cis-4-Alkoxydialkyl- and cis-4-Alkoxydiarylprolinol Organocatalysts: High Throughput Experimentation (HTE)-Based and Design of Experiments (DoE)-Guided Development of a Highly Enantioselective aza-Michael Addition of Cyclic Imides to α,β-Unsaturated Aldehydes

Article abstract of DOI:10.1002/adsc.201700120

A diverse family (37 compounds) of cis-4-alkoxydiorganylprolinol derivatives has been prepared and evaluated in organocatalysis for the first time. The combined use of high throughput experimentation (HTE) techniques with efficient analytical methods has led to the identification of two superior catalysts for the enantioselective addition of succinimide to α,β-unsaturated aldehydes. Further optimization of the reaction conditions with design of experiments (DoE) techniques established the catalyst of choice for the considered aza-Michael reaction, the corresponding adducts (12 examples) being obtained in good yields and excellent enantioselectivities (succinimide and maleimide donors). The synthetic versatility of these Michael adducts is illustrated by a two-step sequence leading to enantiopure 1,3-amino alcohols. (Figure presented.).

Full text of DOI:10.1002/adsc.201700120

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DOI: 10.1002/adsc.201700120
Very Important Publication
cis-4-Alkoxydialkyl- and cis-4-Alkoxydiarylprolinol Organocata-
lysts: High Throughput Experimentation (HTE)-Based and
Design of Experiments (DoE)-Guided Development of a Highly
Enantioselective aza-Michael Addition of Cyclic Imides to a,b-
Unsaturated Aldehydes
Ismael Arenas,+a Alessandro Ferrali,+a Carles Rodrꢀguez-Escrich,a
Fernando Bravo,a,* and Miquel A. Pericꢁsa,b,*
a
Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology, Av. Paꢂsos
Catalans 16, 43007 Tarragona, Spain
Fax : (+34)-977-920-224; phone: (+34)-977-920-200; e-mail: fbravo@iciq.cat or mapericas@iciq.es
Departament de Quꢀmica Orgꢁnica i Inorgꢁnica, Universitat de Barcelona (UB), 08028 Barcelona, Spain
b
+
These authors contributed equally to this work.
Received: January 31, 2017; Revised: February 1, 2017; Published online: && &&, 0000
Dedicated to Professor Sergio Castillꢀn on the occasion of his 65th birthday.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201700120.
Abstract: A diverse family (37 compounds) of cis-4- the corresponding adducts (12 examples) being ob-
alkoxydiorganylprolinol derivatives has been pre- tained in good yields and excellent enantioselectivi-
pared and evaluated in organocatalysis for the first ties (succinimide and maleimide donors). The syn-
time. The combined use of high throughput experi- thetic versatility of these Michael adducts is illustrat-
mentation (HTE) techniques with efficient analytical ed by a two-step sequence leading to enantiopure
methods has led to the identification of two superior 1,3-amino alcohols.
catalysts for the enantioselective addition of succini-
mide to a,b-unsaturated aldehydes. Further optimi-
zation of the reaction conditions with design of ex- Keywords: design of experiments; diarylprolinol cat-
periments (DoE) techniques established the catalyst alysts; high throughput experimentation; organoca-
of choice for the considered aza-Michael reaction, talysis
Introduction
tion modes, including a-sulfenylation,[3] a-fluorina-
tion,[4] a-bromination and a-amination,[5] Michael,[6]
Organocatalysis has become one of the fundamental Diels–Alder,[7] epoxidation,[8] and aziridination[9] reac-
pillars in the preparation of enantioenriched com- tions, among many other examples.
pounds, as it has provided elegant methods which are
In a continuous effort to improve the level of dia-
complementary to biocatalytic and metal-catalyzed stereo- and enantioselectivity in organocatalyzed
reactions. In contrast to enzymes, organocatalysts are transformations, several modifications of the basic
ideally small, inexpensive and highly-tunable mole- pyrrolidine scaffold have been described. Regarding
cules and their use has overcome the problem of the functionalization of the quaternary carbon adja-
heavy metals that may contaminate the final products. cent to C-2, Gilmour et al. described the use of (fluo-
In the realm of organocatalysis,[1] diarylprolinols[2] are rodiphenylmethyl)pyrrolidine (Figure 1, I) in epoxida-
considered as privileged catalysts due to their out- tion and aziridination reactions, in which the fluorine
standing levels of enantiodiscrimination by steric ef- atom proved to be very efficient for controlling the
fects and high catalytic activity in a wide range of or- conformation of the catalyst along the catalytic
ganic transformations under enamine/iminium activa- cycle.[10]
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the good levels of stereocontrol that are frequently
achieved with Jørgensen–Hayashi catalysts, we con-
sidered that cis-4-substituted diorganylprolinols could
exhibit, as a result of steric repulsion caused by the
C-2 and C-4 substituents, an even more efficient
shielding of one of the pyrrolidine faces in the puta-
tive iminium/enamine intermediates, which could lead
to better enantioselectivities in the catalytic processes.
Despite these considerations, there are scarcely any
examples in the scientific literature regarding the use
of these cis-4-substituted diorganylprolinols as orga-
nocatalysts. For example, Lombardo et al. described
the synthesis of 2,4-dioxa-7-aza-3-silabibyclo[4.2.1]no-
nanes (Figure 1, III), which can be considered as con-
strained cis-4-silyloxydiarylprolinol silyl ethers, and
studied their catalytic potential in cyclopropanation,
Michael and Diels–Alder reactions. Remarkably, cata-
Figure 1. a) Selected examples of functionalized diarylproli-
nols. b) cis-4-Substituted diarylprolinols.
