Bifunctional Tripeptide with a Phosphonic Acid as a Br?nsted Acid for Michael Addition: Mechanistic Insights

Article abstract of DOI:10.1002/chem.201700604

Enamine catalysis is a widespread activation mode in the field of organocatalysis and is often encountered in bifunctional organocatalysts. We previously described H-Pro-Pro-pAla-OMe as a bifunctional catalyst for Michael addition between aldehydes and ar

Full text of DOI:10.1002/chem.201700604

A Journal of
Accepted Article
Title: Bifunctional Tripeptide Including a Phosphonic Acid as Brønsted
Acid for Michael Addition: Mechanistic Insights
Authors: Margery Cortes-Clerget, Jesús Jover, Jade Dussart, Emilie
Kolodziej, Maelle Monteil, Evelyne Migianu-Griffoni, Olivier
Gager, Julia Deschamp, and Marc Lecouvey
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To be cited as: Chem. Eur. J. 10.1002/chem.201700604
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Bifunctional Tripeptide Including a Phosphonic Acid as Brønsted
Acid for Michael Addition: Mechanistic Insights
Margery Cortes-Clerget,[a] Jesús Jover,[b][c] Jade Dussart,[a] Emilie Kolodziej,[d] Maelle Monteil,[a]
Evelyne Migianu-Griffoni,[a] Olivier Gager,[a] Julia Deschamp,*[a] Marc Lecouvey*[a]
Abstract: Enamine catalysis is a widespread activation mode in the
field of organocatalysis and is often encountered in bifunctional
organocatalysts. We previously described H-Pro-Pro-pAla-OMe as a
bifunctional catalyst for Michael addition between aldehydes and
aromatic nitroalkenes. As opposite selectivities were observed
compared to its analogue H-Pro-Pro-Glu-NH2 described by
Wennemers, its activation mode was investigated through kinetic,
linear effect studies, NMR analyses and structural modifications. It
appeared that only one bifunctional catalyst was involved in the
catalytic cycle, by activating aldehyde through an (E)-enamine and
nitroalkene via an acidic interaction. A restrained tripeptide structure
was optimal in terms of distance and rigidity for better selectivities
and fast reaction rates. Transition state modeling unveiled the
particular selectivity of this phosphonopeptide.
Combining either amino-, H-bonding or Lewis base catalysis,
hydrophobic effect and in-solvent organization, they were early
introduced to mimic enzyme behavior and selectively interact
with substrates.[7] Beyond the structural peptide complexity,
Miller has recently proposed combinatorial screenings to easily
identify
novel
peptide-based
catalysts
to
promote
enantioselective processes.[8] Afterwards Wennemers has
highlighted the tripeptides H-Pro-Pro-Asp-NH2 and H-Pro-Pro-
Glu-NH2 as efficient catalysts for enantioselective aldol reaction
and Michael addition, respectively (Scheme 1).[7f,9]
Introduction
The asymmetric characteristic of living organisms has long been
a subject of interest especially in terms of stereospecificity and
stereoselectivity. Inspired by enzyme structures, organic
chemists aim at developing more efficient, selective and
sustainable catalysts. Despite the use of proline as catalyst has
been known since the 70s, organocatalysis[1] has truly emerged
as a powerful tool for asymmetric transformation since the
independent works of Barbas, Lerner, List and MacMillan in
2000.[2] Nowadays, organocatalysis via covalent[3] or non-
covalent[4] activations enables the selective formation of one or
several stereogenic centers[5] at once. Moreover these methods
have been successfully employed for the synthesis of
biologically active compounds.[6] Thanks to their multifunctional
structure, amino acids and peptides are especially efficient at
multiactivating easily accessible or natural molecules.
Scheme 1. Wennemers’ catalysts effective on aldolisation and 1,4-addition
reactions
Additionally, the same team showed that multiple modes of
catalyst activation are required, where the absence of either the
N-terminal secondary amine, or the carboxylic acid inhibited the
reaction. They also provided evidence for an enamine rather
than an enol mechanism by ESI-MS investigations.[10]
Our group have recently reported the first example of H-Pro-Pro-
pAla-OMe[11] combining both aminocatalysis and phosphonic
acid-activation for the diastereo- and enantioselective conjugate
addition of aldehydes onto nitroalkenes.[12] We developed a
straightforward synthesis of the modified amino-acids and their
corresponding tripeptides by varying the absolute configuration
of the three stereogenic centers and the lateral chain length of
the amino-acid bearing the phosphonic acid moiety (Figure 1).
