A study of the: Cis - Trans isomerization preference of N -alkylated peptides containing phosphorus in the side chain and backbone

Article abstract of DOI:10.1039/c9nj02234a

The current work provides a study on the cis-trans isomerization behaviour of N-alkylated peptides decorated with phosphonate ester groups. A Ugi four-component reaction was chosen for the synthesis of N-alkylated peptides, where almost only the cis isomer was detected when the phosphonate ester group was incorporated as an amine component in the side chain. However, the phosphonate ester group inserted in the backbone, as an isocyanide component, leads preferably to the trans isomer of this kind of peptides. The diverse behaviour of cis-trans isomerization has been explained via spectroscopic nuclear magnetic resonance analysis and computational calculations.

Full text of DOI:10.1039/c9nj02234a

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DOI: 10.1039/C9NJ02234A
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The study of cis–trans isomerization preference of N–alkylated
peptides containing phosphorus in the side chain and backbone.
a
b
a
c
Alexander F. de la Torre, * Akbar Ali, Odette Concepcion, Ana L. Montero-Alejo, Francisco M.
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
a
d
Muñiz, Claudio A. Jiménez, Julio Belmar, José Luis Velázquez–Libera, Erix W. Hernández
Rodríguez, * and Julio Caballero
–
e
d
DOI: 10.1039/x0xx00000x
The current work provides a study on the cis
–
trans isomerization behaviour of N–alkylated peptides decorated with
phosphonate ester group. Ugi four–component reaction was chosen for the synthesis of N–alkylated peptides, where almost
only the cis isomer was detected when the phosphonate ester group was incorporated as amine component in the side
chain. However, the phosphonate ester group inserted in the backbone, as an isocyanide component, leads preferably to
the trans isomer of this kind of peptides. The diverse behaviour of cis–trans isomerization has been explained via
spectroscopic nuclear magnetic resonance analysis and computational calculations.
Introduction
Phosphopeptides are the class of pseudopeptides in which at
least an amide linkage or C–terminal carboxyl group has been
replaced by
a
phosphoryl, phosphonate ester or
1
phosphonamide functional group. In nature, this class of
compounds represents a versatile group of chemical scaffolds
1
,2
with many biological applications. In this context, it is worth
mentioning that phosphonate moieties inserted in several
1
,3
chemical structures are associated with strong antimicrobial,
4
5
antiparasitic and antiviral activities. Today, the crisis of
bacterial resistance to the antibiotics" is a concern for the
"
pharmaceutical industries and public health sectors around the
globe. One possible solution to this end is to introduce
foldamers to the drug market as a non–biocidal class of
6
,7
compounds to eradicate bacterial resistance. Thus, foldamers
might be the best choice against diseases that are not possible
to treat with small organic molecules. N–alkylated peptides or
Figure 1. Cis
–
trans amide isomerism (A and B) driven by intramolecular n→π* or/and
12, 14
hydrogen interactions occurring in N–alkylated peptides.
C) The current work.
‘
peptoids’ are a class of foldamers constructed to mimic In this scenario, various studies have been focused on the cis–
8
,9
properties of peptides.
Solution– and solid–phase peptide trans amide isomerism, principally on peptoids carrying the
1
1
synthesis are the most recently used techniques to obtain N– main backbone structure like N–alkylglycine peptide, where
1
0
alkylated peptides in an adequate way. Importantly, a well– intramolecular n→π* interactions contribute considerably to
established amino acid sequence may be used to insert the the conformational distribution
Notwithstanding, n→π*
.
desired side chain in N–alkylated peptides structures that could interactions between the carbonyl oxygen of amides and the
be employed for conformational investigations. However, the electron–deficient aromatic group is crucial to induce the
1
2
major challenge is to control the cis/trans conformation yield at controlled production of cis over trans isomer. Besides, the α–
the tertiary amide bond of N–alkylated peptides.
chiral amide side chains also can lead to the conformational cis–
1
2a
trans equilibrium of N–alkylated peptides (Figure 1A).
Hydrogen bond (HB) also plays a pivotal role in the cis–trans
isomerization. In this aspect, N–hydroxy amide or hydroxamic
acid in the side chain of N–alkylated peptide has a preference
a.
Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad
de Concepción, Concepción, Chile. afernandezd@udec.cl
Department of Chemistry, University of Sargodha, 40100, Pakistan.
Departamento de Física, FCNMM, Universidad Tecnológica Metropolitana, José
b.
c.
1
3
for cis (Z) instead of trans (E) isomer.
Also, N–substituted
Pedro Alessandri 1242, Ñuñoa, 780-0002, Santiago, Chile;
MULTIMAT, Chile.
& Núcleo Milenio
amino acid Aib structures shows preference for cis
d.
e.
Centro de Bioinformática y Simulación Molecular (CBSM), Universidad de Talca, 1
Poniente No. 1141, Casilla 721, Talca, Chile.
Escuela de Química y Farmacia. Facultad de Medicina. Universidad Católica del
Maule, 3460000 Talca, Chile. ehernandez@ucm.cl
conformation, driven by an intramolecular HB as can be seen in
1
4
Figure 1B.
†
Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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Despite the numerous available reports on the structural Consequently, we have synthesized a library of sVeievweAnrttieclee nOnNlin–e
analysis of N–alkylated derivates, none describes the three– alkylated peptides with phosphorus atomDOliIn: 1k0e.1d03b9y/Cu9sNinJ0g2U23g4iA–
dimensional structural adaptation of phosphopeptides. 4CR; which induced a high molecular diversity by employing
Therefore, the conformational study of peptoids containing different amino acids (AA), dipeptides and lipidic analogues
phosphorus is of valuable academical, industrial and (Scheme 1 and Scheme 2). Initially, compounds 1, 2 and 3 have
commercial interest due to their potentialities to develop novel been individually chosen in order to match the substitution
therapeutic drugs. Thus, herein we present a study of the cis/ effect (R ) in the side chain. These compounds were achieved in
trans behaviour of synthesized N–alkylated peptides containing high to moderate yields (89%, 78%, and 52%, respectively) by
phosphorus as shown in Figure 1C.
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processing in a one–pot manner where the acetic acid,
paraformaldehyde, cyclohexyl isocyanide, and different amines
have been employed to explore the influence of the side chain
over the cis–trans amide isomerization (Scheme 1). In
compounds 1, 2, and 3, R substituent moieties correspond to
functions, respectively (Scheme
). The cis–trans proportion was determined by the NMR (1D)
Results and discussion
Isocyanide–based multicomponent reactions (IMCR) are
efficient protocols to assemble N–alkylated peptides in a single
operation either in solution or even in the solid phase
approach. A few reports have been referred to obtain N–
alkylated peptides containing phosphorus moiety by
2
α–H, (S)–α–Me and α–PO(OEt)
2
1
1
5
3
study in CDCl (Figure 2). The cis/trans ratio of compounds 1 and
2
was in agreement with similar N–alkylated peptides
1
4
1
1
6
previously reported in 2013. By comparing, the assigned H
multicomponent reactions – e.g. Ugi and Orru reactions –.