Another structural modification was described by lytic properties of these species were comparable and
Oriyama et al., where bulky silyloxy groups at the C- in some cases superior to those of Jørgensen–Hayashi
4 position (Figure 1, II) led to good levels of enantio- catalysts.[21] Zhao reported the use of diarylprolinols
selectivity in conjugate additions of thiols[11] and mal- such as IV in Figure 1 for the epoxidation of
onates[12] to a,b-unsaturated aldehydes. Similarly, enones[22] and Diels–Alder[23] reactions. The group of
Chen et al. described the use of these catalysts for the Zlotin prepared ionic liquids from both trans-
Diels–Alder reaction between electron-deficient b- (Figure 1, II) and cis-4-substituted (Figure 1, IV) di-
substituted 2,4-dienes and 2,4-dienals.[13] Related C-4 phenylprolinols and studied their use as organocata-
substituted diarylprolinols (Figure 1, II) were used by lysts in the addition of nitromethane to enals.[24] To
Jørgensen et al. in the enamine activation of cyclopro- the best of our knowledge, there are no further exam-
panes, yielding tetrasubstituted cyclobutanes,[14] as ples describing the use of cis-4-substituted diorganyl-
well as in the a-alkylation of aldehydes, where the ap- prolinols in organocatalysis.[25]
proach of the electrophile was conveniently directed
In order to systematically address the impact of the
by the bulky OTIPS group in this position.[15] 4-Hy- substitution pattern and to assess the potential of
droxypyrrolidine derivatives have also proven to be these scaffolds in organocatalysis, we have rationally
an excellent choice for catalyst immobilization, lead- designed a completely new set of cis-4-substituted di-
ing to functionalized materials able to mediate
ACHTUNGTRENaNUGN lkyl- or diarylprolinol derivatives (Figure 1, V), in-
aldol,[16] Mannich,[17] Michael[18] and a-amination[19] re- troducing diversity in three different positions:
actions, both in batch and in flow processes.
Nonetheless, there are still unresolved challenges (i) the diorganyl moiety; R1 =3,5-(CF3)2-C6H3, Ph or
regarding the functionalization of the pyrrolidine n-hexyl,
backbone in proline-derived catalysts. Of note, most
of the C-4 substituted analogues are synthesized start- (ii) the alkoxy group at C-4; R2 =Bn, Me, TBS or Bz,
ing from trans-4-hydroxy-l-proline and the introduc-
tion of protecting groups at the secondary alcohol is (iii) the protecting group of the diorganylcarbinol
often plagued by variable degrees of epimerization in moiety at C-2; R3 =H, TMS or TBS.
the C-2 center in the presence of strong bases.[20] To
avoid this, careful control of the reaction conditions is
required. Therefore, it would be useful to develop an Results and Discussion
efficient approach to C-4 substituted diarylprolinols
that avoids by design the possibility of erosion in the We embarked on the synthesis of these new catalysts,
optical purity of the final catalysts.
starting from the commercially available N-Boc-pro-
A salient structural feature of trans-4-substituted di- tected trans-4-hydroxy-l-proline. The synthetic proto-
arylprolinols is the simultaneous steric blocking of cols have been streamlined to give multi-gram
both the upper and the lower face of the pyrrolidine amounts of the intermediates in very high yields
ring. Considering the iminium/enamine manifold that while avoiding chromatographic purifications for most
is usually invoked for these catalysts, the face-shield- steps (see the Supporting Information for details).
ing created by these groups is of paramount impor- trans-4-Hydroxy-l-proline underwent an intramolecu-
tance, being involved in the origin of the stereoselec- lar Mitsunobu reaction in good yield (Scheme 1) to
tivity exhibited by these catalytic reactions. In spite of afford lactone 1.[26] This compound was envisaged as
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Scheme 1. Synthesis of cis-4-substituted dialkyl- and diarylprolinol catalysts.
the relay intermediate for the synthesis of the new set of catalysts to the test. This reaction was first de-
cis-4-substituted dialkyl- or diarylprolinol catalysts; scribed by Jørgensen et al.,[29] achieving good yields
thus, large amounts of this material were required. with a wide range of substrates although moderate ee
Gratifyingly, the reaction could be scaled-up to 10 g values (78%) and yields (65%) were obtained when
with complete avoidance of column chromatography crotonaldehyde was used.
purification. Moreover, X-ray analysis of a single crys-
As one can imagine, it is possible to deal with
tal confirmed the inversion of the configuration at the a large number of experiments at a relatively small-
C-4 stereocenter. Then, reaction with the correspond- scale, but several drawbacks may arise from treating
ing Grignard reagent (R1MgX) under Knochel condi- this new set of catalysts in a “conventional” approach,
tions[27] afforded the unprotected diol intermediates especially when considering that different variables
2a–c, which were further protected by standard proce- will need some optimization. The most evident diffi-
dures (see the Supporting Information for details). culty would be to handle hundreds of reactions with
Considering the possible combinations, thirty-six cata- their generated samples, as well as the time needed to
lysts were synthesized in good to excellent yields. Ad- analyze them. Unless careful design is undertaken,
ditionally, when the 3,5-bis(trifluoromethyl)phenyl de- one might end up with a considerable bottleneck
rivative (2a) was synthesized and further protected along the process of catalyst evaluation. At this stage,
employing MeI, the dimethyl-protected scaffold was we relied on high throughput experimentation
obtained as a by-product (3abd), and it was finally in- (HTE),[30] which has been proven as a powerful meth-
corporated into the set of catalysts. In order to classi- odology for carrying out rapid screenings.[31] To date,
fy the catalysts, we created a code of three letters advantages of this technique are very attractive: (i)
(xyz). The first letter (x) corresponds to the R1 group, a single researcher may run hundreds of simultaneous
the second one (y) to the protecting group of the sec- reactions per day, (ii) analysis of these reactions by
ondary alcohol (R2) and the third letter (z) corre- means of HPLC or GC takes a few hours and can be
sponds to the R3 group (Scheme 1).