[a]
Dr. M. Cortes-Clerget, Dr. O. Gager, Dr. M. Monteil, Dr. E. Migianu-
Griffoni, J. Dussart, Dr. J. Deschamp and Prof. M. Lecouvey
Université Paris 13, Sorbonne Paris Cité – Laboratoire CSPBAT –
CNRS UMR 7244, 1 Rue de Chablis, 93000 Bobigny - France
E-mail: marc.lecouvey@univ-paris13.fr
E-mail: julia.deschamp@univ-paris13.fr
[b]
[c]
[d]
Dr. J. Jover, Institute of Chemical Research of Catalonia (ICIQ), The
Barcelona Institute of Science and Technology, Avgda. Països
Catalans, 16, 43007 Tarragona, Spain
Departament de Química Inorgànica i Orgànica, Secció de Química
Inorgànica, Universitat de Barcelona, Martí i Franquès 1-11, 08028
Barcelona, Spain
Figure 1. Novel bifunctional catalysts including a phosphonic acid moiety
E. Kolodziej, Université Paris Sud, ICMMO, UMR 8182,
15 Rue Georges Clemenceau 91405 Orsay Cedex
Our preliminary studies focused on a Michael addition as a
Supporting information for this article is given via a link at the end of
the document.
model reaction between aldehydes and nitroalkenes. Among our
[13]
catalyst library, the tripeptide Ia11.5
enabled us to obtain the
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corresponding -nitroaldehydes in excellent yields and with good
to excellent stereoselectivities (up to 95:5 d.r.; 93:7 e.r.) without
any external base or side product (Scheme 2).
manner, the phosphonic acid was replaced by a phosphonate.
Even with the terminal secondary amine-free proline, catalyst Ia-
(OMe)2 was significantly poorer than Ia11.5. The reaction rate was
very slow (conversion < 10 % after 48 h) and the selectivities
dropped dramatically (syn:anti 66:34 and 32 % e.r.).
Scheme 2. Michael addition between aldehydes and aromatic nitroalkenes
catalyzed by Ia11.5
In order to propose a sustainable process, the catalyst recycling
was performed. Thanks to their high water solubility, these
catalysts were easily recovered by simple extractions and
lyophilization. Several recycling tests were achieved without any
significant loss of selectivities (10 times). Owing to the
phosphonic acid group, our tripeptides have the advantage to be
directly recyclable and thus, they do not require to be
immobilized on a solid support.
Scheme 4. Michael addition between propanal and trans--nitrostyrene
catalyzed by tripeptides Boc-Ia or Ia-(OMe)2
In view of these results, we conclude that both the secondary
amine and the phosphonic acid groups are essential to keep
good reactivity, diastereo- and enantioselectivities.
After that, 15 diastereoisomers of Ia were prepared to
investigate the variations on both catalyst configurations and
side chain length holding the phosphonic acid group.[14] The
catalysts were screened in the presence of propanal and trans-
-nitrostyrene under the optimized conditions (Figure 2). The
reactivity of the catalysts was excellent as total conversion was
achieved within less than 6 hours for all the evaluated
diastereoisomers. The selectivities varied accordingly to the
catalytic pocket geometry. Changing the terminal proline
absolute configuration can significantly reduce the enantiomeric
(e.g. IId  IIa – row 2) and the diastereoisomeric ratios (e.g. Id
 Ic – row 1). Moreover, opposite absolute configurations were
obtained for product 1 (Figure 2 – red and green).
In our former work, the dependence of various parameters such
as catalyst loading and protonated-state catalyst were
thoroughly explored. Surprisingly, for
a
given spatial
configuration catalyst, we obtained the opposite products when
compared to Wennemers’ catalyst (Scheme 3).
Increasing the side chain length (Figure 2 – columns) extended
the time to completion and reduced the diastereoisomeric ratios
indicating that higher flexibility implies lower selectivities. All
these results showed the specific H-R-Pro-S-Pro-R-pAla-OMe
structure was crucial for a good selectivity but also for a fast
reaction in an intramolecular way. In our former works, we also
noted the importance of the protonated-state of the catalyst as
better selectivities were observed when the tripeptide catalyst
was pre-adjusted at pH = 11.5.
Scheme 3. Wennemers’ catalyst vs. Ia11.5: opposite selectivities
As our research focused on the impact of a phosphonic acid
compared to a carboxylic acid on both reactivity and selectivities,
we have started some mechanistic investigations to understand
our previous observations. Herein, we disclose our results in
order to highlight the potential of our novel tripeptide-catalysts.
Since the geometry of the catalytic pocket is crucial for a good
stereoselectivity, we focused our interest on studying the
importance of the central proline for selectivities (Table 1).
We started replacing the central proline by a less bulky and
more flexible amino acid like glycine, obtaining catalyst Ie that
was then evaluated in standard conditions (Table 1 – entry 2).
The diastereoselectivity dropped ((65:35 vs. 91:9 d.r.) and a
lower enantioselectivity was observed (23:77 vs. 93:7 e.r.)
although the reaction time was extended (35 h vs. 20 h). The
rigidity imposed by the proline residue seems to be crucial for an
efficient diastereo-discrimination. As expected, the opposite
enantiomer product 1 (2S,3R) was obtained as the enantiomer
catalyst Ie was used (Table 1 – entries 2 vs. 1).
