Exploring the Conformation of Mixed Cis- Trans α,β-Oligopeptoids: A Joint Experimental and Computational Study

Article abstract of DOI:10.1021/acs.joc.8b00606

The synthesis and conformational preferences of a set of new synthetic foldamers that combine both the α,β-peptoid backbone and side chains that alternately promote cis- and trans-amide bond geometries have been achieved and addressed jointly by experiment and molecular modeling. Four sequence patterns were thus designed and referred to as cis-β-trans-α, cis-α-trans-β, trans-β-cis-α, and trans-α-cis-β. α- and βNtBu monomers were used to enforce cis-amide bond geometries and α- and βNPh monomers to promote trans-amides. NOESY and molecular modeling reveal that the trans-α-cis-β and cis-β-trans-α tetramers show a similar pattern of intramolecular weak interactions. The same holds for the cis-α-trans-β and trans-β-cis-α tetramers, but the interactions are different in nature than those identified in the trans-α-cis-β-based oligomers. Interestingly, the trans-α-cis-β peptoid architecture allows establishment of a larger amount of structure-stabilizing intramolecular interactions.

Full text of DOI:10.1021/acs.joc.8b00606

Article
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
pubs.acs.org/joc
Exploring the Conformation of Mixed Cis−Trans α,β-Oligopeptoids:
A Joint Experimental and Computational Study
†
‡,§
†,#
†
,†
†
Geoffrey Dumonteil, Nicholus Bhattacharjee, Gaetano Angelici, Olivier Roy, Sophie Faure,
Laurent Jouffret,† Franck Jolibois,* Lionel Perrin,* and Claude Taillefumier*
,‡
,§
†
Universite
Universite
Universite
́
́
́
Clermont Auvergne, CNRS, SIGMA Clermont, ICCF, F-63000 Clermont-Ferrand, France
de Toulouse-INSA-UPS, LPCNO, CNRS UMR 5215, 135 av Rangueil, F-31077, Toulouse, France
de Lyon, Universite Claude Bernard Lyon 1, CPE Lyon, INSA Lyon, ICBMS, CNRS UMR 5246, Equipe ITEMM, Bat
‡
§
́
̂
Curien, 43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne, France
*
S Supporting Information
ABSTRACT: The synthesis and conformational preferences of a set of new
synthetic foldamers that combine both the α,β-peptoid backbone and side
chains that alternately promote cis- and trans-amide bond geometries have
been achieved and addressed jointly by experiment and molecular modeling.
Four sequence patterns were thus designed and referred to as cis-β-trans-α, cis-
α-trans-β, trans-β-cis-α, and trans-α-cis-β. α- and βNtBu monomers were used
to enforce cis-amide bond geometries and α- and βNPh monomers to promote
trans-amides. NOESY and molecular modeling reveal that the trans-α-cis-β and
cis-β-trans-α tetramers show a similar pattern of intramolecular weak
interactions. The same holds for the cis-α-trans-β and trans-β-cis-α tetramers,
but the interactions are different in nature than those identified in the trans-α-
cis-β-based oligomers. Interestingly, the trans-α-cis-β peptoid architecture
allows establishment of a larger amount of structure-stabilizing intramolecular
interactions.
INTRODUCTION
namely peptoids, where the amides can populate both the cis
and trans conformations. Peptoids are glycine oligoamides with6
pendant side chains attached on the amide nitrogen atoms.
Peptoids are thus characterized by tertiary amide bonds (N,N-
disubstituted amides) which are prone to cis−trans-amide
■
In the past two decades, there has been considerable interest in
the construction of synthetic oligomers that are capable of
adopting a three-dimensional conformational preference, with
the ultimate aim of establishing a close relationship between
conformation, properties, and functions. The term foldamer
was proposed by Gellman to designate “polymers with a strong
7
1
isomerism. We are now at a point where it is possible to
control the conformation of every peptoid amide bond within a
sequence. This is a formidable opportunity to expand structural
diversity of peptoid backbones and foldamers. Oligoamides
with an alternating cis−trans-amide sequences are very scarce.
The alternating cis−trans conformation has been observed for
2
tendency to adopt a specific compact conformation”, and
Moore added the notion of structures being “stabilized by a
collection of non-covalent interactions between nonadjacent
3
monomer units”. In this context, a huge number of
8
4
5
oligoprolines with L/D alternating configurations. The 4-
bioinspired and abiotic foldamers whose skeletons do not
resemble those of biopolymers have been constructed and
studied. The chemical linkage between the monomers can also
be varied, expanding backbone chemical diversity and playing a
major role on the whole conformation. Native amide bonds are
by far the most widely used linkages in foldamer chemistry, not
only for its ease of formation but also for conformational
considerations. The amide plane constrains locally the
accessible conformational space in addition to its role in
intramolecular stabilizing hydrogen bonding. Secondary amides
of peptide strands or foldamer structures preferentially exist in
solution in the trans form, which is energetically most favorable.
In peptides, the cis-amide conformation is mainly observed in
proline-rich peptides and N-methylated peptides, notably cyclic
peptides. There is a special class of artificial oligoamides,
aminopyroglutamic acids (aPy) have been used as dipeptide
mimics with an internal amide linkage locked in the cis
9
conformation. The X-ray structure of a trimer of the aPy
building block showed a unique, alternating cis−trans sequence
of amide bonds. In the peptoid field, the Blackwell group has
taken advantage of the strong rotameric preference induced by
aryl and α-chiral aromatic naphthylethyl (1npe) side chains to
construct peptoid oligomers with a succession of cis and trans
main-chain amides. A stable ribbon-like structure was thus
10
revealed by NMR and X-ray crystal analysis. A new and
unique peptoid secondary structure referred as “η-helix” was
Received: March 7, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.8b00606
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The Journal of Organic Chemistry
Article
also demonstrated by both alternation of cis- and trans-
structures. Hence, α-peptoids composed of NCα-chiral
aromatic side chains or bulky side chains fold preferentially
into the PolyProline-type I helical structure (PPI) with all of
promoting side chains and alternation of the side-chain
1
1
configuration. The X-ray structure of a number of constrained
cyclic peptoids also revealed repetition of the cis−trans
15
the amides in the cis form, whereas N-aryl peptoids resemble
the Polyproline-type II helix, with the amides in the trans
12
sequence pattern. Our group has recently described a new
16
peptoid backbone composed of both α- and β-peptoid
form. It should be noted, however, that with the exception of
cyclic peptoids, the number of high-resolution structures is still
scarce. This is for a large part attributable to an imperfect
control of the amide geometry, giving rise to a substantial
conformational heterogeneity. A small number of side chains
have been recently designed to impose tighter control over the
amide geometry through steric and stereoelectronic effects.
One of the most effective ways to induce the cis conformation is
the α-chiral aromatic (S)-1-(1-naphthyl)ethyl (s1npe) group, as
shown in peptoid model systems and homooligomers that
contain exclusively cis-amide bonds above the tetramer
13
monomers in alternation. Herein, we explore the possibility
of alternating both α and β monomers and cis- and trans-amide
main chains within the sequences. α and βNtBu monomers
were used for enforcing cis-amides and α and βNPh monomers
14
for trans-amides. Hence, we designed four novel peptoid
architectures comprising the α,β backbone and alternating cis−
trans-amides. In this study, we present their synthesis, full NMR
analysis, and computational study at the tetramer length
(
compounds 6, 12, 19, and 27 in Figure 1).
15d
17
length.
Other such side chains are the triazolium and
18
tert-butyl (tBu), which strongly favor cis peptoid amides
predominantly based on electronic and steric effects,
respectively. The tert-butyl group even allows a complete
locking of peptoid amides in the cis form, independently of the
solvent. Despite the achirality of tBu groups, it was even shown
that weak noncovalent interactions, including tBu···tBu
18
dispersive interactions, help promote helix folding. The
trans peptoid amide conformation, on the other hand, is mainly
favored by the use N-aryl side chains, with cis/trans ratios
≥
95:5.
We now report on a new peptoid platform design that
combines the α,β-backbone and cis- and trans-amides in
alternation. Four sequence patterns were thus devised from
the above-mentioned structural elements: cis-β-trans-α, cis-α-
trans-β, trans-β-cis-α, and trans-α-cis-β. The corresponding
compounds were synthesized at the tetramer length (com-
pounds 6, 12, 19, and 27) with tBu side chains to impose cis
peptoid amide geometries and phenyl (Ph) side chain for the
trans conformation.
Synthesis of Tetramer 6 (Ac-βNtBu-αNPh-βNtBu-
αNPh-OEt). α-Peptoids are most often synthesized in high
yield and good purity by the solid-phase submonomer protocol
Figure 1. Peptoid architectures based on the alternating α,β-peptoid
backbone and alternation of cis- and trans-amide bond geometries.
19
described by Zuckermann et al. A solid-phase sub-monomer
20
approach has been adapted for the synthesis of β-peptoids,
but efficacy of the two-step iterative process (acylation with
acryloyl chloride followed by aza-Michael addition of primary
amines) has been shown to be limited by the second step of the
iteration. As our goal was to make short oligomers (4-mers),
but also and more importantly due to the deactivated character
of aryl amines and the presence of sterically demanding tBu
groups within the sequences, we decided to synthesize peptoid
oligomers in solution. The initial general synthetic strategy
involving the submonomer synthesis of α,β- and β,α-dimeric
building blocks and their subsequent coupling to form
RESULTS
■
Peptoid oligomers are basically more flexible than many other
oligoamide-based foldamers due to their inability to establish
intramolecular backbone hydrogen-bond networks, achirality of
their backbone, and equilibria between the cis and trans tertiary
amide conformations. The latter should, however, be
considered as an advantage since it allows exploration of a
greater conformational space. A great body of work enabled
identifying requirements for peptoid chain folding into discrete
Scheme 1. Synthesis of Tetramer 6
B
DOI: 10.1021/acs.joc.8b00606
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Scheme 2. Synthesis of Tetramer 12
tetramers was considered the most straightforward. We also
anticipated that the development of a fragment-based coupling
strategy would be suitable for the synthesis of longer oligomers.
This strategy was first assessed for the synthesis of tetramer 6
Scheme 3. Attempted Synthesis of Dimer βNPh-αNtBu-OEt
(cis-β-trans-α) (Scheme 1). The synthesis began by treatment
of ethyl bromoacetate with 2 equiv of aniline in chloroform to
yield the desired peptoid monomer 1 in modest yield. The next
residue (NtBu β-alanine) was constructed by the two-step sub-
monomer approach including acylation with acryloyl chloride
in the presence of triethylamine in THF (2, 77% yield) and aza-
Michael addition of tert-butylamine on the formed acrylamide
at 60 °C in ethanol (93% yield). The formed dimer 3
represents the amine dimeric building block of the forthcoming
peptide coupling reaction. Therefore, half of the material was
kept unchanged and the other half was end-capped by an acetyl
group before saponification of the ethyl ester to give the dimer
acid 5, ready for the coupling with 3. Peptide coupling of
peptoid segments substituted by a sterically hindered tert-butyl
group at the N-terminus is very challenging as shown by us
recently. Taking advantage of our experience, we first examined
the use of pentafluorophenyl diphenylphosphinate (FDPP) and
pentafluorophenyl trifluoroacetate, two reagents that allow
activation of the acid partner as a pentafluorophenyl ester.
Among all the peptide-coupling techniques tested, only these
reagents have allowed us to synthesize NtBu α-peptoids with up
these conditions failed to give the expected dimer βNPh-
αNtBu-OEt.
Tetramer 19 was finally successfully synthesized by a
monomer approach in the N-to-C direction as shown in
Scheme 4. Monomer 7 was first N-capped by an acetyl group
followed by hydrolysis of the ester to give the acid partner 16.