automatized (generally carried out overnight), (iii)
Having established a powerful strategy to synthe- every single experiment needs a very small amount of
size the catalysts, we faced the challenge of testing reagents (around 1–4 mg per reaction), thus maximiz-
such a large number of catalysts in a selected bench- ing the number of possible reactions carried out per
mark reaction. To this end, we searched the literature mg of catalyst synthesized, (iv) it allows the research-
to identify potentially useful transformations mediat- er to discover unexpected products, by means of an
ed by a diarylprolinol derivative that were currently “accelerated serendipity”, as conceptualized by Mac-
underexploited due to unsatisfactory levels of enan- Millan.[32]
tioselectivity. During this screening, we identified the
We conveniently prepared an initial HTE screening
aza-Michael reaction[28] between a,b-unsaturated al- on a mmol scale by using the already described condi-
dehydes and imides as a proper candidate to put our tions in the seminal work of Jørgensen et al.,[29] where
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Table 1. Screening of aza-Michael reaction using cis-4-substituted dialkyl- and diarylprolinol ethers.[a]
[a]
The diorganyl moiety R1 =3,5-(CF3)2-C6H3, Ph or n-hexyl, the alkoxy group at C-4 R2 =Bn, Me, TBS or Bz, the protect-
ing group of the diorganylcarbinol moiety at C-2 R3 =H, TMS or TBS.
10 mol% of catalyst loading and 1.5 equiv. of succini- 2 equiv. of water. The results of this preliminary cata-
mide were used, together with NaOAc as a base and lyst evaluation are shown in Table 1.
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Table 2. aza-Michael reaction catalyzed by cis- and trans-4-
substituted diarylprolinols.
Several conclusions can be extracted from the
screening: (i) the use of the 3,5-bis(trifluoromethyl)-
phenyl scaffold in R1 afforded the best ee values; (ii)
a TBS protecting group in R3 enabled better ees than
TMS, probably due to its increased bulkiness and sta-
bility under reaction conditions; (iii) other things
being equal, the bulkiest OR2 group (OTBS) led to
slightly higher ee values. Overall, these results were in
agreement with our initial hypothesis, in which the
more sterically crowded catalyst could afford the
highest ee. Gratifyingly, we found that derivatives
3aac and 3acc were suitable catalysts for the iminium
activation of crotonaldehyde with excellent enantiose-
lectivities (90 and 93%, respectively), albeit in moder-
ate conversions (41 and 33%). Notably, the range of
enantiomeric excesses obtained with this family of or-
ganocatalysts (from À4 to 93% ee), which are caused
by the subtle differences in the protection pattern,
would have made it very difficult and tedious to iden-
tify suitable catalysts with a strategy different to the
employment of the powerful HTE techniques.
At this point we wondered if the cis-disposition of
substituents was exerting such a difference in the
enantioselection, so we decided to synthesize the ana-
logues of 3aac and 3acc with the trans-configuration
to validate the generality of our concept (see the Sup-
porting Information for details). We observed that
trans-substituted catalysts led to a substantial drop in
yield and ee values. The results are shown in Table 2.
These results are in agreement with our hypothesis
that the cis arrangement of substituents results in
a more effective shielding of the beta face of the pro-
linol moiety. This seems to be confirmed by the solid
state conformation shown by one of the derivatives,
3bdb, from which we were able to obtain single crys-
tals suitable for X-ray analysis (Figure 2). This sub-
strate adopts an envelope conformation of the 5-
membered ring, with the nitrogen positioned in the
upper (beta) face of the plane. As a result, the sub-
stituent at C-4 shields effectively this side of the mol-
ecule. Interestingly, the coupling constants displayed
by 3bdb are almost identical to those of the best cata-
lysts 3aac and 3acc, which indicates that these cis or-
ganocatalysts adopt the same conformation in solu-
tion (NMR and NOE effects are compiled in Section
8 in the Supporting Information).
[a]
Yield estimated by GC using 4,4-dimethylbiphenyl as in-
ternal standard.
Determined by chiral GC.
[b]
Figure 2. X-ray structure of 3bdb.
We then evaluated in depth the reaction conditions
with the most promising catalysts (3aac and 3acc).
Screening of several solvents (CH2Cl2, THF, toluene, of 4a while maintaining a high ee. While reactions at
MeOH, DCE and CHCl3) revealed that CH2Cl2 and room temperature afforded 4a in around 35–40%
CHCl3 were the most appropriate in terms of conver- yield, heating up to 408C delivered the expected
sion and enantioselectivity. Additionally, other bases product in the range of 60% yield, without any signifi-
were tested (K2CO3, DIPEA), but NaOAc and luti- cant erosion in the ee. It was observed again that cata-
dine provided higher yields. Additionally, the pres- lyst 3acc gave slightly better yields than 3aac (com-
ence or absence of water in the reaction mixture was pare entries 1 and 3, or entries 9 and 11), and all reac-
studied. The final screening (Table 3) was carried out tions carried out in CHCl3 gave rise to higher yields
at 408C for 48 h, in an attempt to increase the yield and ee values than those performed in CH2Cl2. As
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Table 3. Final screening in the aza-Michael reaction.
