table routinely reported in the ma-
jority of works dealing with asymmetric catalysis. To select
the most significant experiments, we employed a computer-
assisted set-up of the experiment,[11] which allows a more
complete exploration of the multidimensional chemical
space. This approach is routinely exploited in process chem-
istry (DOE or design of experiment), but we are unaware of
previous systematic applications screening catalysts or con-
ditions for new asymmetric reaction, like the one described
in the present work.[12] The parameters we decided to ana-
A D-optimal design was then built considering 5 factors
(catalyst, addition of [PdACTHNUTRGNE(NUG OAc)2], catalyst amount, solvent,
and time) and the number of experiments to be performed
together with set of design points was selected hypothesizing
a non-linear effect only for three of the factors (the latter
three) and assuming a priori that specific binary interactions
could be considered as insignificant.
The best condition led to the isolated product 4a in 46%
yield with 95% ee (Table 2 entry 2). We stress the fact that
these conditions have been found not by serendipity, but
though a systematic exploration of the chemical space. This
experimental set-up is an approach to gain insight about our
specific problem. To include a statistic treatment of error it
would have been necessary to systematically include repli-
cated runs, which would have been beyond the scope of our
investigation at this stage.[14,15]
We then tested if the optimal reaction conditions found
for the synthesis of compound 4a would have also been a
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M. Bella et al.
Table 2. Design of experiment for the exploratory screening of the asymmetric addi-
tion of 1b to 2a to afford alcohol 4a.
4a in 70% ee (Table 1, entry 1). Then, the family of
catalysts IV increased this value up to 85% ee (cat-
alyst IVh, Scheme 1 and Table 1, entry 3). Finally, a
rational screening on reaction conditions through a
rational set-up of the experiment (Table 2) allowed
us to reach 95% ee (entry 2). We also confirmed
that the results found could be the starting point for
the exploration of chemical space with other imides
1b–f. Was the methodology applied in this work
necessary and appropriate, or could the same re-
sults have been just achieved by “chemical intu-
ition” and serendipity? We were indeed interested
to optimize this specific transformation, but our
long term goal was mainly to develop a logic and
effective protocol to tackle similar problems for
which no acceptable solution currently exists. The
conditions we found are not ideal for a scalable
process because of long reaction times and moder-
ate yield. However, our findings represent today
state-of-the-art to obtain densely functionalized ad-
ducts 4. These conditions have been pinpointed
Exp.[a] Catalyst[b] [Pd
G
t
ACHTUNGTRENNUNG
Yield 4a,
[days] [%][d] ee [%][e]
1
2
3
4
5
6
7
8
0
0
1
1
0
1
1
0
1
0
0
1
1
1
0
1
0
0
0
1
0
1
0
1
1
0
0
0
0
1
0
0
1
0
1
1
0
0
5
20
5
20
20
20
5
3
3
2
2
2
3
3
2
3
2.5
2
2
3
3
3
2
3
9
9
9
9
9
9
9
9
5
5
3
2
2
2
2
2
2
2
2
32
46
<5
33
20
22
11
<5
14
22
25
17
25
15
<5
28
14
12
27
87
95
–
75
85
82
84
–
82
88
86
86
90
84
–
85
85
87
90
5
9
10
20
5
5
20
5
10
11
12
13
14
15
16
17
18
19
5
20
20
10
20
2.5
2
[a] Reaction run employing 2b (75 mg, 0.446 mmol) and 1a (1.5 equiv) in toluene,
with x mol % of catalysts IVg or IVh (the value of x is indicated in column 4) at
À208C and x/2 mol % of (+)-CSA; [b] 0=cinchonidine-derived IVh; 1=quinine-de-
rived IVg; [c] 1=yes; 0=no. [d] Yield of the isolated product determined after flash
chromatography. [e] The ee value determined by HPLC using IA Chiralpack column;
see the Supporting Information for all chromatograms.
with
a
rational investigation, rather than
a
“Eureka” approach. This strategy represents, in our
opinion, the most effective and rational way to ex-
plore the chemical space in the fast growing field of
multiple catalysis, in which several variables should
good starting point for reactions employing similar sub-
strates. Given the different properties of compounds 1, a
separate optimization would have been required for each
entry of Table 3.