Coupling of 16 with the amine 13 using the Mukaiyama
reagent afforded dimer 17 in 87% yield. Saponification of 17
(
77% yield) and subsequent coupling of the formed acid with 7,
22
still with the CMPI reagent but in the presence of DMAP,
afforded trimer 18 (52% isolated yield), which in turn was
hydrolyzed to the corresponding acid and converted by
Mukaiyama peptide coupling into the expected tetramer 19.
Synthesis of Tetramer 27 (Ac-αNPh-βNtBu-αNPh-
βNtBu-OEt). For the synthesis of tetramer 27, the initial [2
1
8
to 15 residues. Surprisingly, these reagents failed to provide
tetramer 6. We then tested for the first time the Mukaiyama
reagent (2-chloro-1-methylpyridinium iodide, CMPI) in the
presence of triethylamine, yielding the expected tetramer 6 in
+
2] fragment based coupling strategy was also considered,
which implied first the submonomer synthesis of dimer amine
2 as shown in Scheme 5. Compound 22 was then converted
2
to the corresponding acid in two steps, consisting of the
capping of the N-terminal as an acetamide and hydrolysis of the
ester function (not shown, see the SI for details). The formed
acid dimer was then reacted with amine 22 under peptide
coupling conditions, with the aim of obtaining the expected
tetramer 27. Three attempts were carried out with the
Mukaiyama reagent, changing the additive base (Et N, Et N/
53% yield after several optimization reactions.
Synthesis of Tetramer 12 (Ac-αNtBu-βNPh-αNtBu-
βNPh-OEt). The same general synthetic approach was applied
to the synthesis of tetramer 12 (cis-α-trans-β) (Scheme 2) via
the submonomer synthesis of a dimer (9), of which a part was
converted into the acid partner (11) and a final coupling using
the Mukaiyama reagent to give tetramer 12. The difference
between compounds 6 and 12 is the inversion between the α-
and β-residues. Thus, the synthesis of 12 started with the
preparation of the βNPh monomer 7 by addition of aniline
onto ethyl acrylate in protic solvents at 100 °C following a
3
3
DMAP, and DBU). None of them allowed us to obtain
tetramer 27. To address this issue, synthesis of 27 was
continued from amine 22 using only sub-monomer protocols.
The synthesis of trimer 24 required acylation of 22 with
acryloyl chloride (97% yield) followed by aza-Michael addition
21
described procedure. Elongation consisted of a bromoacety-
lation reaction and displacement of the bromine with tert-
butylamine to give dimer 9.
of tBuNH in 89% yield. From 24, a last sub-monomer cycle
2
(
bromoacetylation in 34% yield and bromine displacement with
aniline in 63% yield) afforded tetramer 26, which was
subsequently acetylated to give the expected compound 27.
NMR Spectroscopic Studies. The four synthesized
tetramers 6, 12, 19, and 27 were analyzed by a combination
2D NMR experiments ( H, H-COSY, H, C-HMQC, and
HMBC) that allowed full assignment of the proton and carbon
NMR spectra. Of note is the observation of a single set of
Synthesis of Tetramer 19 (Ac-βNPh-αNtBu-βNPh-
αNtBu-OEt). We then synthesized tetramer 19 using the
same general strategy. This involved the synthesis of dimer
βNPh-αNtBu-OEt following the same route as for the synthesis
of compound 3 but switching the amines in the sequence
1
1
1
13
(
Scheme 3). The submonomer compound 14 was thus
1
13
prepared and treated under the same conditions as for the
resonances for every compound as shown by the H− C
HSQC spectra in Figure 2. This is indicative of a full control of
synthesis of 7 (PhNH , TFE, H O, 100 °C). Unfortunately,
2
2
C
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Scheme 4. Synthesis of Tetramer 19
Scheme 5. Synthesis of Tetramer 27
the amide bonds geometry by the side chains. 2D-NOESY
spectra were acquired to verify geometry of the amides, which,
as expected, were found to be cis for NtBu monomers and trans
for N-aryl monomers (Supporting Information).
directionality of the interaction is however opposite to that
which is prevalent in prolyl peptide models (CO ···C′
i−1
i
2
5
O) or revealed in previous X-ray crystallographic studies of
16b,26
peptoids.
X-ray Crystallography of Dimer 17. Single crystals of
dimer 17 suitable for X-ray diffraction were grown from slow
Molecular Dynamics Simulations. To investigate the
folding of oligomers 6, 12, 19, and 27, their dynamic behavior
has been probed by classical molecular dynamics simulations.
For the four types of cis-trans peptoid tetramers (6, 12, 19, and
27), 50 ns simulations were performed. During these
evaporation of a Et O solution (Figure 3, Table 1). Dihedral
2
angles of the NtBu α-monomer at the C-terminus match up
well with those characterizing peptoid monomers in a
polyproline type-I helical secondary structure. Analysis of the
βNPh monomer revealed an extended backbone conformation
18
simulations, and as noticed in our previous study, no change
of peptoid ω dihedral angle was observed. As expected, the tBu
(
θ1 = −172.8, Table 1) as previously observed in the solid-state
and Ph side chains induce cis and trans peptoid amide bond
23
16a,18
structure of β-peptoid model compounds.
geometries, respectively.
As the folding of peptoids is
The crystal structure was analyzed for potential noncovalent
interactions (Figure 3). Since the backbone carbonyl groups
were oriented roughly perpendicular to each other, implications
essentially related to the backbone dihedral angles, the
probability distribution of these angles has been analyzed for
each trajectory and plotted in 1D and 2D Ramachandran maps
as indicated in Figures S1−S4. In this study, all initial structures
display positive values of φ by construction. The mirror image
that would display all negative values of φ would behave
similarly and has not been considered.
From Table 2, which gathers the different angle combina-
tions, it appears that tetramers 12 and 19 display similar
conformational features. The same conclusion can be drawn for
tetramers 27 and 6. As a consequence, regarding the
Ramachadran maps provided in the Supporting Information
of n → π*
interactions were considered. One potential n
interaction was detected between the carbonyl
CO
→
π*
CO
oxygen atom of the ester and the carbonyl amide of the
precedent residue. The carbonyl oxygen atom to carbonyl
24
carbon distance is 3.2 Å, as for an ideal polyproline II helix,
and the O ···C′ O angle is 128°, which is only slightly
i+1
i
outside of the 109 ± 10° window for an optimal orbital overlap.
Such CO ···C′ O interactions have been observed in a β-
i+1
i
2
3
10
peptoid monomer and in an N-aryl/Ns1npe tetramer. The
D
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1
13
Figure 2. H− C HSQC spectra of tetramer 6, 12, 19, and 27. (B) Principle of atom labeling is shown in (A).
Table 1. Dihedral Angles in Dimer 17
ω1 (trans)
175.80
φ1
θ1
ψ1
ω2 (cis)
φ2
ψ2
+
−75.6
−172.8
−171.1
+4.9
+81.9
+166.8
value of the φ angle. The tBu group, which induces a cis-amide
conformation, constrains the φ angle value that remains
unchanged during the simulation time as previously shown
18
by us for αNtBu oligopeptoids. In contrast, the phenyl group,
which induces a trans-amide conformation, also allows more
flexibility and fluxionality of the residue with a larger range of
accessible φ angle values. In addition, a second constraint is
imposed by the α or β nature of the peptoid residue. This
parameter specifically influences the value of the ψ angle. As
expected, α peptoid residues are less flexible and induce a
narrower range of ψ angle values than β residues.
Figure 3. Solid-state structure of dimer 17 (Ac-βNPh-αNtBu-OEt)
determined by X-ray crystallography: (A) single molecule; (B) packing
of 17 within unit cell.
and the associated remarkable angles summarized in Table 2,
general conformational trends can be highlighted. It appears
that the nature of the side chain (i.e., tBu vs Ph) influences the
Considering all these features, and in accordance with
Ramachandran maps, each of the four residues involved in the
E
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Article
Table 2. Conformational Trends of Tetramers 6, 12, 19, and
couple of angles is at (+90, 180), as for αNtBu residues, but two
additional regions are also populated. One corresponds to
(−90, 180) and is the symmetric of the previous mainly
populated area, while the second is characterized by a new set
of angles (−160, +70) with its symmetric counterpart (160,
2
7 Given by Averaged Simulated and Experimentally
a
Determined Dihedral angles
residue id
ω
ϕ
ψ
θ
Ac-αNtBu-βNPh-αNtBu-βNPh-OEt (12)
−
70) that is slightly populated for the third residue of tetramer
7 and the final fourth residue of tetramer 6. Finally, the more
flexible” residue appears to be the βNPh that is included in
αNtBu (1)
αNtBu (3)
βNPh (2)
−10
−10
180
+90 ± 10
+90 ± 10
−100 ± 10
+170 ± 20
+170 ± 20
+90 ± 10
+90 ± 10
180 ± 10
180 ± 10
2
“
+60 ± 10
+60 ± 10
180 ± 10
180 ± 10
180 ± 10
tetramers 12 and 19. For this residue, the associated
Ramachandran plots exhibit a larger number of populated
regions. However, depending on the location of this residue
within the tetramer, these regions are not equally populated.
While residue 4 of tetramer 12 almost populates equally the (φ,
ψ) regions (±90, 180), (±90, +90), (±90, −90) for symmetric
reasons, these populations are less pronounced for the other
βNPh residue locations. For residue 1 in tetramer 19, six
regions are distinguishable in the (ψ, φ) Ramachadran maps.
This large amount of conformations that are explored by these
two residues can be explained by the fact that they are terminus
residues in the foldamer. In the case of “internal” βNPh
residues, the population of these regions is more heteroge-
neous. Residue 3 of 19 clearly shows a preference for the (+90,
+
85 ± 10
+90 ± 10
90 ± 10
90 ± 10
Ac-βNPh-αNtBu-βNPh-αNtBu-OEt (19)
βNPh (4)
180
−
±
±90 ± 10
αNtBu (2)
αNtBu (4)
−10
−10
+5
+90 ± 10
+90 ± 10
+82
+170 ± 20
+170 ± 20
+167
17 (X-ray)
βNPh (1)
180
±90 ± 10
90 ± 10
+90 ± 10
−170 ± 20
+100 ± 20
+100 ± 20
−170 ± 20
+100 ± 20
−171
180 ± 10
180 ± 10
−170 ± 10
−170 ± 10
−170 ± 10
−172
±
βNPh (3)
180
±
90 ± 10
−
90 ± 10
17 (X-ray) +176
−76
+
100) region, even if (±90, −170) and (−90, +100) regions
Ac-αNPh-βNtBu-αNPh-βNtBu-OEt (27)
remain slightly populated. The scenario is completely different
for residue 2 of tetramer 12. In this case, the only region of the
αNPh (1)
αNPh (3)
180
180
±90 ± 20
160 ± 20
±90 ± 20
160 ± 20
180 ± 20
+70 ± 20
180 ± 20
+70 ± 20
−70 ± 20
180 ± 20
+90 ± 20
−90 ± 20
180 ± 20
+90 ± 20
−90 ± 20
−
(
(
ψ, φ) Ramachadran plot that is populated corresponds to
−100, +90). This can be correlated to the value of the θ angle
−
that characterizes β peptoid units and that has not yet been
taken into account. Indeed, for all βNtBu residues, the θ angle
is equal to 180°. For βNPh monomers, this angle is also mostly
equal to 180°, except for residue 2 in tetramer 12 for which this
angle is +60°. The (ψ, φ, θ) combination of (−100, +90, +60)
seems to be also slightly populated for some other βNPh
moieties but to a lesser extent. Longer simulations or Replica
exchange molecular dynamics would be necessary in order to
improve our ergodicity and to improve the population of each
highlighted region. However, 150 ns of simulation for such
tetramers already allows highlighting conformational trends
that match experimental spectroscopic analysis as discussed
below. In addition, it is worth to note that concerning peptoid
+160 ± 20
βNtBu (2)
βNtBu (4)
+10
+10
+90 ± 10
90 ± 10
90 ± 10
+90 ± 10
180 ± 10
180 ± 10
180 ± 20
180 ± 10
180 ± 20
180 ± 20
+
+
+
90 ± 10
90 ± 10
+
Ac-βNtBu-αNPh-βNtBu-αNPh-OEt (6)
αNPh (2)
αNPh (4)
180
±90 ± 20
160 ± 20
±90 ± 20
160 ± 20
160 ± 20
180 ± 20
+70 ± 20
180 ± 20
+70 ± 20
−70 ± 20
180 ± 20
+90 ± 20
−90 ± 20
180 ± 20
+90 ± 20
−90 ± 20
−
180
−
+
19, simulated structural parameters are in agreement with the
βNtBu (1)
βNtBu (3)
+10
+10
+90 ± 10
180 ± 20
+170 ± 20
−170 ± 20
180 ± 20
+170 ± 20
−170 ± 20
experimental values determined by X-ray crystallography (see
Table 2).
