Organocatalytic enantio- and diastereoselective conjugate addition to nitroolefins: When ketoamides surpass ketoesters

Article abstract of DOI:10.1002/chem.201402192

Our findings on the bifunctional squaramide-catalyzed enantioselective conjugate addition of ketoamides to nitroolefins are disclosed. It appears that simple acyclic methylene ketoamides, unlike the extensively studied ketoesters, afford the products in excellent diastereoselectivities, and maintain high yields and enantioselectivities. Moreover, competition and kinetic studies were conducted to rationalize the observed reactivity and selectivity. The high level of diastereocontrol, along with the amenability of the amide group to postfunctionalization, dramatically increase the synthetic usefulness of the transformation.

Full text of DOI:10.1002/chem.201402192

DOI: 10.1002/chem.201402192
Full Paper
&
Organocatalysis
Organocatalytic Enantio- and Diastereoselective Conjugate
Addition to Nitroolefins: When b-Ketoamides Surpass
b-Ketoesters
Haiying Du, Jean Rodriguez, Xavier Bugaut,* and Thierry Constantieux*[a]
Dedicated to Professor Max Malacria on the occasion of his 65th birthday
Abstract: Our findings on the bifunctional squaramide-cata-
lyzed enantioselective conjugate addition of b-ketoamides
to nitroolefins are disclosed. It appears that simple acyclic
methylene b-ketoamides, unlike the extensively studied b-
ketoesters, afford the products in excellent diastereoselectiv-
ities, and maintain high yields and enantioselectivities. More-
over, competition and kinetic studies were conducted to ra-
tionalize the observed reactivity and selectivity. The high
level of diastereocontrol, along with the amenability of the
amide group to postfunctionalization, dramatically increase
the synthetic usefulness of the transformation.
Introduction
The ideal enantioselective catalytic reaction consists of mixing
stoichiometric amounts of starting materials in the presence of
a low loading of a chiral non-racemic catalyst able to efficiently
control all the bond- and stereogenic center-forming events of
the process; that is, to deliver a highly functionalized product
in high yield and enantio- and diastereoselectivity. Easy access
to the substrates and catalyst, atom economy, high functional-
group tolerance, operationally simple reaction conditions, and
scalability are also important criteria.
The conjugate addition of readily available b-dicarbonyl
compounds to nitroolefins is a fully atom-economic transfor-
mation with high synthetic potential because it delivers prod-
ucts with different functionalities that can be selectively react-
ed in subsequent steps.[1] In 2003, Takemoto and co-workers
identified bifunctional thiourea–tertiary amine catalysts as effi-
cient tools to control the enantioselectivity of this reaction.[2]
Follow-up studies exemplified and broadened the scope of
this transformation,[3] and include a milestone report by the
group of Rawal, which showed that replacement of the thiour-
ea function by a squaramide as the hydrogen-bond donor unit
allows a dramatic decrease in the catalyst loading.[4] A signifi-
cant limitation of this transformation for acyclic methylene b-
ketoesters (Scheme 1a) is that despite good yields and enan-
Scheme 1. Challenges for the conjugate addition of b-dicarbonyls to nitro-
olefins (ee=enantiomeric excess).
tioselectivities, the products are obtained with low or no dia-
stereoselectivity (generally the diastereomeric ratio (d.r.) is 1:1
to 2:1),[2b,4,5] which damages the synthetic usefulness of the
process. Contrary to the abundant literature available for b-di-
ketones or b-ketoesters, only specific examples of amide-con-
taining b-dicarbonyl compounds have been studied in these
transformations.[6] Based on our interest in the use of a- and b-
ketoamides as pronucleophiles in organocatalysis,[6g,7,8] we hy-
pothesized that acyclic methylene b-ketoamides might be in-
teresting candidates to achieve highly diastereo- and enantio-
selective additions to nitroolefins (Scheme 1b).