Table 3. Scope of the reaction of imides 1b–f with enone 2b.
Maleimide 1b was also a suitable substrate to afford prod-
uct 4a (sodium borohydride reduced the double bond
moiety to give 4a, in 41–64% yield, with 90–91% ee, en-
tries 1 and 2, Table 3). Imides bearing a cleavable function-
ality, and therefore more potentially useful as ammonia syn-
thetic equivalent, such as phthalimides 1c–e afforded the de-
sired adducts (25–56% yield, 75–85% ee, Table 3, entries 3–
7). The amide and ester functionalities of compound 4b
were cleaved to afford biologically interesting cyclic hydroxy
amino acid 5, see the Supporting Information for details.[16]
It is also worth noting that we were able to introduce
imide 1 f, which presents a moiety found in products of phar-
maceutical interest such as trazodone.[17] We are unaware if
compound 1 f has been employed in any other asymmetric
transformation. The reaction afforded compound 4e in good
yield (Table 3, entry 8, 77%); in this case we did not ob-
serve the reduction of the amide moiety, which was presum-
ably the main reason why the other compounds 4a–e were
obtained in moderate yields. The reaction enantioselectivity
observed for this reaction was high (89% ee).
Entry[a]
Imide 1
Yield
[%][b]
t
d.r.[c]
ee
A
[%][c]
1
2
3
4
5
6
7
8
1b
1b
1c
1c
1d
1e
1e
1 f
4a, 41[d]
4a, 64[d,e]
4b, 36
3
6
4
4
7
5
5
2
>20:1
>20:1
7:1
7:1
>20:1
5:1
91
90
80
82
75
82
85
89
4b, 40[e]
4c, 56[e]
4d, 30
4d, 25[e]
4e, 77
5:1
>20:1
[a] Reaction run employing 2b (100 mg, 0.595 mmol) and 1b–f
(1.5 equiv) in toluene (0.198m, 3 mL), with catalysts IVh (20 mol%) at
À208C. [b] Yield of the isolated product determined after flash chroma-
tography. [c] Diastereomeric ratio (d.r. determined by 1H NMR spectro-
scopy; ee value determined by HPLC. [d] The isolated product of this re-
action is the fully reduced compound 4a. [e] Substrate (75 mg, 0.250m)
was employed.
Conclusion
An integrated strategy involving several approaches was
pursued to obtain compound 4a with the highest enantiose-
lectivity possible. Initially, the privileged catalyst II afforded
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Enantioselective Aza-Michael Addition
FULL PAPER
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[5] a) M. Shizuka, M. L. Snapper, Angew. Chem. 2008, 120, 5127–5129;
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Experimental Section
Typical experimental procedure (optimized) for asymmetric synthesis of
cyclohexanol 4a: Succinimide 1a (66 mg, 0.666 mmol, 1.5 equiv), catalysts
IVh–g, (20 mol%, 0.2 equiv), and (+)-CSA (10 mg, 10 mol%, 0.1 equiv)
were placed in a vial with toluene (2.5 mL). The resulting suspension was
stirred and cooled at À208C and then 2-ethoxycarbonyl 2-cyclohexen-1-
one 2b (75 mg, 0.446 mmol, 1.0 equiv) was added dissolved in 0.5 mL of
toluene (cooled at À208C). After 9 days, the reaction mixture was added
to MeOH (10 mL) placed at À788C and NaBH4 (66 mg, 1.786 mmol,
4.0 equiv) was added. The reaction was stirred at À788C for 30 min , and
then warmed up within 30 min at À208C. Water (2.5 mL) and ammonium
chloride (80 mg) were then added. The resulting mixture was extracted
with ethyl acetate (3ꢁ20 mL). The combined organic layers were dried
over magnesium sulfate and the filtered solution evaporated in vacuo.