+
90 ± 10
90 ± 10
+
Quantum Chemical Calculations. Energetics and
Conformations. The energetics associated with the φ angle
rotation of αNPh and βNPh residues has been evaluated in
tetramers 6 and 12, respectively, by means of a relaxed energy
potential scan computed at the HF/Ahlrichs-VDZ level for
optimizations and refined at the M06-2X/6-311G(d,p) level for
energy evaluations. See the Experimental Section for details. In
both cases, two minima are clearly identified (Figure S5) and
dihedral angles corresponding to the most stable conformers
match the distribution of the φ angle obtained by molecular
dynamics (see Figures S1 and S4). For both the αNPh and
βNPh residues, the most stable conformers are interconnected
+90 ± 10
+
90 ± 10
90 ± 10
+
a
Dihedral angles definition: ω [C (i−1); C(i−1); N; C or Cβ],
α‑monomer)
α
α
φ(
[C(i−1); N; C ; C], φ
[C(i−1); N; C ; C ]
[C ; C ; C; N(i+1)].
α
(β‑monomer)
β
α
ψ(α‑monomer) [N; C ; C; N(i+1)], ψ
α
(β‑monomer)
β α
Values in bold indicate preferential conformation(s).
tetramers under study have different conformational behaviors.
Tetramers 12 and 19 that contain αNtBu residues are
characterized by a couple of angles (φ, ψ) = (+90, +170). In
the case of tetramers 6 and 27 that comprise βNtBu moieties,
this combination of angles takes predominantly the same values
−1
by low energy transition states (below 6 kcal mol ). This
suggests a similar fluxionality of these two residues regarding
the φ torsion angle.
(
+90, 180). However, for 6 and 27, two other regions of the
Ramachandran plots start to be populated. These regions that
spread toward the values of +90 and −90° correspond to the
modification of ψ angle distribution allowed by the β character
of the residue. If tetramers 6 and 27 that include a αNPh
residue are now considered, the main population of the (φ, ψ)
From the optimized geometries at the quantum level (Figure
4) and analysis of conformational parameters of each tetramer
(Table 2), it appears that two main driving forces are
responsible for the conformational features of tetramers 6,
12, 19, and 27. One should mention that some interaction
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Figure 4. 3D representation of the optimized geometry at the DFT level of tetramers 6, 12, 19, and 27 in which representative key weak (CH···O)
dispersive interactions are identified by their distances (Å). Intraresidue interactions are displayed in black, and inter-residue interactions are
displayed in red. Residue indices are given in orange. For these calculations, C-termini of tetramers have been capped by the NMe (prime tag)
2
amide group in place of the ester function used experimentally.
Figure 5. Main-chain CH···OC interactions in tetramers 6, 12, 19, and 27. Blue (type I), pink (type II), and green (type III) tags refers to
(
i)
(i+1)
(i)
(i+1)
(i)
(i+1)
(i+1)
α C H···OC , β C H···OC , and β C H···OC
interactions types, respectively. The arrows (type IV) denotes (tBu) CH···
α
α
β
(i)
OC interactions. Number labels tag the groups in interactions.
types displayed in Figure 4 on structures optimized at the
quantum level could differ from those integrated along classical
molecular dynamic trajectories. First, intraresidue (Ph−H···
OC) hydrogen bondings seem to govern specific conforma-
tional properties. In the case of tetramers 6 and 27 for which
the phenyl side chains are attached to α-peptoid monomers,
this specific interaction is systematically encountered. This can
be related to almost identical dihedral angles of the αNPh
residues for these two tetramers (Table 2). By contrast, when
the phenyl groups are attached to β peptoid residues, the
enhanced local flexibility in conjunction with the trans character
of the peptoid amide bond cannot ensure a systematic (Ph−
H···OC) hydrogen bond. This is reflected by a greater
fluctuation of the ψ torsion angles of βNPh residues of
tetramers 12 and 19. Second, the cis conformation imposed by
(i+1)
the tBu side chains results in systematic weak (tBu) CH···
(
i)
18
OC interactions independently of the α or β nature of
the NtBu monomers. This induces conserved local conforma-
tions as reflected by similar dihedral angle for the NtBu residues
of tetramers 12 and 19 on one hand and tetramers 6 and 27 on
the other (Table 2).
G
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Table 3. Correlation between Computed and Experimental NMR Chemical Shifts of Tetramers 6, 12, 19, and 27
compd
27 Ac-(αNPh-βNtBu) -OEt
12 Ac-(αNtBu-βNPh) -OEt
19 Ac-(βNPh-αNtBu) -OEt
6 Ac-(βNtBu-αNPh) -OEt
2
2
2
2
13C
0.9992
0.92
R2
0.9992
0.92
0.9993
0.92
0.9992
0.92
slope
a
intercept
5.11
5.03
5.00
5.47
a
RMSD
5.14
5.21
5.10
5.28
1H
R2
0.9988
1.07
0.9981
1.05
0.9978
1.06
0.9987
1.05
slope
intercept
a
−0.41
0.22
−0.28
0.20
−0.30
0.22
−0.28
0.18
a
RMSD
a
2
In ppm. R , slope, and intercept result from a linear interpolation. RMSD: root-mean-square difference.
Folding Driving Forces. In our previous study on αNtBu
peptoids oligomers, we have shown that weak dispersive
traduces a random proximity. The other one traduces a edge-to-
face stacking between two Ph groups.
18
NMR Spectra Simulation. H and 13C isotropic chemical
shifts have been computed for the four tetramers. For that
purpose, a set of 500 structures has been extracted from each
MD trajectory. Chemical shielding were calculated at the DFT
1
interactions play a significant role to the peptoid folding. One
(
i)
of these contributions is the dispersive backbone CH···O
(
i+1)
C
interaction. This interaction has been monitored for all
the simulations of each tetramer, and the results are plotted in
Figure S6. For tetramers 12 and 19 the carbonyl oxygen atoms
of βNPh residues (i+1) interact with the Cα methylene protons
of the precedent NtBu residue (i), not vice versa (blue label,
Figure 5). Interestingly, interactions implying the carbonyl
oxygen of NPh residues are also revealed in compounds 6 and
27
28
29
B3LYP /6-31G(d,p) GIAO level for each structure and
averaged in order to produce simulated NMR spectra.
1
Computed chemical shifts are relative to the theoretical H
and 13C chemical shielding computed at the same level of
30
theory. The fit between experimental and theoretical NMR
data has been assessed for the four tetramers by means of a
linear interpolation. Table 3 summarizes the parameters related
to these interpolations together with additional RMSD
calculations.
2
7, in this case between the CO of αNPh (i+1) residues and
the Cβ methylene protons of βNtBu (i) residues (Figure 5,
green label and Figure S7).
Interestingly, only the Cα methylene groups of βNPh
residues (i) show a significant amount of dispersive interactions
with the CO groups of αNtBu residues (i+1) (Figure 5, pink
label and Figure S7). In summary, for the β-residues, the Cα-
methylene groups are involved in CH···OC interactions in
For each tetramer, an excellent correlation between
1
13
computed and experimental H and C NMR shifts was
obtained as illustrated by correlation coefficient higher than
9
9.78%. The deviation between computed and ideal slope and
y-axis intercept, 1 and 0, respectively, traduces approximations
that are inherent to our computational strategy, e.g., empirical
force field for the structure, solvation models, quantum
chemical approximation for the NMR calculations. The quality
of these results makes us confident in the relevance of our
molecular dynamics simulations. This also raises the confidence
regarding the analysis of the molecular conformations
generated by molecular dynamic simulations.
he case of NPh monomers, whereas the C -methylenes are
β
involved in the case of NtBu monomers. (CH···O) dispersive
interactions can also develop between the backbone carbonyl
18
oxygens and peptoid side chains. Whereas no significant
interaction is observed between CO and Ph side chains, the
CO of NPh residues (i) interact with the methyl groups of
the NtBu side chains (i+1) (Figure S8). No significant
difference was found for this interaction with respect to the
four different peptoid chains studied in this work.
DISCUSSION
Aside from the interactions that involve the polar backbone
carbonyl groups, additional weak interactions can develop
between side chains. Recently, we have demonstrated that side-
chain tBu···tBu interactions help promote helix folding of α-
■
Synthesis. The initial plan to synthesize the four target
tetramers was based on convergent [2 + 2]-fragment coupling
reactions, with the view that this strategy would be very
convenient for the preparation of longer oligomers. This
strategy was effectively applied for synthesizing tetramers 6 and
12 using the Mukaiyama reagent (2-chloro-1-methylpyridinium
iodide, CMPI) as the coupling reagent. These compounds were
isolated with average yields of 50%, highlighting the difficulties
1
8
peptoids. In the present case, alternation of tBu and Ph side
chains prevents tBu/tBu contact. However, a significant amount
of interactions is observed between tBu and Ph side chains
(Figure S9). As expected, these interactions are prominent
between adjacent residues. However, peptoids that include
αNPh residues show a larger amount of interactions than those
containing βNPh residues. For tetramer 12, exclusively, an
interaction is pinpointed between the tBu and Ph side chains at
the N- and C-termini, respectively. This proximity is supported
by the NOESY spectrum of tetramer 12 (Supporting
Information).
Finally, a significant amount of Ph−Ph interactions were
observed during the simulations (Figure S10 and illustration in
Figure S11). Peptoids with αNPh residues show more
interactions than those that comprise βNPh residues. From
Figure S10, two patterns of interaction can be highlighted. One
18
in coupling terminal NtBu peptoids amines. In contrast, the
peptoid fragment coupling strategy was not effective to prepare
tetramers 19 and 27. Regarding the synthesis of tetramer 27,
the coupling of the two dimer blocks Ac-αNPh-βNtBu-OH and
αNPh-βNtBu-OEt (22) failed, likely due to the deactivated
character of the terminal aryl amine moiety of dimer 22. The
submonomer approach using highly reactive halogenoacyl
reagents, bromoacetyl bromide, and acryloyl chloride for α-
and β-monomer synthesis, respectively, was then implemented
for synthesizing tetramer 27. Turning now to the synthesis of
tetramer 19, comprising βNPh and αNtBu residues: Synthesis
H
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of the required dimer βNPh-αNtBu-OEt, for subsequent
coupling with a dimer acid partner, was not feasible because
of the low reactivity of the submonomer acrylamide compound
carbonyl groups of the βNPh residues (i) and the methyl
protons of the tBu side chains of the (i+1) residues was found
omnipresent within 12 and 19 (type IV). Hence, two type I,
one type II, and two type IVtaking into account the N-
terminus acetyl groupinteractions participate in the con-
formational stabilization of tetramer 12. In tetramer 19,
alternation between the same αNtBu and βNPh residues is
maintained. Thus, one type I, two type II, and two type IV
interactions are identified. At the tetramer stage, differences in
relative conformational stability of 12 and 19 can be expected,
but these differences may vanish for longer oligomer length.
