Multicomponent combinatorial development and conformational analysis of prolyl peptide-peptoid hybrid catalysts: Application in the direct asymmetric michael addition

Article abstract of DOI:10.1021/jo401609z

A solution-phase combinatorial approach based on the Ugi four-component reaction was implemented for the development of new prolyl peptide-peptoid hybrid catalysts. Three different elements of diversity were varied during the creation of the set of cataly

Full text of DOI:10.1021/jo401609z

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Article
Multicomponent Combinatorial Development and
Conformational Analysis of Prolyl Pseudo-Peptide Catalysts:
Application in the Direct Asymmetric Michael Addition
Alexander Fernandéz de la Torre, Daniel García Rivera, Marco
A. B. Ferreira, Arlene G. Corrêa, and Marcio Weber Paixao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo401609z • Publication Date (Web): 22 Sep 2013
Downloaded from http://pubs.acs.org on September 28, 2013
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Multicomponent Combinatorial Development and Conformational Analysis
of Prolyl Peptide-Peptoid Hybrid Catalysts: Application in the Direct
Asymmetric Michael Addition
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Alexander F. de la Torre,† Daniel G. Rivera,†,‡,* Marco A. B. Ferreira,† Arlene G. Corrêa† and
Márcio W. Paixão†,*
†Departamento de Química, Universidade Federal de São Carlos, São Carlos, SP, 97105-900,
Brazil.
‡Center for Natural Products Study, Faculty of Chemistry, University of Havana, Zapata y G,
10400, La Habana, Cuba.
Corresponding Authors *Emails: dgr@fq.uh.cu (D. G. Rivera); mwpaixao@ufscar.br (M.
W. Paixão). Tel. and Fax: +55-16-220 8075.
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Graphical Abstract
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Abstract
A solution-phase combinatorial approach based on the Ugi four-component reaction was
implemented for the development of new prolyl peptide-peptoid hybrid catalysts. Three
different elements of diversity were varied during the creation of the set of catalysts, i.e., the
amine, the oxo and the isocyano components. The multicomponent nature of this process
enabled the straightforward generation of a series of peptide-peptoid hybrids having the
generic sequences Pro-N-R1-Xaa-NHR3, being Xaa either Gly (R2 = H) or Aib (R2 = gem-
Me), and R1 and R3 either alkyl or amino acid substituents. The catalytic behavior of the
peptide-peptoid hybrids was assessed in the asymmetric conjugate addition of aldehydes to
nitroolefins, where most catalysts showed great efficacy and rendered the Michael adducts in
good to excellent enantio- and diastereoselectivity. A molecular modeling study was
performed for two distinct catalysts aiming to understand their conformational features. The
conformational analysis provided important information for understanding the remarkable
stereocontrol achieved during the organocatalytic transformation.
Keywords: organocatalysis, Michael addition, multicomponent reactions, peptides,
combinatorial chemistry, conformational analysis
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Introduction
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The pursuit of novel chiral molecules for applications in metal-free asymmetric catalysis has
inspired intensive research activity in the last decade. This massive effort has resulted in the
discovery of several efficient organocatalysts for highly enantio- and diastereoselective
organic reactions as well as cascade reaction sequences.1 Among them, an important class of
organocatalysts is that composed of oligopeptidic scaffolds, which have found remarkable
applications in a wide range of catalytic asymmetric transformations such us: acylation,
oxidation, ester hydrolysis, Aldol reaction, conjugate addition, etc.2 Although rational design
plays an important role in the discovery of organocatalysts, usually further optimization steps
including the variation of the nature and position of substituents around the chiral motif are
required. In such a lead-catalyst optimization stage, combinatorial chemistry frequently plays
a pivotal role owing to its capacity to efficiently produce and screen hundreds of substances in
a massive, parallel manner.3 This strategy has been crucial in peptide catalyst discovery and
development,2,3 mainly due to the great advances in the solid-phase combinatorial synthesis
and high-throughput screening of peptide libraries.
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However, a different scenario shows up in solution-phase approaches for organocatalyst
development, as these latter are less straightforward and thus require a much higher synthetic
effort on the preparation of compound libraries for catalytic activity screening. A solution for
this may be the utilization of multicomponent reactions (MCRs),4 i.e., one-pot procedures that
incorporate at least three starting materials into a single structure. MCRs are almost
unraveling approaches in terms of chemical efficiency, atom economy and diversity
generation.5 Hence, their utilization is of high incidence in drug discovery and development
strategies based on the production of hetero- and polycyclic scaffolds, whereas the number of
relevant hits can be significantly increased by taking advantage of the diversity-oriented
character of such transformations.6 However, despite the discovery of new catalysts can be
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approached in a similar way as drug discovery, the interest of the catalysis community in
MCRs does not yet reflect the proven impact of such processes in other important areas like
medicinal6 and natural products chemistry.7
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Among the different types of peptide catalysts, those having proline at the N-terminus are
especially suitable for both enamine and iminium ion activation. In a series of recent reports,
Wennemers and co-workers used a combination of rational design and combinatorial
chemistry for the development of tripeptides based on the generic structure Pro-Pro-Xaa (Xaa
being an acidic α-amino acid).8 Thus, the so-called Wennemers catalyst
D-Pro-Pro-Glu-NH2
(Fig. 1A) has been recognized as one of the most effective for the asymmetric conjugate
addition of aldehydes to nitroolefins, while other analogs have been also developed for the
catalytic asymmetric Aldol reaction.9
A)
H
H
N
O
N
H
H
N
O
N
NH2
O
N
O
H
O
N
H
CO2H
HO2C
Wennemers catalyst
Ugi-derived Orru catalyst
B)
O
CN
CO2H
N
N
N
Ugi-4CR
H
+
Pg
N
H
O
O
H2N
Three elements of diversity tunable in a one-pot process
Figure 1. A) Prolyl peptide catalysts for asymmetric conjugate additions. B) Combinatorial
multicomponent strategy for the preparation of prolyl peptide-peptoid hybrids.
Perhaps the MCR of greater promise in the field of peptide catalysis is the Ugi four-
component reaction (Ugi-4CR).10 This reaction has proven to be a powerful tool for the
efficient preparation of peptidic skeletons, including N-alkylated peptides and a wide variety
of peptidomimetic.3,11 Recently, Orru and co-workers implemented a highly diastereoselective
Ugi reaction for the straightforward synthesis of a prolyl peptide12 (Fig. 1A) resembling the
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structure and catalytic behavior of Wennemers catalyst, which proved the potential of such a
reaction for accessing target peptides.
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Herein we report the application of the Ugi-4CR for the combinatorial development of novel
peptide-peptoid hybrid catalysts as well as the assessment of their catalytic behavior in the
asymmetric conjugate addition of aldehydes to nitroolefins. As depicted in figure 1B, our
strategy focuses on exploiting the diversity-generating capability of this reaction in the
solution-phase production of a collection of compounds integrating structural elements of
peptides and peptoids (in sensu strictu peptoids are defined as N-substituted polyglycines).
Thus, this approach differs from that of Orru et al.12 in the sense that the use of the MCR does
not aim the synthesis of a target peptide catalyst, but a collection of them for addressing the
effect of the structural variations on the catalytic profile.
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Results and Discussion
Solution-Phase Multicomponent Synthesis of Prolyl Peptide-Peptoid Hybrid Catalysts.
The classic Ugi-4CR10 is the one-pot condensation of a primary amine, an oxo compound
(i.e., ketone or aldehyde), a carboxylic acid, and an isocyanide to produce an N-substituted
dipeptide backbone, which may be considered as a peptide-peptoid hybrid13 when α-amino
acids are used either as carboxylic or amino components. As early proposed by Ugi himself,
the multicomponent nature of this process enables the development of powerful combinatorial
procedures through variation of each of the four starting materials. Whereas this concept has
been previously applied in drug discovery,6 we are not aware of its implementation in
organocatalysts discovery.14 As illustrated in figure 1B, we planned the installation of three
elements of tunable diversity, i.e., the amine, the oxo and the isocyanide components, while
proline remains as a fixed substrate aiming to enable enamine catalysis. As a result, the
simple variation of highly available substrates like primary amines, carbonyl compounds and
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isocyanides may give rise to a medium-size library of structurally novel prolyl peptide-
peptoid hybrids for screening of their catalytic behavior.