Table 4. Factors and their ranges studied in the DoE.
Factor
Ranges to study Central point
Temperature [8C]
Reaction time [h]
Catalyst loading [mol%]
Equiv. succinimide
Equiv. lutidine
15–35
30–66
10–20
1.1–1.9
0.1–0.5
25
48
15
1.5
0.3
0.50
Reaction concentration (M) 0.25–0.75
Entry Cat. Base
Solvent[a]
Yield[b] [%] ee[c] [%]
1
2
3
4
5
6
7
8
3aac NaOAc CH2Cl2/H2O 52
3aac NaOAc CHCl3/H2O 60
3acc NaOAc CH2Cl2/H2O 61
3acc NaOAc CHCl3/H2O 65
87
89
88
89
88
89
88
89
88
89
87
90
89
90
89
90
ware has greatly facilitated the interpretation of the
results. For all these reasons, multivariate optimiza-
tion guided by the DoE commercially available soft-
ware Design Expertꢄ v. 8.0.7.1 from StatEase. Inc.
was adopted (details of the analysis of the results of
the DoE can be found in the Supporting Informa-
tion).[33]
The addition of succinimide to crotonaldehyde cat-
alyzed by diarylprolinols can be impacted by several
reaction parameters. We concentrated in optimizing
the factors presented in Table 4, and the ranges were
selected so that the central conditions were close to
those optimized after Table 3.
3aac NaOAc CH2Cl2
3aac NaOAc CHCl3
3acc NaOAc CH2Cl2
3acc NaOAc CHCl3
56
59
61
63
9
3aac lutidine CH2Cl2/H2O 57
3aac lutidine CHCl3/H2O 64
3acc lutidine CH2Cl2/H2O 61
3acc lutidine CHCl3/H2O 66
10
11
12
13
14
15
16
3aac lutidine CH2Cl2
3aac lutidine CHCl3
3acc lutidine CH2Cl2
3acc lutidine CHCl3
62
66
66
70
The optimization focused on two responses, the iso-
lated reaction yield and the enantiomeric excess. In
total, 20 experiments were performed, which were
run at 1 mmol scale. The results of these experiments
showed high variability of the reaction yield depend-
ing on the reaction conditions, whereas the results of
enantiomeric excesses were always high. In any case,
the statistical approach of DoE allows for simultane-
[a]
[b]
[c]
Concentration of the reaction was 0.5M. When stated,
2 equiv. of water were added to the reaction mixture.
Yield estimated by GC using 4,4-dimethylbiphenyl as in-
ternal standard.
Determined by chiral GC analysis.
a summary, we chose lutidine as a base in the absence ously maximizing both responses.
of water (entry 12 vs. 16) and CHCl3 as solvent for
the reaction.
The optimized conditions (highlighted in bold in
Table 4) gave rise to 4a in 75% yield with 93% ee.
At this point, we decided to scrutinize the reaction Suitably, these conditions imply that the required
conditions in a systematic manner to further optimize amount of the synthesized catalyst 3acc and of luti-
the yield and enantioselectivity. Two general ap- dine are at the minimum in the range studied. An ad-
proaches can be followed for systematic reaction opti- ditional experiment was performed at a 2 mmol scale
mization: namely modifying one reaction condition and the yield and ee were exactly reproduced. An im-
whilst keeping the others constant (one factor at portant aspect to take into consideration when work-
a time approach, OFAT), or the multivariate ap- ing with the DoE approach is that the conclusions are
proach, which implies modifying all of them at the only suitable inside the design space studied, and it is
same time in a rational way (design of experiments, not convenient to extrapolate the trends outside these
DoE). The advantages of the latter approach are: (i) ranges. For example, seeing that higher amounts of
despite the initial load of reactions to perform, it gen- succinimide increased the reaction yield without im-
erally requires less experimentation to provide the pacting the ee, we decided to add 2.5 equiv. of succini-
conclusions; (ii) a mathematical model for the reac- mide to the reaction, keeping all other parameters at
tion conditions explored (design space) will be pro- their optimal level, but this resulted in a decrease of
vided and, if the model is adequate, it is possible to yield (52%). Remarkably, we have been able to
visualize and predict which could be the results at any obtain optimal reaction conditions with only 20 ex-
point within the design space; and (iii) interactions periments out of 64 that would have been required in
between reaction parameters (factors, in the DoE ter- a full factorial design. Furthermore, we believe that
minology), which would be overseen with the OFAT the optimized conditions (lower concentration, mini-
approach, can be detected and taken into account in mal amounts of organocatalyst and base, high temper-
the search for optimal conditions. Moreover, the ap- ature, etc.) would have been elusive on carrying out
pearance of computer-aided tools, such as DoE soft- the more traditional OFAT approach.