[a] H. Du, Prof. Dr. J. Rodriguez, Dr. X. Bugaut, Prof. Dr. T. Constantieux
Aix Marseille Universitꢀ
Our working hypothesis relied on the fundamental structural
differences between b-ketoamides and b-ketoesters (Figure 1):
Centrale Marseille, CNRS
iSm2 UMR 7313, 13397, Marseille (France)
Fax: (+33)491-289-187
E-mail: xavier.bugaut@univ-amu.fr
thierry.constantieux@univ-amu.fr
1) The a position of acyclic methylene b-ketoamides is 10000
times less acidic relative to their ester counterparts.[9] Acti-
vation of b-ketoamides will therefore be more difficult.
However, this phenomenon could also prevent the epimeri-
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402192.
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Table 1. Selection of the acyclic b-ketoamide substrate.[a]
Figure 1. Comparison of the properties of b-ketoesters and b-ketoamides.
Entry Ketoamide R2, R3
Time [h] Yield [%][b] d.r.[c] ee[d] [%]
zation probably responsible for the low diastereoselectivity
observed with b-ketoesters.
1
2
3
1a
1b
1c
Ph, H
CH2Ph, H 43
OMe, Me 28
43
73
78
97
2:1 95, 69
2:1 69, 58
15:1 95
2) Amides are generally better Lewis bases than esters and ke-
tones.[10] This larger difference between the Lewis basicity
of the two carbonyl units of the substrate might assist
more differentiated interactions with the catalyst and result
in better facial selectivity of the approach in the stereo-
chemistry-determining step.
[a] A solution of 1 (2 equiv), 2a (1 equiv), and catalyst I (2 mol%) in
CH2Cl2 (0.33m) was stirred at 258C until full conversion was achieved.
[b] Isolated after silica gel column chromatography. [c] Determined by
1H NMR spectroscopy of the crude reaction mixture. [d] Determined by
HPLC on a chiral stationary phase.
3) Because the nitrogen atom can hold two additional sub-
stituents, whereas the oxygen atom can accommodate only
one, more diversified amides can be prepared, which per-
mits easier variation of the electronic and steric properties
of the substrate.
under the conditions designed by Rawal for the corresponding
reaction with b-ketoesters,[6,11] the addition to (E)-b-nitrostyrene
(2a) afforded the adduct 3a with good yield and enantioselec-
tivity but a disappointing d.r of 2:1. Results were not improved
with the corresponding N-benzyl secondary b-ketoamide 1b
(Table 1, entry 2). We then turned our attention towards Wein-
reb b-ketoamide 1c (Table 1, entry 3).[12] Although Weinreb b-
ketoamides are not yet known as pronucleophiles in such reac-
tions,[13] we hypothesized that they might be interesting candi-
dates to reach our goal because of their increased steric hin-
drance and Lewis basicity, without too much restriction of
their reactivity; indeed, the enolic positions of Weinreb amides
usually exhibit higher acidity than other amide derivatives,
which ensures easier activation by the organocatalyst. More-
over, the rich reactivity of Weinreb amides would increase the
synthetic usefulness of the transformation.[14] Pleasingly, effi-
ciency (97% yield) and enantioselectivity (95% ee) were as
high as those observed with b-ketoesters and the product 3c
was formed with an unprecedented d.r. of 15:1.
Herein, we wish to discuss our results on the use of bifunc-
tional organocatalysts to efficiently control the diastereo- and
enantioselectivity of the conjugate addition of acyclic methyl-
ene b-ketoamides to nitroolefins. Gratifyingly, we found gener-
al conditions to afford the expected Michael adducts with ex-
cellent yields and stereoselectivities. This transformation, which
involves equimolar ratios of the reactants with a low loading
of the bifunctional organocatalyst, can be easily performed on
a synthetically useful scale. The adducts can be further pro-
cessed to afford highly valuable chiral scaffolds that contain up
to three adjacent stereogenic centers with full retention of the
stereoselectivity. Additionally, we conducted competition and
kinetic experiments to determine the factors that influence the
reactivity of b-ketoamides and the stereoselectivity of their re-
action with nitroolefins.