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As shown in table 1, the implementation of the multicomponent combinatorial approach
required a two-step procedure comprising the one-pot assembly of the peptidic skeleton by
the Ugi-4CR followed by N-terminus deprotection. Among the three distinct elements of
diversity, initial attention was posed on the variation of the amine (entries 1-8), while
paraformaldehyde and cyclohexylisocyanide were kept as fixed components. A typical Ugi
protocol10b was implemented for all catalysts in a first instance, which proved to be suitable
for reactive amines (entries 1, 7-12) but gave poor results when sterically congested α-amino
acid methyl esters were used (entries 2-6).
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Table 1. Multicomponent combinatorial synthesis of prolyl peptide-peptoid hybrid catalysts
using the Ugi-4CR either at room temperature or under microwave irradiation.
Entry Acid
R1
R2
R3
Catalyst Yieldc
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2
L
L
L
L
L
L
L
L
L
L
L
L
-Pro Gly-OMea
-Pro Val-OMeb
-Pro Leu-OMeb
-Pro Ile-OMeb
-Pro Phe-OMeb
-Pro tBuGly-OMeb
-Pro (S)-α-MeBna
-Pro Bna
-Pro (S)-α-MeBna
-Pro Bna
-Pro (S)-α-MeBna
-Pro (S)-α-MeBna
H
H
Cy
Cy
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2
78%
81%
85%
77%
83%
61%
91%
93%
77%
73%
88%
82%
79%
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H
Cy
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H
Cy
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H
Cy
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H
Cy
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H
Cy
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H
Cy
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Me
Me
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Cy
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Cy
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t-Bu
Gly-OMe
Cy
H
D
-Pro (S)-α-MeBna
Me
aReaction conducted at room temperature in MeOH for 24h.
bReaction conducted under microwave irradiation. cYield of
isolated pure product over two steps.
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The solution for this was the use of microwave irradiation, which comprised good efficiency
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in the multicomponent preparation of the catalysts 2-6, whereas up to three cycles (30 min,
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150 W, 70 °C) of irradiation were required in the reaction of the unreactive L-t-butylglycine
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methyl ester (entry 6). We next looked onto the variation of the oxo and isocyano
components, again relying on the use of readily available starting materials to produce
accessible catalysts. Thus, acetone was utilized as oxo component in combination with both
(S)-α-methylbenzyl and benzyl amines (entries 9 and 10), leading to catalysts 9 and 10 having
the secuence Pro-N-alkyl-Aib (Aib is α-aminoisobutyric acid). Alternatively, t-
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butylisocyanide and methyl isocyanoacetate were combined with (S)-α-methylbenzylamine
and paraformaldehyde (entries 11 and 12) to produce the catalysts 11 and 12. In a last
instance, (S)-α-methylbenzyl amine, acetone and cyclohexylisocyanide were combined with
D-Pro to produce catalyst 13, an analog of 9 having the opposite stereochemistry at proline.
With this we might be able to assess the actual role of the pyrrolidine-ring stereochemistry on
the sterecocontrol performed by such catalysts. Alternatively, with the change of the amino
and isocyano components we aimed to address the influence on the catalytic profile of the
bulky character of substituents at both the internal and C-terminal amides. On the other hand,
the variation of N-alkyl-Gly by N-alkyl-Aib – derived from the change of formaldehyde by
acetone, respectively – aims to address the influence of the peptide conformational flexibility
in the catalytic performance. It must be noticed that the utilization of prochiral aldehydes and
ketones is certainly possible in this combinatorial protocol, whereas this initial report skips
the difficulty associated with the separation and identification of the resulting diastereomers.
Assessment of the enamine-type catalytic performance
With the library of peptide-peptoid hybrid catalysts in hand, we turned to the evaluation of
their organocatalytic performance in the Michael addition. This class of chemical
transformation is recognized as one of the most powerful C-C bond-forming reactions,15 and –
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since the discovery of its aminocatalytic version16 – it has been traditionally selected for
assessing the potential of new catalysts acting through enamine catalysis.1 Important insights
into the mechanism of the catalytic conjugate addition of aldehydes to nitroolefins have been
reported in recent years17 with the use of the diphenylprolinol silyl ether, one of the most
effective catalysts in the stereoselective version of this process.18 To screen the performance
of peptide-peptoid hybrids 1-12, their catalytic efficiency and stereoselection were initially
assessed in the model system consisting in the conjugate addition of n-butanal to trans-β-
nitrostyrene. During the initial screening, standard reaction conditions consisting in the use of
10 mol% of catalyst in toluene as solvent at room temperature were chosen.
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Table 2. Screening of the enamine-catalytic performance of peptide-peptoid hybrids 1-12 in
the asymmetric Michael addition.
Entry
Acid/R1/R2/R3
Yield (%)b dr (syn/anti)c ee (%)d
1
2
L
L
L
L
L
L
L
L
L
L
L
L
-Pro/Gly-OMe/H/Cy (1)
-Pro/Val-OMe/H/Cy (2)
-Pro/Leu-OMe/H/Cy (3)
-Pro/Ile-OMe/H/Cy (4)
-Pro/Phe-OMe/H/Cy (5)
-Pro/tBuGly-OMe/H/Cy (6)
-Pro/MeBn/H/Cy (7)
87
92
83
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74
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93
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92:8
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90:10
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89:11
84:16
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-86
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-Pro/Bn/H/Cy (8)
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-Pro/MeBn/Me/Cy (9)
-Pro/Bn/Me/Cy (10)
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11
12
13
-Pro/MeBn/H/t-Bu (11)
-Pro/MeBn/H/Gly-OMe (12)
D
-Pro/MeBn/Me/Cy (13)
aAll reactions were conducted, using 3 equivalents of the aldehyde. bYield of
isolated product as mixture of syn/anti adducts. cDetermined by 1H NMR
d
spectroscopy (of the crude mixture) and HPLC analysis. Determined by chiral
stationary phase HPLC analysis on the major diastereomer.
As illustrated in table 2, most compounds catalyzed the Michael addition with good to
excellent enantio- and diastereoselectivity, showing catalysts 9 the best results in terms of
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stereocontrol (98% ee, 94:6 dr). Analysis of these results provides important insights into the
structural requirements (derived from the three elements of diversity) for this new class of
catalysts to be effective. Thus, in terms of chemical efficiency and diastereoselection, it does
not seem to be great differences between all catalysts, whereas the enantioselection resulted
more dependent on some of the variable structural elements. Among these tunable structural
elements, variation of the chirality and bulky character of the N-substituent derived from the
amino component (entries 1-8, table 2) did not lead to a clear tendency in the
enantioselectivity behavior when formaldehyde was employed as the oxo component. As
depicted in table 2, the presence of the achiral N-substituents Gly-OMe (entry 1) and
benzylamine (entry 8) provided similar results (i.e., ca. 90% ee) that the chiral ones Val-OMe
(entry 2), Ile-OMe (entry 4) and (S)-α-methylbenzylamine (entry 7). Alternatively, Val-OMe
(entry 2) and Ile-OMe (entry 4) showed much better enantioselectivity than Leu-OMe (entry
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3) and Phe-OMe (entry 5), but – intriguingly – L-tBuGly (entry 6) gave only moderate results
despite of having the bulkiest side chain among all aminoacid methyl esters incorporated as
N-substituents.
On the other hand, the incorporation of the aminoacid residue Aib – derived from the use of
acetone instead of formaldehyde as oxo component – shed additional light into the structure
catalytic-activity relationship. Thus, the combination of Aib (R2 = Me) and the chiral (S)-α-
methylbenzyl group as N-substituent led to the most effective catalyst 9 (98% ee, entry 9).
Intriguingly, catalyst 10 bearing benzyl as N-substitution exhibited only moderate
enantioselectivity (entry 10), despite of also having the aminoacid residue Aib (R2 = Me)
derived from the use of acetone in the Ugi-4CR.