In tetramers 6 and 27, a fourth type of interaction (Cβ−
Hβ···OC) is identified between the αNPh carbonyl back-
bone oxygens and the Cβ methylene protons of βNtBu residues
(type III, Figure 5). As a result, in tetramer 27, one type III and
two type IV interactions can develop; in tetramer 6, two type
III and two type IVtaking into account the N-terminus acetyl
groupand interactions were pinpointed. The same analysis
conducted for tetramers 12 and 19 regarding the length of the
oligopeptoids can be transposed to tetramers 6 and 27.
Interestingly, the amount and the nature of interactions differ
between the oligopeptoids comprising αNtBu and βNPh
monomers in alternation, on the one hand (exemplified by
tetramers 12 and 19), and those based on αNPh and βNtBu on
the other (exemplified by tetramers 6 and 27). More backbone
inter-residue (CH···O) hydrogen bonding can be established in
oligomers based on the αNtBu-βNPh dimer unit than in
oligomers based on the αNPh-βNtBu one. By contrast,
interactions involving only peptoid side chains (tBu/Ph and
Ph/Ph H···H contacts) are more numerous for tetramers 6 and
27 (αNPh-βNtBu-based oligomers) than for 12 and 19
(αNtBu-βNPh-based oligomers). It therefore appears that in
these systems, the more backbone−backbone interactions are
present, the less side chain-side chain interactions are found
and vice versa.
14 toward the aza-Michael addition of aniline. Fortunately
tetramer 19 could be synthesized by a monomer approach in
the N-to-C direction using the Mukaiyama reagent. Synthesis of
tetramers 6, 12, 19, and 27 were thus realized in different ways,
involving submonomer, monomer, and fragment-coupling
strategies or any combination thereof.
Conformational Studies. As the set of structures used to
1
13
simulate H and C NMR spectra are extracted from the
Molecular Dynamic simulations initially performed to explore
the conformation and the dynamics of the four tetramers, the
remarkable fit between experimental and computed NMR
spectra strongly support both the NMR attribution and the MD
simulation protocol. It also validates the parameters and
topologies developed for the nonstandard αNPh, αNtBu,
βNPh, and βNtBu residues.
A comparative study of the dihedral angle distribution and
intramolecular interactions highlights similarities between
tetramers 6 Ac-(βNtBu-αNPh) -OEt and 27 Ac-(αNPh-
2
βNtBu) -OEt on one hand and 12 Ac-(αNtBu-βNPh) -OEt
2
2
and 19 Ac-(βNPh-αNtBu) -OEt on the other hand (Table 2).
2
For compounds 6 and 27, analysis of the probability
distribution of dihedral angles reveals common trends. For
example, the αNPh residues 2 and 3 of tetramers 6 and 27,
respectively, which are positioned internally within the
sequences, display a conformation featuring torsion angles
around (ϕ, ψ) = (+75°, 180°). These values are consistent with
those measured in the crystal structure of N-aryl peptoid
dimers, but a deviation is observed from the computationally
predicted values (ϕ, ψ) = (+60°, ±150°) for N-aryl
1
6a
oligomers.
Regarding now the internal βNtBu residues 3
(
tetramer 6) and 2 (tetramer 27), they predominantly populate
a conformational state around (ϕ, ψ, θ) = (+90°, 180°, +175°).
Interestingly, these torsion angles are very similar to those
measured in the crystal structure of a β-peptoid helix with the
Finally, for compounds 12 and 19 on the one hand and for 6
and 27 on the other, similar conformational characteristics have
been highlighted by NOESY and molecular dynamic
simulations. This suggests that the shift in indexation between
analogues 12 and 19, and 6 and 27, does not affect the folding
of the tetramers. However, the short length of the oligomers
limits the number of accessible weak interactions and thus
hampers the folding of the peptoid tetramers under study
31
amide bonds in the cis geometry. Similarly, the αNtBu
residues of tetramers 12 and 19 adopt common conformational
features with (ϕ, ψ) torsion angles values at about (+90°,
+
170°), which are reminiscent of those characterizing polypro-
18
line type I helices. Lastly, similarities between the dihedral
angles of the βNPh residues of 12 and 19 are also observed,
with essentially two set of values, (ϕ, ψ, θ) = (±90, +100,
CONCLUSION
+
180) and (ϕ, ψ, θ) = (±90, ±170, +180). This latter set of
■
dihedral angles matches up well with those determined from
the X-ray crystallographic structure of dimer 17 (Ac-βNPh-
αNtBu-OEt). With the exception of a θ value around (+60) for
residue 2 of tetramer 12, the θ dihedral angles are
systematically observed at about 180°, which means that the
βNtBu and βNPh residues adopt an extended conformation
within the oligomers. Analysis of the intramolecular interactions
also revealed similar characteristics between pair of compounds
In this study, we have achieved the synthesis and assessed the
conformational preference of a set of new oligopeptoid
scaffolds that combine an alternated α,β-backbone with a cis
and trans alternation of the amide links. With this combination,
four sequence patterns were designed and named cis-β-trans-α,
cis-α-trans-β, trans-β-cis-α, and trans-α-cis-β. The strict control
of the cis/trans conformation of the peptoid amide bonds was
enabled, respectively, by the use of α and βNtBu and α and
βNPh monomers. The conformation of the four target
tetramers was probed by NMR spectroscopy and explored by
molecular modeling. Both experimental and theoretical analyses
reveal that the cis-α-trans-β (12) and trans-β-cis-α (19)
tetramers, comprising both αNtBu and βNPh monomers,
display similar patterns of weak intramolecular interactions.
Similarly, the trans-α-cis-β (27) and cis-β-trans-α (6) com-
pounds involving αNPh and βNtBu residues show similar
patterns of weak inter-residues interactions, which are different
in nature from those identified in 12 and 19. Among them,
1
1
2/19 and 6/27. As highlighted in Figure 5, tetramers 12 and
9 composed of αNtBu and βNPh monomers display (i, i+1)
inter-residue (CH···O) hydrogen bonding involving one
backbone methylene atom of the αNtBu (i) residues and the
carbonyl oxygen atom of the (i+1) βNPh residues (type I
interaction, Figure 5). An additional (CH···O) interaction
between adjacent residues is identified in 12 and 19. This
involves the backbone Cα methylene protons of βNPh
monomers and the CO of the (i+1) αNtBu residues (type
II). Finally, a third interaction between the oxygen atom of the
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The Journal of Organic Chemistry
Article
(
i)
(i+1)
several backbone CH···OC
dispersive interactions
X-ray data were collected at 100 K with an Oxford Diffraction Xcalibur
2
diffractometer equipped with a copper microsource (λ = 1.5418 Å).
General Procedure A: Acetylation of the N-Terminal Amine
between neighboring residues: (i) αNtBu/βNPh, (ii) (C H)
α
βNPh/αNtBu, (iii) (C H) βNtBu/αNPh; and backbone-side
β
of Peptoids Using Ac O. To a solution of peptoid (1 equiv) and
chain (i)CH···OC
(i−1)
2
interactions: (i) αNtBu/βNPh, (ii)
Et N (4 equiv) in EtOAc (0.2 M) was added Ac O (8 equiv). After
3
2
βNtBu/αNPh.
being stirred overnight at room temperature, the precipitate was
filtered off and rinsed with EtOAc. The filtrate was then concentrated
under reduced pressure and purified by column chromatography on
silica gel.
Finally, less intramolecular interactions can be established in
oligomers constructed from the αNtBu and βNPh units than
from oligomers based on the αNPh and βNtBu monomers. In
contrast with NtBu α-oligopeptoids, fewer intramolecular side
chain to side chain interactions can be established in these
novel peptoid families. This study also stresses the diversity of
weak interactions that can be established within oligopeptoids
bearing both aromatic and aliphatic side chains as well as the
importance of their collectivity along the sequence to ensure
folding. Considering our experience in synthesizing peptoids
with tBu side chains and the electronically deactivated character
of NPh amines, solution-phase syntheses were conducted in
this work. Two tetramers (12 and 19) have been constructed
from the αNtBu and βNPh monomers and two others (6 and
General Procedure B: Saponification Using LiOH.H O. To a
2
solution of peptoid (1 equiv) in a mixture THF/MeOH/H O (4/1/1,
2
v/v) was added LiOH.H O (3 equiv). After being stirred for 3 h at
2
room temperature, the mixture was acidified with HCl 1 N and
extracted with EtOAc. The organic layer was dried over Na SO and
2
4
then concentrated in vacuo. The crude peptoid acid was used in the
peptide-type coupling reaction without further purification.
General Procedure C: Coupling Reaction with the Mukaiya-
ma Reagent (2-Chloromethylpyridinium Iodide). To a solution
of the peptoid acid (1.0 equiv) in CH Cl (0.03 M) was added the
2 2
Mukaiyama reagent (1.5 equiv). The mixture was stirred at room
temperature for 1 h, and then a mixture of peptoid amine (1.0 equiv)
and Et N (3.0 equiv) in solution in CH Cl was added dropwise. After
3
2
2
2
7) from the αNPh and βNtBu monomers. In either case,
being stirred for 2 h at room temperature, the resulting mixture was
diluted with EtOAc and washed with water. The resulting organic layer
was dried over Na SO and concentrated under reduced pressure.
different synthetic strategies were needed to get the target
molecules highlighting expected difficulties arising from the tBu
and Ph side chains. From this work, it appears that only
tetramers 6 and 12, prepared from dimers 3 (βNtBu-αNPh-
OEt) and 9 (αNtBu-βNPh-OEt), could be synthesized
following a convergent fragment-based coupling strategy.
These dimer building blocks will serve to construct longer
oligomers whose folding will depend on a collection of local
interactions that have been detected in the short peptoids. We
anticipate that these new systems could serve as suitable
platforms to construct high order nanostructures showing
various features and applications.
2
4
General Procedure D: Coupling Reaction with the Mukaiya-
ma Reagent and DMAP. To a solution of the peptoid acid (1.0
equiv) in CH Cl (0.03 M) were added the peptoid amine (1.0 equiv),
2 2
Et N (6.0 equiv), DMAP (1.0 equiv), and the Mukaiyama reagent (1.5
3
equiv). After being stirred for 3 h at room temperature, the resulting
mixture was diluted with EtOAc and washed with water. The organic
layer was dried over Na SO4 and concentrated under reduced
2
pressure.
Ethyl 2-[3-(N-tert-Butylacetamido)-N-phenylpropanamido]-
acetate (4). To a solution of aniline (3.21 mL, 23.95 mmol,) in
CHCl (10 mL) was added ethyl bromoacetate (1.33 mL, 11.98
3
mmol). The reaction was stirred at room temperature for 2 h and then
concentrated under reduced pressure. The crude was dissolved in
EtOH (10 mL) and cooled to 0 °C, and cold water (1−2 mL) was
added to the mixture resulting in the appearance of a precipitate. The
solid was filtered off, washed with cold water, and dried to provide
EXPERIMENTAL SECTION
■
General Information and Materials. THF, CH Cl , and MeOH
were dried over aluminum oxide via a solvent purification system.
2
2
3
2
1
EtOAc, CH Cl , cyclohexane, and MeOH for column chromatography
ethyl 2-(phenylamino)acetate 1 (1.16 g, 54%) as a dark solid: H
NMR (400 MHz, CDCl ) δ 1.30 (t, J = 7.1 Hz, 3H, H ), 3.91 (s, 2H,
2
2
were obtained from commercial sources and were used as received.