Results and Discussion
Optimization of the reaction conditions
Organocatalytic addition of acyclic b-ketoamides to nitro-
olefins
Having selected Weinreb ketoamide 1c as the model substrate,
the optimization of the reaction conditions was carried out
with the standard 2:1 1c/2a ratio, usually used for reactions
with related 1,3-dicarbonyl compounds. First, different bifunc-
tional organocatalysts were evaluated in the present transfor-
mation (Table 2). Both catalysts II and III (Table 2, entries 2 and
3), which were prepared from hydroquinine and quinine, re-
spectively, afforded the target product 3c with yields and dia-
stereoselectivities similar to those obtained with catalyst I
(Table 2, entry 1). Pleasingly, a significant increase of the enan-
tiomeric excess from 95 to 98% ee was also observed. Con-
versely, replacement of the 3,5-bis(trifluoromethyl)benzylamine
unit in the catalyst structure by its aromatic counterpart (cata-
lysts IV and V) severely impeded the enantioselectivity and to-
tally annihilated the diastereoselectivity of the reaction
Choice of b-ketoamide substrates
The first challenge of our study was to identify acyclic methyl-
ene b-ketoamide substrates that could combine both good re-
activity and selectivity. Our former studies of the organocata-
lytic Michael addition of cyclic a-substituted b-ketoamides to
a,b-unsaturated carbonyl compounds[7d,8a,d–e] or nitroolefins[6g]
highlighted the importance of the presence of a proton on the
nitrogen atom. Its absence generally resulted in no reactivity
and the acidity of the secondary amide could be correlated
with the observed enantioselectivities.
For this reason, we began our screening with N-phenyl-sub-
stituted secondary b-ketoamide 1a (Table 1, entry 1). In the
presence of cinchonine-derived bifunctional squaramide I,
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ence of 1c. A large variety of electrophilic substrates bearing
aromatic rings substituted with both electron-donating and
electron-withdrawing groups, including sterically demanding
ortho functionalization (as in 3 f), reacted successfully; hetero-
aromatic rings participated equally well in the reaction. Prod-
ucts 3c–h were all obtained in high yields with d.r. values
greater than 10:1 and enantioselectivities in the range 90–
99% ee. Pleasingly, 3 f was crystallized and an analysis by X-ray
diffraction allowed the absolute and relative configurations of
the product to be identified as (2S,3S) [Figure 2].[16] A b-alkyl ni-
Table 2. Optimization of the reaction conditions with acyclic Weinreb
ketoamide 1c.[a]
Figure 2. Determination of absolute and relative configurations by X-ray dif-
fraction.
troolefin exhibited the same behavior as its aromatic counter-
parts and adduct 3i was also formed in a highly stereoselec-
tive manner under the standard reaction conditions. As usual
in this kind of transformation, more-substituted nitroolefins are
more challenging substrates,[17] for example, product 3j was
obtained with somewhat reduced enantioselectivity and lower
yield. However, the stereogenic center between the two car-
bonyl groups was still efficiently controlled and the mixture of
diastereomers is due to the presence of an additional stereo-
genic center a to the nitro group.
Entry
Catalyst
Yield[b] [%]
d.r.[c]
ee[d] [%]
1
2
3
4
5
6
7
8[e]
I
II
97
94
99
91
89
95
97
92
15:1
17:1
16:1
1:1
1:1
3:1
95
98
98
73, 76
83, 81
83, 67
60, 66
98
III
IV
V
VI
VII
III
1:1
18:1
The influence of the ketone substituent of the pronucleo-
phile was also investigated. Starting materials with linear alkyl
chains were accommodated and delivered products 3k and 3l
with a similar efficiency as the model substrate. Both a bulkier
ramified alkyl chain or an aromatic R1 substituent on the
ketone somewhat impeded the diastereoselectivity, but the
major diastereomers of products 3m and 3n were still ob-
tained with high enantioselectivities.