We next looked into the effect of varying the isocyanide component in the stereocontrol of the
conjugate addition, while keeping the oxo and amino components fixed (i.e.; R1 = (S)-α-
t
MeBn and R2 = H). Thus, catalysts 11 (entry 11, R3 = Bu) showed slightly higher
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enantioselectivity than its analogue 7 (entry 7, R3 = Cy), probably due to bulkier character of
the t-butyl amide substituent compared to the cyclohexyl one. In contrast, the incorporation of
the less bulky methyl isocyanoacetate in catalyst 12 (entry 12, R3 = Gly-OMe) led to a drop in
both the enantio- and diastereoselectivity with respect to catalyst 7. Based on these results, it
can be stated that the incorporation of an isocyanide component with certain steric hindrance
is important, although there are no great differences between catalysts having the terminal t-
butyl and cyclohexyl carboxamides. Thus, the use of cyclohexylisocyanide becomes more
feasible than the t-butyl one owing to the lower price and simpler synthesis of the former.
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Finally, catalyst 13 provided good enantio- and diastereoselectivity while producing the
Michael adduct with the reversed configuration at the asymmetric centers (entry 13), thus
proving that the stereocontrol is mainly biased by the pyrrolidine-ring stereochemistry.
Nevertheless, in this case the topological matching with the (S)-α-methylbenzyl N-substituent
is less effective than for catalyst 9 based on L-Pro, as the enantioselection of the latter was
significantly higher.
At this stage, we anticipated that the increased conformational rigidity provided by the
incorporation of both the aminoacid Aib instead of Gly (e.g., comparison of 9 with 7) and the
chiral N-substituent (S)-α-MeBn instead of Bn (e.g., comparison of 9 with 10) is the crucial
factor in the higher enantioselectivity of catalyst 9 compared with its congeners. Such a
greater conformational rigidity of 9 – derived from both the geminal methyl groups and the
chiral N-substituent – was confirmed by NMR analysis. Thus, duplicate sets of signals was
observed in the NMR spectra of most catalysts – due to the presence of the cis and trans
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isomers of the N-substituted amide bond.19 However, the H NMR spectrum of catalyst 9
showed a single configurational isomer in solution, thus confirming the conformational
fixation effect provided by its key structural elements.
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Indeed, the above findings were only possible due to the multicomponent nature of the
combinatorial procedure, in which three elements of diversity can be parallelly varied keeping
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L-proline as a fixed component. Whereas it was proven that slight structural variations may
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allow for a fine tuning of the enantioselectivity, we were prompted to the preparation of
peptide-peptoid hybrid catalysts including Aib in the backbone and aminoacid methyl esters
as N-substituents instead of aliphatic amines. Unfortunately, the yields of such Ugi-4CRs
were rather poor – even with the utilization of microwave irradiation – presumably due to the
inefficient imine formation starting from acetone and aminoacid methyl ester hydrochlorides
in presence of 1 equivalent of Et3N.
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Table 3. Substrate scope of the asymmetric Michael addition of aldehydes to trans-β-
nitrostyrenes catalyzed by peptide-peptoid hybrid 9.
Entry
R1
R2
Compound Yield (%)b dr (syn/anti)c ee (%)d
1
2
3
4
5
6
7
8
9
Et
Ph
14
15
16
17
18
19
20
21
22
85
81
83
89
86
84
91
70
83
94:6
91:9
98
67
93
96
88
86
89
78
82
i-Pr Ph
Et
Et
Et
Et
Et
Et
Et
4-MeOC6H4
82:18
92:8
4-FC6H4
4-ClC6H4
4-BrC6H4
2-BrC6H4
3-NO2C6H4
2-Furyl
94:6
86:14
88:12
81:19
93:7
aAll reactions were conducted using 3 equivalents of the aldehyde. bYield of isolated
product as mixture of syn/anti adducts. cDetermined by 1H NMR spectroscopic.
dDetermined by chiral-phase HPLC analysis on the major diastereomer.
By analysis of table 2, peptide-peptoid hybrid 9 proved to be the most effective one in the
initial reaction conditions. Therefore, we next turned to assess the substrate scope of the
conjugate addition catalyzed by organocatalyst 9. As depicted in table 3, a variety of
substituted trans-
β
-nitrostyrenes were utilized to afford the Michael adduct in good to
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excellent enantioselectivity, albeit in some cases only with moderate diastereoselectivity.
Utilization either of trans-2-furyl-nitroolefin as acceptor (entry 9) or isovaleraldehyde as
donor (entry 2) provided Michael adducts in high diastereoselectivity but only moderate
enantioselectivity.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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43
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To assess the effect of reaction conditions in the catalytic efficiency and stereocontrol of this
type of catalysts, a variety of solvents, conditions and additives were studied. As shown in
table 4, catalyst 2 was initially chosen to accomplish this study considering that its
performance in the model system was high (entry 1) but yet improvable. In this sense, catalyst
9 was not selected for this purpose owing to the fact that its enantioselection was already quite
high, and thereby difficult to improve through variation of conditions. Thus, neither
decreasing the temperature to 5 ºC (entry 1) nor adding 10 mol% of either benzoic acid (entry
3) or p-nitrophenol (entry 4) provoked a significant change in the reaction yield and
stereoselection. In the case of p-nitrophenol as additive, a qualitative study revealed an initial
acceleration of the reaction, although the yield was not increased after 24 h. Alternatively,
decreasing the catalyst loading to 5 mol% (entry 5) and 2.5 mol% led to an erosion in the
reaction yield, albeit the enantio- and diastereoselectivity remained high. The solvent change
also decreased the effectiveness of the catalyst, especially when very polar solvents were
employed. Hence, either DCM or mixtures containing a small amount of i-PrOH (entries 8
and 9) were less successful than pure toluene, while both pure i-PrOH and THF provoked an
improvement in the reaction yield but a marked drop of the enantio- and diastereoselection.
Whereas this proves that non-protic, hydrophobic solvents are required for a good
stereocontrol, the results are quite intriguing since the mixture CHCl3/i-PrOH is the solvent of
choice for Michael additions with Wennemers’ peptide catalysts.8
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Table 4. Effect of reaction conditions on the asymmetric Michael addition catalyzed by
peptide-peptoid hybrids 2 and 3.
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
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49
50
51
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59
60
Entry Catalyst Solvent
mol% Yield (%)b dr (syn/anti)c ee (%)d
1
2
2
2
2
2
2
2
2
2
2
2
3
3
3
3
PhMe
PhMe e
PhMe f
PhMe g
10
10
10
10
5
92
89
88
92
76
45
74
90
63
98
98
83
57
61
91
92:8
95:5
94:6
93:7
94:6
96:4
94:6
95:5
93:7
85:15
88:12
68:32
94:6
94:6
90:10
91
90
87
90
89
91
79
80
62
34
73
79
49
47
64
2
3
4
5
PhMe
6
PhMe
2.5
10
10
10
10
10
10
10
10
10
7
DCM
8
PhMe/i-PrOH h
CH3Cl/i-PrOHh
i-PrOH
THF
9
10
11
12
13
14
15
PhMe
PhMe f
CH3Cl/i-PrOHh
THF
aReactions were conducted using 3 equivalents of the aldehyde, and unless otherwise specified, at
room temperature for 24 h. bYield of isolated product as mixture of syn/anti adducts. cDetermined by
1H NMR spectroscopic (of the crude mixture) and HPLC analysis. Determined by chiral-stationary
d
e
f
phase HPLC analysis on the major diastereomer. Reaction conducted at 5 ºC. 10 mol% of benzoic
acid was used as additive. g10 mol% of p-nitrofenol was used as additive. hSolvent mixture 9:1 (v/v).
As illustrated in table 4, we also decided to evaluate catalyst 3 in a variety of conditions,
considering that the effectiveness of this catalyst might be yet improvable. However, neither
the presence of an acid additive (entry 13) nor the utilization of more polar solvents like
CHCl3/i-PrOH (entry 14) and THF (entry 15) led to higher enantio- and diastereoselectivity
compared to the original conditions (entry 12).