3
8
Et N was dried over KOH. All other solvents and chemicals obtained
H ), 4.25 (q, J = 7.1 Hz, 2H, H ), 6.60−6.67 (m, 2H, H ), 6.77 (td, J =
3
2
7
5
from commercial sources were used as received. Melting points were
determined on a Stuart Scientific SMP3 microscope apparatus and are
uncorrected. IR spectra were recorded on a Shimadzu FTIR-8400S
spectrometer equipped with a Pike Technologies MIRacle ATR and ν
1.1, 7.3 Hz, 1H, H ), 7.15−7.24 (m, 2H, H ). To a solution of amine 1
6
4
(872.3 mg, 4.87 mmol) in dry THF (10 mL) at 0 °C were added Et N
3
(2.04 mL, 14.60 mmol) and acryloyl chloride (475 μL, 5.84 mmol).
The reaction was stirred at 0 °C for 3 h, and the solid was filtered off.
The filtrate was concentrated under reduced pressure and purified by
flash chromatography on silica gel, eluting with cyclohexane/EtOAc
−1
are expressed in cm . NMR spectra were recorded on a 400 MHz
Bruker Avance III HD spectrometer or a 500 MHz Bruker AC-500
spectrometer. Chemical shifts are referenced to the residual solvent
peak and J values are given in hertz. The following multiplicity
abbreviations are used: (s) singlet, (ls) large singlet, (d) doublet, (t)
triplet, (q) quartet, (m) multiplet, and (br) broad. Where applicable,
(7/3, v/v), to provide ethyl 2-(N-phenylprop-2-enamido)acetate 2
1
(876 mg, 77%) as a yellow oil: H NMR (400 MHz, CDCl ) δ 1.27 (t,
3
J = 7.1 Hz, 3H, H
), 4.20 (q, J = 7.2 Hz, 2H, H ), 4.45 (s, 2H, H ),
8
7
2
5.57 (dd, J = 2.0, 10.3 Hz, H11trans), 6.09 (dd, J = 10.3, 16.8 Hz, 1H,
1
3
assignments were based on COSY, HMBC, HSQC, and C-
experiments. TLC was performed on Merck TLC aluminum sheets,
silicagel 60, F254. Progression of reactions was, when applicable,
followed by NMR and/or TLC. Visualizing of spots was effected with
UV-light and/or vanillin in EtOH/H SO . Flash chromatography was
H
10), 6.41 (dd, J = 1.9, 16.8 Hz, 1H, H11cis), 7.30−7.45 (m, 5H, H4−6);
13
C NMR (101 MHz, CDCl ) δ 14.3 (C ), 51.7 (C ), 61.4 (C ), 127.9
3
8
2
7
(C ), 128.2 (C ), 128.6 (C ), 129.8 (C ), 142.3 (C ), 166.0 (C ),
10
ar
11
ar
3
9
169.1 (C ). To a solution of acrylamide 2 (876 mg, 3.76 mmol) in
1
2
4
EtOH (10 mL) was added tert-butylamine (1.58 mL, 15.02 mmol).
The reaction was stirred at 55 °C for 16 h and then concentrated
under reduced pressure. The crude ethyl 2-[3-(tert-butylamino)-N-
phenylpropanamido]acetate 3 (1.067 g, 93%) obtained as a yellow oil
performed with Merck silica gel 60, 40−63 μm. HRMS was recorded
on a Micromass Q-Tof Micro (3000 V) apparatus or a Q Exactive
Quadrupole-Orbitrap Mass Spectrometer. LC−MS was recorded a Q
Exactive Quadrupole-Orbitrap mass spectrometer coupled to a UPLC
Ultimate 3000 (Kinetex EVO C18; 1.7 μm; 100 mm × 2.1 mm
1
was used in the next step without further purification. H NMR (400
MHz, CDCl ) δ 1.07 (s, 9H, H ), 1.26 (t, J = 7.2 Hz, 3H, H ), 2.33 (t,
3
13
8
−1
column with a flow rate of 0.45 mL min with the following gradient:
J = 6.7 Hz, 2H, H ), 2.78 (t, J = 6.7 Hz, 2H, H ), 4.19 (q, J = 7.2 Hz,
10 11
13
a linear gradient of solvent B from 5% to 95% over 7.5 min (solvent A
2H, H ), 4.34 (s, 2H, H ), 7.31−7.43 (m, 5H, H4−6); C NMR (101
7
2
=
H O + 0.1% formic acid, solvent B = acetonitrile + 0.1% formic acid)
2
MHz, CDCl ) δ 14.3 (C ), 29.0 (C ), 35.4 (C ), 38.4 (C ), 50.6
3 8 13 10 11
equipped with a DAD UV/vis 3000 RS detector. HPLC analysis was
performed on a Dionex instrument equipped with an Uptisphere
(C ), 51.4 (C ), 61.4 (C ), 128.3 (C ), 128.5 (C ), 129.9 (C ), 142.7
12 2 7 4 6 5
(C ), 169.3 (C ), 172.8 (C ). Compound 3 (644.5 mg, 2.10 mmol)
3
1
9
(
ODB, 5 μm, 120 Å, 4.6 × 250 mm) and a Dionex UVD 340 detector.
was submitted to general procedure A. The crude was purified by flash
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The Journal of Organic Chemistry
Article
chromatography, eluting with cyclohexane/EtOAc (4/6, v/v) to afford
the expected compound 4 (546.0 mg, 75%) as a pale yellow oil: H
128.7 (C ), 130.1 (C ), 140.9 (C ), 171.1 (C ), 171.4 (C ).
Compound 9 (639 mg, 2.09 mmol) was submitted to general
procedure A. The crude was purified by flash chromatography on silica
7
5
4
10
1
1
NMR (400 MHz, CDCl ) δ 1.21−1.32 (m, 12H, H and H ), 1.94 (s,
3
8
13
3
=
H, H ), 2.32−2.41 (m, 2H, H ), 3.52−3.61 (m, 2H, H ), 4.21 (q, J
gel, eluting with EtOAc/cyclohexane (6/4, v/v) to afford compound
1
5
10
11
13
1
7.1 Hz, 2H, H ), 4.34 (s, 2H, H ), 7.31−7.48 (m, 5H, H );
C
10 (565.3 mg, 78%) as a yellow oil: H NMR (400 MHz, CDCl ) δ
7
2
4−6
3
NMR (101 MHz, CDCl ) δ 14.3 (C ), 24.9 (C ), 29.0 (C ), 36.0
1.20 (t, J = 7.1 Hz, 3H, H ), 1.36 (s, 9H, H ), 1.97 (s, 3H, H ), 2.57
3
8
15
13
9
12
13
(
(
C ), 42.8 (C ), 51.3 (C ), 57.1 (C ), 61.5 (C ), 128.0 (C ), 128.9
(t, J = 7.1 Hz, 2H, H ), 3.69 (s, 2H, H ), 3.93−4.12 (m, 4H, H and
10
11
2
12
7
4
2
11
8
13
C ), 130.2 (C ), 142.5 (C ), 169.1 (C ), 170.8 (C ), 171.4 (C );
H ), 7.21−7.25 (m, 2H, H ), 7.37−7.53 (m, 3H, H and H );
C
6
5
3
1
9
14
3
6
5
7
+
HRMS (ESI) calcd for C H O N [M + H] 349.2122, found
NMR (101 MHz, CDCl ) δ 14.2 (C ), 25.1 (C ), 28.6 (C ), 33.1
19
29
4
2
3 9 13 12
349.2116.
(C ), 45.9 (C ), 49.2 (C ), 57.3 (C ), 60.8 (C ), 128.2 (C ), 129.1
2 3 11 14 8 6
Ethyl 2-(3-[N-tert-Butyl-2-[3-(N-tert-butylacetamido)-N-
(C ), 130.5 (C ), 140.9 (C ), 169.1 (C ), 171.4 (C or C ), 171.8
7
5
4
10
1
15
+
phenylpropanamido]acetamido]-N-phenylpropanamido)-
acetate (6). Compound 4 (220.0 mg, 0.63 mmol) was submitted to
general procedure B to afford the crude 2-[3-(N-tert-butylacetamido)-
N-phenylpropanamido]acetic acid 5 (97.0 mg, 48%) as a white solid:
(C or C ); HRMS (ESI) calcd for C H O N [M + H] 349.2122,
1 15 19 29 4 2
found 349.2115.
Ethyl 3-(2-[N-tert-Butyl-3-[2-(N-tert-butylacetamido)-N-
phenylacetamido]propanamido]-N-phenylacetamido)-
propanoate (12). Compound 10 (565.3 mg, 1.62 mmol) was
submitted to general procedure B to afford the crude 3-[2-(N-tert-
1
H NMR (400 MHz, CDCl ) δ 1.28 (s, 9H, H ), 1.97 (s, 3H, H ),
3
11
13
2
7
.33−2.44 (m, 2H, H ), 3.55−3.61 (m, 2H, H ), 4.38 (s, 2H, H ),
8
9
2
.31−7.50 (m, 5H, H ). General procedure C was applied using
butylacetamido)-N-phenylacetamido]propanoic acid 11 (387.0 mg,
4
−6
1
carboxylic acid 5 (97.0 mg, 0.30 mmol) and amine 3 (91.9 mg, 0.30
mmol). The crude was purified by flash chromatography, eluting with
75%) as a white solid: H NMR (400 MHz, CDCl
3
) δ 1.35 (s, 9H,
), 3.71 (s, 2H, H ),
), 7.47 (m, 3H, H and H ). The
H
11), 1.99 (s, 3H, H13), 2.58 (t, J = 6.8 Hz, 2H, H
4.03 (s, 2H, H ), 7.27 (s, 2H, H
2
9
cyclohexane/EtOAc (1/9, v/v), to provide the expected tetramer 6
3
6
5
7
1
(
1
2
97.8 mg, 53%) as a pale yellow gum: H NMR (400 MHz, CDCl ) δ
general procedure C was applied using the carboxylic acid 11 (50 mg,
0.16 mmol) and the amine 9 (50 mg, 0.16 mmol). The crude was
purified by flash chromatography on silica gel, eluting with EtOAc to
3
.25 (d, J = 7.7 Hz, 21H, H21 and H10 and H ), 1.90 (s, 3H, H ),
25 23
.30−2.38 (m, 2H, H ), 2.41−2.48 (m, 2H, H ), 3.44−3.56 (m, 4H,
18
7
1
H and H ), 4.18 (q, J = 7.2 Hz, 2H, H ), 4.22 (s, 2H, H ), 4.31 (s,
afford the tetramer 12 (43.2 mg, 46%) as a yellow gum: H NMR (400
8
19
24
12
13
2
H, H ), 7.28−7.48 (m, 10H, H
CDCl ) δ 14.3 (C ), 24.9 (C ), 28.8 (C ), 28.9 (C ), 35.9 (C ),
and H4−6); C NMR (101 MHz,
MHz, CDCl
(s, 9H, H26), 2.01 (s, 3H, H12), 2.50−2.60 (m, 4H, H
(s, 2H, H10), 3.88 (s, 4H, H and H ), 4.00 (t, J = 7.3 Hz, 2H, H
4.06 (q, J = 7.1 Hz, 2H, H13), 7.23 (d, J = 7.6 Hz, 2H, H22), 7.33 (d, J
3
) δ 1.20 (t, J = 7.1 Hz, 3H, H14), 1.31 (s, 9H, H20), 1.38
and H ), 3.73
),
2
14−16
3
25
23
10
20
7
2
7
3
5
(
1
6.1 (C ), 41.0 (C ), 43.0 (C ), 51.4 (C ), 53.1 (C ), 57.0 (C ),
5
8
3
18
8
19
2
12
9
7.7 (C ), 61.5 (C ), 128.0 (C ), 128.2 (C ), 128.4 (C ), 128.8
20
24
4
14
6
13
C ), 129.8 (C ), 130.1 (C ), 142.4 (C ), 143.2 (C ), 167.5 (C ),
= 7.5 Hz, 2H, H16), 7.38−7.52 (m, 6H, Har); C NMR (101 MHz,
CDCl ) δ 14.3 (C14), 25.2 (C12), 28.5 (C20), 28.7 (C26), 33.0 (C ),
35.1 (C ), 45.9 (C ), 47.5 (C or C ), 48.5 (C or C ), 49.2 (C10), 57.3
16
5
15
3
13
11
69.0 (C ), 170.3 (C ), 170.7 (C ), 171.5 (C ); HRMS (ESI) calcd
3
2
1
17
6
22
+
for C H O N [M + H] 609.3647, found 609.3650.