[a] A solution of 1c (2 equiv), 2a (1 equiv), and catalyst I–VII (2 mol%) in
CH2Cl2 (0.33m) was stirred at 258C until full conversion was achieved.
[b] Isolated after silica gel column chromatography. [c] Determined by
1H NMR spectroscopy of the crude reaction mixture. [d] Absolute value;
determined by HPLC on a chiral stationary phase. [e] 1c (1 equiv), reac-
tion time=14 h.
(Table 2, entries 4 and 5). In the same way, thiourea-containing
catalysts VI and VII furnished 3c in high yield with moderate
enantioselectivity, but were unable to control the diastereose-
lectivity of the process (Table 2, entries 6 and 7). Finally, we
were pleased to find that by mixing equimolar quantities of
both reactants in the presence of selected catalyst III (2 mol%),
product 3c was formed with unchanged efficiency (92% yield,
d.r.=18:1, 98% ee; Table 2, entry 8).[15] We also realized that
the reaction was faster than we had initially assumed and full
conversion was reached within 14 h at 258C.
Use of other acyclic b-ketoamides
We continued our study by investigation of less-activated acy-
clic tertiary b-ketoamides (Table 4). We were delighted to see
that they generally reacted smoothly with 2a under the stan-
dard reaction conditions. Despite an increase of the reaction
time, products 3o–r were obtained with similar yields and
enantioselectivitites to their Weinreb amide counterparts.
Pleasingly, the diastereoselectivity of the process was even im-
proved and the second diastereomer of the product was gen-
erally not observed in the crude reaction mixture. Once again,
the substrate with an aromatic ketone R1 substituent proved
to be more challenging. Under the standard reaction condi-
tions, full conversion was not reached even after 6 d and prod-
uct 3s was isolated in only 38% yield (Table 4, entry 1). Howev-
Scope and limitations of the reaction with acyclic Weinreb
b-ketoamides
With these optimized conditions in hand, the generality of the
title transformation was explored (Table 3). At first, different ni-
troolefins were exposed to the reaction conditions in the pres-
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reb b-ketoamide 3n (Table 3). In-
creasing the amount of catalyst
improved the yield but reduced
the diastereoselectivity (Table 4,
entry 2). Conversely, keeping the
catalyst loading at 2 mol% with
a three-fold excess of nitroolefin
delivered a good yield of prod-
uct and maintained a 6:1 d.r.
(Table 4, entry 3).
Table 3. Scope of the reaction between acyclic Weinreb b-ketoamides and nitroolefins.[a]
Rationalization of the reactivity
and the selectivity
Kinetic studies
Having shown that a variety of
acyclic methylene b-ketoamides
could efficiently and stereoselec-
tively be coupled with nitroole-
fins, we aimed to understand
the similarities they share with
other 1,3-dicarbonyl compounds
and also the differences in their
behavior that could account for
the diastereoselectivity of the re-
action. First, the kinetic profiles
with four different pronucleo-
[a] A solution of 1 (1 equiv), 2 (1 equiv), and catalyst III (2 mol%) in CH2Cl2 (0.33m) was stirred at 258C until full
conversion was achieved. Yields of isolated product after silica gel column chromatography. Diastereomeric
1
ratio was determined by H NMR spectroscopy of the crude reaction mixture. The ee value for the major diaste-
reomer was determined by HPLC on a chiral stationary phase. [b] The presence of diastereomers is due to epi-
merization a to the nitro group.
philes under the standard reac-
1
tion conditions were monitored by H NMR spectroscopy (Fig-
ure 3a).[18] For both the secondary b-ketoamide 1a and ethyl
acetoacetate (4), 50% conversion was reached in less than
5 min, which highlighted the exceptional reactivity of squara-
mide catalyst III. Substrate 1a seemed to be more reactive
than 4: full conversion was attained within 15 min. The use of
the more-hindered Weinreb ketoamide 1c and tertiary amide
1p resulted in significantly slower reactions (45 and 90 min, re-
spectively) to obtain a 50% conversion. However, full conver-
sion was still observed after a few hours of reaction.