NMR spectra of compounds 1, 2 and 3, it is easy to identify that
compound 3 shows a preference towards a single isomer
Figure 2). Compounds 1 and 2 shows two broad signals
corresponding to the NH group (labelled as A, see Figure 2),
while compound 3 only shows one. These signals occur between
and 7 ppm, and the deshielded signals should correspond to
the isomer that involves the strongest non–covalent
intramolecular interaction with the NH group. It is also expected
Thus, our group, on the ongoing study of the rational design and
synthesis of new potential LasB inhibitor ligand with an
embedded phosphorus moiety through Ugi four–component
reaction (Ugi–4CR), we decided to investigate the amide bond
isomerization of the N–alkylated peptide obtained. To be more
precise, we restricted our study to the N–substituted amino acid
Gly compounds particularly where phosphonate ester group
(POEG) was incorporated either as an amine in the side chain or
isocyanide component in the backbone of the peptoids.
Besides, paraformaldehyde was mostly used as the oxo
(
5
2
that the CH groups that support R substitutions interact with
both, the carbonyl and methyl of the acetyl groups, and
consequently two signals of the CH groups should appear
whether both isomers are present. These are the cases of
compounds 1 and 2 with the signals (labelled as B in Figure 2) at
3
component (R = H) in the Ugi–4CR (see Scheme 1 and Scheme
2). However, aromatic and aliphatic aldehyde were also
introduced (e.g. compounds 7 and 8, Scheme 1). Compounds 3
to 8 were obtained with the commercially available amine
diethyl (α–aminobenzyl) phosphonate as racemic form.
4
.66/4.62 and 6.16/5.13 ppm, respectively.
Scheme 1. N–alkylated peptides model system structures 1–6 synthesized by Ugi–4CR.
Cis/trans ratios (K cis/trans) and corresponding free energy differences (ΔG).
2
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were employed instead of paraformaldehyde (compounds 7
and 8, Scheme 1). As we can observe inDOthI:e10 H and C NMR
spectra in Supporting Information (part A), for both
compounds, a diastereomeric ratio of 1:1 was obtained.
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1 13
.1039/C9NJ02234A
Unfortunately, this poor diastereoselectivity does not allow us
3
to clearly evaluate the effect of
isomerization.
R
on the cis/trans
The POEG was also incorporated into the backbone of the N–
alkylated peptide skeleton for the study of cis–trans
equilibrium. Diethylisocyanomethyl phosphonate was also
utilized in the Ugi–4CR protocol (Scheme 2). Both compounds 9
and 11 are the structural references of the peptoids 1 and 2,
excepting the changes on the isocyanide component. The
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combination of H, C, DEPT–135°, COSY, HSQC, and HMBC
spectra allowed to perform the assignment of all carbon and
proton of 9 as well as to reveal the preference of trans
conformer over the cis one, i.e., in a 3:1 trans/cis ratio (See
Supporting Information, Part A). The protons of NH group,
methylene of the peptide backbone and methyl of the acetyl
groups, are each distributed in two signals corresponding to the
presence of both isomers. Through the NOESY spectrum, a NOE
was detected between the methylene protons associated with
the side chain at 4.65 ppm and the methyl of the acetyl group
at 2.20 ppm, assigned to the trans isomer. To verify the
intramolecular interaction strengths that provide the ratio of
1
3
Figure 2. 400 MHz H NMR spectra in CDCl of compounds 1 (redline), 2 (greenline) and
3 (blueline). (A) correspond to NH of secondary amide and (B) correspond to protons of
CH groups that support R substitutions.
2
In contrast, the CH group linked to POEG in compound 3 shows
a single doublet signal at 5.92 ppm. The high chemical shift
corresponds to the strong intramolecular interaction with the
carbonyl group in the cis isomers. The complete assignment of
1
13
the H and C NMR spectra, and the bidimensional COSY, HSQC
and HMBC spectra of peptoid 3 explain that it should preferably
be in cis conformation (Supporting information, part A).
Consequently, the NOESY spectrum shows a cross peak
between the protons of methyl of the acetyl group and the
methylene group of the backbone peptidic skeleton (Xaa = Gly)
at 2.14 and 4.10–4.05 ppm, respectively. In addition, there is no
cross–peak of NOE between the signals at 5.92 ppm of CH
attached to POEG and methyl of the acetyl group (2.14 ppm),
which prevents the assignment of the trans conformation of this
compound.
1
isomers obtained, we measured the H–NMR spectrum of
compound 9 in four different deuterated solvents (CDCl
DMSO–d , D O, and CD OD). Table 1 shows the corresponding
3
,
6
2
3
Kcis/trans values. Notice that, unlike the experience with peptide
6
, here the trans/cis ratio is significantly affected while the
polarity of the solvent increases. This result suggests a weaker
intramolecular HB than that observed for compounds 3 and 6.
According to the structure, a seven–member ring formed by a
HB between the NH group with the carbonyl of the acetyl
groups (–NH∙∙∙∙O=C–) (see Table 1), could explain this sensitive
stabilization of the trans conformer.
The phosphonic acid group in the N–alkylated peptide
backbone lead to a slight drop in the Kcis/trans value (0.44 for
compound 10, Scheme 2). The insertion of the phosphonic acid
group (compound 10) increases the trans/cis amide conformer
ratio because the acidic OH groups can establish a HB with the
amide moiety, and compete with the HB between acetyl and
amide moiety (–C=O∙∙∙∙HN– ) as shown in Table 1.
We also introduce different substituent by changing the
isocyanide component in the Ugi–4CR. Subsequently,
compounds 4 and 5 were obtained maintaining the effect of the
PO(OEt)2 group in the side chain as in compound 3. NMR
analysis shows a high cis/trans ratio suggesting that stability is
governed by intramolecular interactions similar to those of
compound 3. However, the considerable ability to form
intramolecular interactions of the R anchor groups in 4 and 5,
could explain some stabilization of the trans conformers.
Additionally, we investigated the conformational behaviour of
4
compound
6 by using different acidic and isocyanide
Subsequently, we introduce a chiral substituent in the side
components (e.g. hexynoic acid and tert–butyl isocyanide).
Again, a preference for the cis isomer was detected for this
compound, which shows that neither a long chain as an acid
component nor bulkiest substituent affect the population of the
2
chain (R = (S)–α–Me) identifying that this steric hindrance has
no effects in the isomer ratio, having similar K cis/trans values for
both compounds 9 and 11. Similarly, a lipidic amino acid, as the
acid component inserted in the synthesized N–alkylated
1
adopted isomer (Scheme 1). We also recorded H–NMR spectra
14,15b
peptide,
induces predominantly a trans conformation of
in four different deuterated solvents (see Supporting
Information, Part A) in order to verify the interaction strengths
that provide this stereoselectivity. The polarity of the solvent
did not affect the cis conformation, suggesting that this N–
alkylated peptide variant is stabilized by strong intramolecular
interactions, as was interpreted above. In order to evaluate the
1
2 (see Scheme 2). Importantly, when the N–protected AA Boc–
Pro was employed as the acid component (compound 13)
instead of acetic acid, the cis/trans ratio was affected.
Moreover, the integrated aminoisobutyric (Aib) structures
(
compound 14) by using propanone as the oxo component of
N–alkylated peptide showed more favourable cis
a
3
effect of the oxo component R in the cis–trans isomerization of
peptoids, 4–hydroxybenzaldehyde and hydrocinnamaldehyde
conformation with respect to N–alkylglicine (compound 13).