7
3
5
8
5
8
34
49
6
4
Ethyl 3-[2-(N-tert-Butylacetamido)-N-phenylacetamido]-
propanoate (10). To a solution of aniline (490 μL, 5.37 mmol) in
water (1 mL) were added ethyl acrylate (16.11 mmol, 1.78 mL) and
trifluoroethanol (10.74 mmol, 782 μL). After one night at reflux, the
reaction was cooled to room temperature and extracted with EtOAc.
The organic layer was dried over Na SO and concentrated under
(C25), 57.7 (C19), 60.8 (C13), 128.0 (C22), 128.4 (C15), 128.8 (C24),
129.1 (C ), 130.3 (C ), 130.5 (C ), 140.7 (C ), 141.5 (C ), 169.2
18
23
17
15
21
(C or C or C ), 169.3 (C or C or C ), 171.3 (C ), 171.5 (C or C
9
5
4
9
5
4
1
9
5
+
or C ), 171.9 (C ); HRMS (ESI) calcd for C H O N [M + H]
4
11
34 49
6
4
609.3647, found 609.3650.
Ethyl 2-(N-tert-Butylprop-2-enamido)acetate (14). To a
solution of ethyl bromoacetate (1.33 mL, 11.98 mmol) in dry THF
2
4
reduced pressure. The crude was purified by flash chromatography,
eluting with cyclohexane/EtOAc (8/2, v/v), to yield ethyl 3-
(20 mL) at room temperature were added Et N (3.34 mL, 23.95
3
3
3
(
phenylamino)propanoate 7 (635.5 mg, 61%) as a pale yellow oil:
mmol) and tert-butylamine (5.03 mL, 47.90 mmol). The reaction was
stirred overnight. After completion of the reaction, as monitored by
TLC, the mixture was filtered, and the liquid was concentrated under
reduced pressure. The crude ethyl 2-(tert-butylamino)acetate 13 (1.17
g, 62%, colorless oil) was used in the next step without further
1
H NMR (400 MHz, CDCl ) δ 1.26 (t, J = 7.2 Hz, 3H, H ), 2.61 (t, J
3
9
=
6.4 Hz, 2H, H ), 3.46 (t, J = 6.4 Hz, 2H, H ), 4.09 (s, 1H, NH), 4.16
2
3
(
q, J = 7.1 Hz, 2H, H ), 6.61−6.66 (m, 2H, H ), 6.72 (tt, J = 1.1, 7.3
8
5
Hz, 1H, H ), 7.15−7.22 (m, 2H, H ). To a solution of 7 (661 mg, 3.42
7
6
1
mmol) in dry THF (5 mL) at −20 °C were added Et N (4.11 mmol,
purification: H NMR (400 MHz, CDCl ) δ 1.04 (s, 9H, H ), 1.21 (t, J
3
3
4
5
73 μL) and bromoacetyl bromide (4.11 mmol, 358 μL). The reaction
= 7.1 Hz, 3H, H ), 3.33 (s, 2H, H ), 4.12 (q, J = 7.2 Hz, 2H, H ). To a
6
2
5
was stirred at −20 °C for 2−3 h. After completion of the reaction, as
monitored by TLC, the mixture was filtered, and the filtrate was
concentrated under reduced pressure. The crude was purified by flash
chromatography, eluting with cyclohexane/EtOAc (6/4, v/v), to
solution of amine 13 (500.0 mg, 3.14 mmol) in dry THF (20 mL) at 0
°C were added Et N (1.31 mL, 9.42 mmol) and acryloyl chloride (306
3
μL, 3.78 mmol). The reaction was stirred at 0 °C for 2 h, and the solid
was filtered off. The filtrate was concentrated under reduced pressure
and purified by flash chromatography on silica gel, eluting with
provide ethyl 3-(2-bromo-N-phenylacetamido)propanoate 8 (633.0
1
mg, 59%) as a pale yellow oil: H NMR (400 MHz, CDCl ) δ 1.20 (t,
cyclohexane/EtOAc (7/3, v/v) to provide the expected compound 14
3
1
J = 7.1 Hz, 3H, H ), 2.60 (t, J = 7.3 Hz, 2H, H ), 3.62 (s, 2H, H ),
(524.4 mg, 78.3%) as a yellow oil: H NMR (400 MHz, CDCl ) δ 1.29
9
2
11
3
3
.97−4.10 (m, 4H, H and H ), 7.26−7.30 (m, 2H, H ), 7.36−7.51
(t, J = 7.1 Hz, 3H, H ), 1.45 (s, 9H, H ), 4.11 (s, 3H, H ), 4.22 (q, J =
3
8
6
9
4
2
1
3
(
(
(
2
m, 3H, H and H ); C NMR (101 MHz, CDCl ) δ 14.2 (C ), 27.2
C ), 32.7 (C ), 46.2 (C ), 60.8 (C ), 128.2 (C ), 129.0 (C ), 130.2
C ), 141.3 (C ), 166.6 (C ), 171.3 (C ). To a solution of 8 (633 mg,
.01 mmol) in dry THF (5 mL) at room temperature were added
7.1 Hz, 2H, H ), 5.58 (dd, J = 1.9, 10.5 Hz, 1H, H7trans), 6.18 (dd, J =
5
7
3
6
8
2.0, 16.8 Hz, 1H, H ), 6.38 (dd, J = 10.4, 16.8 Hz, 1H, H7cis).
11
2
3
8
6
7
6
Ethyl 2-[N-tert-Butyl-3-(N-phenylacetamido)propanamido]-
acetate (17). Compound 7 (434 mg, 2.24 mmol) was submitted to
general procedure A. The crude was purified by flash chromatography,
eluting with EtOAc/cyclohexane (3/7, v/v), to provide ethyl 3-(N-
5
4
10
1
Et N (4.03 mmol, 562 μL) and tert-butylamine (8.06 mmol, 847 μL).
3
The reaction was stirred overnight. After completion of the reaction, as
monitored by TLC, the mixture was filtered, and the liquid was
concentrated under reduced pressure. The crude ethyl 3-[2-(tert-
butylamino)-N-phenylacetamido]propanoate 9 (582 mg, 94%)
obtained as a pale yellow oil was engaged in the next step without
purification: H NMR (400 MHz, CDCl ) δ 0.99 (s, 9H, H ), 1.19 (t,
J = 7.1 Hz, 3H, H ), 2.58 (t, J = 7.4 Hz, 2H, H ), 3.05 (s, 2H, H ),
1
phenylacetamido)propanoate 15 (482 mg, 91%) as a colorless oil: H
NMR (400 MHz, CDCl
), 2.57 (t, J = 7.3 Hz, 2H, H
(d, J = 7.5 Hz, 2H, H ), 7.34 (m, 1H, H
C NMR (101 MHz, CDCl3) δ 14.2 (C11), 22.8 (C
(C ), 60.7 (C ), 128.3 (C ), 129.9 (C ), 142.9 (C ), 170.5 (C ),
) δ 1.19 (t, J = 7.1 Hz, 3H, H11), 1.82 (s, 3H,
), 3.97−4.08 (m, 4H, H and H10), 7.17
), 7.42 (t, J = 7.5 Hz, 2H, H );
), 33.1 (C ), 45.2
3
H
9
2
3
6
7
5
1
13
3
12
9
2
9
2
11
3
10
ar
ar
ar
8
4
.03 (m, 4H, H and H ), 7.14−7.21 (m, 2H, H ), 7.34−7.51 (m, 3H,
171.6 (C ). Compound 15 (482.0 mg, 2.05 mmol) was submitted to
3
8
6
1
13
H and H ); C NMR (101 MHz, CDCl ) δ 14.2 (C ), 28.5 (C ),
general procedure B to afford the crude 3-(N-phenylacetamido)-
5
7
3
9
12
1
32.9 (C ), 44.7 (C ), 45.7 (C ), 50.9 (C ), 60.7 (C ), 128.2 (C ),
propanoic acid 16 (340.0 mg, 80%) as a white solid: H NMR (400
2
11
2
13
8
6
K
DOI: 10.1021/acs.joc.8b00606
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
MHz, CDCl ) δ 1.84 (s, 3H, H ), 2.62 (t, J = 7.2 Hz, 2H, H ), 4.00 (t,
(t, J = 6.8 Hz, 3H, H ), 2.49 (t, J = 6.5 Hz, 2H, H ), 2.82 (t, J = 6.6 Hz,
3
9
2
7
2
13
J = 7.2 Hz, 2H, H ), 7.19 (dd, J = 1.7, 7.3 Hz, 2H, H ), 7.32−7.47 (m,
2H, H ), 4.14 (q, J = 7.2 Hz, 2H, H ); C NMR (101 MHz, CDCl ) δ
3
ar
3
6
3
13
3
H, H ); C NMR (101 MHz, CDCl ) δ 22.7 (C ), 32.8 (C ), 45.4
14.4 (C ), 29.1 (C ), 35.8 (C ), 38.2 (C ), 50.6 (C ), 60.5 (C ), 173.1
7 5 2 3 4 6
ar
3
9
2
(
C ), 128.1 (C ), 128.5 (C ), 130.1 (C ), 142.5 (C ), 171.5 (C ),
(C ). To a solution of 20 (1.02 g, 5.88 mmol) in dry THF (5 mL) at
1
3
ar
ar
ar
4
8
1
75.6 (C ). General procedure C was applied using carboxylic acid 16
−20 °C were added Et N (985 μL, 7.07 mmol) and bromoacetyl
2
3
(
100.0 mg, 0.48 mmol) and monomer amine 13 (76.4 mg, 0.48
bromide (615 μL, 7.07 mmol). The reaction was stirred at −20 °C for
2−3 h. After completion, monitored by TLC, the reaction was filtered,
and the liquid was concentrated under reduced pressure. The crude
was purified on flash chromatography, eluting with cyclohexane/
EtOAc (8/2, v/v), to provide ethyl 3-(2-bromo-N-tert-
butylacetamido)propanoate 21 (1.33 g, 77%) as a pale yellow oil:
mmol). The crude was purified by flash chromatography, eluting with
cyclohexane/EtOAc (3/7, v/v) to provide dimer 17 (146 mg, 87%) as
a white solid: H NMR (400 MHz, CDCl ) δ 1.27 (t, J = 7.2 Hz, 3H,
H ), 1.37 (s, 9H, H ), 1.82 (s, 3H, H ), 2.56 (bs, 2H, H ), 3.95 (t, J =
1
3
15
4
13
6
7
7
.6 Hz, 2H, H ), 4.10 (s, 2H, H ), 4.20 (q, J = 7.2 Hz, 2H, H ), 7.09−
7
2
14
13
1
.18 (m, 2H, H ), 7.29−7.43 (m, 3H, H and H ); C NMR (101
H NMR (400 MHz, CDCl ) δ 1.27 (t, J = 7.3 Hz, 3H, H ), 1.45 (s,
9
10
11
3
7
MHz, CDCl ) δ 14.3 (C ), 22.9 (C ), 28.7 (C ), 34.2 (C ), 46.6
9H, H ), 2.60−2.67 (m, 2H, H ), 3.64−3.76 (m, 2H, H ), 3.91 (s, 2H,
3
15
13
4
6
5
2
3
13
(
C ), 47.4 (C ), 57.8 (C ), 61.6 (C ),128.0 (C and C ), 129.8 (C ),
H ), 4.16 (q, J = 7.2 Hz, 2H, H ); C NMR (101 MHz, CDCl ) δ
9 6 3
7
2
3
14
10
11
9
143.4 (C ), 170.7 (C ), 170.8 (C ), 171.7 (C ); HRMS (ESI) calcd
14.3 (C ), 28.7 (C ), 29.9 (C ), 36.9 (C ), 41.9 (C ), 58.1 (C ), 61.2
7 5 9 2 3 4
(C ), 167.5 (C ), 170.8 (C ). To a solution of 21 (665.0 mg, 2.26
6 8 1
8
12
1
5
+
for C H N O [M + H] 349.2121, found 349.2121.