Table 4. Scope of the reaction with other acyclic tertiary b-ketoamides.[a]
Intrigued by the difference in the behaviors of catalysts with
either an electron-poor benzylic or aromatic unit, the advance-
ment of the reaction in the presence of these catalysts III and
V was monitored (Figure 3b). It is commonly accepted that
both the activity and the selectivity of hydrogen-bonding orga-
nocatalysts are correlated to their acidities.[19] In the studied re-
action, III, which is less acidic than V,[19c] was not only far more
selective (d.r.=18:1, 98% ee versus d.r.=1:1, 83 and 81% ee;
see Table 2, entries 8 and 5, respectively), but also 12 times
more active. These observations are in accordance with rare re-
ports that show N-alkyl catalysts perform better than would be
expected based on their acidity.[19a,20]
Entry
Modification of the reaction
conditions[b]
Time
[d]
Yield
[%]
d.r.[c]
ee[d]
[%]
1
2
3
none
6
6
5
38[e]
68
8:1
2:1
6:1
95, 68
92, 89
95, 69
III (10 mol%), 2a (1.2 equiv)
2a (3 equiv)
75
[a] A solution of 1o–s (1 equiv), 2a (1 equiv), and catalyst III (2 mol%) in
CH2Cl2 (0.33m) was stirred at 258C until full conversion was achieved.
Yields of isolated product after silica gel column chromatography. [b] Re-
optimization of the reaction conditions to obtain product 3s. [c] Deter-
mined by 1H NMR spectroscopy of the crude reaction mixture. [d] The ee
value of the major diastereomer was determined by HPLC on a chiral sta-
tionary phase. [e] Incomplete conversion.
Origin of the diastereoselectivity
Two different hypotheses can be proposed to explain the high
diastereoselectivity of the reaction: 1) the kinetic scenario, in
which the CÀC bond-forming step is intrinsically diastereose-
lective and the remaining proton in the a position cannot be
er, the enantioselectivity remained high and the d.r. was im-
proved relative to the reaction with the corresponding Wein-
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Figure 4. Reversibility and epimerization studies.
Figure 3. Kinetic study: comparison of the different 1,3-dicarbonyl sub-
strates.
ting the free-energy relationship between log(d.r.) and the
Charton steric parameters of the ketone substituents allowed
identification of a linear relationship for aliphatic ketones 1c
and 1k–m, with an acceptable correlation factor
(Figure 5).[18,21,22] Accordingly, an increase in the steric differen-
tiation between both carbonyl groups by replacing Weinreb b-
ketoamides by bulkier tertiary amides resulted in an improve-
ment of the d.r. (Table 3 versus 4). For aromatic ketones, such
abstracted by the catalyst; 2) the thermodynamic scenario, in
which the catalyst epimerizes the final product into its more
stable diastereomer. Before the epimerization studies were per-
formed, we determined that the reaction was irreversible
under the standard reaction conditions based on the results of
crossover experiments with 3d/3e and 2d/2e (Figure 4a).[18]
Afterwards, 3c (18:1 d.r.) was exposed to unselective catalyst
VII, whereas 3c (1:1 d.r.) was placed in the presence of the
best catalyst III (Figure 4b). In both cases, no change of the
d.r. of the final product was observed, which is clearly in favor
of the kinetic scenario with a catalyst-controlled highly diaste-
reoselective CÀC bond-forming step. Conversely, the d.r. of 5
was monitored during the course of the reaction with b-ke-
toester substrate 4; we observed that the product is first
formed with moderate diastereoselectivity and unselectively
epimerizes over time (Figure 4c), as already observed by Pe-
drosa and co-workers in the corresponding thiourea-catalyzed
transformation.[5d]
When trying to identify which structural elements influence
the diastereoselectivity of the reaction with b-ketoamides, we
realized that the diastereoselectivity tended to decrease with
more bulky substrates (products 3c and 3k–n in Table 3). Plot-
Figure 5. Linear free-energy relationship between d.r. and Charton steric pa-
rameters of the ketone substituents.