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With the optimal conditions in hand, we next evalu- lein did not undergo the reaction, probably because
ated the scope and limitations of 3acc as a catalyst in steric hindrance precludes the formation of the imini-
the aza-Michael reaction (Table 5). Good yields and um ion intermediate. Cinnamaldehyde could be em-
exquisite ee values were recorded when different ali- ployed in the reaction, in contrast with previous stud-
phatic enals were used under the optimized reaction ies,[29,34] affording the corresponding product 4i in
conditions (4b, 4c and 4f). Branched a,b-unsaturated modest yield but still good ee (88%). Furthermore,
aldehydes were also tolerated (4d and 4e) as well as other imides such as maleimide (4j) and tetrafluoro-
aldehydes containing non-conjugated double bonds
ACHTUNGTRENpNGNU hthalimide were also suitable for the reaction, af-
(4g) or other protected functionalities (4h). Substrates fording the products in excellent yield although the ee
bearing an a-substituent such as E-2,3-dimethylacro- value dropped substantially for 4l. In the case of
phthalimide (4k), a lower yield was obtained, proba-
Table 5. Scope of the reaction.[a]
bly due to its poor solubility in the reaction mixture.
For a catalytic, enantioselective method to be con-
sidered useful, the access to both enantiomers of the
final product must be secured at a reasonable cost.
This concept has posed some problems in the field of
organocatalysis, since various catalyst scaffolds come
directly from the chiral pool, with little or no availa-
bility of the corresponding enantiomer. Therefore,
and as a proof-of-concept, we decided to synthesize
the enantiomer of catalyst 3acc, taking advantage
from the elegant work described by La Rosa et al.,[35]
in which epimerization of the C-2 center of natural
trans-4-hydroxy-l-proline[36] was carried out in the
presence of acetic anhydride at 908C. After opening
of the lactone, followed by cleavage of the acetyl
group and TBS protection, ent-3acc (Scheme 2, a) was
obtained in good yield (see the Supporting Informa-
tion).
We believe that this synthetic protocol could be fur-
ther applied to the synthesis of the corresponding
enantiomers of the new set of cis-4-substituted di-
[a]
All reactions were carried out at 1 mmol scale; isolated
yields were obtained after FCC purification; ee values
were determined by chiral GC
Reaction time: 7 days.
[b]
Scheme 2. Synthesis of ent-3acc and ent-4a.
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ACHTUNGTRENNUNGalkyl- and diarylprolinols, since the generated lactone X-ray structures confirmed the R-configuration of the
can act as a common intermediate for them. When stereocenter at C-3, in agreement with the proposed
ent-3acc was used under optimized reaction condi- model (see Table 2) as well as by comparison with the
tions, ent-4a was obtained in good yield and excellent reported optical rotations. 1,3-Amino alcohols are
ee value, displaying the opposite value of optical rota- useful synthetic intermediates and, for example, both
tion than that measured for 4a (Scheme 2, b).
8a[37] and 8f[38] or their derivatives have been used in
The aza-Michael reaction is a useful tool to obtain the synthesis of natural products and non-natural al-
a wide range of b-amino aldehydes, which can be ma- kaloids.
nipulated conveniently to yield 1,3-amino alcohols
(Scheme 3). In the case of 4a, we found that reduction
of the aldehyde functionality with NaBH4 led to com- Conclusions
plex mixtures, probably as a result of a partial reduc-
tion of the imide moiety as well as an intramolecular In summary, we have developed an efficient synthetic
attack of the resulting alcohol to the imide. This was route towards cis-4-substituted dialkyl- and diarylpro-
suppressed by using a milder reducing agent, such as linols, which relies on a scalable Mitsunobu lactoniza-
sodium triacetoxyborohydride. In this case, 7a was ob- tion followed by ring-opening with the corresponding
tained in 62% and 7f in 90% yield. Further cleavage Grignard reagent. A library of 37 members involving
of the succinimide group by a reported protocol[29] three points of diversity has been generated and, by
gave access to enantiopure 3-amino 1-alcohols 8a and means of a rapid screening performed by HTE, we
8f. The absolute configuration of these materials was have been able to identify optimal catalysts for the
determined through the formation of the correspond- aza-Michael addition of cyclic imides to enals. Re-
ing salts with p-bromobenzoic acid. In both cases, the markably, the cis-array of substituents in the pyrroli-
dine backbone proved to be crucial for high enantio-
selectivity in the considered reactions. Thus, the high-
est values of enantioselectivity ever reported for aza-
Michael reactions between aliphatic a,b-unsaturated
aldehydes and succinimide as a nitrogen nucleophile
are achieved with the optimal catalyst 3acc. In view
of future practical applications, we have developed
a rational design of experiments (DoE) approach
which has enabled the localization of a chemical
space where yield and enantioselectivity of the aza-
Michael reactions are simultaneously maximized. Ac-
cording to these findings, cis-4-silyloxydiarylprolinols
stand as a most promising new type of organocatalysts
that further expand the potential of the Jørgensen–
Hayashi class. Applications of these species in either
homogeneous or immobilized form to other processes
involving iminium catalysis are currently under study
and will be reported in due course.
Experimental Section
General Procedure for the Conjugate Addition of
Succinimide to a,b-Unsaturated Aldehydes
Catalyst 3acc (77 mg, 0.1 mmol), succinimide (188 mg,
1.9 mmol), CHCl3 (4 mL) and 2,6-lutidine (12 mL, 0.1 mmol)
were added to a 10-mL vial equipped with a stirring bar.
The mixture was stirred at room temperature for 10 min and
then the corresponding aldehyde (1 mmol) was added in
one portion. The mixture was then stirred at 358C for 66 h.
Chloroform was evaporated under reduced pressure and the
crude reaction mixture was purified by column chromatog-
raphy on silica gel, eluting with mixtures of CH2Cl2/Et2O.
The ee was determined by GC using chiral columns. Method
Scheme 3. Synthesis of 9a and 9f.