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intramolecular interactions such as HB and could lead to an
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DOI: 10.1039/C9NJ02234A
increase in the cis population by decreasing the energetic
barrier of cis–trans isomerization. We also introduced POEG as
the isocyanide dipeptide (i.e., CN–Gly–Phg–PO(OEt)
preparation of N–alkylated tetrapeptide 15 (Scheme 2).
2
) for the
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Interestingly, even when the aforementioned trans
conformation should be more favourable for compound 15
however, the NMR analysis reveals the contrary, only the cis
rotamer was observed.
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Table 1. K cis/trans ratios for compound 9 in various deuterated solvents and their free
energies differences (ΔG) expressed in kcal/mol. The structural representation of
compound 9.
a
ΔG b
0.71
0.23
0.23
0.17
Solvent
CDCl
DMSO–d
K
cis/trans
0.29
0.67
0.67
0.75
3
6
D
2
O
CD
3
OD
1
a) Determined by H NMR spectroscopy analysis of 15 mM compound solutions at
RT x ln (K cis /trans) reported in kcal/mol.
25°C. b) ΔG cis /trans
= ̶
Under the same idea explored in compounds 7 and 8, we also
introduced the oxo component 4–hydroxybenzaldehyde and
hydrocinnamaldehyde into the skeleton of peptoids, but in this
case, the phosphorus atom is placed at the backbone of the
1
13
skeleton (compounds 16 and 17, Scheme 2). In the H and
C
NMR spectra of both compounds, solely the trans conformer
were observed (see Supporting Information, Part A). This
1
2
behaviour can be explained for the n→π*Ar interaction
between the carbonyl oxygen of the acetyl group and the
aromatic group employed as oxo component (R ) and do not by
3
HB as previously discussed. In order to assess which isomer was
obtained, we used compound 16 for further NMR spectroscopic
characterization (See Supporting Information, Part A). The
NOESY and ROESY experiments permits to ensure the
preference of trans conformer over cis. A NOE between the
protons of methyl related to the acetyl group at 2.06 ppm and
the protons of methylene associated with the benzyl group at
4
.65 ppm and 4.52 ppm has been detected. Also, a NOE
between the α–CH of 16 in the backbone at 5.77 ppm and the
protons of methyl at 2.06 ppm was observed. Besides, a NOE
between the methyl of the acetyl group at 2.06 ppm and the
3
protons of the aromatic ring in R also show that the preferred
isomer is the trans.
Computational analysis
1
8
A conformational analysis using the OPLS–2005 force–field
Scheme 2. Peptoids structures 9–17 with the cis/trans ratios (Kcis/trans) and their free
energy differences (ΔG).
19
and a GB/SA chloroform solvent model was performed to
achieve a better understanding of the cis/trans preference of
the synthesized N–alkylated peptides 3 and 9 by using Monte
Carlo multiple–minimum (MCMM) method as implemented in
Macromodel version 9.9. Thus, we were able to identify 228
conformers for each enantiomer (S)–3 or (R)–3 clustered in 11
and 15 groups, respectively; as well as 333 conformers clustered
in 28 groups corresponding to the compound 9 (see Supporting
Information, Part B) with energy within 5 kcal/mol. The low
The adopted structure by this type of backbone remains over a
beta–turn motif that is more favourable for the trans
conformation in the N–alkylated peptide. Thus, a unique
rotamer of Aib compound 14 has been identified by the NMR
analysis. The chain elongation of pseudopeptides usually causes
destabilization of the trans conformation as other
2
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energy structures of each group were recalculated at the ring; that kind of hydrogen bond (NH∙∙∙∙N) has been well
quantum mechanics (QM) level (M06–2X/6–31G(d)// M06– described in peptidic structures.
View Article Online
1,22 DOI: 10.1039/C9NJ02234A
2
On the other hand,
2
X/6–31+G(d, p)) considering the universal solvation model compound 9 is mainly represented by a structure stabilized by
based on the density (SMD) to simulate the effect of a seven–membered ring formed by a HB between the NH group
chloroform. This procedure leads to verify the quality of the and the carbonyl of the acetyl groups (–NH∙∙∙∙O=C–), which is
MCMM method in the conformational search since the type of very sensitive to the polarity of the solvent according to the
isomer or the number of non–redundant conformers practically NMR analysis. In addition, there are important interactions
did not change while using QM. There were only two involving the POEG in the analysed peptides that will be
conformations of 9 converging with each other. From the analysed below.
refined energies, electronic and Gibbs free, the analysis of The positive (+) and negative (–) orientations of the dihedrals φ
Boltzmann populations at 25 C shows that the representative (C=N–C
populations of these models of N–alkylated peptide in solution conformer (Tables S4 and S5, Supporting Information –Part B).
are in agreement with the NMR analysis. Compound 3, either S A unique cis isomer was calculated for the compound (S)–3
or R enantiomer, preferentially adopts cis conformations (over exhibiting a cis/trans isomer ratio of 100:0, this isomer form is
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8
9
0
1
2
3
4
5
6
7
8
9
0
°
α
–C) and ψ (N–C
α
–C=N) have also assigned in each
9
9 % Boltzmann populations), while the models of compound 9 distributed among the +/+ and –/– orientations of ψ/φ angles
appears like a mixture of isomers of cis/trans conformations (Table 2). Similarly, the cis isomer of the compound (R)–3
27:73 % Boltzmann populations), see Figures S1–S3; Tables S1– appears as the more energetically favourable conformation
S5 in the Supporting Information Part B. showing a more accentuated tendency to the +/+ dihedral
(
Figure 3 shows the superpositions of the lower energy orientation. Most of the minority cis isomers identified for
structures obtained (optimized QM) from (S)–3 and 9. These compound 9 show the dihedral ψ/φ orientations +/+ and –/–
representations illustrate the conformational rigidity of 3 with whereas the trans conformations were almost totally
respect to 9. On the right side of the overlay, the geometry of distributed between orientations +/– and –/+.
the lowest energy conformer shows the typical intramolecular
interactions observed in each case (green dotted lines, Figure Table 2. Isomers and dihedral distributions for peptoids (S)
–3, (R)–3, and 9,
according to the sum of the corresponding Boltzmann populations.
3
).
Peptoid
S)–3
Isomer
cis
ψ(+)/φ(–)
ψ(–)/φ(+)
ψ(+)/φ(+)
ψ(–)/φ(–)
*
0,00
0,00
4,62
0,00
0,00
14,56
21,28
52,30
0,00
78,27
0,00
5,20
0,00
26,34
0,00
6,94
0,00
19,24
1,21
(
**
trans
0,08
cis
10,1
0,08
2,71
(R)–3
trans
cis
9
trans
57,08
*
Sum of the Boltzmann population corresponding to the cis conformation of the
global minimum, obtained from the most populated cis (starting conformation)
after performing Intrinsic Reaction Coordinate (IRC) calculations; sum of the
**
Boltzmann population corresponding to the final trans conformation obtained
after performing IRC calculations to simulate the cis–trans isomerization of (S)
–
3.