The crude material was purified by column chromatography (CH2Cl2/
ethyl acetate) to afford 55 mg (46% yield) of compound 4a with 95% ee
isolated as single stereoisomer.
2005, 4481–4483. For
a review, see: e) S. J. Connon, Chem.
Commun. 2008, 2499–2510.
[7] We also isolated about 15% of a mixture of other diastereoisomers.
For a complete discussion on yield and byproducts see the Support-
ing Information. The moderate yield of the isolated product ob-
served during the reduction of compound 3 is due to the formation
of water-soluble adducts from the partial reduction of the amide
moiety. HPLC analysis of the crude reaction mixture before reduc-
tion shown only catalysts I–IV, regents 1a and 2b (at low conver-
sion) and intermediate 3a (see the Supporting Information for chro-
matograms of Table 1). The partial reduction of phthalimides with
sodium borohydride is well-known; see, for example: Z.-I Horii, C.
Iwata, Y. Tamura, J. Org. Chem. 1961, 26, 2273–2276. To evaluate
the racemization rate, a sample prepared from of the crude mixture
of 3a (0.1 mL) obtained employing catalysts IVg and diluted in
CH2Cl2 (0.5 mL) was injected immediately after dilution (RT) and
gave 80% ee. The same sample injected after one hour standing at
RT gave 73% ee.
[8] For the use of similar trifunctional catalysts, see Q. Zhu, Y. Lu,
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Eur. J. Org. Chem. 2012, 5919–5927.
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Y. Zhou, J. Wang, H. Jiang, Z.-J. Yao, H. Liu, Adv. Synth. Catal.
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Acknowledgements
We are grateful to Dr. Federico Marini, Sapienza, University of Roma,
and Dr. Matteo Stocchero, S·IN, Vicenza, Italy, for help with the Design
of Experiment (DOE) and to Mr. Carlo Sperilli, Sapienza University of
Roma, for invaluable technical assistance. Funding from Progetto di
Ateneo, 2009–2011, Sapienza University of Roma, Ottopermillevaldese
(Chiesa Valdese Italiana), COST action ORCA 0905 are gratefully ac-
knowledged.
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Chem. Eur. J. 2013, 00, 0 – 0
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M. Bella et al.
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[14] To gain an estimated of this data reproducibility, we replicated in a
new experimental set-up the reaction to prepare 4a with the optimal
condition reported in Table 2 (entry 2, 9 day reaction time). Results
found in entry 2: compound 4a: isolated in 46% yield, with 95% ee.
Replicated run 1; 4a: 51% yield, 95% ee. Replicated run 2; 4a:
56% yield, 94% ee; see the Supporting Information for details.
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hexyl cyclic amino acids analogous to 5 have been found to exhibit
Received: April 19, 2013
Published online: && &&, 2013
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These are not the final page numbers!

Enantioselective Aza-Michael Addition
FULL PAPER
Eureka! versus rational: No “eureka!”
moment, but rather a rational step-by-
step improvement. The optimization of
a challenging reaction was achieved by
using an integrated approach involving
the synthesis of a family of organocata-
lysts, multiple catalysis, and through a
rational exploration of chemical space
with the application of the experiment
design in asymmetric catalysis (see
figure).
Asymmetric Catalysis
M. Silvi, P. Renzi, D. Rosato,
C. Margarita, A. Vecchioni,
I. Bordacchini, D. Morra, A. Nicolosi,
R. Cari, F. Sciubba,
D. M. Scarpino Schietroma,
M. Bella* ...................... &&&& — &&&&
Enantioselective Aza-Michael Addi-
tion of Imides by Using an Integrated
Strategy Involving the Synthesis of a
Family of Multifunctional Catalysts,
Usage of Multiple Catalysis, and
Rational Design of Experiment
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!