For catalysts derived from L-proline, the absolute configuration of Michael adducts was
unambiguously established to be 2R,3S according to chemical correlation with previous
reports (see the Experimental Part). This enantioselection can be explained according to the
Seebach’s topological model,20 in which the anti enamine approaches to the nitroolefin by the
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less hindered face through a synclinal transition state. To understand the enantioselectivity
observed in this work, the peptidic substituent at the pyrrolidine ring must favor the formation
of the enamine with the E configuration while providing an important shielding to the Re-
face. Accordingly, we were prompted to undertake a conformational study aimed at
understanding both the actual shielding effect to one of the pyrrolidine (and therefore
enamine) faces and the dissimilar cis-trans isomerizations detected by NMR in catalysts
incorporating either N-substituted Gly or Aib.
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Conformational Analysis
A conformational analysis was accomplished for the parent catalysts 7 and 9, keeping in mind
that: i) the sterocontrol provided by 9 was higher that of 7 and ii) NMR analysis of 9 shows
almost a single configurational isomer while that of 7 shows a mixture of cis and trans
isomers in solution (see NMR spectra in the Supporting Information A).
To cover the conformational space of catalyst 7, we initially conducted a conformational
search by Monte Carlo Molecular Mechanics (MCMM) as implemented in Macromodel 9.9.
We were able to find 673 different conformers with energies within 5 kcal.mol-1 relative to
the lowest-energy conformation. Clustering according to the atomic distances of heavy-atoms
eliminated the redundant conformers, resulted in 42 groups (see in the Supporting Information
B). The same conformational search was performed with catalyst 9, resulting in 182 different
conformers and 26 groups after clustering analysis. Representative structures of low-energy
clustered conformers were selected and re-optimized at M06-2X/6-31G(d). The electronic
energies were refined by a single point using the 6-31+G(d,p) basis set. The relative Gibbs
energies and Boltzmann population at 25 ºC in CDCl3 of all re-optimized low-energy
conformers are shown in supporting information B (see Tables S1, S2, S3, and S4).
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Catalyst 7
Catalyst 9
Figure 2. Low-energy clustered-superposed conformers of catalysts 7 and 9 calculated at
M06-2X/6-31+G(d,p) // M06-2X/6-31G(d) [SDM, chloroform] level.
As shown in Figure 2, analysis of superposed geometries of these re-optimized low-energy
conformers indicated that a restricted conformational space was adopted by the conformers.
Nevertheless, it is evident that the conformational rigidity of catalyst 9 is higher than that of 7,
which confirms the NMR behavior of both catalysts. The notation used to represent the
conformations of catalysts 7 and 9 was focused on the plane through the tertiary amide bond.
As can be seen in the graphical representation of Table 5, the Ph- and NH-cyclohexyl groups
were selected to define either the positive (+) or negative (-) orientation of the dihedrals Ψ1
and Ψ2 (see in Tables S2 and S4 of SI-B the assignment in each conformer of this notation).
After examination of dihedral orientation of the different conformers of catalysts 7 (Table 5),
a ratio of 42:58 of cis/trans isomers was determined. In contrast, conformational analysis of
catalyst 9 revealed an inversion in the equilibrium – with a ratio of 98:2 of cis/trans isomers –
as well as a marked difference in the orientations of the dihedrals compared to catalyst 7.
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Table 5. Graphical representation and excerpt of dihedral distribution for catalysts 7 and 9.
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
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26
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Ψ1(+)/Ψ2(-)
Ψ1(-)/Ψ2(+)
Ψ1(+)/Ψ2(+)
Ψ1(-)/Ψ2(-)
0.0
0.1
42.0
17.3
0.0
39.2
0.0
2.6
0.7
cis
trans
cis
Cat 7
(R = H)
15.2
9.9
17.3
0.0
53.6
Cat 9
( R = Me)
0.0
1.9
trans
The fact that cis-conformers of 9 (R = Me) are lower in energy – and thus most populated –
than those of catalyst 7 (R = H), seems to be a crucial factor to understand the difference in
the enantioselectivities. As depicted in figure 2, partial shielding to one of the pyrrolidine-ring
faces is observed in the low-energy clustered conformers of both 7 and 9, albeit this is indeed
more marked in the case of catalyst 9 that is populated in 98% with cis-conformers. To further
confirm these results experimentally, two NOESY spectra were recorded for catalyst 9 in
CDCl3 in order to determine the disposition of the peptidic chain with respect to the
pyrrolidine faces (see the Supporting Information A). Initially, a NOESY spectrum with
irradiation of the CH signal of the methylbenzyl N-substituent at 5.11 ppm showed NOE
effects with one of the methylene β-protons of proline, which proves the cis configuration
proposed by molecular modeling. Alternatively, a second NOESY experiment was
accomplished with irradiation of the signal (NH) of the cyclohexylamide at 5.74 ppm,
resulting in NOE effects with protons of the cyclohexyl ring, with the ortho protons of the
phenyl ring, with one of the gem-dimethyl groups of the Aib residue and with a β-proton of
proline. However, the lack of NOE effect of the α-proton proline at 4.30 ppm – positioned at
the non-substituted pyrrolidine face – is a clear indication that the peptidic skeleton is located
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directing to the substituted pyrrolidine face. This fully agrees with the cis-isomer structures of
catalyst 9 shown in figure 2, 3 and 5, wherein the terminal cyclohexyl moiety is positioned at
the opposed face of the proline α-proton, thus setting free the non-substituted face upon the
enamine formation and further addition to the Michael acceptor. Indeed, such a shielding
effect over a specific pyrrolidine face is biased by the proline stereochemistry, and it is
hypothesized to be reversed in a catalyst having the opposite configuration at the proline and
methylbenzyl stereocenters.
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To assess whether the blocking of one of the pyrrolidine faces remains upon enamine
formation, a conformational search was performed for the anti enamine derived from catalyst
9 and the aliphatic aldehyde. As shown in figure 3, the optimized lowest-energy structure of
the enamine with E configuration shows a significant shielding of the peptidic skeleton to the
Re-face, which according to the Seebach’s topological model explains the high
enantioselection provided by catalyst 9.
Figure 3. Lowest-energy structure of the anti enamine derived from catalyst 9.
As shown in figure 4, conformational analysis of 7 shed additional light into the cis-trans
isomerization. We detected that the most populated trans-conformers of 7 were the Ψ1-
dihedral rotamers 11-trans (38%) and 36-trans (13%). Another significant feature was the
relative orientation of dihedrals Ψ1 and Ψ2. Thus, cis-conformers of 7 adopt a Ψ1(-)/Ψ2(+)
orientation and trans-conformers a Ψ1(+)/Ψ2(-), with both the Ph and N-cyclohexyl groups
positioned in an opposite direction. We also noticed a persistent hydrogen bonding (HB)
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between the oxygen lone pairs LPO(1 and 2) of the tertiary amide carbonyl group and the
pyrrolidine σ*N−H group (NH--O=C) in a wide set of conformers of catalyst 7 (see S1 section
in Supporting Information B). In addition, we investigated the transition states TS-1 that
represents the cis-trans equilibration from the more populated 11-trans (31%) to 20-cis (26%)
conformers. The result was an activation energy of 21 kcal/mol, which explains the detection
of both configurational isomers of catalyst 7 in the NMR time-scale. The natural bond orbital
(NBO) analysis of selected structures 36-trans, 11-trans, TS-1 and 20-cis showed
delocalization energies in the range from 1.64 to 4.57 kcal.mol-1. The geometries, Boltzmann
population, and Gibbs energies of conformers involving the main cis-trans isomerization of
catalyst 7 are also represented in Figure 4.
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11
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Interestingly, an additional stabilizing intramolecular seven-membered rings hydrogen-
bonded was detected, which involves the same LPO(1 and
and the amide σ*N−H group
2)
(CONH--O=C) of the more hindered 20-cis conformer, with energy of 6.12 kcal.mol-1 (see
Supporting Information B). This explains the slightly higher stability of the lowest-energy 11-
trans isomer compared with 20-cis. Although such a hydrogen bonding may be relevant for
this analysis only in the ground state of the catalyst, it must be noted that is even preserved in
the TS-1, comprising a high stabilization energy of 11.55 kcal.mol-1.