From the lowest–energy conformations of the stereoisomer
(S)–3 and peptoid 9, we evaluated the energetic cost of the
isomerization by modelling the transition state (TS). We start to
consider the conformer 8 of (S)–3, which represent the largest
percentage of the population (25 %) in its cis configuration (8–
cis). This conformation evolves to a close rotamer (rot–8–cis)
from which the TS yields a trans conformation with an
activation energy of 21 kcal/mol, using the same level of theory
as the QM optimization, see Figure 4 (top). The weighted values
of Gibbs free energies and Boltzmann populations, as well as the
ψ/φ dihedral distributions were also calculated for the rot–8–
cis (12–cis) and 13–trans rotamers. These intermediate
Figure 3. Overlay of the representative (lower–energy) structures of the compounds (S)–
3
(top), (R)–3 (medium), and 9 (bottom) reoptimized at the M06–2X/6–31+G(d,p)//M06– conformers were obtained along the reaction path between the
2X/6–31+G(d) theory level with implicit chloroform as the solvent.
lowest–energy cis and final trans isomers of compound (S)–3, as
shown in Figure 4 (top), and highlighted in the Supporting
Information, Part B. While, the molecular–mechanics starting
structures used to obtain the quantum mechanics optimized
conformers from 1 to 11, coming from MCMM simulations
(Supporting Information, Part B). Neither rot–8–cis nor the
trans conformation has been obtained as representative
Notice that, according to the NMR predictions, strong
intramolecular interactions prevail in all representations of
compound 3 (Figure 3). One between the CH groups that
support the R substitution with the carbonyl of the acetyl
group, and the other between the NH group and the nitrogen
2
atom of the tertiary amide, that forms a stable five–membered
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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Pl eNa es we dJ oo u nr no at l ao df j Cu hs et mm i as tr rgy ins
Page 6 of 11
ARTICLE
structures of conformational sampling. Nonetheless, they were
added as conformers 12 and 13 respectively in Table S5 of the condition does not seem to be enough tDoOsIt:a1b0.i1l0iz3e9/tCh9eNgJ0r2o2u3n4dA
SI, to analyse their probability of occurrence according to the state. For instance, the lower energy structures of the (S)–3
weighted energies. Notice that for 3, the trans conformer (13– peptoid are all cis configurations and do not show this
trans) is significantly less stable than 8–cis and only represent interaction. The presence of other intramolecular interactions
Journal Name
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
from 5 to 7 kcal/mol. However, according to thisVaienwaAlrytisciles,Otnhlinies
0
.1 % of the population according to the Boltzmann distribution.
in
a cooperative effect seems sufficient to explain the
This means that the equilibrium is shifted towards the less
energetic cis isomers, which explains the configurational
stiffness of this compound.
propensity to adopt the cis conformation. The lowest energy
structure of the (S)–3 (8–cis), in addition to the stable five–
membered ring explained by the interaction NH–N, shows a
network of the relatively strong interactions (~2.5 kcal/mol)
that includes the oxygen lone pairs, either of the carbonyl or the
phosphonate ester group, with the CH groups of backbone, side
chains and even phenyl group (see Figure 4 and Table S7). The
representative trans isomer of the peptide 9 (21–trans) shows
the strongest HB interactions (LPC=O → σ*H–N), but also a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
stabilizing n–
→
*interaction with the phosphonate group (LPP=O
C=O). The latest interaction does not appear in the
*
representative 5–cis conformer. However, the 5–cis conformer
is stabilized principally by the LPP=O(OEt)2 → σ*H–C (2.3 kcal/mol)
and the NH—π interaction (1.75 kcal/mol). From the NBO
analysis, the sum of these relatively weak interactions could
explain the stability of the cis conformation of 9. In general, the
influence of the phosphonate ester group is less significant
when it is attached in the backbone. However, according to our
analysis, the phosphonate ester group attached to the side
chain mediates stabilizing interactions of the cis isomer. This is
expected in some way since the presence of the phosphonate
2
ester group at R supports the steric control.
Experimental
Figure 4. Gibbs free energy profile of the isomerization mechanism of (S)–3 (top) and 9 Material and methods
bottom) at the M06 2X/6 31+G(d,p) // M06 2X/6 31+G(d) theory level with implicit
chloroform as the solvent.
(
–
–
–
–
Materials and reagents were of the highest commercially
1
available grade and used without further purification. H NMR
13
1
In contrast, the isomerization of the compound 9 models leads and C NMR spectra were recorded at 400 MHz for H and 100
to stable products (ΔGrel = 0.3 kcal/mol); both appear as MHz for C, respectively. Chemical shifts (δ) are reported in
13
representative at room temperature (15 % and 9 % for trans and parts per million relative to the residual solvent signals, and
cis Boltzmann population respectively), see Figure 3 (bottom). coupling constants (J) are reported in hertz. High–resolution
The activation energy, in this case, is practically the same as mass spectra (HRMS) were recorded using electron spray
required to isomerize compound 3 from cis to trans and is in the ionization (ESI) (Hybrid linear ion trap–orbitrap FT–MS and
range of those obtained for similar N–alkylated peptides but QqTOF/MS – Microtof – QII models).
14
with different anchor groups. In order to gain more insight
into the interactions stabilizing cis/trans conformations, we General procedure for the Ugi–4CR
used the natural bond orbital population analysis (NBO).
We considered the stabilization energy (delocalization energy) The N–alkylated peptides were prepared according to literature
of the relevant intramolecular (spatial) interactions between procedure. Dissolution of the amine (0.5 mmol, 1.0 equiv.),
the NBO orbitals (represented as dashed green lines in Figure 4 the aldehyde (or ketone) (0.5 mmol, 1.0 equiv.), the carboxylic
and quantitatively in Table S7 of the SI). In general, the analysis acid (0.5 mmol, 1.0 equiv.) and the isocyanide (0.5 mmol, 1.0
revealed that the HB interactions between the oxygen lone pair
LPC=O of the tertiary amide carbonyl group and the NH group
15b
equiv.) in MeOH (5 mL) were stirred at 25°C for 24 h.
Compound 1. Yield: 129 mg (89%) as colourless oil. A mixture of
rotamers was observed by NMR (ratio 6:4). Assigned signals
(i.e., amide group) of the contiguous peptoid bond (LPC=O → σ*H–
N
) seem to be necessary to stabilize the trans conformation for
belong to the mixture of rotamers where (*) correspond to the
both compounds. Note that the delocalization energies of these
interactions in the ground–state conformations are in the range
1
major rotamer. R
f
= 0.51 (hexane/EtOAc 1:1 v/v). H NMR (400
6
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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Page 7 of 11
Pl eNa es we dJ oo u nr no at l ao df j Cu hs et mm i as tr rgy ins
Journal Name
MHz, CDCl ) δ 7.39 – 7.28 (m, 4H), 7.18 (d, J = 7.3 Hz, 1H), 6.23*,
ARTICLE
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
View Article Online
5
(
(
1
1
1
4
2
C
.53 (2×d, J = 6.8 Hz, 1H, NH), 4.66*, 4.62 (2×s, 2H), 3.93*, 3.90 Compound 5. Yield: 128 mg (43%); as a wDhOitIe: 1a0m.10o3r9p/Ch9oNuJs0s2o23li4dA.