Results & Discussion
The first experiment was intended to elucidate which functional
groups were required for asymmetric catalysis (Scheme 4). The
reaction was carried out between propanal and trans--
nitrostyrene in presence of the N-Boc-protected tripeptide Boc-
Ia in the optimized conditions that we previously reported.[12] The
ionization state of the phosphonic salt was pre-adjusted to pH =
7.5 with a sodium hydroxide solution during the catalyst
preparation. As expected, no reaction occurred, demonstrating
that the amine group is essential for activation. In the same
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Figure 2. Influence of catalyst I-IV absolute configurations and lateral chain lengths on 1,4-conjugated addition of propanal onto trans--nitrostyrene
After that, the central proline was suppressed and dipeptides If
and Ig were tested but, no total conversion was reached after a
week (Table 1 - entries 3 and 4). As predicted by Wennemers,[9a]
the catalytic pocket of these compound might be too small for a
-position attack and consequently an intermolecular reaction
probably occurred with a drop of selectivities. However, it was
noted that better selectivities were obtained in presence of Ig
rather than If. The link between the two activating functions was
then suppressed in order to investigate the synergic catalysis; it
was done by replacing the tripeptide by amino-acid “cocktails”. It
was firstly noted that modified amino acid AA1 alone gave less
than 1 % conversion after 5 days (Table 1 – entry 5). The
primary amine appears not to be nucleophilic enough to form an
enamine with propanal. Proline alone allowed the formation of
the -nitroaldehyde 1 after a long reaction time with a low
enantioselectivity (Table 2 – entry 6). A mixture of proline and
amino acid AA1, named cocktail A (1:1) and a mixture of H-Pro-
OMe and N-Boc-protected AA1, called cocktail B (1:1) were
evaluated under the optimized conditions (Table 1 – entries 7
and 8). We observed that the reaction rates were 6 times slower
for both mixtures. The diastereoisomeric ratio slightly decreased
for cocktail A while remained the same for cocktail B. In both
cases, the enantiomeric ratios were lower compared to those
obtained with Ia11.5. Although these two cocktails have the same
absolute configurations, interestingly, the opposite products
were obtained. We suppose that this discrepancy arises from
the difference between the transition states leading to the
formation of the corresponding products (Figure 3).
Table 1. Influence of the catalyst structure.
Entry
Catalyst
t [h][a]
syn:anti [b]
e.r.[c]
Abs. conf.[d]
1
2
3
4
5
6
7
8
Ia11.5
Ie
20
35
91:9
65:35
70:30
85:15
-
93:7
23:77
38:62
28:72
-
2R,3S
2S,3R
2S,3R
2S,3R
-
If
(64)[e]
(76)[e]
n.d.[f]
216
Ig
AA1
proline[g]
cocktail A
cocktail B
93:7
87:13
91:9
41:59
38:62
70:30
2S,3R
2S,3R
2R,3S
120
120
[a] Time to completion, estimated by GC analysis. [b] Determined by 1H
NMR spectroscopy on the crude material. [c] e.r. of the syn-adduct were
determined by chiral-HPLC analysis. [d] Compared to optical rotation given
in literature. [e] Expressed in conversion rate after a week. [f] Less than 1%
of conversion after a week. [g] The reaction was conducted at pH = 11.5
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In the case of cocktail A, an electrostatic interaction allows the
self-assembly of the amino-acids while for cocktail B the steric
bulkiness of the dangling tert-butyl group pulls away the two
partners. The same enantioselectivity was obtained with
cocktail A and catalyst If but the diastereoisomeric ratio is
higher for the former (Table 1 – entries 3 vs 7). Cocktail B and
catalyst Ia11.5 gave the same diastereoselectivity albeit a lower
enantiomeric ratio was obtained with cocktail B (Table 1 –
entries 1 vs 8).
and 10 mol% of Ia at pH = 6.6 or 11.5. The partial order with
regard to the catalyst was respectively 0.8 and 0.9 at pH = 6.6
and 11.5.[16] Both these values are close to 1, indicating that the
rate of the reaction increases linearly with the catalyst loading.
Although Kagan and Agami had observed a slight non-linear
effect on the proline-catalyzed Hajos-Parrish reaction.[17] List[18]
contradicted these results by providing evidences for the
involvement of only one pyrrolidine in the transition state of intra-
and intermolecular aldol reaction.[19] To verify the linear
relationship between the enantiomeric excess of the catalyst and
the product, the reaction above was catalyzed by a mixture of Ia
and its enantiomer in several ratios at 0 or 25 °C, with catalyst
loadings of 1 or 10 mol% and pre-adjusted pH values of 6.6 or
11.5.
A
linear effect was observed regardless of the
experimental conditions.[20] Both kinetic studies and non-linear
effect experiments provide proofs that only one molecule of
catalyst was involved in the catalytic process.