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Figure 4. Relevant low-Gibbs energy cis-trans conformers and transition state of catalyst 7 at
M06-2X/6-31+G(d,p)//M06-2X/6-31G(d) [SDM, chloroform] level.
As depicted in figure 5, conformational analysis of catalyst 9 revealed that 1-trans (2%) and
the lowest-energy 26-cis (33%) conformers adopted a Ψ1(-)/Ψ2(-) orientation, directing
axially (according to the imaginary plane of the tertiary amide carbonyl) to the methyl group
of (S)-α-MeBn N-substituent. This orientation is directed by steric clashes involving the
equatorial N-alkyl H ꢀ Me interaction presented in 1-trans, while the Me ꢀ Me interaction
increases the energy of 17-cis (8%) – a Ψ1 dihedral-rotamer of 26-cis (Figure 3) – in 1
kcal.mol-1. Similarly to catalyst 7, it was observed for 9 a persistent hydrogen bonding
involving the pyrrolidine σ*N−H group (NH--O=C) (see S2 section in the SI). NBO analysis of
structures 1-trans and its rotamer (not located by MM conformational search and drawn
manually), as well as 17-cis, 26-cis, and TS-2, showed delocalization energies in the range of
1.68 to 4.59 kcal.mol-1. Interestingly, the located transition state TS-2 comprises an activation
energy of 15 kcal.mol-1 (6 kcal.mol-1 lower in energy than that observed for catalyst 7), which
allows for a relatively fast shift of the equilibrium to the less energetic cis isomer.
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Figure 5. Relevant low-Gibbs energy cis-trans amide conformers and transition state of
catalyst 9 at M06-2X/6-31+G(d,p) // M06-2X/6-31G(d) [SDM, chloroform] level.
The additional intramolecular hydrogen-bonded seven-membered ring (CONH--O=C) was
absented in the lowest-energy conformer 26-cis, but it was founded in the 17-cis conformer
(8.26 kcal.mol-1) and in the TS-2 (13.76 kcal.mol-1) as well. Unexpectedly, the TS-2 leads to a
shorten HB than TS-1 (1.886 Å and 1.952 Å, respectively), thus reflecting the crowed
transition structure. The geometries, Boltzmann population, and Gibbs energies of these
representative structures are represented in figure 5.
Conclusion
This study showed that solution-phase combinatorial approaches based on isocyanide-based
MCRs are convenient tools for the discovery of organocatalysts for asymmetric organic
transformations. We have illustrated this by the Ugi-4CR-based generation of a small
combinatorial collection of new prolyl peptide-peptoid hybrids and the screening of their
catalytic efficacy in the asymmetric conjugate addition of aldehydes to nitroolefins. Thus,
variation of three elements of diversity at the Ugi-derived N-substituted peptide led to the
discovery of catalysts providing good to excellent stereocontrol and catalytic efficacy, while
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provided new insights into their structure catalytic-activity relationship. A conformational
study explained the greater conformational rigidity and stereoselection provided by catalyst 9,
bearing the N-substituted amino acid Aib as C-terminal residue, compared to 7 that has Gly at
the same position. Considering the diversity-oriented character of MCRs, further exploitation
of this capacity in the combinatorial discovery of catalysts is foreseeable.
10
11
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Experimental Section
General
Melting points are uncorrected. 1H NMR and 13C NMR spectra were recorded at 400 MHz for
1H and 100 MHz for 13C, respectively. Chemical shifts (δ) are reported in parts per million
relative to tetramethylsilane (TMS), and coupling constants (J) are reported in hertz. High
resolution ESI mass spectra were obtained from a Fourier transform ion cyclotron resonance
(FT-ICR) mass spectrometer, an RF-only hexapole ion guide and an external electrospray ion
source. Flash column chromatography was carried out using silica gel 60 (230-400 mesh) and
analytical thin layer chromatography (TLC) was performed using silica gel aluminum sheets.
HPLC chromatograms were obtained on an apparatus with a LC-10AT Pump, SPD-10A UV-
Vis Detector, SCL-10A System Controller, using a Chiralpak AD-H (4,6 mmØ × 250 mmL,
particle size 5 ꢀm). Optical rotations were measured with a Polarimeter at 589 nm, 30 °C.
General Ugi-4CR-based procedure: A suspension of the amine (1.0 mmol) and the
aldehyde (or ketone) (1.0 mmol) in MeOH (5 mL) was stirred for 1 h at room temperature.
NEt3 (1.0 mmol) was added when α-amino acid methyl ester hydrochlorides were employed.
The carboxylic acid (1.0 mmol) and the isocyanide (1.0 mmol) were then added and the
reaction mixture was stirred at room temperature for 24 h. The volatiles were concentrated
under reduced pressure and the resulting crude product was dissolved in 100 mL of CH2Cl2.
The organic phase was washed sequentially with aqueous saturated solution of citric acid (50
mL), aqueous 10% NaHCO3 (50 mL), and brine (50 mL), and then dried over anhydrous
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Na2SO4 and concentrated under reduced pressure. The resulting amorphous solid was used in
the Boc deprotection step without further purification.
6
7
8
9
Microwave-assisted Ugi-4CR-based: The amine (1.0 mmol) and the aldehyde (1.0 mmol)
were dissolved in MeOH (5 mL) and added to a 10 mL glass tube. NEt3 (1.0 mmol) was
added when α-amino acid methyl ester hydrochlorides were employed. The suspension was
treated with the carboxylic acid (1.0 mmol) and the isocyanide (1.0 mmol) and the glass tube
was sealed and introduced in the microwave reactor. The flask was irradiated for 30 min (150
W) under high-speed magnetic stirring, while the temperature was raised up to 70 °C. The
reaction course was monitored by TLC, and additional cycles of 30 min were applied in cases
of poor consumption of the starting material. The volatiles were concentrated under reduced
pressure and the resulting crude product was dissolved in 100 mL of CH2Cl2. The organic
phase was washed sequentially with aqueous saturated solution of citric acid (50 mL),
aqueous 10% NaHCO3 (2×50 mL), and brine (50 mL), and then dried over anhydrous Na2SO4
and concentrated under reduced pressure. The resulting amorphous solid was used in the Boc
deprotection step without further purification.
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11
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General Boc deprotection procedure: The crude product resultant form the Ugi-4CR was
dissolved in 3 mL of CH2Cl2 and treated with 1 mL of trifluoroacetic acid at 0 °C. The
reaction mixture was allowed to reach room temperature, stirred for 4 h and then concentrated
to dryness (TFA was removed completely by repetitive addition and evaporation of further
CH2Cl2). The crude product was re-dissolved in 10 mL of CH2Cl2, treated with solid K2CO3
until basic pH and the solution was filtered and evaporated under reduced pressure.
Peptide-peptoid hybrid 1: HCl⋅Gly-OMe (125 mg, 1 mmol), triethylamine (140 µL, 1
mmol) paraformaldehyde (30 mg, 1 mmol), Boc-L-Pro-OH (215 mg, 1 mmol) and
cyclohexylisocyanide (125 µL, 1 mmol) were reacted in MeOH (5 mL) according to the
general Ugi-4CR-based procedure. The resulting Boc protected compound was subjected to
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the general deprotection procedure. Flash column chromatography purification
4
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6
(MeOH/EtOAc 4:1) afforded peptide-peptoid hybrid 1 (254 mg, 78%) as a colorless oil. Rf =
7
8
0.25 (n-hexane/EtOAc 1:1).