2×s, 1H), 3.75 – 3.62 (m, 1H), 2.21*, 2.12 (2×s, 3H), 1.91 – 1.82 = 0.20 (hexane/EtOAc 1:1 v/v). A mixture of rotamers was
m, 1H), 1.76 – 1.54 (m, 4H), 1.41 – 1.04 (m, 5H), 0.89 (qd, J = observed by NMR (ratio 6:4). Assigned signals belong to the
R
f
1
3
2.1, 2.9 Hz, 1H). C NMR (100 MHz, CDCl
3
) δ 172.05*, 171.66, mixture of rotamers where (*) correspond to the major
1
68.04*, 166.98, 137.10, 135.93*, 129.18, 129.11, 128.76, rotamer. H NMR (400 MHz, CDCl
3
) δ 7.83 (t, J = 5.8 Hz, 1H), 7.55
28.18, 127.99, 126.71, 53.45*, 52.67, 50.83, 50.60*, 48.38, – 6.95 (m, 10H), 6.83 (d, J = 7.1 Hz, 1H), 6.11 (d, J = 23.8 Hz, 1H),
8.24*, 32.95*, 32.85, 25.60*, 25.42, 24.86, 24.80*, 21.81, 4.85 (m, 2H), 4.25 – 4.07 (m, 6H), 4.03 – 3.84 (m, 5H), 3.75 (s,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
1.56*. HRMS (ESI–FT–ICR) m/z: 311,1729 [M+Na] ; calcd. for 3H), 3.72 – 3.64 (m, 5H), 3.23 – 3.06 (m, 6H), 2.12*, 2.04 (2×s,
17
H
24
N
2
O
2
Na: 311,1735.
3H), 1.31 (m, 5H), 1.18 (t, J = 7.1 Hz, 3H) 1.12 (t, J = 7.1 Hz, 3H).
C NMR (101 MHz, CDCl ) δ 172.20, 171.91, 171.18, 169.05,
3
1
3
Compound 2. Yield: 118 mg (78%); as a colourless oil. A mixture 168.53, 162.75, 162.17, 136.39, 136.23, 135.92, 135.23, 135.06,
of rotamers was observed by NMR (ratio 1:0.9). Assigned signals 133.37, 129.81, 129.33, 129.25, 128.98, 128.86, 128.65, 127.62,
belong to the mixture of rotamers where (*) correspond to the 127.24, 127.13, 63.67, 63.36, 62.86, 61.32, 59.85, 53.54, 53.32,
1
major rotamer. R
MHz, CDCl
H), 6.47*, 5.32 (2×d, J = 6.7 Hz, 1H), 6.16*, 5.13 (2×q, J = 7.1 546,2131
Hz, 1H), 5.13 (q, J = 6.9 Hz, 1H), 4.13 (d, J = 15.2 Hz, 1H), 3.73 (d,
f
= 0.54 (hexane/EtOAc 1:1 v/v). H NMR (400 52.73, 52.40, 50.67, 45.19, 43.16, 37.77, 37.54, 21.80, 16.34.
+
3
) δ 7.34 (dq, J = 8.6, 7.0 Hz, 1H), 7.24 (d, J = 7.5 Hz, HRMS (ESI–FT–ICR) m/z: 542,2020 [M] ; calcd. for C27
H
35
N
2
O
8
P:
1
J = 14.6 Hz, 1H), 3.66 (t, J = 9.2 Hz, 1H), 3.62 – 3.54 (m, 1H), 3.38 Compound 6. Yield: 131 mg (58%); as a white amorphous solid.
1
(
d, J = 15.3 Hz, 1H), 2.30*, 2.08 (2×s, 3H), 1.80 (m, 1H), 1.66*,
R
f
= 0.45 (hexane/EtOAc 1:1 v/v). H NMR (400 MHz, CDCl
3
) δ
1
1
CDCl
1
5
2
.28 (2×d, J = 7.0 Hz, 3H), 1.65 – 1.53 (m, 1H), 1.40 – 1.06 (m, 7.62 – 7.50 (m, 2H), 7.36 (m, 3H), 6.19 (d, J = 23.1 Hz, 1H), 6.06
H), 0.95–0.80*, 0.80 – 0.68 (2×m, 1H). 13C NMR (100 MHz, (b.s, 1H, NH), 4.20 – 4.13 (m, 2H), 4.09 (m, 2H), 2.46 (qd, J = 16.4,
) δ 171.90, 169.11, 167.64, 140.31, 139.69, 129.19, 8.0 Hz, 2H), 2.29 (td, J = 6.8, 2.6 Hz, 2H), 1.96 – 1.87 (m, 3H),
29.02, 128.81, 128.26, 128.06, 127.71, 127.16, 126.69, 57.11, 1.34 (t, J = 7.1 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H), 1.17 (s, 9H). 13
5.75, 50.97, 48.25, 47.99, 47.88, 47.54, 32.91, 32.75, 32.61, NMR (101 MHz, CDCl ) δ 173.84, 167.41, 133.45, 130.02,
3
C
3
5.64, 25.43, 24.80, 24.76, 22.33, 22.04, 18.44, 16.31. HRMS 129.94, 129.29, 128.97, 83.54, 69.41, 63.58, 63.51, 62.96, 62.89,
+
(
ESI–FT–ICR) m/z: 303,2073 [M+H] ; calcd. for C18
H
27
N
2
O
2
Exact 51.40, 50.94, 31.80, 28.46, 23.88, 17.86, 16.59, 16.53, 16.38,
+
Mass: 303,2071.
16.32. HRMS (ESI–FT–ICR) m/z: 473,2169 [M+Na] ; calcd. for
23 35 2 5
C H N O PNa Exact Mass: 473,2181
Compound 3. Yield: 110 mg (52%); as a colourless oil. R
f
= 0.54
) δ 7.57 – 7.51 Compound 7. Yield: 91 mg (35%); as a light yellow amorphous
m, 2H), 7.41 – 7.34 (m, 3H), 6.72 (bs, 1H), 5.92 (d, J = 23.1 Hz, solid. A mixture of diastereoisomers was observed by NMR
H), 4.21 – 4.11 (m, 4H), 4.10 – 4.05 (m, 2H), 3.69 – 3.61 (m, 1H), (ratio 1:1). R
.14 (s, 3H), 1.84 – 1.55 (m, 7H), 1.33 (t, J = 7.1 Hz, 3H), 1.28 (m, MHz, CDCl
H), 1.21 (t, J = 7.1 Hz, 3H), 1.17 – 1.06 (m, 2H), 1.00 (dt, J = 20.9, 6.95 (m, 3H), 6.85 (m, 3H), 6.75 – 6.58 (m, 3H), 6.42 (m,
1
(
(
hexane/EtOAc 1:1 v/v). H NMR (400 MHz, CDCl
3
1
2
2
6
1
5
1
f
= 0.30 (hexane/EtOAc 1:3 v/v). 1H NMR (400
) δ 7.64 – 7.41 (m, 3H), 7.35 (m, 7H), 7.16 –
3
1
3
.4 Hz, 1H). C NMR (100 MHz, CDCl
3
) δ 172.13, 167.32, 133.49, 2H), 5.67 – 5.45 (m, 2H), 4.29 – 3.79 (m, 10H), 3.67 (m,
29.66, 129.58, 129.19, 128.89, 63.82, 63.75, 62.85, 62.78, 1H), 3.45 (m, 1H), 2.30 (s, 3H), 2.04 (s, 3H), 1.84 – 1.29 (m,
1
3
1.85, 48.59, 32.82, 32.69, 25.47, 25.00, 21.79, 16.56, 16.50, 10H), 1.23 (m, 12H). C NMR (100 MHz, CDCl
3
) δ 172.28,
+
6.39, 16.33. HRMS (ESI–FT–ICR) m/z: 447,2021 [M+Na] ; calcd. 169.73, 164.34, 160.49, 157.46, 157.41, 136.51, 136.44,
for C21
H
33
N
2
O
5
PNa Exact Mass: 447,2025
134.66, 132.35, 131.17, 130.45, 129.21, 129.12, 128.95,
28.66, 128.60, 128.47, 128.33, 128.29, 128.13, 127.92,
Compound 4. Yield: 95 mg (41%); as a brown amorphous solid. 127.89, 127.81, 127.38, 124.35, 116.17, 115.99, 115.96,
= 0.35 (hexane/EtOAc 1:1 v/v). A mixture of rotamers was 74.18, 72.64, 67.67, 65.04, 64.97, 63.85, 63.78, 63.41,
1
R
f
observed by NMR (ratio 6:4). Assigned signals belong to the 63.34, 61.76, 61.68, 60.53, 49.67, 48.59, 32.94, 32.76,
mixture of rotamers where (*) correspond to the major 32.59, 25.42, 25.34, 25.28, 24.95, 24.78, 22.46, 21.15,
1
rotamer. H NMR (400 MHz, CDCl
3
) δ 9.13*, 8.67(2×s, 1H, NH), 18.45, 16.52, 16.46, 16.40, 16.36, 16.29, 16.23, 14.29,
7
2
4
.92 – 7.60 (m, 8H), 7.56 – 7.32 (m, 10H), 6.36*, 5.32 (2×d, J = 14.22.