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as 1n, d.r.=3:1 was obtained instead of the predicted d.r.=
15:1.[23] Of course, the aromatic group influences not only the
steric properties of the substrate but also its electronic proper-
ties. The reduced diastereoselectivity can thus be ascribed to
an epimerization of the more acidic a position, illustrated by
the sensibility of product 3s to the amount of catalyst (Table 4,
entry 2).
lectivity of the N-aryl catalysts IV–VII could be explained by
the lower flexibility of the aryl group in transition state lk-C rel-
ative to its benzyl counterpart, which results in an absence of
discrimination between both topicities.
Synthetic usefulness of the transformation
Scale-up of the reaction
Having studied the scope and limitations of the title reaction
and rationalized several aspects of the observed reactivity and
selectivity, we aimed to study its synthetic potential. First, we
needed to show that the reaction could be run on a syntheti-
cally useful scale (Scheme 2). Scale-up of the standard reaction
conditions proceeded without any difficulty.[18] Moreover,
Proposed transition state to account for the stereoselectivity
Several transition states can be envisaged to explain how bi-
functional organocatalysts are able to activate the substrates.
For thioureas, the two main models were proposed by the
groups of Takemoto and Pꢁpai.[2,24] Although the models differ
significantly in their organization, they predict the same abso-
lute configuration for the stereogenic center created during
the reaction. A similar mode of action has been anticipated for
squaramides, with the Takemoto-type model being favor-
ed.[4,6g,25] In accordance with the observed absolute and rela-
tive configurations of products 3, we propose transition state
A with like (lk) rather than unlike (ul) topicity for the stereode-
termining step (Figure 6). The nitroolefin is positioned and acti-
vated by double hydrogen bonding to the squaramide motif.
Scheme 2. Scale-up under neat reaction conditions.
2 mmol of each reactant and
only 0.5 mol% of catalyst III[26]
could be mixed without solvent
at room temperature for 3 h to
afford product 1c with a slightly
lower yield (82%) and virtually
unchanged
stereoselectivity
(d.r.=17:1, 97% ee) to obtain
more than 480 mg of highly
enantioenriched product with
only 6.4 mg of catalyst under
these neat reaction conditions.
Figure 6. Proposed transition states to explain the stereoselectivity of the reaction.
Because of the absolute configurations of the stereogenic cen-
ters of the quinine-derived catalyst III, the quinuclidine moiety
controls the facial selectivity of the nitroolefin by guiding the
approach of the b-dicarbonyl compound to its lower face. The
observed diastereoselectivity stems from the addition of the Si
face of the b-ketoamide to the Si face of the nitroolefin. We
surmise that the substituent of the ketone is placed on the
side of the catalyst, whereas the bulkier tertiary amide points
out of the catalytic pocket to minimize steric interactions. Ad-
ditional hydrogen bonding between the ammonium nitrogen
atom and the Lewis basic oxygen atom of the amide might
also help to rigidify the transition state and improve the ste-
reoselectivities. In accordance with the linear free energy/Char-
ton steric parameter relationship (Figure 5), with bulkier R1
groups there is less difference between the size of the two
substituents and transition states lk-A and ul-B are thus closer
in energy, which thereby reduces the diastereoselectivity. Ac-
cordingly, switching from Weinreb amides to other bulkier ter-
tiary amides improves the facial selectivity responsible for the
higher diastereoselectivity observed. Besides this, the non-se-
Postfunctionalization of the adducts
Products 3 possess several functional groups (ketone, Weinreb
amide, and nitro group), therefore they are interesting plat-
forms from which various chiral enantioenriched motifs of syn-
thetic interest can be accessed. First, because the main im-
provement provided by the use of acyclic methylene b-ketoa-
mides is the control of the relative configuration of the stereo-
genic center between the two carbonyl groups, the diastereo-
selective reduction of the ketone was investigated to enable
efficient access to densely functionalized stereotriads (Table 5).