-15.1 (c 0.62, MeOH, 25°C). A mixture of conformers in a
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6:4 ratio was observed by NMR. H NMR (400 MHz, CDCl3): δ = 1.09-1.40 (m, 6H); 1.55-
1.95 (m, 6H); 1.99-2.17 (m, 3H); 2.41 (m, 1H); 3.37-3.50 (m, 2H); 3.67-3.80 (m, 1H); 3.76,
3.80 (2×s, 3H); 4.10 (d, 1H, J = 17.2 Hz); 4.15 (m, 1H); 4.31 (d, 1H, J = 17.2 Hz); 4.96 (m,
1H); 6.95, 7.48 (2×d, 1H, J = 8.0 Hz). 13C NMR (100 MHz, CDCl3): δ = 24.8, 24.9, 25.3,
29.0, 32.5, 46.4, 49.4, 51.7, 52.7, 53.4, 57.9, 165.9, 169.6, 170.1. HRMS (ESI-FT-ICR) m/z:
326.2072 [M+H]+; calcd. for C16H28N3O4: 326.2069.
Peptide-peptoid hybrid 2: HCl⋅Val-OMe (168 mg, 1 mmol), triethylamine (140 µL, 1
mmol) paraformaldehyde (30 mg, 1 mmol), Boc-L-Pro-OH (215 mg, 1 mmol) and
cyclohexylisocyanide (125 µL, 1 mmol) were reacted in MeOH (5 mL) according to the
microwave-assisted Ugi-4CR-based procedure, using two cycles of 30 min. The resulting Boc
protected compound was subjected to the general deprotection procedure. Flash column
chromatography purification (MeOH/EtOAc 4:1) afforded peptide-peptoid hybrid 2 (297.7
mg, 81%) as a colorless oil. Rf = 0.45 (n-hexane/EtOAc 1:1).
-56.1 (c 0.56, MeOH,
1
25°C). A mixture of conformers in a 7:3 ratio was observed by NMR. H NMR (400 MHz,
CDCl3): δ = 0.87 (d, 3H, J = 6.6 Hz); 0.98 (d, 3H, J = 6.6 Hz); 1.06-1.39 (m, 5H); 1.54-1.91
(m, 5H); 1.94-2.54 (br. m, 5H); 3.16-3.34 (m, 1H); 3.38-3.53 (m, 2H); 3.72, 3.74 (2×s, 3H);
3.62-3.76 (m, 1H); 3.95, 4.15 (2×d, 1H, J = 16 Hz); 4.13, 4.25 (2×d, 1H, J = 18 Hz); 3.81,
4.46 (2×d, 1H, J = 10.4/9.7 Hz); 4.78, 4.85(2×m, 1H); 6.59, 7.11 (2×d, 1H, J = 7.8 Hz). 13C
NMR (100 MHz, CDCl3): δ = 15.8, 20.0, 21.7, 24.6, 25.5, 29.5, 30.9, 32.8, 32.9, 44.5, 48.2,
51.1, 58.8, 67.6, 163.1, 167.5, 168.2. HRMS (ESI-FT-ICR) m/z: 368.2543 [M+H]+; calcd. for
C19H34N3O4: 368.2538.
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Peptide-peptoid hybrid 3: HCl⋅Leu-OMe (182 mg, 1 mmol), triethylamine (140 µL, 1
5
6
mmol) paraformaldehyde (30 mg, 1 mmol), Boc-L-Pro-OH (215 mg, 1 mmol) and
7
8
9
cyclohexylisocyanide (125 µL, 1 mmol) were reacted in MeOH (5 mL) according to the
microwave-assisted Ugi-4CR-based procedure, using two cycles of 30 min. The resulting Boc
protected compound was subjected to the general deprotection procedure. Flash column
chromatography purification (MeOH/EtOAc 4:1) afforded peptide-peptoid hybrid 3 (324 mg,
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85%) as a colorless oil. Rf = 0.50 (n-hexane/EtOAc 1:1).
-42.7 (c 0.66, MeOH, 25°C). A
mixture of conformers in a 7:3 ratio was observed by NMR. 1H NMR (400 MHz, CDCl3): δ =
0.84-1.00 (m, 6H); 1.07-1.39 (m, 5H); 1.54-1.91(m, 7H); 1.98-2.23 (m, 2H); 2.44 (m, 1H);
3.05 (br. s, 1H); 3.40-3.50 (m, 2H); 3.64-3.71 (m, 2H); 3.74 (s, 3H); 4.04 (d, 1H, J = 18.2
Hz); 4.19 (d, 1H, J = 18.2 Hz); 4.32 (2×d, 1H, J = 8.8/5.1 Hz); 4.66 (t, 1H, J = 7.1 Hz ); 4.79
(t, 1H, J = 7.1 Hz); 6.59, 7.56 (2×d, 1H, J = 7.7 Hz). 13C NMR (100 MHz, CDCl3): δ = 22.1,
22.4, 24.6, 24.9, 25.0, 25.3, 29.1, 32.3, 37.6, 38.4, 46.2, 49.2, 49.4, 52.7, 58.1, 58.3, 166.5,
170.4, 172.2. HRMS (ESI-FT-ICR) m/z: 382.2700 [M+H]+; calcd. for C20H36N3O4: 382.2698.
Peptide-peptoid hybrid 4: HCl⋅Ile-OMe (182 mg, 1 mmol), triethylamine (140 µL, 1 mmol)
paraformaldehyde (30 mg,
1
mmol), Boc-
L-Pro-OH (215 mg,
1
mmol) and
cyclohexylisocyanide (125 µL, 1 mmol) were reacted in MeOH (5 mL) according to the
microwave-assisted Ugi-4CR-based procedure, using two cycles of 30 min. The resulting Boc
protected compound was subjected to the general deprotection procedure. Flash column
chromatography purification (MeOH/EtOAc 4:1) afforded peptide-peptoid hybrid 4 (294 mg,
77%) as a colorless oil. Rf = 0.50 (n-hexane/EtOAc 1:1).
-59.1 (c 0.65, MeOH, 25°C). A
mixture of conformers in a 1:1 ratio was observed by NMR. 1H NMR (400 MHz, CDCl3): δ =
0.86 (t, 3H, J = 7.35 Hz); 0.94 (d, 3H, J = 6.5 Hz); 1.01-1.44 (m, 6H); 1.49-2.26 (m, 10H);
2.40, 2.49 (2×m, 1H); 3.46 (m, 2H); 3.63-3.71 (m, 1H); 3.73 (s, 3H); 4.02, 4.16 (2×d, 1H, J =
16.0 Hz); 4.14, 4.26 (2×d, 1H, J = 18.2 Hz); 3.88, 4.66 (2×d, 1H, J = 10.0 Hz); 4.81, 4.90
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(2×t, 1H, J = 8.0 Hz); 6.46, 6.85 (2×d, 1H, J = 8.0 Hz). 13C NMR (100 MHz, CDCl3): δ =
11.4, 15.7, 24.8, 25.2, 25.3, 25.6, 29.5, 32.4, 34.1, 46.3, 46.6, 47.00, 47.8, 48.9, 52.6, 58.4,
63.1, 166.6, 169.4, 170.9. HRMS (ESI-FT-ICR) m/z: 382.2700 [M+H]+; calcd. for
C20H36N3O4: 382.2695.
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Peptide-peptoid hybrid 5: HCl⋅Phe-OMe (216 mg, 1 mmol), triethylamine (140 µL, 1
mmol) paraformaldehyde (30 mg, 1 mmol), Boc-L-Pro-OH (215 mg, 1 mmol) and
cyclohexylisocyanide (125 µL, 1 mmol) were reacted in MeOH (5 mL) according to the
microwave-assisted Ugi-4CR-based procedure, using two cycles of 30 min. The resulting Boc
protected pseudo-peptide was subjected to the general deprotection procedure. Flash column
chromatography purification (MeOH/EtOAc 4:1) afforded peptide-peptoid hybrid 5 (345 mg,
83%) as a light yellow oil. Rf = 0.35 (n-hexane/EtOAc 1:1).