3.1 Hz, 1H), 4.47 (d, J = 18.1 Hz, 1H), 4.32 (d, J = 18.0 Hz, 1H),
.22 – 4.05 (m, 4H), 2.46, 2.31* (2×s, 3H), 1.37 (dd, J = 8.1, 4.2 Compound 8. Yield: 101 mg (38%); as a colourless oil. A mixture
Hz, 1H), 1.28 (t, J = J = 6.9 Hz, 3H), 1.17 (t, J = 6.9 Hz, 3H), 1.04 of diastereoisomers was observed by NMR (ratio 1:1). R
f
= 0.40
) δ 172.55*, (hexane/EtOAc 1:3 v/v). 1H NMR (400 MHz, CDCl3) δ 7.48 – 7.02
72.50, 167.63, 134.27*, 133.28, 133.24, 132.04, 129.95, (m, 20H), 6.72 (bs, 1H), 6.63 (bs, 1H), 4.24 (d, J = 17.2 Hz, 2H),
29.87, 129.41, 129.26, 129.06, 128.64, 128.55, 127.77, 126.42, 4.01 (t, J = 9.8Hz, 2H), 4.17 – 3.73 (m, 10H), 3.44 (m 1H), 2.87 –
26.36, 126.14, 125.61, 121.48, 121.44, 63.83, 63.76*, 63.31, 2.62 (m, 2H), 2.18 (s, 3H), 2.01 (s, 3H), 1.95 – 1.41 (m, 7H), 1.30
1
3
(
dd, J = 14.6, 7.2 Hz, 1H). C NMR (100 MHz, CDCl
3
1
1
1
6
1
4
1
3
3.23*, 51.94*, 22.23, 22.09*, 16.71, 16.67, 16.62, 16.57, – 1.21 (m, 10H), 1.18 – 1.04 (m, 10H). C NMR (100 MHz, CDCl3)
6.48*, 16.42*, 16.35*, 16.29*. HRMS (ESI–FT–ICR) m/z: δ 171.67, 171.63, 168.91, 167.26, 141.90, 137.72, 137.69,
+
91,1702 [M+Na] ; calcd. for C25
H
29
N
2
O
5
PNa: 491,1712.
129.92, 129.48, 129.10, 128.82, 128.62, 128.55, 128.50, 128.44,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
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Pl eNa es we dJ oo u nr no at l ao df j Cu hs et mm i as tr rgy ins
Page 8 of 11
ARTICLE
Journal Name
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
1
6
4
2
1
28.36, 128.07, 128.01, 127.94, 127.91, 127.87, 127.83, 127.80,
27.74, 127.71, 127.68, 127.65, 127.62, 127.59, 125.96, 63.82, 7.0 Hz, 2H), 2.32 – 2.27 (m, 1H), 1.73 – 1.56 (m, 2H), 1.45 (s, 9H),
3.75, 62.94, 62.87, 62.80, 62.73, 62.27, 62.20, 54.86, 53.38, 1.34 (t, J = 7.1 Hz, 6H), 1.28 (m, 14H). C NMR (100 MHz, CDCl3)
9.52, 48.52, 34.61, 32.73, 32.59, 32.36, 30.90, 25.50, 25.35, δ 174.71, 169.14, 156.12, 136.10, 129.11*, 128.87, 128.49,
4.92, 24.81, 22.64, 22.19, 21.71, 16.51, 16.46, 16.39, 16.33, 127.96*, 126.66*, 62.77, 62.71*, 52.43*, 49.67, 40.74, 35.52,
(s, 2H), 3.69 (dd, J = 12.0, 5.9 Hz, 2H), 3.11 (m, 2HV)ie,w2A.4rti3cle(tO,nJlin=e
DOI: 10.1039/C9NJ02234A
1
3
6.27, 16.22.
33.96*, 33.32, 33.10*, 30.16, 29.57, 29.46*, 29.36, 28.55, 26.90,
5.24*, 25.02, 16.55*, 16.49. HRMS (ESI–FT–ICR) m/z: 598,3610
2
+
Compound 9. Yield: 108 mg (60%); as a colourless oil. A mixture [M+H] ; calcd. For C30
of rotamers was observed by NMR (ratio 6:4). Assigned signals
belong to the mixture of rotamers where (*) correspond to the Compound 13. Yield: 115mg (65%); as a white amorphous solid.
major rotamer. R
MHz, CDCl
H
53
N
3
O
7
P: 598,3621
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
f
= 0.40 (hexane/EtOAc 1:1 v/v). H NMR (400 A mixture of rotamers was observed by NMR (ratio 6:4).