Figure 3. Postulated transition states involving cocktail A and cocktail B
NMR experiments were performed to possibly identify some
iminium/enamine intermediates. The catalyst Ia was mixed with
an excess of propanal in a mixture of chloroform-d: methanol-d4
(1:1). The signal of propanal (9.44 ppm) decreased and two new
signals were detected at 6.26 ppm and 9.04 ppm which could
correspond to enamine and iminium intermediates (Figure 4).[21]
After studying the importance of the catalyst structure, we
decided to explore the catalyst activation mode. According to the
literature,[15] the postulated mechanism should involve the
formation of an E-enamine between the secondary amine group
and the aldehyde (Scheme 5). Then, the nitroalkene activation
through an acidic interaction should increase the electrophilicity
of the -carbon and allow the enamine attack. Thanks to the
geometry of the catalytic pocket, the C-C bond could be created
in
a
stereoselective way. The final hydrolysis should
concomitantly permit the liberation of the expected
-nitroaldehyde and regenerate the active catalyst.
Figure 4. Identification of iminium and (E)-enamine by 1H (in black) and 13C
NMR (in blue)
2D NMR studies were conducted to confirm the nature of the
new products. COSY experiment highlighted the scalar
correlation between the enamine proton (3) (6.26 ppm) and the
CH3 group (1) (1.42 ppm).
Scheme 5. Postulated catalytic cycle for the Ia11.5-catalyzed 1,4-addition
reaction
In order to validate the involvement of only one molecule of
catalyst, kinetic studies and non-linear effect experiments were
conducted in presence of catalyst Ia. The 1,4-addition between
propanal and trans--nitrostyrene was catalyzed at 1, 2.5, 5, 7.5
Figure 5. Enamine/iminium formation followed by 1H NMR
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The protonated-state of the catalyst is strongly correlated with
the partial orders of the aldehyde while its effect is limited on the
nitroalkene partial order. Regardless of the pH pre-adjusted
catalysts, enamine formation seems not to be the rate-limiting
step. These kinetic studies corroborate our initial experimental
observations about the postulated enamine formation.
Table 2. Influence of the pH and counter-cation nature in catalysis
Nevertheless, several questions remain concerning the influence
of the peptide protonated-state on the catalytic process. We
supposed that nitroalkene is activated by the phosphonic acid
through an acidic interaction.
However, Ishihara showed that the calcium salt of the BINOL-
phosphoric acid was as effective as the acidic form itself.[23] In
order to identify the real activation mode of our tripeptide Ia, we
studied the influence of its protonated-state (Table 2). The
d.r. [b]
syn:anti
Entry
1
Cat*
t [h][a]
e.r.[c]
24
89:11
89:11
reaction still occurred with the all-deprotonated catalyst Ia11.5
,
while no reaction was observed in presence of Ia2.3 (Table 2 –
entries 2 and 3). Moreover, Ia11.5 was surprisingly a more
reactive and selective catalyst than Ia6.6 and the reaction was
completed after only 20 h. Nevertheless, when the reaction was
conducted between propanal and trans--nitrostyrene in
presence of Ia11.5, the pH was monitored during the reaction. A
drop of pH from 11.5 to 6.6 was early observed, which seems to
confirm the presence of the acidic species. We tested the same
reaction in presence of Ia11.5 and 2 equivalents of triethylamine
in order to keep the pH value around 8-9 (Table 2 – entry 4).
Here, the reaction rate dramatically dropped and slightly lower
selectivities were obtained. This observation provides the
evidence that an acidic hydrogen on the phosphonic acid should
be responsible for the nitroalkene activation, through a hydrogen
bonding or ion-pairing.
2
-
-
-
3
4
5
20
168
20
91:9
90:10
92:8
93:7
90:10
92:8
[d]
Ia11.5
6
192
94:6
94:6
To confirm the previous observations, the nature of the counter-
cation was investigated by replacing the sodium salt by its
lithium or calcium analogues (Table 2). The lithium salt Ia’11.5
gave the same results whereas the calcium salt Ia”11.5 showed
poor reactivity (20 h vs. 192 h). It is not surprising that lithium
which is quite similar to sodium, does not modify the catalytic
pocket. On the other hand, calcium is bigger and divalent and
probably disrupts the peptide conformation.
Based on our experiments, we propose the revised catalytic
cycles in order to include the pH effect (Scheme 6). By
comparing the initial rate for each protonated-state, it appears
the reaction starts faster in the presence of Ia11.5 rather than Ia6.6
(Figure 6).
[a] Time to completion, estimated by GC analysis. [b] Determined by 1H
NMR spectroscopy of the crude material. [c] The e.r. of the syn-adduct
were determined by chiral-phase HPLC analysis. [d] The reaction was
carried out in presence of 2 equiv. of trimethylamine.
Moreover, NOESY showed a dipolar correlation with the -
proton (4) of the pyrrolidine (3.25 ppm) (Figure 4). These
observations confirm the formation of an enamine with an E-
configuration in agreement with the results reported by
Blackmond, who observed an enamine proton at 6.1 ppm.[22] The
addition of pre-activated molecular sieves in the NMR tube
induced an increasing 6.26 ppm enamine signal at 9.44 ppm
propanal signal expense. This observation seems to confirm the
existing equilibrium at this step.