A: b-Dex 120 column, 30ꢅ0.25 mm, 0.25 mm, T=1408C
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(hold for 40 min), then rate 208CminÀ1 to 2308C and hold
for 20 min. Method B: b-Dex 225 column, 30ꢅ0.25 mm,
0.25 mm, T=1408C (hold for 60 min), then rate 208CminÀ1
to 2308C and hold for 5 min.
(R)-3-(2,5-Dioxopyrrolidin-1-yl)octanal (4f): 1H NMR
(400 MHz, chloroform-d): d=9.69 (t, J=1.3 Hz, 1H), 4.58
(tt, J=9.3, 5.5 Hz, 1H), 3.23 (ddd, J=17.9, 9.2, 1.6 Hz, 1H),
2.84 (ddd, J=17.9, 5.2, 1.0 Hz, 1H), 2.65 (s, 4H), 1.92 (dtd,
J=13.7, 9.6, 5.2 Hz, 1H), 1.62 (ddt, J=13.6, 10.9, 5.5 Hz,
1H), 1.31–1.11 (m, 6H), 0.88–0.81 (m, 3H); 13C NMR
(100 MHz, chloroform-d): d=199.56, 177.37, 46.63, 45.42,
31.63, 31.35, 28.04, 25.97, 22.55, 14.06. The ee was deter-
mined by GC analysis, Method B (R-isomer=104.9 min, S-
isomer=109.5 min). [a]2D5: +26.3 (c=0.5, CH2Cl2); HR-MS:
m/z=248.1245, calcd. for C12H19NNaO3: 248.1257 [M+
Na]+; FT-IR (neat): n=2930, 2860, 1772, 1694, 1396, 1369,
1176 cmÀ1.
(R)-3-(2,5-Dioxopyrrolidin-1-yl)butanal (4a): 1H NMR
(500 MHz, chloroform-d): d=9.69 (t, J=1.2 Hz, 1H), 4.76–
4.49 (m, 1H), 3.24 (ddd, J=18.1, 8.5, 1.4 Hz, 1H), 2.89 (ddd,
J=18.1, 5.9, 1.0 Hz, 1H), 2.65 (s, 4H), 1.38 (d, J=7.0 Hz,
3H); 13C NMR (125 MHz, chloroform-d): d=199.36, 177.15,
46.43, 42.14, 28.09, 18.02. The ee was determined by GC
analysis, Method
A
(R-isomer=30.1 min, S-isomer=
30.9 min); [a]2D5: +4.8 (c=0.5, CH2Cl2). The spectroscopic
data of this compound are consistent with the data available
in the literature.[29]
(R)-(Z)-3-(2,5-Dioxopyrrolidin-1-yl)non-6-enal
(4g):
1H NMR (500 MHz, chloroform-d): d=9.69 (t, J=1.3 Hz,
1H), 5.42–5.33 (m, 1H), 5.24 (dtt, J=10.4, 6.9, 1.6 Hz, 1H),
4.62 (tt, J=9.2, 5.4 Hz, 1H), 3.22 (ddd, J=17.9, 9.1, 1.7 Hz,
1H), 2.85 (ddd, J=17.9, 5.3, 1.0 Hz, 1H), 2.65 (s, 4H), 2.10–
1.93 (m, 5H), 1.75–1.66 (m, 1H), 0.93 (t, J=7.6 Hz, 3H);
13C NMR (125 MHz, chloroform-d): d=199.37, 177.32,
133.03, 127.21, 46.48, 45.45, 31.54, 28.05, 24.11, 20.68, 14.34.
The ee was determined by GC analysis, Method B (R-
isomer=165.9 min, S-isomer=173.9 min). [a]2D5: +27.3 (c=
0.5, CH2Cl2). The spectroscopic data of this compound are
consistent with the data available in the literature.[29]
(R)-3-(2,5-Dioxopyrrolidin-1-yl)pentanal (4b): 1H NMR
(500 MHz, chloroform-d): d=9.70 (d, J=1.3 Hz, 1H), 4.55–
4.49 (m, 1H), 3.25 (ddt, J=17.9, 9.3, 1.2 Hz, 1H), 2.86 (ddd,
J=17.9, 5.2, 1.0 Hz, 1H), 2.67 (s, 4H), 1.93 (ddt, J=14.6,
9.1, 7.2 Hz, 1H), 1.76–1.66 (m, 1H), 0.85 (t, J=7.4 Hz, 3H);
13C NMR (125 MHz, chloroform-d): d=199.56, 177.43,
48.04, 45.12, 28.01, 24.84, 10.79. The ee was determined by
GC analysis, Method B (R-isomer=35.5 min, S-isomer=
39.5 min). [a]2D5: +17.5 (c=0.5, CH2Cl2). The spectroscopic
data of this compound are consistent with the data available
in the literature.[29]
(R)-5-[(tert-Butyldimethylsilyl)oxy]-3-(2,5-dioxopyrroli-
din-1-yl)pentanal (4h): 1H NMR (500 MHz, chloroform-d):
d=9.69 (dd, J=1.8, 1.2 Hz, 1H), 4.79 (tt, J=9.0, 5.6 Hz,
1H), 3.60 (qdd, J=10.7, 6.8, 4.9 Hz, 2H), 3.19 (ddd, J=17.7,
9.1, 1.8 Hz, 1H), 2.90 (ddd, J=17.7, 5.3, 1.1 Hz, 1H), 2.63 (s,
4H), 2.14 (dddd, J=13.9, 9.0, 6.5, 4.8 Hz, 1H), 1.89 (dddd,
J=14.1, 7.0, 5.8, 5.0 Hz, 1H), 0.87 (s, 9H), 0.01 (s, 6H);
13C NMR (125 MHz, chloroform-d): d=199.56, 177.22,
60.35, 45.50, 44.45, 34.41, 28.08, 26.00, 18.41, À5.33, À5.37.