) δ 7.40 – 7.29 (m, 4H), 7.18 (d, J = 7.1 Hz, 1H), Assigned signals belong to the mixture of rotamers where (*)
3
6
4
2
.77*,6.43 (2×t, J = 4.0 Hz, 1H, NH), 4.65 (s, 2H), 4.17 – 4.08 (m, correspond to the major rotamer. R
H), 4.01*,3.92 (2xs, 2H), 3.68 (dd, J = 12.1, 6.0 Hz, 2H), 2.21*, v/v). H NMR (400 MHz, CDCl
.14 (2×s, 3H), 1.33 (t, J = 7.1 Hz, 6H). 13C NMR (100 MHz, CDCl
f
= 0.45 (hexane/EtOAc 1:1
) δ 8.23, 7.66* (2×s, 1H, NH), 7.44
– 7.15 (m, 5H), 5.16 (d, J = 15.8 Hz, 1H), 4.83 (d, J = 16.4 Hz, 1H),
1
3
3
)
δ 172.09*, 171.59, 169.01*, 168.30, 136.84, 135.83*, 129.10, 4.53 – 4.41 (m, 2H), 4.28 – 4.04 (m, 4H), 3.65 – 3.57 (m, 1H),
1
4
28.84, 128.45, 127.99, 127.81, 126.65, 62.77, 53.24*, 50.92, 3.42 (m, 4H), 2.24 – 2.11 (m, 1H), 2.08 – 1.82 (m, 4H), 1.81 –
9.80, 49.38*, 35.48, 33.92, 21.64, 21.40*, 16.49. DEPT 135° 1.67 (m, 2H), 1.46 (s, 9H), 1.33 (2×t, J = 7.1 Hz, 6H). C NMR (100
) δ 129.08 (CH), 128.89(CH), 128.47 (CH), MHz, CDCl ) δ 174.66*, 173.13, 168.50*, 168.06, 155.15,
1
3
(
100 MHz, CDCl
3
3
1
5
2
3
27.98 (CH), 126.58 (CH), 62.69 (CH
1.16 (CH
1.34 (CH
2
), 62.62 (CH ), 53.19 (CH
2
), 35.46 (CH ), 33.91 (CH
2
2
), 136.61, 129.19, 128.85, 128.60, 128.03, 127.84, 126.53, 80.43,
), 62.66*, 62.60, 62.34, 56.29, 55.66, 52.66*, 51.02, 50.67, 49.84,
2
), 49.85 (CH
2
), 49.63 (CH
), 16.38 (CH
2
2
3
), 16.44 (CH
3
3
). HRMS (ESI–FT–ICR) m/z: 47.29*, 47.19, 35.73, 34.17, 30.22*, 29.79, 28.63*, 28.54, 25.00,
+
+
79,1395 [M+Na] ; calcd. for C16
H
25
N
2
O
5
PNa: 379,1399
16.59. HRMS (ESI–FT–ICR) m/z: 356,1376 [M+H] ; calcd. for
15 23 3 5
C H N O P: 356,1375
Compound 10. Yield 25mg (90%); as light yellow amorphous
solid. A mixture of rotamers was observed by NMR (ratio 6:4). Compound 14. Yield: 161 mg (60%); as a white amorphous solid.
1
Assigned signals belong to the mixture of rotamers where (*)
correspond to the major rotamer. R
R
f
= 0.51 (hexane/EtOAc 1:1 v/v). H NMR (400 MHz, CDCl
3
) δ
f
= 0.35 (MeOH/EtOAc 1:9 7.55 – 7.25 (m, 5H), 6.63 (d, J = 2.7 Hz, 1H), 5.01 (d, J = 18.6 Hz,
1
v/v). H NMR (400 MHz, DMSO–d6) δ 8.25*, 8.03 (2×t, J = 5.3 1H), 4.71 (t, J = 15.2 Hz, 1H), 4.44 – 4.29 (m, 1H), 4.20 – 4.00 (m,
Hz, 1H, NH), 7.44 – 7.15 (m, 5H), 3.88 (d, J = 11.2 Hz, 2H), 3.45 – 4H), 3.61 – 3.46 (m, 1H), 3.41 – 3.33 (m, 1H), 3.21 (ddd, J = 13.0,
3
.32 (m, 2H), 2.05, 2.01* (2×s, 3H). 13C NMR (101 MHz, DMSO– 8.6, 4.0 Hz, 1H), 2.27 – 2.08 (m, 1H), 2.02 (ddd, J = 20.0, 13.2,
d6) δ 171.45*, 171.09, 168.47*, 168.42, 138.12*, 137.67, 7.0 Hz, 1H), 1.95 – 1.81 (m, 2H), 1.81 – 1.68 (m, 1H), 1.54 (s, 3H),
1
6
2
29.20, 128.85, 128.21, 128.08, 127.79, 127.49, 127.20, 62.31, 1.46 (s, 7H), 1.34 (t, J = 6.9 Hz, 3H), 1.28 (dd, J = 12.1, 5.0 Hz,
2.25, 52.59, 50.56*, 49.21*, 48.04, 37.67, 37.59, 36.16, 36.08, 3H). C NMR (101 MHz, CDCl ) δ 175.03, 174.68, 154.92,
3
1
3
1.84*, 21.70, 16.73*, 16.67. HRMS (ESI–FT–ICR) m/z: 299,0802 139.00, 129.06, 128.97, 127.59, 127.45, 126.39, 126.15, 80.12,
+
[
M–H] ; calcd. for C12
H
17
N
2
O
5
P Exact Mass: 300,0875
63.37, 62.69, 62.43, 62.38, 62.24, 62.17, 57.32, 48.11, 47.42,
5.55, 33.99, 31.71, 30.51, 28.75, 28.62, 25.30, 24.75, 23.57,
3
Compound 11. Yield: 126 mg (68%); as a colourless oil. A 16.62, 16.56, 16.50, 16.44. HRMS (ESI–FT–ICR) m/z: 540,2833
mixture of rotamers was observed by NMR (ratio 6:4). Assigned [M+H] ; calcd. for C26
signals belong to the mixture of rotamers where (*) correspond
+
H
43
N
3
O
7
P: 540, 2839
1
to the major rotamer. R
400 MHz, CDCl
f
= 0.50 (hexane/EtOAc 1:1 v/v). H NMR Compound 15. Yield: 139 mg (45%); as a white amorphous solid.
1
(
3
) δ 7.43 – 7.31 (m, 3H), 7.25 (d, J = 7.5 Hz, 2H),
R
f
= 0.30 (hexane/EtOAc 1:1 v/v). H NMR (400 MHz, CDCl
3
) δ
6
1
2
1
1
1
3
.90*, 5.93 (2×t, J = 4.0 Hz, 1H, NH), 6.16, 5.16* (2×q, J = 6.8 Hz, 7.81 (d, J = 23.7 Hz, 3H), 7.55 (dd, J = 18.0, 7.5 Hz, 7H), 7.44 (t, J
H), 4.26 (d, J = 15.4 Hz, 1H), 4.19 – 4.06 (m, 4H), 3.84 – 3.70 (m, = 9.2 Hz, 5H), 7.38 – 7.19 (m, 44H), 5.66 – 5.41 (m, 7H), 4.96 (t,
H), 3.54 (ddd, J = 22.4, 13.9, 8.0 Hz, 1H), 3.40 (d, J = 15.4 Hz, J = 15.1 Hz, 3H), 4.75 – 4.51 (m, 7H), 4.22 – 4.05 (m, 17H), 4.00
H), 2.32*, 2.12 (2×s, 1H), 1.69*, 1.51 (2×d, J = 7.0 Hz, 1H), 1.42, – 3.85 (m, 10H), 3.85 – 3.61 (m, 13H), 1.45 – 1.21 (m, 73H), 1.09
.35* (2×t, J = 7.1 Hz, 6H). C NMR (101 MHz, CDCl ) δ 172.17, (qd, J = 7.0, 4.3 Hz, 16H). C NMR (100 MHz, CDCl ) δ 168.86,
3 3
69.96, 139.48, 129.11, 128.13, 126.61, 62.64, 57.26, 47.09, 168.55, 156.19, 135.86, 134.94, 129.25, 129.16, 128.80, 128.69,
1
3
13
5.66, 33.71, 22.37, 18.48, 16.56, 16.50. HRMS (ESI–FT–ICR) 128.29, 127.11, 127.00, 80.33, 63.56, 53.11, 52.90, 51.19, 49.64,
+
m/z: 371,1738[M+H] ; calcd. for C18
H
27
N
2
O
5
P: 370,1658
46.49, 43.18, 28.50, 17.97, 16.58, 16.24. HRMS (ESI–FT–ICR)
+
m/z: 619,1825 [M+H] ; calcd. for C30
H
44
N
4
O
8
P: 618,2819
Compound 12. Yield: 180 mg (62%); as a colourless oil. A
mixture of rotamers was observed by NMR (ratio 6:4). Assigned Compound 16. Yield: 90 mg (40%); as a light yellow amorphous
signals belong to the mixture of rotamers where (*) correspond solid. R
to the major rotamer. R
= 0.25 (hexane/EtOAc 1:3 v/v). 1H NMR (400 MHz,
) δ 7.22 – 7.05 (m, 5H), 6.99 (d, J = 7.1 Hz, 2H), 6.62 (d, J =
f
1
f
= 0.40 (hexane/EtOAc 3:1 v/v). H NMR CDCl
3
(
400 MHz, CDCl3) δ 7.43 – 7.23 (m, 4H), 7.18 (d, J = 7.2 Hz, 1H), 8.3 Hz, 2H), 6.41 (s, 1H), 5.81 (s, 1H), 4.67 (d, J = 17.6 Hz, 1H),
6
.83, 6.65 (2xs, 1H, NH), 4.66 (s, 2H), 4.14 (p, J = 7.2 Hz, 4H), 4.01 4.49 (d, J = 17.5 Hz, 1H), 4.16 – 3.99 (m, 4H), 3.90 – 3.73 (m, 1H),
8
| J. Name., 2012, 00, 1-3
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
.61 (m, 1H), 2.06 (s, 3H), 1.32 – 1.23 (m, 6H). 13C NMR (100
Conclusions
View Article Online
DOI: 10.1039/C9NJ02234A
3
MHz, CDCl ) δ 172.92, 170.48, 157.54, 137.41, 131.31, 128.58,
In conclusion, we performed an NMR study and MCMM/QM
calculations which reveal a different behaviour on the cis–trans
isomerization of N–alkylated peptides synthesized by Ugi–4CR.