-87.6 (c 0.47, MeOH,
1
25°C). A mixture of conformers in a 7:3 ratio was observed by NMR. H NMR (400 MHz,
CDCl3): δ = 1.06-1.43 (m, 5H); 1.52-1.99 (m, 5H); 2.08 (m, 2H); 2.30 (m, 1H); 3.22-3.54 (m,
4H); 3.66 (m, 1H); 3.77 (s, 3H); 4.20 (m, 1H); 4.25 (dd, 1H, J = 10.0/5.9 Hz); 4.55 (dd, 1H, J
= 7.2 Hz); 7.12-7.14 (m, 1H); 7.18-7.38 (m, 4H); 7.71 (d, 1H, J = 7.8 Hz). 13C NMR (100
MHz, CDCl3): δ = 24.7, 24.9, 25.0, 25.3, 29.1, 32.4, 34.4, 46.1, 49.2, 52.6, 53.0, 57.9, 63.8,
127.5, 128.4, 129.0, 129.2, 129.9, 136.2, 165.4, 169.5, 170.4. HRMS (ESI-FT-ICR) m/z:
416.2541 [M+H]+; calcd. for C23H34N3O4: 416.2535.
Peptide-peptoid hybrid 6: HCl⋅tBuGly-OMe (182 mg, 1 mmol), triethylamine (140 µL, 1
mmol) paraformaldehyde (30 mg, 1 mmol), Boc-L-Pro-OH (215 mg, 1 mmol) and
cyclohexylisocyanide (125 µL, 1 mmol) were reacted in MeOH (5 mL) according to the
microwave-assisted Ugi-4CR-based procedure, using three cycles of 30 min. The resulting
Boc protected compound was subjected to the general deprotection procedure. Flash column
chromatography purification (MeOH/EtOAc 4:1) afforded peptide-peptoid hybrid 6 (233 mg,
61%) as a colorless oil. Rf = 0.55 (n-hexane/EtOAc 1:1).
-5.9 (c 0.43, MeOH, 25°C). A
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7
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9
mixture of conformers in a 1:1 ratio was observed by NMR. 1H NMR (400 MHz, CDCl3): δ =
1.05, 1.09 (2×s, 9H); 1.00-1.43 (m, 3H); 1.55-2.02 (m, 13H); 2.19 (m, 1H); 2.50 (m, 1H);
2.81 (m, 1H); 3.13 (m, 1H); 3.55-3.65 (m, 1H); 3.73, 3.80 (2×s, 3H); 3.67-3.77 (m, 1H); 4.12
(dd, 1H, J = 7.7/3.1 Hz); 4.18, 4.29 (2×d, 1H, J = 18.4 Hz); 5.12 (s, 1H). 13C NMR (100
MHz, CDCl3): δ = 23.2, 25.1, 25.4, 25.6, 27.8, 28.1, 28.6, 30.8, 32.8, 36.4, 45.6, 47.8, 50.7,
51.8, 59.2, 62.0, 164.3, 169.6, 170.0 HRMS (ESI-FT-ICR) m/z: 382.2700 [M+H]+; calcd. for
C20H36N3O4: 382.2695.
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Peptide-peptoid hybrid 7: (S)-α-Methylbenzylamine (128 µL, 1 mmol), paraformaldehyde
(30 mg, 1 mmol), Boc-L-Pro-OH (215 mg, 1 mmol) and cyclohexylisocyanide (125 µL, 1
mmol) were reacted in MeOH (5 mL) according to the general Ugi-4CR-based procedure.
The resulting Boc protected compound was subjected to the general deprotection procedure.
Flash column chromatography purification (MeOH/EtOAc 4:1) afforded peptide-peptoid
hybrid 7 (325 mg, 91%) as a colorless oil. Rf = 0.55 (n-hexane/EtOAc 1:1).
-62.8 (c
0.64, MeOH, 25°C). A mixture of conformers in a 6:4 ratio was observed by NMR. 1H NMR
(400 MHz, CDCl3): δ = 1.01-1.36 (m, 5H); 1.49, 169 (2×d, 3H, J = 7.2 Hz); 1.47-1.84 (m,
4H); 2.17 (m, 2H); 3.40, 2.54 (2×m, 1H); 2.85 (br. m, 1H); 3.45 (m, 2H); 3.61 (m, 1H); 3.71,
3.89 (2×d, 1H, J = 18.0 Hz); 3.51, 3.93 (2×d, 1H, J = 16.0 Hz); 4.70, 5.10 (2×m, 1H); 5.87,
6.35 (2×q, 1H, J = 7.25 Hz); 7.22-7.40 (m, 5H); 7.72 (br. s, 1H). 13C NMR (100 MHz,
CDCl3): δ = 17.4; 24.9, 25.3, 29.8, 32.2, 32.5, 46.1, 46.6, 48.7, 49.2, 55.6, 58.2, 60.4, 127.1,
127.4, 128.6, 128.8, 129.1, 137.7, 162.7, 166.5. HRMS (ESI-FT-ICR) m/z: 358.2489 [M+H]+;
calcd. for C21H32N3O2: 358.2483.
Peptide-peptoid hybrid 8: Benzylamine (110 µL, 1 mmol), paraformaldehyde (30 mg, 1
mmol), Boc-L-Pro-OH (215 mg, 1 mmol) and cyclohexylisocyanide (125 µL, 1 mmol) were
reacted in MeOH (5 mL) according to the general Ugi-4CR-based procedure. The resulting
Boc protected compound was subjected to the general deprotection procedure. Flash column
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chromatography purification (MeOH/EtOAc 4:1) afforded peptide-peptoid hybrid 8 (639 mg,
4
5
6
93%) as a pale green oil. Rf = 0.35 (n-hexane/EtOAc 1:1).
-21.1 (c 0.41, MeOH, 25°C).
7
8
9
A mixture of conformers in a 7:3 ratio was observed by NMR. 1H NMR (400 MHz, CDCl3): δ
= 1.05-1.37 (m, 5H); 1.52-1.85 (m, 4H); 1.96-2.10 (m, 3H); 2.23, 2.38 (2×m, 1H); 2.83 (br. s,
1H); 3.39-3.55 (m, 2H); 3.69 (m, 1H); 3.97 (m, 2H); 4.66 (m, 2H); 4.79, 4.90 (2×m, 1H); 6.76
(d, 1H, J = 8.0 Hz); 7.18-7.40 (m, 5H). 13C NMR (100 MHz, CDCl3): δ = 24.8, 25.0, 25.4,
29.5, 32.5, 45.9, 48.8, 49.3, 50.8, 52.2, 58.3, 127.3, 128.3, 128.5, 128.9, 129.3, 134.2, 166.4,
170.0. HRMS (ESI-FT-ICR) m/z: 344.2331 [M+H]+; calcd. for C20H30N3O2: 344.2328
Peptide-peptoid hybrid 9: (S)-α-Methylbenzylamine (128 µL, 1 mmol), acetone (74 µL, 1
10
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12
13
14
15
16
17
18
19
20
21
22
23
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51
52
53
54
55
56
57
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59
60
mmol), Boc-L-Pro-OH (215 mg, 1 mmol) and cyclohexylisocyanide (125 µL, 1 mmol) were
reacted in MeOH (5 mL) according to the general Ugi-4CR-based procedure. The resulting
Boc protected compound was subjected to the general deprotection procedure. Flash column
chromatography purification (MeOH/EtOAc 4:1) afforded peptide-peptoid hybrid 9 (309 mg,
1
77%) as a colorless oil. Rf = 0.35 (n-hexane/EtOAc 1:1).
-1.9 (c 0.38, MeOH, 25°C). H
NMR (600 MHz, CDCl3): δ = 1.17-1.23 (m, 4H, CH2); 1.27-1.37 (m, 2H, CH2); 1.41-1.46 (m,
2H, CH2); 1.48 (s, 3H, CH3); 1.55 (m, 3H, CH3); 1.66-1.92 (m, 4H, CH2); 1.87 (d, 3H, J = 7.0
Hz, CH3); 2.13 (m, 1H, CH2); 2.33 (m, 1H, CH2); 3.24 (m, 2H, CH2); 3.37 (m, 1H, CH2); 3.60
(m, 1H, CH); 4.30 (m, 1H, CH); 5.11 (m, 1H, CH); 5.74 (d, 1H, J = 7.3 Hz, NH); 7.24 (t, 1H,
J = 7.5 Hz, CH); 7.36 (t, 2H, J = 7.6 Hz, CH); 7.57 (d, 2H, J = 7.7 Hz, CH). 13C NMR (150
MHz, CDCl3): δ = 19.2 (CH3); 24.3, 24.7, 24.9, 25.0, 25.5 (CH2); 27.8, 28.4 (CH3); 28.9,
32.7, 46.3 (CH2); 48.9, 51.8, 59.7 (CH); 64.9 (C); 127.3, 128.0, 129.2 (CH); 140.8 (C); 170.8,
173.4 (C=O). HRMS (ESI-FT-ICR) m/z: 386.2800 [M+H]+; calcd. for C23H36N3O2: 386.2802.