The reaction between propanal and trans--nitrostyrene was
then carried out in presence of Ia and monitored by 1H NMR
(Figure 5). Enamine intermediate appeared at the first scan at
6.26 ppm. This signal rapidly decreased in favor of the formation
of a novel signal which could correspond to a second iminium
compound (9.2 ppm).
Thereafter, kinetic studies were performed to determine the
reaction partial orders with regard to the aldehyde and the
nitroalkene in presence of Ia, initially pre-adjusted at pH = 6.6
and 11.5.[13] The partial order of propanal is 0.4 in presence of
catalyst Ia6.6 and drops to 0.1 for catalyst Ia11.5. Concerning
trans--nitrostyrene, the partial order is 0.3 in presence of
Figure 6. Comparison of initial rates depending on the catalyst protonated-
state
catalyst Ia6.6 and 0.2 for catalyst Ia11.5
.
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Scheme 6. Revised catalytic cycle
The catalyst Ia11.5 already has the reactive amine on the terminal
proline that could readily enable the formation of the iminium
and then, enamine intermediates with propanal.
At this stage, the catalyst could be protonated allowing the
nitroalkene H-bonding activation. The second iminium formation
in presence of water could concomitantly release the expected
-nitroaldehyde and regenerate the catalyst Ia6.6 that permits the
catalytic process to proceed.
Thereafter, the reaction was performed in presence of activated
molecular sieves. The achieved conversion was never higher
than 10 %. Besides, the 1,4-addition was carried out between
propanal and trans--nitrostyrene in presence of Ia11.5 and water,
and no conversion was obtained. These results confirmed the
harmful effect of water excess in the catalytic cycle, notably for
the enamine formation. However the released water during the
enamine formation is essential because it allows the second
iminium hydrolysis. These observations support the formation of
all the iminium/enamine intermediates.
experimentally. Figure 7 shows the transition states leading to
these products and includes some selected bond distances.
The C–C bond distances in these transition states are quite
long: 2.41 and 2.24 Å for the syn- and anti-species respectively,
indicating the early character of these structures. As may be
observed, the presence of the sodium cation actively
participates in the reaction by binding the nitro group of the
substrate, the Na–Onitro distances are always shorter than
2.5 Å. As predicted in our experiments, the binding between
trans--nitrostyrene and the peptide is reinforced by the
hydrogen bond interaction established between the nitro and
phosphoric groups, which show very short distances in both
cases (ca. 1.85 Å).
The alternative syn (2S, 3R) and anti (2S, 3S) products are
obtained in a much lower extent because they require the
formation of a starting (Z)-enamine between Ia and propanal.
This process is highly unlikely since this latter species is almost
10 kcal/mol higher than its (E)-counterpart.
Density functional theory (DFT) theoretical studies have been
carried out in order to explain the observed enantioselectivity
with peptide Ia.[20] The four transition states determining the final
stereochemistry of the product i.e. syn (2R, 3S), anti (2R, 3R),
syn (2S, 3R) and anti (2S, 3S), in the reaction between propanal
and trans--nitrostyrene with peptide Ia6.6 were computed. Their
relative free energy barriers for the (E)-enamine attack onto
trans--nitrostyrene are 4.5, 4.9, 9.4 and 10.8 kcal/mol for the
above products, respectively (Scheme 7).
These results clearly indicate that product syn (2R, 3S) is the
most favored reaction outcome, in a perfect agreement with our
NMR experiments. The free energy difference between the syn
(2R, 3S) and anti (2R, 3R) diastereoisomers also agrees with
the experimentally observed proportions, a difference of 0.4
Figure 7. Transition states leading to the major products (distances in Å, color
code: C = gray, N = blue, O = red, P = tan, Na = pink, H = white; for clarity
most H-atoms have been omitted)
kcal/mol at room temperature should roughly produce
a
selectivity ratio of 70:30, not very far of that observed
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Scheme 7. Computed free energy profiles (kcal/mol) for the reaction of trans--nitrostyrene with the propanal (E)-enamine of peptide Ia6.6 leading to the syn (2R,
3S) and anti (2R, 3R) products
The free energy profiles describing the reaction of trans--
nitrostyrene with the propanal (E)-enamine of peptide Ia6.6 are
shown in Scheme 7. As expected, the barrier for the formation of
the syn (2R, 3S) product remains lower than that for the
obtention of the anti analogue: 12.4 and 16.9 kcal/mol,
respectively. These calculations show also that the highest free
energy barriers of the reaction are not those determining the
final product configuration but the ones corresponding to the
protonation after the new C–C bond formation.
The experimental and computed studies enable us to propose
the following transition state in which the phosphonic acid
activations lead to the formation of the opposite enantiomers
compared to those obtained by Wennemers (Figure 8). The
opposite selectivity could be explained by the different nature of
the phosphonic acid moiety in terms of size and geometry. The
nitroalkene is indeed oriented inside the catalytic pocket and is
both activated by the acidic proton of the phosphonic acid group
and its sodium countercation.