19
29
2
4
E th yl 2-( N- t e r t-But yl -3 -[2 -[ N -t ert -b u ty l- 3 - (N-
phenylacetamido)propanamido]-N-phenylacetamido]-
propanamido)acetate (19). Compound 17 (146.0 mg, 0.42 mmol)
was submitted to general procedure B to afford the crude 2-[N-tert-
mmol) in dry THF (5 mL) was added Et N (4.52 mmol, 631 μL) and
3
aniline (9.04 mmol, 826 μL). The reaction was stirred at room
temperature for 3 days. After completion of the reaction, as monitored
by TLC, the mixture was filtered, and the liquid was concentrated
under reduced pressure. The crude was purified on flash
chromatography, eluting with cyclohexane/EtOAc (7/3, v/v) to
provide the expected compound 22 (541 mg, 78%) as a colorless
butyl-3-(N-phenylacetamido)propanamido]acetic acid (103.0 mg,
1
7
7%) as a withe solid: H NMR (400 MHz, CDCl ) δ 1.41 (s, 9H,
3
H ), 1.87 (s, 3H, H ), 2.66 (t, J = 7.9 Hz, 2H, H ), 3.96 (t, J = 7.6 Hz,
4
13
6
2
H, H ), 4.16 (s, 2H, H ), 7.20 (d, J = 7.6 Hz, 2H, H ), 7.39 (m, 3H,
1
7
2
ar
oil: H NMR (400 MHz, CDCl ) δ 1.29 (t, J = 7.1 Hz, 3H, H ), 1.49
3
13
H ). The general procedure D was applied using the crude 2-[N-tert-
ar
(s, 9H, H ), 2.61 (dd, J = 6.8, 9.3 Hz, 2H, H ), 3.65 (dd, J = 6.7, 9.5
5
2
butyl-3-(N-phenylacetamido)propanamido]acetic acid (100.0 mg, 0.31
mmol) and the monomer amine 7 (59.9 mg, 0.31 mmol). The crude
was purified by flash chromatography, eluting with cyclohexane/
EtOAc (3/7, v/v) to provide ethyl 3-[2-[N-tert-butyl-3-(N-
Hz, 2H, H ), 3.90 (s, 2H, H ), 4.18 (q, J = 7.2 Hz, 2H, H ), 6.67 (d, J
3
7
12
=
7.9 Hz, 2H, H ), 6.74 (t, J = 7.4 Hz, 1H, H ), 7.20 (t, J = 7.4 Hz,
10 11
13
2
H, H ); C NMR (101 MHz, CDCl ) δ 14.3 (C ), 28.9 (C ), 36.5
9 3 13 5
(
(
C ), 39.8 (C ), 47.5 (C ), 58.1 (C ), 61.2 (C ), 113.6 (C ), 118.1
2 3 7 4 12 10
phenylacetamido)propanamido]-N-phenylacetamido]propanoate 18
C ), 129.4 (C ), 147.2 (C ), 169.2 (C ), 170.8 (C ); HRMS (ESI)
11
9
8
6
1
1
(
80 mg, 52%) as a colorless oil: H NMR (400 MHz, CDCl ) δ
+
3
calcd for C H N O [M + H] 307.2016, found 307.2019.
17 27 2 3
1
2
.18−1.23 (m, 3H, H ), 1.31 (s, 9H, H ), 1.84 (s, 3H, H ), 2.52 (m,
2
2
11
20
E t hy l 3 -( N -t ert -But yl -2- [3- [ N -te rt - bu tyl -2 -( N -
phenylacetamido)acetamido]-N-phenylpropanamido]-
acetamido)propanoate (27). To a solution of 22 (541.0 mg, 1.77
H, H ), 2.59 (t, J = 7.4 Hz, 2H, H ), 3.79 (s, 2H, H ), 3.91 (m, 2H,
13
2
9
H ), 3.97−4.12 (m, 4H, H and H ), 7.19 (d, J = 7.7 Hz, 2H, H ),
1
4
3
21
ar
13
7
2
5
.28−7.57 (m, 8H, H ); C NMR (101 MHz, CDCl3) δ 14.3 (C ),
3.0 (C ), 28.6 (C ), 33.0 (C ), 34.5 (C ), 45.9 (C ), 48.3 (C ),
mmol) in dry THF (5 mL) at 0 °C were added Et N (738 μL, 5.30
ar
23
3
mmol) and acryloyl chloride (172 μL, 2.12 mmol). The reaction was
stirred at 0 °C for 3 h. After completion of the reaction, as monitored
by TLC, the mixture was filtered, and the liquid was concentrated
under reduced pressure. The crude was purified by flash chromatog-
raphy, eluting with cyclohexane/EtOAc (1/1, v/v), to provide ethyl 3-
20
11
2
13
3
14
7.5 (C ), 60.8 (C ), 128.0 (C ), 128.1 (C ), 128.3 (C ), 129.0
15
21
ar
ar
ar
(
C ), 129.8 (C ), 130.4 (C ), 140.9 (C ), 143.6 (C ), 169.2 (C ),
ar ar ar ar ar 8
1
70.7 (C ), 171.4 (C ), 171.8 (C ). The general procedure B was
19 1 12
applied using the ester 18 (60 mg 0.12 mmol) to afford the crude ethyl
3
-[2-[N-tert-butyl-3-(N-phenylacetamido)propanamido]-N-
[N-tert-butyl-2-(N-phenylprop-2-enamido)acetamido]propanoate 23
1
1
phenylacetamido]propanoic acid (44.0 mg, 77%) as a white solid: H
(617 mg, 97%) as a pale yellows oil: H NMR (400 MHz, CDCl )
3
NMR (400 MHz, CDCl ) δ 1.28 (s, 9H, H ), 1.94 (s, 3H, H ), 2.47
δ 1.25 (t, J = 7.1 Hz, 3H, H ), 1.44 (s, 9H, H ), 2.67−2.76 (m, 2H,
3
11
20
16
5
(
m, 4H, H and H ), 3.68 (s, 2H, H ), 4.03 (bs, 4H, H and H ),
H ), 3.56−3.67 (m, 2H, H ), 4.12 (q, J = 7.2 Hz, 2H, H ), 4.50 (s,
2
13
9
3
14
2
3
15
7
.28−7.66 (m, 10H, H ). The general procedure D was applied using
2H, H15), 5.54 (d, J = 10.4 Hz, 1H, H14), 6.13 (dd, J = 10.6, 16.2 Hz,
ar
1
3
ethyl 3-[2-[N-tert-butyl-3-(N-phenylacetamido)propanamido]-N-
phenylacetamido]propanoic acid (100.0 mg, 0.31 mmol,) and the
monomer amine 13 (49.3 mg, 0.31 mmol). The crude was purified by
flash chromatography, eluting with cyclohexane/EtOAc (3/7, v/v) to
1H, H13), 6.37 (d, J = 16.8 Hz, 1H, H14), 7.29−7.44 (m, 5H, Har).
NMR (101 MHz, CDCl3) δ 14.3 (C16), 29.0 (C ), 36.3 (C ), 40.3
(C ), 53.7 (C ), 57.9 (C ), 61.0 (C15), 127.8 (C14), 128.0 (C13), 128.3
(Car), 128.4 (Car), 129.5 (Car), 143.1 (C ), 166.0 (C12), 167.8 (C ),
171.1 (C ). To a solution of 23 (617.0 mg, 1.71 mmol) in EtOH (10
mL) at room temperature was added tBuNH (720 μL, 6.85 mmol).
C
5
2
3
7
4
8
6
1
afford the expected tetramer 19 (80 mg, 52%) as a colorless oil: H
1
NMR (400 MHz, CDCl ) δ 1.26 (t, J = 7.1 Hz, 3H, H ), 1.31 (s, 9H,
2
3
26
H ), 1.38 (s, 9H, H ), 1.83 (s, 3H, H ), 2.52 (bs, 2H, H ), 2.60 (bs,
The reaction was stirred at 65 °C for 16 h. After completion of the
reaction, as monitored by TLC, the reaction was concentrated under
reduced pressure. The crude ethyl 3-[N-tert-butyl-2-[3-(tert-butylami-
no)-N-phenylpropanamido]acetamido]propanoate 24 (659 mg, 89%)
15
4
24
17
2
7
7
H, H ), 3.79 (s, 2H, H ), 3.91 (t, J = 7.0 Hz, 2H, H ), 3.99 (t, J =
6 13 18
.0 Hz, 2H, H ), 4.13 (s, 2H, H ), 4.19 (q, J = 7.1 Hz, 2H, H ), 7.15−
7
2
25
13
.22 (m, 2H, H ), 7.27−7.50 (m, 7H, H ); C NMR (101 MHz,
ar
ar
CDCl3) δ 14.3 (C ), 23.0 (C ), 28.6 (C ), 28.7 (C ), 34.2 (C ),
obtained as a pale yellows oil was used in the next step without further
26
24
15
4
6
1
3
5
4.6 (C ), 46.9 (C ), 47.0 (C ), 47.4 (C ), 48.4 (C ), 57.6 (C ),
purification: H NMR (400 MHz, CDCl
3
) δ 1.09 (s, 9H, H16), 1.24 (t,
), 2.38 (t, J = 6.9 Hz, 2H, H13),
), 2.81 (t, J = 6.7 Hz, 2H, H14), 3.58
), 4.11 (q, J = 7.3 Hz, 2H, H17), 4.40 (s,
3
17
18
7
2
13
14
7.8 (C ), 61.6 (C ), 127.9 (C ), 128.1 (C ), 128.2 (C ), 128.8
J = 7.2 Hz, 3H, H18), 1.43 (s, 9H, H
2.65 (dd, J = 6.6, 9.7 Hz, 2H, H
(dd, J = 6.6, 9.7 Hz, 2H, H
2H, H ), 7.27−7.50 (m, 5H, Har); C NMR (101 MHz, CDCl3) δ
14.3 (C18), 28.8 (C15), 29.0 (C ), 35.1 (C13), 36.3 (C ), 38.6 (C14),
40.2 (C ), 53.4 (14), 51.0 (C ), 57.9 (C ), 61.0 (C ), 128.1 (C ),
5
3
25
Ar
Ar
Ar
(
C ), 129.8 (C ), 130.3 (C ), 141.5 (C ), 143.6 (C ), 169.2 (C ),
2
Ar
Ar
Ar
Ar
Ar
12
1
70.6 (C ), 170.9 (C ), 171.5 (C or C ), 171.6 (C or C ); HRMS
24
1
5
16
5
16
+
13
(
ESI) calcdfor C H O N [M + H] 609.3647, found 609.3652.