The ee was determined by GC analysis, Method B (R-
isomer=105.6 min, S-isomer=107.7 min). [a]2D5: +19.0 (c=
0.5, CH2Cl2). The spectroscopic data of this compound are
consistent with the data available in the literature.[29]
(R)-3-(2,5-Dioxopyrrolidin-1-yl)hexanal (4c): 1H NMR
(500 MHz, chloroform-d): d=9.68 (t, J=1.3 Hz, 1H), 4.60
(tt, J=9.3, 5.5 Hz, 1H), 3.22 (ddd, J=18.0, 9.1, 1.6 Hz, 1H),
2.84 (ddd, J=18.0, 5.2, 1.1 Hz, 1H), 2.64 (s, 4H), 1.92 (dtd,
J=13.7, 9.5, 5.7 Hz, 1H), 1.59 (dddd, J=13.7, 9.8, 6.4,
5.6 Hz, 1H), 1.29–1.13 (m, 2H), 0.89 (t, J=7.3 Hz, 3H);
13C NMR (125 MHz, chloroform-d): d=199.55, 177.37,
46.33, 45.39, 33.73, 28.02, 19.53, 13.65. The ee was deter-
mined by GC analysis, Method B (R-isomer=44.2 min, S-
isomer=46.4 min). [a]D25: +17.5 (c=0.5, CH2Cl2). The spec-
troscopic data of this compound are consistent with the data
available in the literature.[29]
(S)-3-(2,5-Dioxopyrrolidin-1-yl)-4-methylpentanal
(4d):
(S)-3-(2,5-Dioxopyrrolidin-1-yl)-3-phenylpropanal
(4i):
1H NMR (500 MHz, chloroform-d): d=9.68 (dd, J=1.9,
0.9 Hz, 1H), 4.22 (td, J=10.2, 4.0 Hz, 1H), 3.33 (ddd, J=
17.8, 10.5, 1.9 Hz, 1H), 2.83 (ddd, J=17.8, 4.0, 0.9 Hz, 1H),
2.65 (s, 4H), 2.27 (dp, J=9.7, 6.7 Hz, 1H), 0.96 (d, J=
6.7 Hz, 3H), 0.80 (d, J=6.7 Hz, 3H); 13C NMR (125 MHz,
chloroform-d): d=199.88, 177.51, 52.63, 43.09, 29.60, 27.95,
19.98, 19.58. The ee was determined by GC analysis, Method
B (R-isomer=190.8 min, S-isomer=200.5 min). [a]2D5: +15.5
(c=0.5, CH2Cl2); HR-MS: m/z=220.0940, calcd. for
C10H15NNaO3: 220.0944 [M+Na]+; FT-IR (neat): n=2966,
2876, 1771, 1692, 1390, 1369, 1182 cmÀ1.
1H NMR (500 MHz, chloroform-d): d=9.74 (t, J=0.8 Hz,
1H), 7.48–7.45 (m, 2H), 7.35–7.27 (m, 4H), 5.72 (dd, J=9.9,
5.5 Hz, 1H), 3.93 (ddd, J=18.5, 9.9, 1.1 Hz, 1H), 3.26 (ddd,
J=18.6, 5.5, 0.7 Hz, 1H), 2.64 (s, 4H); 13C NMR (125 MHz,
chloroform-d): d=198.81, 177.15, 138.12, 128.93, 128.53,
128.03, 49.69, 44.42, 28.10. The ee was determined by UPC2,
using an IC column with CO2/i-PrOH=90:10, P=1500 psi,
flow=3 mLminÀ1 (R-isomer=2.4 min, S-isomer=2.6 min).
[a]2D5: À5.1 (c=0.5, CH2Cl2); HR-MS: m/z=254.0784, calcd.
for C13H13NNaO3: 254.0788 [M+Na]+; FT-IR (neat): n=
3402, 1772, 1694, 1391, 1363, 1173 cmÀ1.
(R)-3-(2,5-Dioxopyrrolidin-1-yl)-5-methylhexanal
(4e):
(R)-3-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)butanal (4j):
1H NMR (500 MHz, chloroform-d): d=9.70 (t, J=1.2 Hz,
1H), 6.64 (s, 2H), 4.78–4.61 (m, 1H), 3.18 (ddd, J=17.9, 8.4,
1.4 Hz, 1H), 2.89 (ddd, J=18.0, 6.1, 1.1 Hz, 1H), 1.39 (d, J=
6.9 Hz, 3H); 13C NMR (125 MHz, chloroform-d): d=199.26,
170.57, 134.16, 47.36, 41.41, 19.00. The ee was determined by
GC analysis, Method B (R-isomer=12.7 min, S-isomer=
13.3 min). [a]2D5: +12.6 (c=0.5, CH2Cl2); HR-MS: m/z=
190.0475, calcd. for C8H9NNaO3: 190.0475 [M+Na]+; FT-IR
(neat): n=3102, 2941, 1696, 1404, 1367, 1173, 829, 694 cmÀ1.