The computed barriers are, however, too low to account for the
observed reaction rate. This is probably due to a different
reaction stage e.g. the (E)-enamine formation or the final
product release. Indeed, the latter is not directly related to the
enantioselection process and has a higher free energy barrier in
the overall reaction pathway.
Conclusions
This study shows that peptide H-R-Pro-S-Pro-R-pAla-OMe Ia11.5
is a catalyst with multifunctional activations. Covalent activation
of carbonyl compounds through secondary amine and non-
covalent activation by the phosphonic acid moiety allowed the
1,4-addition between aldehydes and nitroalkenes. NMR and
modelisation studies confirmed the (E)-enamine formation while
the presence of an acidic proton on the phosphonic acid seems
to be crucial for the nitroalkene activation. The distance and the
rigidity between both activating sites are also decisive for a good
selectivity while replacing the central proline with a more flexible
amino acid reduces the selectivities. Finally, the replacement of
the carboxylic acid (a glutamic acid in Wennemer’s catalyst) by a
phosphonic acid has truly a striking impact in the reaction
outcome, producing products with opposite configurations.
These two groups have a strong influence in the transition state
determining the final products, probably because the nitroalkene
orientation is different in both catalytic pockets that differ in
terms of nature and size.
Figure 8. Postulated transition states leading to the two enantiomers
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8779; h) H. Pellissier, Chem. Rev. 2013, 113, 442-524. i) K. S. Halskov,
B. S. Donslund, S. Barfusser, K. A. Jorgensen, Angew. Chem., Int. Ed.
2014, 53, 4137-4141.
Experimental Section
General Procedure for the Asymmetric Michael Reaction
[6]
For selected examples of bioactive molecule syntheses by
organocatalysis, see: a) R. Marcia de Figueiredo, M. Christmann, Eur. J.
Org. Chem. 2007, 2575–2600; b) E. Marqués-López, R. P. Herrera, M.
Christmann, Nat. Prod. Rep. 2010, 27, 1138–1167; c) S. B. Jones, B.
Simmons, A. Mastracchio, D. W. C. MacMillan, Nature 2011, 475, 183–
188; d) Z. Zhang, J. C. Antilla, Angew. Chem. Int. Ed. 2012, 51, 11778–
11782; e) M. E. Abbasov, D. Romo, Nat. Prod. Rep. 2014, 31, 1318–
1327; f) J. McNulty, C. Zepeda-Velazquez, Angew. Chem., Int. Ed.
2014, 53, 8450-8454; g) Y. Hayashi, S. Ogasawara, Org. Lett. 2016,
18, 3426-3429.ꢀh) M. Candy, T. Durand, J.-M. Galano, C. Oger, Eur. J.
Org. Chem. 2016, 5813-5816.
1 mol% of catalyst was dissolved in methanol and chloroform
(1:1) (20 mL). trans--nitrostyrene (1.0 mmol, 1.0 equiv.) and
propanal (3.0 mmol, 3.0 equiv.) were added and the reaction
mixture (homogeneous solution) was stirred at 0 °C. The
reaction conversion was monitored by GC. After completion, the
reaction mixture was concentrated under vacuum and the
residue was dissolved in ethyl acetate. This solution was
washed twice with water (2 x 20 mL), dried over magnesium
sulfate and concentrated to yield the desired product.
[7]
For selected pioneer works and reviews on peptides as organocatalysts,
see: a) S. Inoue, Adv. Polym. Sci. 1976, 21, 78-106; b) J.-I. Oku, N. Ito,
S. Inoue, Makromol. Chem. 1979, 180, 1089-1091; c) E. R. Jarvo, S. J.
Miller, Tetrahedron 2002, 58, 2481-2495; d) A. Berkessel, Curr. Opin.
Chem. Biol. 2003, 7, 409-419; e) E. A. Colby Davie, S. M. Mennem, Y.
Xu, J. A. Miller, Chem. Rev. 2007, 107, 5759-5812; f) Y. Arakawa, M.
Wiesner, H. Wennemers, Adv. Synth. Catal. 2011, 353, 1201-1206; g) J.
Li, G. Yang, Y. Qin, X. Yang, Y. Cui, Tetrahedron: Asymmetry 2011, 22,
613-618; h) X. Fan, S. Sayalero, M. A. Pericàs, Adv. Synth. Catal. 2012,
354, 2971-2976; i) B. Lewandowski, H. Wennemers, Curr. Opin. Chem.
Biol. 2014, 22, 40-46; j) K. S. Feu, A. F. de la Torre, S. Silva, M. A. F.
de Moraes Junior, A. G. Corrêa, M. W. Paixão, Green Chem. 2014, 16,
3169-3174; k) C. Rodríguez-Escrich, M. A. Pericàs, Eur. J. Org. Chem.
2015, 1173-1188.
Acknowledgements
The Université Paris 13, Sorbonne Paris Cité, Centre National
de la Recherche Scientifique (CNRS) and Ministère de
l’Enseignement Supérieur et de la Recherche (MESR) are
gratefully acknowlegded for financial support.
Keywords: organocatalysis • mechanism studies • Michael
addition • DFT calculations • phosphonopeptide
[8]
a) S. J. Miller, Acc. Chem. Res. 2004, 37, 601-610; b) P. A. Jordan, K.
J. Kayser-Bricker, S. J. Miller, Proc. Natl. Acad. Sci. 2010, 107, 20620-
20624; c) P. A. Lichtor, S. J. Miller, ACS Comb. Sci. 2011, 13, 321-326;
d) D. K. Romney, S. J. Miller, Org. Lett. 2012, 14, 1138-1141; e) L.
Tuchman-Shukron, S. J. Miller, M. Portnoy, Chem. Eur. J. 2012, 18,
2290-2296; f) C. T. Mbofana, S. J. Miller, J. Am. Chem. Soc. 2014, 136,
3285-3292; g) M. E. Diener, A. J. Metrano, S. Kusano, S. J. Miller, J.
Am. Chem. Soc. 2015, 137, 12369-12377; h) C. R. Shugrue, S. J.
Miller, Angew. Chem. Int. Ed. 2015, 54, 11173-11176; i) A. J. Metrano,
N. C. Abascal, B. Q. Mercado, E. K. Paulson, S. J. Miller, Chem.
Comm. 2016, 52, 4816-4819.
[1]
[2]
D. W. MacMillan, Nature. 2008, 455, 304-308.
a) B. List, R. A. Lerner, C. F. Barbas, J. Am. Chem. Soc. 2000, 122,
2395-2396; b) K. A. Ahrendt, C. J. Borths, D. W. C. MacMillan, J. Am.
Chem. Soc. 2000, 122, 4243-4244.
[3]
For selected reviews of enamine and iminium catalysis, see: a) S.
Mukherjee, J. W. Yang, S. Hoffmann, B. List, Chem. Rev. 2007, 107,
5471-5569; b) A. Erkkilä, I. Majander, P. M. Pihko, Chem. Rev. 2007,
107, 5416−5470. c) M. Nielsen, D. Worgull, T. Zweifel, B. Gschwend, S.
Bertelsen, K. A. Jorgensen, Chem. Commun. 2011, 47, 632-649; d) P.
Melchiorre, M. Marigo, A. Carlone, G. Bartoli, Angew. Chem. Int. Ed.
2008, 47, 6138-6171.
[9]
a) P. Krattiger, C. McCarthy, A. Pfaltz, H. Wennemers, Angew. Chem.
Int. Ed. 2003, 42, 1722-1724; b) P. Krattiger, R. Kovasy, J. D. Revell, S.
Ivan, H. Wennemers, Org. Lett. 2005, 7, 1101-1103; c) M. Wiesner, J.
D. Revell, S. Tonazzi, H. Wennemers, J. Am. Chem. Soc. 2008, 130,
5610-5611; d) M. Wiesner, J. D. Revell, H. Wennemers, Angew. Chem.
Int. Ed. 2008, 47, 1871-1874; e) M. Wiesner, H. Wennemers, Synthesis,
2010, 9, 1568-1571; f) J. Duschmalé, H. Wennemers, Chem. Eur. J.
2012, 18, 1111-1120; g) J. Duschmale, S. Kohrt, H. Wennemers,
Chem. Comm. 2014, 50, 8109-8112; h) C. E. Grunenfelder, J. K.
Kisunzu, H. Wennemers, Angew. Chem. Int. Ed. 2016, 55, 8571-8574.
[4]
For pioneer works on chiral phosphoric acid for organocatalytic reaction,
see: a) D. Uraguchi, M. Terada, J. Am. Chem. Soc. 2004, 126, 5356-
5357; b) T. Akiyama, J. Itoh, K. Yokota, K. Fuchibe, Angew. Chem. Int.
Ed. 2004, 43, 1566-1568; for selected general reviews for non-covalent
activation mode, see: c) J.-F. Brière, S. Oudeyer, V. Dalla, V. Levacher,
Chem. Soc. Rev. 2012, 41, 1696; d) M. Mahlau, B. List. Angew. Chem.
Int. Ed. 2013, 52, 518–533; e) K. Brak, E. N. Jacobsen. Angew. Chem.
Int. Ed. 2013, 52, 534–561; f) A. Zamfir, S. Schenker, M. Freund, S. B.
Tsogoeva, Org. Biomol. Chem. 2010, 8, 5262–5276; for selected
reviews on thiourea as H-bond donating catalyst, see: g) Z. Zhang, P.
R. Schreiner, Chem. Soc. Rev. 2009, 38, 1187–1198; h) M. S. Taylor,
E. N. Jacobsen, Angew. Chem. Int. Ed. 2006, 45, 1520–1543; i) M.
Terada, Bull. Chem. Soc. Jpn. 2010, 83, 101–119; j) S. Schenker, A.
Zamfir, M. Freund, S.B. Tsogoeva, Eur. J. Org. Chem. 2011, 2209–
2222; k) D. Parmar, E. Sugiono, S. Raja, M. Rueping, Chem. Rev.