Reduction of a-chiral b-dicarbonyl compounds by NaBH4 in the
presence of a Lewis acid is known to proceed with syn selectiv-
ity.[27] When 3c was treated with NaBH4 and MnBr2 in MeOH at
08C, the reaction proceeded with high diastereoselectivity
(13:1) and syn-6 was isolated in 75% yield (Table 5, entry 1). A
thorough optimization of the conditions was necessary to
favor the formation of its epimer.[18] Non-coordinating
[28]
Me4NBH4 in MeOH at À408C allowed the d.r. to reach 1:7
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unprecedented features were uncovered during this study:
1) with acyclic tertiary methylene b-ketoamides, the second
stereogenic center between the two carbonyl groups could be
forged with high diastereocontrol; 2) an excess of pronucleo-
phile is not required for the reaction to proceed with high effi-
ciency; 3) quantitative evaluation of the structural elements
that influence the selectivity will help to improve the predicta-
bility of the results in related transformations; 4) the dramatic
differences in terms of reactivity and selectivity between N-
benzyl- and N-aryl-squaramides in the studied reaction could
be quantified, which may be helpful in the selection of the
ideal catalyst when developing new transformations; 5) origi-
nal, highly enantioenriched stereotriads and functionalized a-
chiral aldehydes could be accessed by postfunctionalization of
the Michael adducts. Based on these results, our next efforts
will focus on extending the reactivity of hitherto overlooked
acyclic methylene b-ketoamides in other organocatalytic trans-
formations.
Table 5. Diastereoselective reduction of the ketone group of 3c.
Entry
Reaction conditions
Yield[a] [%] d.r. (syn/anti)[b]
1
2
NaBH4, MnBr2, MeOH, 08C, 10 min 75 (syn)
Me4NBH4, MeOH, À408C, 4 h 78 (anti)
13:1
1:7
[a] Yields of isolated major diastereomer of the product after silica gel
column chromatography. [b] Determined by 1H NMR spectroscopy of the
crude reaction mixture.
Experimental Section
General procedure for the enantioselective conjugate addi-
tion of acyclic tertiary methylene b-ketoamides to nitro-
olefins
Substituted nitroolefin 2 (0.200 mmol, 1.0 equiv) was added to a so-
lution of chiral squaramide catalyst III (2.6 mg, 4.0 mmol, 2 mol%)
and b-ketoamide 1 (0.200 mmol, 1.0 equiv) in dry CH2Cl2 (0.6 mL)
under argon. The reaction mixture was stirred at 258C until com-
plete conversion of the b-ketoamide was detected by TLC. The so-
lution was filtered through a short pad of silica gel, which was
thoroughly washed with CH2Cl2. The solvent was evaporated under
reduced pressure to obtain the crude product, which was analyzed
by NMR spectroscopy to determine the diastereomeric ratio. Purifi-
cation by flash column chromatography on silica gel provided the
pure product 3.
Scheme 3. Postfunctionalization of the Weinreb amide.
(Table 5, entry 2). After purification, anti-6 was isolated in a syn-
thetically useful 78% yield.
Because Weinreb amides can be selectively reduced to alde-
hydes,[14] the hydroxyl derivatives 6 can be viewed as potential
precursors of synthetically challenging a-chiral b-hydroxyalde-
hydes (Scheme 3). Exposure of syn-6 to LiAlH4 in THF at 08C re-
sulted, not only in reduction of the Weinreb amide to the alde-
hyde, but also in elimination of the alcohol to afford enal 7 in
68% yield as a single diastereomer, without erosion of its ee
value. Although two stereogenic centers are destroyed in the
process, this transformation is interesting because 7 is the
product of a formal Rauhut–Currier reaction between crotonal-
dehyde and b-nitrostyrene and previous attempts to prepare it
in enantioenriched form have been unsuccessful.[29] To avoid
dehydration of the fragile b-hydroxyaldehyde, the alcohol func-
tionality was protected as the tert-butyldimethylsilyl ether 8.