(R)-3-(1,3-Dioxoisoindolin-2-yl)butanal (4k): 1H NMR
(500 MHz, chloroform-d): d=9.75 (t, J=1.3 Hz, 1H), 7.82
1H NMR (500 MHz, chloroform-d): d=9.67 (t, J=1.4 Hz,
1H), 4.68 (ddt, J=10.0, 9.0, 5.0 Hz, 1H), 3.19 (ddd, J=17.8,
9.1, 1.7 Hz, 1H), 2.80 (ddd, J=17.8, 5.3, 1.1 Hz, 1H), 2.64 (s,
4H), 2.01–1.90 (m, 1H), 1.42–1.33 (m, 2H), 0.91 (d, J=
6.1 Hz, 3H), 0.87 (d, J=6.3 Hz, 3H); 13C NMR (125 MHz,
chloroform-d): d=199.56, 177.34, 45.69, 44.78, 40.46, 28.04,
25.12, 23.00, 21.93. The ee was determined by GC analysis,
Method B (R-isomer=46.4 min, S-isomer=47.9 min). [a]2D5:
+30.0 (c=0.5, CH2Cl2); HR-MS: m/z=234.1102, calcd. for
C11H17NNaO3: 234.1101 [M+Na]+; FT-IR (neat): n=2961,
2872, 1770, 1689, 1367, 1176 cmÀ1.
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(dd, J=5.4, 3.1 Hz, 2H), 7.74–7.67 (m, 2H), 4.91 (dqd, J= References
8.1, 6.9, 6.1 Hz, 1H), 3.30 (ddd, J=18.0, 8.2, 1.4 Hz, 1H),
3.01 (ddd, J=18.0, 6.2, 1.1 Hz, 1H), 1.50 (d, J=7.0 Hz, 3H);
13C NMR (125 MHz, chloroform-d): d=199.45, 168.22,
134.16, 131.97, 123.39, 47.50, 41.53, 18.99. The ee was deter-
mined by GC analysis, Method B (R-isomer=112.6 min, S-
isomer=116.2 min). [a]2D5: +3.4 (c=0.5, CH2Cl2); HR-MS:
m/z=240.0633, calcd. for C12H11NNaO3: 240.0631 [M+
Na]+; FT-IR (neat): n=3046, 2991, 2862, 1769, 1718, 1703,
1390, 1375, 1359, 1334, 1032, 719 cmÀ1.
(R)-3-(4,5,6,7-Tetrafluoro-1,3-dioxoisoindolin-2-yl)butanal
(4l): 1H NMR (500 MHz, chloroform-d): d=9.73 (t, J=
0.9 Hz, 1H), 4.84 (dqd, J=8.9, 6.9, 5.6 Hz, 1H), 3.35 (ddd,
J=18.5, 8.8, 1.1 Hz, 1H), 2.97 (ddd, J=18.5, 5.7, 0.8 Hz,
1H), 1.47 (d, J=7.0 Hz, 3H); 13C NMR (125 MHz, chloro-
form-d): d=198.82, 162.31, 145.2 (m, C-F), 143.58 (m, C-F),
113.67 (m), 46.78, 42.41, 18.79; 19F NMR (376 MHz, chloro-
form-d): d=À136.02 (q, J=9.4 Hz), À142.40 (q, J=9.4 Hz).
The ee was determined by GC analysis, Method B (R-
isomer=96.2 min, S-isomer=112.4 min). [a]2D5: +4.0 (c=0.5,
CH2Cl2); HR-MS: m/z=312.0269, calcd. for C12H7F4NNaO3:
312.0254 [M+Na]+; FT-IR (neat): n=2914, 2848, 1789,
1707, 1497, 1410, 1362, 1038, 939 cmÀ1.
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4.49 (m, 1H), 3.24 (ddd, J=18.1, 8.5, 1.4 Hz, 1H), 2.89 (ddd,
J=18.1, 5.9, 1.0 Hz, 1H), 2.65 (s, 4H), 1.38 (d, J=7.0 Hz,
3H). The ee was determined by GC analysis, Method A (R-
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CH2Cl2).
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Crystal Data
CCDC 1528369 (1), CCDC 1528367 (2a), CCDC 1528368
(3bdb) CCDC 1528365 (9a) and CCDC 1528366 (9f) contain
the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The
Cambridge
www.ccdc.cam.ac.uk/data_request/cif.
Crystallographic
Data
Centre
via
Supporting Information
Synthetic procedures, characterization data, copies of NMR
spectra, GC chromatograms, ANOVA analysis, graphics and
predictions from the DoE are presented in the Supporting
Information.
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to acknowledge the help provided by the Research Support
Unit at ICIQ, with particular mention to HTE and Dr. Xisco
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NMR units. We thank CERCA Programme/Generalitat de
Catalunya and the CELLEX foundation for financial sup-
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lence Accreditation 2014–2018 (SEV-2013–0319) and for the
Grant CTQ2015- 69136-R. AF thanks the CELLEX founda-
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Adv. Synth. Catal. 0000, 000, 0 – 0
11
ꢃ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

FULL PAPERS
12 cis-4-Alkoxydialkyl- and cis-4-Alkoxydiarylprolinol
Organocatalysts: High Throughput Experimentation
(HTE)-Based and Design of Experiments (DoE)-Guided
Development of a Highly Enantioselective aza-Michael
Addition of Cyclic Imides to a,b-Unsaturated Aldehydes
Adv. Synth. Catal. 2017, 359, 1 – 12
Ismael Arenas, Alessandro Ferrali,
Carles Rodrꢀguez-Escrich, Fernando Bravo,*
Miquel A. Pericꢁs*
Adv. Synth. Catal. 0000, 000, 0 – 0
12
ꢃ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!