Peptide-peptoid hybrid 10: Benzylamine (110 µL, 1 mmol), acetone (74 µL, 1 mmol), Boc-
L-Pro-OH (215 mg, 1 mmol) and cyclohexylisocyanide (125 µL, 1 mmol) were reacted in
MeOH (5 mL) according to the general Ugi-4CR-based procedure. The resulting Boc
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protected compound was subjected to the general deprotection procedure. Flash column
4
5
6
chromatography purification (MeOH/EtOAc 4:1) afforded peptide-peptoid hybrid 10 (229
7
8
mg, 73%) as a colorless oil. Rf = 0.35 (n-hexane/EtOAc 1:1).
-20.6 (c 0.41, MeOH,
9
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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32
33
34
35
36
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41
42
43
44
45
46
47
48
49
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53
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59
60
25°C). H NMR (400 MHz, CDCl3): δ = 1.06-1.39 (m, 5H); 1.46 (s, 3H); 1.50 (s, 3H); 1.55-
1.75 (m, 3H); 1.78-2.06 (m, 6H); 3.03 (br. m, 1H); 3.40 (m, 2H); 3.68 (m, 1H); 4.69 (m, 1H);
13
4.76 (d, 2H, J = 6.91 Hz); 5.98 (d, 1H, J = 8.0 Hz); 7.22-7.44 (m, 5H). C NMR (100 MHz,
CDCl3): δ = 24.1, 24.5, 24.9, 25.4, 29.7, 32.6, 32.7, 46.0, 47.9, 48.8, 58.9, 64.1, 126.4, 128.0,
129.2, 136.9, 169.9, 173.0. HRMS (ESI-FT-ICR) m/z: 372.2651 [M+H]+; calcd. for
C22H33N3O2: 372.2654.
Peptide-peptoid hybrid 11: (S)-α-Methylbenzylamine (128 µL, 1 mmol), paraformaldehyde
(30 mg, 1 mmol), Boc-L-Pro-OH (215 mg, 1 mmol) and t-butylisocyanide (125 µL, 1 mmol)
were reacted in MeOH (5 mL) according to the general Ugi-4CR-based procedure. The
resulting Boc protected compound was subjected to the general deprotection procedure. Flash
column chromatography purification (MeOH/EtOAc 4:1) afforded peptide-peptoid hybrid 11
(298 mg, 88%) as a light yellow oil. Rf = 0.55 (n-hexane/EtOAc 1:1).
-78.9 (c 0.65,
MeOH, 25°C). A mixture of conformers in a 8:2 ratio was observed by NMR. 1H NMR (400
MHz, CDCl3): δ = 1.23, (2×s, 6H); 1.49 (2×s, 3H); 1.46, 1.68 (2×d, 3H, J = 6.88 Hz); 1.87-
2.25 (m, 3H); 2.42, 2.58 (2×m, 1H); 3.32-3.55 (m, 1H); 3.61, 3.88 (2×d, 1H, J = 18.0 Hz);
3.45, 3.95 (2×d, 1H, J = 16.0 Hz); 4.98, 5.11 (2×m, 1H); 5.78 (m, 1H); 7.24-7.39 (m, 5H);
7.80 (br. s, 1H). 13C NMR (100 MHz, CDCl3): δ = 17.4, 24.9, 28.4, 28.5, 29.9, 46.9, 47.0,
51.3, 53.6, 55.5, 58.2, 125.8, 127.0, 128.6, 128.8, 129.2, 137.9, 167.2, 170.2. HRMS (ESI-FT-
ICR) m/z: 332.2330 [M+Na]+; calcd. for C19H30N3O2: 332.2327.
Peptide-peptoid hybrid 12: (S)-α-Methylbenzylamine (128 µL, 1 mmol), paraformaldehyde
(30 mg, 1 mmol), Boc-L-Pro-OH (215 mg, 1 mmol) and methyl isocyanoacetate (91 µL, 1
mmol) were reacted in MeOH (5 mL) according to the general Ugi-4CR-based procedure.
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The resulting Boc protected compound was subjected to the general deprotection procedure.
Flash column chromatography purification (MeOH/EtOAc 4:1) afforded peptide-peptoid
6
7
8
hybrid 12 (590.6 mg, 82%) as a light yellow oil. Rf = 0.45 (n-hexane/EtOAc 1:1).
-18.9
9
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(c 0.65, MeOH, 25°C). A mixture of conformers in a 7:3 ratio was observed by NMR. H
NMR (400 MHz, CDCl3): δ =1.55, 1.71 (2×d, 3H, J = 6.8 Hz); 2.17 (m, 3H); 2.51 (m, 4H);
3.37-3.55 (m, 2H); 3.65, 3.70 (2×s, 3H); 3.62, 3.81 (2×d, 1H, J = 18.0 Hz); 3.55, 4.02 (2×d,
1H, J = 16.2 Hz); 4.69, 4.98 (2×m, 1H); 5.08, 5.95 (2×m, 1H); 7.22-7.36 (m, 5H); 8.35 (m,
1H). 13C NMR (100 MHz, CDCl3): δ = 17.4, 24.6, 29.1, 40.8, 45.6, 46.3, 52.2, 52.3, 55.6,
58.8, 127.0, 127.1, 128.6, 128.9, 129.0, 137.6, 168.8, 171.1. HRMS (ESI-FT-ICR) m/z:
348.1917 [M+H]+; calcd. for C18H25N3O4: 348.1915.
Peptide-peptoid hybrid 13: (S)-α-Methylbenzylamine (128 µL, 1 mmol), acetone (74 µL, 1
mmol), Boc-D-Pro-OH (215 mg, 1 mmol) and cyclohexylisocyanide (125 µL, 1 mmol) were
reacted in MeOH (5 mL) according to the general Ugi-4CR-based procedure. The resulting
Boc protected compound was subjected to the general deprotection procedure. Flash column
chromatography purification (MeOH/EtOAc 4:1) afforded peptide-peptoid hybrid 13 (317
mg, 77%) as a colorless oil. Rf = 0.36 (n-hexane/EtOAc 1:1).
+15.6 (c 0.44, MeOH,
1
25°C). H NMR (400 MHz, CDCl3): δ = 1.07-1.41 (m, 8H); 1.54 (s, 3H); 1.57 (s, 3H); 1.61
(m, 2H); 1.67-1.83 (m 2H); 1.87 (d, 3H, J = 7.2 Hz); 1.89-2.00 (m, 3H); 2.71 (m, 1H); 3.09
(m, 2H); 3.70 (m, 2H); 5.17 (m, 1H); 5.58 (d, 1H, J = 6.3 Hz); 7.28-7.27-7.41 (m, 3H); 7.49
(d, 2H, J = 8.0 Hz). 13C NMR (100 MHz, CDCl3): δ = 20.8, 25.2, 24.9, 25.6, 26.5, 28.5, 31.4,
32.9, 47.5, 48.4, 60.0, 64.4, 126.0, 127.2, 128.8, 142.2, 170.4, 173.9. HRMS (ESI-FT-ICR)
m/z: 386.2807 [M+H]+; calcd. for C23H36N3O2: 386.2802.
General procedure for the 1,4-addition of aldehydes to nitroolefins (Michael reaction):
The nitroolefin (0.25 mmol, 1.0 equivalent) and the aldehyde (0.75 mmol, 3.0 equivalents)
were added to a solution of the pseudo-peptide (0.025 mmol, 0.01 equivalent.) in the solvent
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