Pleasingly, reduction of 8 with LiAlH4 afforded the versatile
protected b-hydroxyaldehyde 9 in synthetically useful yield,
even though the formation of 7 could not be completely sup-
pressed.
Representative description of product (3c): Reaction time=14 h;
crude product was obtained with 18:1 d.r. Purification by column
chromatography (CH2Cl2/EtOAc 50:1) afforded 3c (53.3 mg,
0.184 mmol, 92% yield, 98% ee). Rf =0.57 (CH2Cl2/EtOAc 50:1; UV,
1
vanillin); [a]2D0 =À67.4 (c=0.23 in CHCl3); H NMR (400 MHz, CDCl3):
d=7.33–7.23 (m, 5H), 4.96 (dd, J=13.1, 9.2 Hz, 1H), 4.87 (dd, J=
13.1, 4.0 Hz, 1H), 4.35 (d, J=8.4 Hz, 1H), 4.28 (td, J=8.8, 4.0 Hz,
1H), 3.45 (s, 3H), 3.21 (s, 3H), 1.98 ppm (s, 3H); 13C NMR (101 MHz,
CDCl3): d=201.3 (C), 168.4 (C), 137.0 (C), 129.3 (2ꢂCH), 128.4 (CH),
128.2 (2ꢂCH), 77.5 (CH2), 61.3 (CH3), 58.9 (CH), 42.9 (CH), 32.6
(CH3), 29.5 ppm (CH3); HRMS (ESI): m/z calcd for [C14H18N2O5+H]+:
295.1288; found: 295.1289; HPLC (Chiralpak AS-H, hexane/EtOH
90:10, 258C, 1.0 mLminÀ1, l=220 nm): retention time tmajor
8.10 min, tminor =14.56 min.
=
Procedure for the preparative scale neat reaction
Conclusion
Chiral squaramide catalyst III (6.4 mg, 10.0 mmol, 0.5 mol%), 1c
(290 mg, 2.00 mmol, 1.0 equiv), and 2a (298 mg, 2.00 mmol,
1.0 equiv) were mixed without solvent under argon. After 3 h of
stirring at 258C, the reaction mixture had solidified and was ana-
lyzed by NMR spectroscopy to measure the d.r. (17:1). Purification
by column chromatography (CH2Cl2) afforded 3c (486 mg,
1.64 mmol, 82%, 97% ee). Analytical data were in accordance with
For the first time, the behavior of simple linear b-ketoamides
towards nitroolefins in the presence of bifunctional organoca-
talysts was evaluated. Similar to other b-dicarbonyl com-
pounds, they deliver the products of conjugate addition with
high yields and enantioselectivities. Additionally, interesting
Chem. Eur. J. 2014, 20, 8458 – 8466
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Acknowledgements
We thank Dr. N. Vanthuyne and M. Jean for chiral HPLC analy-
ses, Dr. M. Giorgi for X-ray diffraction analyses, and the whole
team at Spectropole (www.spectropole.fr). Dr. Cyril Bressy is ac-
knowledged for helpful discussions and proofreading of the
manuscript. Financial support from Aix Marseille Universitꢃ,
Centrale Marseille, the CNRS, the COST action CM0905 ORCA,
and the China Scholarship Council (scholarship for H.D.) is ac-
knowledged.
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Keywords: diastereoselectivity
·
enantioselectivity
·
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Received: February 14, 2014
Published online on June 4, 2014
Chem. Eur. J. 2014, 20, 8458 – 8466
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8466
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim