Peptide-Catalyzed Stereoselective Conjugate Addition Reactions of Aldehydes to Maleimide

Article abstract of DOI:10.1002/anie.201602230

The tripeptide H-dPro-Pro-Asn-NH₂is presented as a catalyst for asymmetric conjugate addition reactions of aldehydes to maleimide. The peptidic catalyst promotes the reaction between various aldehydes and unprotected maleimide with high stereoselectivities and yields. The obtained products were readily derivatized to the corresponding pyrrolidines, lactams, lactones, and peptide-like compounds.¹H NMR spectroscopic, crystallographic, and computational investigations provided insight into the conformational properties of H-dPro-Pro-Asn-NH₂and revealed the importance of hydrogen bonding between the peptide and maleimide for catalyzing the stereoselective C?C bond formation.

Full text of DOI:10.1002/anie.201602230

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201602230
German Edition: DOI: 10.1002/ange.201602230
Organocatalysis
Peptide-Catalyzed Stereoselective Conjugate Addition Reactions of
Aldehydes to Maleimide
Claudio E. Grꢀnenfelder, Jessica K. Kisunzu, and Helma Wennemers*
Abstract: The tripeptide H-dPro-Pro-Asn-NH is presented as
tripeptidic catalysts by structural modification. For example,
2
a catalyst for asymmetric conjugate addition reactions of
aldehydes to maleimide. The peptidic catalyst promotes the
reaction between various aldehydes and unprotected malei-
mide with high stereoselectivities and yields. The obtained
products were readily derivatized to the corresponding pyrro-
lidines, lactams, lactones, and peptide-like compounds.
while H-Pro-Pro-Asp-NH is a powerful catalyst for aldol
2
[
7]
reactions, the close analogue H-dPro-Pro-Glu-NH2 (1a)
catalyzes conjugate addition reactions of aldehydes to nitro-
olefins and products of the competing homoaldol reaction do
[
8]
not form. This tunability of the steric and stereoelectronic
properties had even enabled the development of tripeptidic
catalysts for conjugate addition reactions of aldehydes to
disubstituted nitroolefins where homoaldol reactions are
typically the main pathway when other amine-based catalysts
1
H NMR spectroscopic, crystallographic, and computational
investigations provided insight into the conformational proper-
ties of H-dPro-Pro-Asn-NH and revealed the importance of
2
[9]
hydrogen bonding between the peptide and maleimide for
catalyzing the stereoselective CÀC bond formation.
are employed. We therefore envisioned that tripeptides of
the type H-Pro-Pro-Xaa would also allow for the identifica-
tion of a catalyst that accommodates the requirements for
addition reactions of aldehydes to unprotected maleimides.
S
uccinimides are common motifs in natural products and
versatile platforms for further transformations into, for
example, pyrrolidines, lactams, or lactones, compounds that
Herein, we present the peptide H-dPro-Pro-Asn-NH as
2
a catalyst for stereoselective 1,4-addition reactions of alde-
hydes to unprotected maleimide (Scheme 1). We show that
hydrogen bonding of the catalyst to maleimide is key to
overcoming unproductive side reactions and gearing the
system towards the desired CÀC bond formation. Further-
[1]
are widespread in therapeutically active compounds. Effec-
tive methods for the stereoselective synthesis of succinimides
are therefore valuable.
tions between carbon-based nucleophiles and maleimides are
[1–5]
Stereoselective CÀC bond forma-
[1,3–5]
attractive for obtaining succinimides.
Typically, N-pro-
more, we show that the obtained succinimides can readily be
converted into other synthetically useful compounds, such as
pyrrolidines, lactams, and lactones.
tected maleimides are employed, presumably to circumvent
potential side reactions arising from the nucleophilicity of
[
3,4]
unprotected maleimides.
cumbersome additional deprotection step to obtain the N-
This strategy requires an often
[
4,6]
unfunctionalized succinimide.
The use of unprotected
maleimide in conjugate additions with aldehydes would
avoid this additional step, but has generally resulted in low
product yields and/or stereoselectivities and required the use
[5]
of comparatively high catalyst loadings of 10–20 mol%. We
envisioned that the hydrogen-bonding properties of peptide-
based catalysts may allow us to overcome these limitations
and provide controlled activation of unprotected maleimide
towards the desired CÀC bond formation.
Scheme 1. Conjugate addition of aldehydes to maleimide and the
equilibrium between aldehydes and maleimide to form adduct A.
Our group has previously introduced tripeptides of the
general type H-Pro-Pro-Xaa (Xaa = any residue) as highly
reactive and stereoselective catalysts for CÀC bond formation
[
7–9]
reactions.
Tripeptides were developed that provide the
We started by exploring the reactivity of hydrocinnam-
aldehyde and maleimide and observed the reversible forma-
products of aldol and conjugate addition reactions between
aldehydes and nitroolefins in high yields as well as high
tion of an addition product A that can no longer engage in the
[
7–9]
[10]
enantio- and diastereoselectivities.
The modularity of the
desired conjugate addition reaction (Scheme 1).
This
H-Pro-Pro-Xaa motif enabled tuning of the reactivity, ste-
reoselectivity, and, remarkably, the chemoselectivity of the
undesired side reaction can be prevented by using N-
protected maleimides, which is likely the reason why previous
studies focused on CÀC bond formations with protected
[
4]
maleimides. We speculated that the conjugate addition
pathway could also be favored by coordination of unprotected
[
*] C. E. Grꢀnenfelder, Dr. J. K. Kisunzu, Prof. Dr. H. Wennemers
Laboratorium fꢀr Organische Chemie, ETH Zꢀrich
Vladimir-Prelog-Weg 3, 8093 Zꢀrich (Switzerland)
E-mail: Helma.Wennemers@org.chem.ethz.ch
maleimide to an appropriate catalyst. Since the pK values of
a
[
11]
[12]
maleimide (pK = 10.8)
and succinimide (pK = 14.6)
a
a
have been reported to differ by four units, we further
hypothesized that the coordination of the formed succinimide
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201602230.
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product to the catalyst would be sufficiently weaker com-
pared to that of maleimide to allow for catalytic turnover.
Reassuringly, upon addition of tripeptides 1a–h to mix-
tures of hydrocinnamaldehyde 2a and maleimide the desired
conjugate addition product 3a formed (Table 1). Significant
With the optimized reaction conditions in hand, we
explored the scope of the peptide-catalyzed conjugate
addition reaction and allowed a range of different aldehydes
to react with maleimide in the presence of 5 mol% of peptide
1c (Table 2). Aliphatic aldehydes readily reacted with mal-
Table 1: Conjugate addition reactions of hydrocinnamaldehyde and
maleimide catalyzed by peptides 1a–h.
Table 2: Scope of conjugate addition reactions between aldehydes and
maleimide.
[
a]
1
2
[a]
[a]
[b]
Entry Cat.
R
R
Conc. Conv.[%]
M]
d.r.
ee
[
[%]
[
[
[
[
c]
c]
c]
c]
1
2
3
4
5
6
7
8
9
1a CONH2 CH CO H
0.5
0.5
0.5
0.5
1.0
1.0
1.0
1.0
1.0
34
64
93
<5
quant
50
59
45
54
88:12
89:11
86:14
91
95
98
n.d.
98
81
83
88
88
2
2
1b CONH2 CH CONH2
2
1c CONH2 CONH2
[d]
[d]
1d CO Me Ph
n.d.
2
1c CONH2 CONH2
1e CONH2 Me
88:12
88:12
89:11
91:9
1 f
H
CH CONH2
2
1g CONH2 Ph
1h CONH2 iPr
92:8
1
[
[
a] Determined by H NMR spectroscopy of the crude reaction mixture.
b] Determined by HPLC on a chiral stationary phase. [c] A 9:1 ratio of
[
a] Yields correspond to the isolated addition products as a mixture of
1
diastereoisomers. The d.r. and ee values were determined by H NMR
spectroscopy and HPLC on a chiral stationary phase, respectively.
[
CHCl /iPrOH was used. [d] not determined. NMM=N-methyl-
3
morpholine.
b] 10 mol% of catalyst were used.
differences in the conversion of the starting materials into the
product were observed depending on the functional groups of
the C-terminal amino acid of the catalysts. Studies with H-
eimide and provided conjugate addition products 3a–3e in
high yields (91–99%) and stereoselectivities (92–98% ee,
88:12–94:6 d.r.). Aldehydes bearing ester, a,b-unsaturated
ester, and even carbamate functionalities, which could
potentially interfere by hydrogen bonding to the catalyst,
were tolerated and yielded the corresponding products 3 f–3i
with very good stereoselectivities (94–97% ee, 83:17–95:5
d.r.) albeit in slightly lower yields (80–98%).
dPro-Pro-Glu-NH (1a) and related catalysts bearing carbox-
2
ylic acid and amide moieties led to the desired product but
with unsatisfactory conversion and significant amounts of
[
13]
products from homoaldol reactions.
Higher product for-
mation was observed with peptides 1b and 1c bearing C-
terminal amino acids with two amide moieties (Table 1,
entries 2 and 3), suggesting that coordination between the
catalyst and maleimide by hydrogen bonding rather than the
presence of a proton donor is critical for enhancing the CÀC
We then probed the synthetic utility of the conjugate
addition products and used succinimide 3a as a model
compound. Reduction of the aldehyde and succinimide
moieties yielded the corresponding pyrrolidine 4, which
crystallized after tosylation and allowed for the unambiguous
assignment of the absolute and relative configuration of the
bond-formation pathway. In experiments with peptide 1d that
lacks coordinating moieties, conjugate addition product 3a
hardly formed, which highlighted the importance of inter-
molecular interactions between the peptide and maleimide
for catalysis (Table 1, entry 4). Further variations in the
catalyst structure by replacing one of the amide moieties with
non-coordinating functional groups (peptides 1e–h, Table 1,
entries 6–9; see also Table S1 in the Supporting Information)
corroborated that H-dPro-Pro-Asn-NH2 (1c) is the best
catalyst with respect to reactivity and stereoselectivity. In
addition, hardly any product from the homoaldol reaction of
hydrocinnamaldehyde formed in the presence of peptide 1c.
[15]
stereogenic centers (Scheme 2, top). Lactone 5 and lactam
6 were also obtained in high yields by straightforward two-
step procedures that involved reduction of the aldehyde
moiety, or that of an initially formed imine, followed by
intramolecular ring opening of the succinimide moiety.
Oxidation of the aldehyde moiety yielded acid 7 that could
be easily used in a peptide coupling with, for example,
l-phenylalanine methyl ester hydrochloride to yield 8
(Scheme 2). All of these reactions proceeded essentially
with retention of diastereo- and enantioselectivity.
[14]
Under optimized reaction parameters with respect to, for
example, solvent, stoichiometry, and concentration, the con-
jugate addition reaction proceeded quantitatively to succini-
mide 3a, which was obtained with a diastereoselectivity of
Next, we performed studies to gain an understanding of
the role of the two amide moieties within peptide 1c that had
proven to be important for the catalytic efficiency. The
experiments with analogues 1d–1h had shown that both
8
8:12 and an enantioselectivity of 98% ee (Table 1, entry 5).
2
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[15]
Figure 1. a) Crystal structure of the TFA salt of catalyst 1c. Atom
colors in (a): C=gray; H=white; O=red; N=blue; F=green.
b) Lowest energy structure of the catalyst enamine/maleimide complex
[
16]
calculated by MacroModel. H-bonds indicated in yellow.
This dual role of the two amide moieties was supported by
conformational searches using MacroModel 11.0 with the
OPLS 2005 force field and the GB/SA model for chloro-
[
16]
form. The enamine derived from the crystal structure of 1c
and hydrocinnamaldehyde was used as a starting structure for
coordination to maleimide. Within the resulting lowest energy
conformation, the maleimide is coordinated to the asparagine
side chain and allows for an attack of the enamine from below
that supports the observed stereoselectivity (Figure 1b).
Finally, we probed the interaction between catalyst 1c and
Scheme 2. Derivatization of conjugate addition product 3a and crystal
structure of pyrrolidine 4. EDC·HCl=N-(3-dimethylaminopropyl)-N’-
ethylcarbodiimide hydrochloride; HOBt=N-hydroxybenzotriazole.
[
15]
1
maleimide in the solution phase and used H NMR spectros-
amides within 1c are critical to obtain the product in high
yields and stereoselectivities, which suggests that coordina-
tion between peptide 1c and maleimide is key to the catalysis.
This finding was further corroborated by reaction of N-
protected phenylmaleimide that lacks the NH group as a H-
bond donor. Reaction with hydrocinnamaldehyde in the
presence of 1c provided the product in lower yield (24%) and
stereoselectivity (88:12 d.r., 93% ee, Scheme 3) compared to
copy to monitor the interaction. N-terminally acetylated 1c
(Ac-dPro-Pro-Asn-NH ; 1c-Ac) was used for these studies in
2
order to avoid interference by the secondary amine of the
catalyst. Upon addition of maleimide to a solution of 1c-Ac,
pronounced downfield shifts of both the signals correspond-
ing to the C-terminal and the side-chain amide-NH moieties
[
14]
of the Asn residue were detected. In addition, significant
changes in the chemical shifts of the signals corresponding to
the H atom of the N-terminal Pro and one of the H atoms of
a
d
the middle Pro residue were detected. Both protons are in the
vicinity of the maleimide in the calculated structure of the
catalyst–maleimide complex (Figure 1b). Thus, the NMR
spectroscopic studies support the proposed coordination
mode between the peptidic catalyst 1c and maleimide.
Titration studies allowed for the determination of a binding
Scheme 3. Conjugate addition reaction of hydrocinnamaldehyde and
N-phenylmaleimide catalyzed by peptide 1c.
À1 [14,17]
affinity of DG = À1.1 Æ 0.2 kcalmol .
In summary, we have developed an effective catalyst for
conjugate addition reactions of aldehydes to unprotected
maleimide. The resulting succinimides were obtained in high
yields and stereoselectivities and further transformations to
pyrrolidine, lactone, lactam, and peptide-like building blocks
were straightforward. Coordination of the catalyst to mal-
eimide by H-bonding proved to be key as revealed by studies
the identical reaction utilizing unprotected maleimide
(
Table 1, entry 5).
Since crystal structures can provide insight into the
preferred conformation of peptides, we were pleased that
the trifluoroacetic acid (TFA) salt of peptide 1c crystallized
from a mixture of CHCl , MeOH, and n-hexane (Fig-
3
[
15]
1
ure 1a).
In the solid state, peptide 1c adopts a b-turn
with analogues as well as H NMR spectroscopy and crystal-
structure within which the C-terminal amide NH moiety
forms a H-bond with the CO group of the N-terminal proline.
The side-chain amide of the asparagine (Asn) residue is
coordinating a co-crystallized TFA molecule. This suggests
that the C-terminal amide of the Asn residue plays a structural
role whereas the side-chain amide moiety provides a binding
site for the maleimide.
lography. The results highlight the value of peptidic cata-
[
18]
lysts
and their structural modularity, which allows for
tuning of the chemoselectivity and thereby catalysis of
reactions where undesired reaction pathways need to be
avoided. Furthermore, these findings indicate that differential
coordination, which is key for the substrate specificity of
[
19]
enzymes, can also be implemented into peptidic catalysts.
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Angewandte
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General procedure for the 1,4-addition reactions: The peptide (TFA
salt, 20.0 mmol, 5 mol%) was added to a solution of N-methylmor-
pholine (NMM; 20.0 mmol, 5 mol%) in CHCl3 and iPrOH (1:1,
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5] a) J. Flores-Ferrꢃndiz, R. Chinchilla, Tetrahedron: Asymmetry
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[
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Keywords: addition reactions · asymmetric catalysis ·
maleimide · organocatalysis · peptides
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Received: March 3, 2016
Published online: && &&, &&&&
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Communications
Organocatalysis
C. E. Grꢁnenfelder, J. K. Kisunzu,
H. Wennemers*
&&&& — &&&&
Peptide-Catalyzed Stereoselective
Conjugate Addition Reactions of
Aldehydes to Maleimide
Imide dances to amide tunes: Unpro-
tected maleimide reacts readily with
aldehydes in the presence of a peptidic
catalyst to form succinimides with high
diastereo- and enantioselectivities.
Hydrogen bonding between the peptide
and maleimide is key for catalysis and the
chemoselective formation of conjugate
addition products. NMM=N-methyl-
morpholine.
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