7
34
49
6
4
Ethyl 3-[N-tert-Butyl-2-(phenylamino)acetamido]-
propanoate (22). To a solution of ethyl acrylate (10.00 g, 99.88
mmol) in EtOH (0.2 M) at room temperature was added tBuNH2
5
2
3
15
4
17
ar
128.4 (C ), 129.7 (C ), 143.3 (C ), 167.9 (C ), 171.1 (C ), 172.5
ar
ar
8
6
1
(29.22 g, 42 mL, 4 equiv). After being stirred for 16 h at 60 °C, the
(C ). To a solution of 24 (659 mg, 1.52 mmol) in dry THF (5 mL) at
12
mixture was cooled, concentrated, and dried in vacuo, yielding the
crude ethyl 3-(tert-butylamino)propanoate 20. The crude was purified
on flash chromatography, eluting with cyclohexane/EtOAc (8/2, v/v)
to provide the expected compound 20 (14.47 g, 83.51 mmol, 84%) as
−20 °C were added Et N (254 μL, 1.82 mmol) and bromoacetyl
3
bromide (159 μL, 1.82 mmol). The reaction was stirred at −20 °C for
2−3 h. After completion, as monitored by TLC, the reaction was
filtered, and the liquid was concentrated under reduced pressure. The
crude was purified by flash chromatography, eluting with cyclohexane/
1
a colorless oil: H NMR (400 MHz, CDCl ) δ 1.11 (s, 9H, H ), 1.26
3
9
L
DOI: 10.1021/acs.joc.8b00606
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
EtOAc (1/1, v/v), to provide ethyl 3-[2-[3-(2-bromo-N-tert-
butylacetamido)-N-phenylpropanamido]-N-tert-butylacetamido]-
propanoate 25 (283 mg, 34%) as a pale yellow oil: H NMR (400
performed on the constrained optimized structure at DFT level
using above-mentioned functional and basis sets. All minima and
transition states were finally fully optimized at M06-2X level using the
polarized all electron 6-311G(d,p) basis set for all atoms.
1
MHz, CDCl ) δ 1.25 (t, J = 7.1 Hz, 3H, H ), 1.30 (s, 9H, H or H5),
3
20
16
1
.44 (s, 9H, H16 or H ), 2.37−2.50 (m, 2H, H ), 2.56−2.72 (m, 2H,
Setup for Molecular Dynamics (MD) Simulation. The Generalized
AMBER Force Field (GAFF) parameters were used to describe the
5
13
4
0
H ), 3.54−3.65 (m, 4H, H and H ), 3.67 (s, 2H, H ), 4.12 (q, J =
2
3
14
18
13
7
.2 Hz, 2H, H ), 4.41 (s, 2H, H ), 7.34−7.46 (m, H ); C NMR
potential of NtBu peptoid monomers. The RESP charges were
19
7
ar
4
1
42
(
101 MHz, CDCl3) δ 14.31 (C ), 28.59 (C or C ), 28.99 (C or
generated using RED server followed by the antechamber module
19
16
5
16
C ), 30.20 (C ), 36.33 (C ), 36.75 (C ), 40.27 (C ), 42.65 (C ),
of AMBER to make the parameter/topology (parm) file. The peptoid
oligomers were capped by an acetyl group at the N-terminus and N,N-
dimethyl at C-terminus. The peptoid oligomers were solvated in
acetonitrile box with a buffer of 16 Å toward each direction.
5
16
2
13
3
14
5
3.44 (C ), 57.97 (C or C ), 58.03 (C or C ), 61.03 (C ), 128.27
ar ar ar 8 6
7 15 4 15 4 19
(
C ), 128.69 (C ), 130.06 (C ), 143.17 (C ), 167.43 (C ), 167.46
(
C ), 170.31 (C ), 171.06 (C ). To a solution of 25 (283.0 mg, 0.51
17
12
1
mmol) in dry THF (5 mL) were added Et N (142 μL, 1.02 mmol)
Molecular Dynamics Simulation. All Molecular Dynamics
3
43
and aniline (186 μL, 2.04 mmol). The reaction was stirred at room
temperature for 48 h. After completion, as monitored by TLC, the
reaction was filtered, and the liquid was concentrated under reduced
pressure. The crude was purified by flash chromatography, eluting with
cyclohexane/EtOAc (6/4, v/v), to provide ethyl 3-(N-tert-butyl-2-[3-
simulations were performed using the NAMD software package.
A
timestep of 1 fs was applied for each simulation. A cutoff of 14 Å was
applied for nonbonded interactions, while Particle Mesh Ewald
summation was applied for electrostatic interactions. The system
was initially minimized for 200 steps. This was followed by
equilibration at NVT ensemble. During this NVT equilibration, the
temperature was gradually raised from 5 to 315 K with increments of
10 K. At each temperature, 5000 steps (5 ps) of simulation was
performed. This was followed by 200 ps of NVT equilibration at 300
K. Thereafter, the system was subjected to 400 ps of equilibration at
NPT ensemble. The temperature was kept fixed at 300 K through
Langevin dynamics with a damping coefficient of 5/ps while the
pressure was controlled at 1 atm using a Nose−Hoover Langevin
piston. From the equilibrated system, two initial production runs of
each 10 ns were performed. The resultant snapshots were subjected to
another two similar production run each. A final production run of 50
ns was performed from the final snapshot of the initial production run.
The trajectory was stored for every 2 ps. The trajectory from this final
production run was used for calculation of all equilibrium properties. A
similar protocol was followed for peptoid oligomers with alternating
positive and negative φ dihedral angles.
[
N-tert-butyl-2-(phenylamino)acetamido]-N-phenylpropanamido]-
1
acetamido)propanoate 26 (183 mg, 63%) as a pale yellow oil: H
NMR (400 MHz, CDCl ) δ 1.26 (t, J = 7.1 Hz, 3H, H ), 1.33 (s, 9H,
3
24
H ), 1.45 (s, 9H, H ), 2.39−2.48 (m, 2H, H ), 2.59−2.71 (m, 2H,
5
16
13
H ), 3.59 (t, J = 7.0 Hz, 4H, H and H ), 3.78 (s, 2H, H ), 4.13 (q, J
2
3
14
18
=
7.1 Hz, 2H, H ), 4.42 (s, 2H, H ), 6.65−6.84 (m, 3H, H ), 7.17−
23
7
ar
13
7
.24 (m, 2H, H ), 7.28−7.49 (m, 5H, H ); C NMR (101 MHz,
ar
ar
CDCl ) δ 14.3 (C ), 28.8 (C ), 29.0 (C ), 36.0 (C ), 36.4 (C ) 40.3
3
24
5
16
13
2
(
(
1
C ), 40.7 (C ), 47.7 (C ), 53.5 (C ), 58.0 (C ), 58.1 (C ), 61.4
3
14
18
7
16
5
C ), 114.2 (C ), 128.1 (C ), 128.7 (C ), 129.4 (C ), 130.1 (C ),
23
Ar
Ar
Ar
Ar
Ar
43.1 (C ), 167.5 (C ), 168.9 (C ), 170.4 (C ), 171.0 (C ). The
Ar
6
17
12
1
general procedure A was applied using compound 26 (183.0 mg, 0.32
mmol) as starting material. The crude was purified by flash
chromatography, eluting with cyclohexane/EtOAc (3/7, v/v) to afford
1
the expected compound 27 (167 mg, 85%) as a pink oil: H NMR
(
400 MHz, CDCl ) δ 1.20−1.29 (m, 12H, H and H ), 1.43 (s, 9H,
3
26
16
H ), 1.89 (s, 3H, H ), 2.44−2.52 (m, 2H, H ), 2.60−2.69 (m, 2H,
5
24
13
H ), 3.48−3.54 (m, 2H, H ), 3.54−3.60 (m, 2H, H ), 4.12 (q, J = 7.1
ASSOCIATED CONTENT
Supporting Information
2
14
3
■
Hz, 2H, H ), 4.20 (s, 2H, H ), 4.38 (s, 2H, H ), 7.27−7.45 (m, H );
25
18
7
ar
*
S
1
3
C NMR (101 MHz, CDCl3) δ 14.3 (C ), 22.4 (C ), 28.8 (C ),
26
24
16
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.8b00606.
2
5
1
9.0 (C ), 36.1 (C ), 36.3 (C ), 40.3 (C ), 41.2 (C ), 53.1 (C ),
5 13 2 3 14 18
3.4 (C ), 57.7 (C ), 57.9 (C ), 61.0 (C ), 127.8 (C ), 128.2 (C ),
7
15
4
25
ar
ar
1
13
28.3 (C ), 128.4 (C ), 129.5 (C ), 129.9 (C ), 143.2 (C ), 144.3
H and C NMR spectra for all compounds, 2D NOESY
ar
ar
ar
ar
8
(
C ), 167.6 (C ), 168.0 (C ), 170.6 (C and C ), 171.0 (C );
19 6 17 12 23 1
spectra for tetramers 6, 12, 19, and 27, crystal structure
report for dimer 17, supporting Tables and Figures,
Cartesian coordinates of optimized structures, and fully
detailed computational procedures (PDF)
+
HRMS (ESI) calcd for C H O N [M + H] 609.3647, found
34
49
6
4
6
09.3742.
Computational Details. Preparation of Structures for Quantum
Calculations. The structures for quantum calculations were prepared
34
with the help of the GaussView package. The ω dihedral angle was
considered to be in the cis conformation for the NtBu residues and the
trans conformation for NPh residues. Dihedrals angles were initially set
from those determined by X-ray crystallography of oligopeptoids that
display an analogy of backbone. All oligomers were capped with acyl
X-ray data for dimer 17 (CIF)
AUTHOR INFORMATION
Corresponding Authors
*claude.taillefumier@univ-bpclermont.fr
*lionel.perrin@univ-lyon1.fr
franck.jolibois@univ-tlse3.fr
■
and NMe groups at N- and C- termini, respectively, in order to mimic
2
a full polypeptide backbone and avoid spurious capping effects. This
capping can from the ester termination of some oligopeptoids
synthesized.
*
ORCID
Quantum Calculations. All quantum calculations were performed
35
Geoffrey Dumonteil: 0000-0002-7386-6281
Sophie Faure: 0000-0001-5033-9481
Laurent Jouffret: 0000-0003-0196-7128
Lionel Perrin: 0000-0002-0702-8749
Claude Taillefumier: 0000-0003-3126-495X
with the Gaussian09 suite of programs. All full optimizations, as well
as frequency calculations, were performed at the density functional
3
6
theory (DFT) level M06-2X hybrid meta-GGA functional. Carbon
and hydrogen atoms were represented with the polarized all-electron
6
-311G(d,p) basis sets, while nitrogen and oxygen atoms were
represented with the augmented and polarized all electron 6-311+
+
37
G(d,p) basis sets. No symmetry or geometry constrain was
Present Address
#
included during the optimization. An implicit solvent environment was
considered using the SMD solvent model parametrized for dichloro-
Department of Chemistry and Industrial Chemistry, Uni-
versity of Pisa, via G. Moruzzi 13, 56124 Pisa, Italy.
38
methane. The energetics related to a φ dihedral angle sign change
has been assessed by means of a relaxed energy scan was performed for
this angle. The scan was performed from +90° to −90° with increment
of 5° at the restricted Hartree Fock level using an Ahlrichs-VDZ split
Notes
The authors declare no competing financial interest.
CCDC 1824207 contains the supplementary crystallographic
data for this paper. The data can be obtained free of charge
39
valence basis set. A single-point energy calculation was then
M
DOI: 10.1021/acs.joc.8b00606
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/structures.
(10) Crapster, J. A.; Guzei, I. A.; Blackwell, H. E. A Peptoid ribbon
secondary structure. Angew. Chem., Int. Ed. 2013, 52, 5079−5084.
(11) Gorske, B. C.; Mumford, E. M.; Gerrity, C. G.; Ko, I. A. A
Peptoid square helix via synergistic control of backbone dihedral
angles. J. Am. Chem. Soc. 2017, 139, 8070−8073.
ACKNOWLEDGMENTS
■
This work was supported by a grant overseen by the French
National Research Agency project ARCHIPEP. L.P. and N.B.
thank CCIR of ICBMS and P2CHPD of Univ. Lyon 1 for
providing computational resources. N.B. and F.J. thank the
CALcul en MIdi-Pyrenees (CALMIP, grant P0758) for
́ ́
generous allocations of computer time. The DRX department
of ICCF thanks the Auvergne region, the European Union
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