We detected, that, when the POEG was introduced in the side
chain of N–alkylated peptides, the three–dimensional structure
preferentially adopts a cis conformation as occurring in 3.
However, when the POEG was introduced in the backbone (i.e.
compound 9), a mixture of cis/trans ratio was observed. Thus,
these experimental findings are in full agreement with the
quantum mechanics results, which allow rationalizing the trans
and cis isomer preferences for the compounds 9 and 3,
respectively. Finally, we introduced different oxo components
in the Ugi–4CR. The NMR spectra exhibit only a trans isomer for
the compounds 16 and 17, which was attributed to the n→π*Ar
interaction.
1
2
27.15, 126.26, 125.04, 115.93, 63.06, 50.85, 35.72, 34.15,
2.55, 16.48, 16.43, 14.31.
Compound 17. Yield: 97 mg (42%); as a colourless oil. R
f
= 0.25
) δ 7.22 – 7.05
1
(
(
hexane/EtOAc 1:3 v/v). H NMR (400 MHz, CDCl
m, 5H), 6.99 (d, J = 7.1 Hz, 2H), 6.62 (d, J = 8.3 Hz, 2H), 6.41 (s,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
1
H), 5.81 (s, 1H), 4.67 (d, J = 17.6 Hz, 1H), 4.49 (d, J = 17.5 Hz,
H), 4.16 – 3.99 (m, 4H), 3.90 – 3.73 (m, 1H), 3.61 (m, 1H), 2.06
1
3
(
1
1
s, 3H), 1.32 – 1.23 (m, 6H). C NMR (100 MHz, CDCl
3
) δ 172.92,
70.48, 157.54, 137.41, 131.31, 128.58, 127.15, 126.26, 125.04,
15.93, 63.06, 50.85, 35.72, 34.15, 22.55, 16.48, 16.43, 14.31.
Computational methods
The conformational landscape of cis–trans isomers of N–
alkylated peptides was explored in the gas phase by using the
1
8
OPLS–2005 force–field
and a GB/SA chloroform solvent
Conflicts of interest
The authors declare no conflicts of interest.
1
9
20
model, as implemented in Macromodel version 9.9. A 1000
2
3
steps Monte Carlo multiple minimum (MCMM)
Mode” search algorithms
conformational space of investigated peptoids, recording
structure coordinates through an energy window of 5.0
and “Low–
were combined to sample the
2
4
Acknowledgements
kcal/mol relative to the lowest–energy conformation. It was This work was founded by the CONICYT FONDECYT 3170003. A. F. de
carried out the clustering of conformers based on the distance la Torre is grateful to FONDECYT project No. 3170003 for financial
between heavy atoms by using the Maestro program in version support. We also thanks to VRID technician K. Bustamante for NMR
2
5
5
.7.
A maximum atom deviation of 0.5 Ǻ was applied, measurements at the University of Concepcion. Akbar Ali is thankful
including both heavy and hydrogen atoms to generate the root–
mean–square matrix. The best cluster number was calculated
through the average method for each case. A quantum
mechanics (QM) energy minimization was carried out on each
representative and clustered low–energy structure. Gaussian
program in version 09 was used to perform the QM calculations
using the M06–2X functional in combination with the 6–31G(d)
to the TWAS–CNPq and HEC Pakistan (Project no. 21–
2037/SRGP/R&D/HEC/2018). A.L.M.A is thankful to
CONICYT/FONDECYT Iniciación 11180984 grant and Núcleo Milenio
MULTIMAT, Chile. Powered@NLHPC: This research was partially
supported by the supercomputing infrastructure of the NLHPC (ECM-
2). E.W.H.R. and J.C. are thankful to CONICYT FONDECYT /INACH /
POSTDOCTORADO/ No 3170107. We also thank the computing
resources provided by the Department of Applied Physical Chemistry
at the Universidad Autónoma de Madrid.
0
2
6
basis set.
The pathway between minima separated by the
transition state (TS) of the compounds (S)-3 and 9 was
characterized by internal reaction coordinate (IRC) calculations.
It was ensured the identification of the stationary points
corresponding to minima or transition states on the potential
energy hypersurface of 9. Subsequently, we choose a higher
theory level (i.e. M06–2X/6–31+G(d,p)) to refine the electronic
energies through further QM singlet–point calculations. In all
QM calculations, the solvation contribution was included with
the polarizable continuum solvation model SMD using
chloroform as the solvent. Thus, the relative Gibbs free energies
and Boltzmann populations at 25 °C were calculated from zero–
point vibrational energy, entropic and thermal correction as
described for each low–energy conformer quantically
reoptimized in chloroform. The Cartesian coordinates are
available in the Supporting Information, Part B, for all QM–
optimized structures. Finally, a Natural Bond Orbital (NBO)
analysis was performed at the M06–2X/6–31+G(d,p) level by
Notes and references
1
J. G. Allen, F. R. Atherton, M. J. Hall, C. H. Hassall, S. W.
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978, 272, 56–58.
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P. Kafarski and B. Lejczak, The biological activity of
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a) FR. Atherton, CH. Hassall and RW. Lambert, J. Med. Chem.
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2
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J. Name., 2013, 00, 1-3 | 9
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0 For solid phase peptoids synthesis see: a) T. S. Burkoth, A. T. 21 R. N. V. K. Deepak, and R. Sankararamakrishnan, Biochemistry,
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1 For cis–trans studies see: a) B. C. Gorske, B. L. Bastian, G. D. 24 M. Saunders, K. N. Houk, Y.–D. Wu, W. Still, C. M. Lipton, G.
Geske and H. E. Blackwell, J. Am. Chem. Soc., 2007, 129 (29),
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