2014, 114, 9047–9153.
[10] a) M. Wiesner, M. Neuburger, H. Wennemers, Chem. Eur. J. 2009, 15,
10103-10109; b) M. Wiesner, G. Upert, G. Angelici, H. Wennemers, J.
Am. Chem. Soc. 2010, 132, 6-7 ; c) F. Bächle, J. Duschmalé, C. Ebner,
A. Pfaltz, H. Wennemers, Angew. Chem. Int. Ed. 2013, 52, 12619–
12623.
[11] We define our modified amino-acid H-AA1-OMe bearing a phosphonic
acid as pAla for phosphonoalanine.
[5]
For selected exemples of asymmetric C-C bond creation by
organocatalysis, see: a) G. Masson, C. Housseman, J. Zhu, Angew.
Chem. Int. Ed. 2007, 46, 4614-4628; b) D. Enders, C. Grondal, M. R.
Huttl, Angew. Chem., Int. Ed. 2007, 46, 1570-1581; c) J. M. Verkade, L.
J. van Hemert, P. J. Quaedflieg, F. P. Rutjes, Chem. Soc. Rev. 2008,
37, 29-41; d) V. Terrasson, R. Marcia de Figueiredo, J. M. Campagne,
Eur. J. Org. Chem. 2010, 2635-2655; e) S. B. Tsogoeva, Eur. J. Org.
Chem. 2007, 1701-1716; f) A. Moyano, R. Rios, Chem. Rev. 2011, 111,
4703-4832; g) S. V. Pansare, E. K. Paul, Chem. Eur. J. 2011, 17, 8770-
[12] M. Cortes-Clerget, O. Gager, M. Monteil, J.-L. Pirat, E. Migianu-Griffoni,
J. Deschamp, M. Lecouvey, Adv. Synth. Catal. 2016, 358, 34–40.
[13] 11.5, 6.6 and 2.3 refer to the pH adjustment during the catalyst
preparation. 11.5 refer to the all-deprotonated catalyst while 6.6 refer to
the NH2+/OH/O- form and 2.3 refer to the all-protonated catalyst.
[14] The syntheses of Ia-d and IIa-d were reported in our previous work (ref
12). IIIa-d and IVa-d were synthesized starting from aspartic acid and
glutamic acid respectively according to the same strategy than Ia-d and
IIa-d. For more details, see supporting information.
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10.1002/chem.201700604
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[15] M. Wiesner, G. Upert, G. Angelici, H. Wennemers. J. Am. Chem. Soc
2010, 132, 6–7.
[16] Initial rates were determined by GC. For more details, see Supporting
information.
[17] C. Puchot, O. Samuel, E. Duiiach, S. Zhao, C. Agami, H. B. Kagan, J.
Am. Chem. Soc. 1986, 108, 2353-2357.
[18] L. Hoang, S. Bahmanyar, K. N. Houk, B. List, J. Am. Chem. Soc. 2003,
125, 16-17.
[19] Blackmond interpreted the first results by a solubility issues for more
details see a) M. Klussmann, H. Iwamura, S. P. Mathew, D. H. Wells,
Jr., U. Pandya, A. Armstrong, D. G. Blackmond, Nature 2006, 441, 621-
623 b) M. Klussmann, S. P. Mathew, H. Iwamura, D. H. Wells, Jr., A.
Armstrong, D. G. Blackmond, Angew. Chem. Int. Ed. 2006, 45, 7989-
7992.
[20] For more details, see Supporting Information
[21] Preliminary Mass experiment were performed and the two new species
were detected at m/z = 416 (enamine) and m/z = 417 (iminium
intermediate). For more details see Supporting Information.
[22] J. E. Hein, J. Bures, Y. H. Lam, M. Hughes, K. N. Houk, A. Armstrong,
D. G. Blackmond, Org. Lett. 2011, 13, 5644-5647.
[23] M. Hatano, K. Moriyama, T. Maki, K. Ishihara, Angew. Chem. Int. Ed.
2010, 49, 3823-3826.
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
FULL PAPER
One catalyst to rule them all.
Margery Cortes-Clerget, Jesús Jover,
Jade Dussart, Emilie Kolodziej, Maelle
Monteil, Evelyne Migianu-Griffoni, Olivier
Mechanistic
performed in order to unveil the
activation modes and catalytic
investigations
were
Gager,
Julia
Deschamp,*
Marc
efficiency of the H-Pro-Pro-pAla-OMe
catalyst in the 1,4-addition between
aldehydes and nitroalkenes. This
tripeptide behaves as a multiactivating
catalyst, able to interact through a
secondary amine group and non-
Lecouvey*
((Insert TOC Graphic))
Page No. – Page No.
Bifunctional Tripeptide Including a
Phosphonic Acid as Brønsted Acid
for Michael Addition: Mechanistic
Insights
covalent activations.
A
restrained
tripeptide is optimal for better
selectivities and fast reaction.
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