Effects of thionation and fluorination on cis-trans isomerization in tertiary amides: An investigation of N -alkylglycine (Peptoid) rotamers

Article abstract of DOI:10.1021/acs.joc.5b00048

Peptoids constitute a class of peptidomimetics with potential as protease resistant, biologically active ligands. To harness the full potential of such compounds, however, detailed predictive insight into their propensity to adopt well-defined secondary s

Full text of DOI:10.1021/acs.joc.5b00048

Article
pubs.acs.org/joc
Effects of Thionation and Fluorination on Cis−Trans Isomerization in
Tertiary Amides: An Investigation of N‑Alkylglycine (Peptoid)
Rotamers
Jens Engel-Andreasen,†,# Kathrine Wich,‡,# Jonas S. Laursen,‡ Pernille Harris,†
and Christian A. Olsen*,†,‡,§
†Department of Chemistry, Technical University of Denmark, Kemitorvet 207, DK-2800 Kongens Lyngby, Denmark
‡Center for Biopharmaceuticals and Department of Drug Design & Pharmacology, University of Copenhagen, Universitetsparken 2,
DK-2100 Copenhagen, Denmark
S
* Supporting Information
ABSTRACT: Peptoids constitute a class of peptidomimetics
with potential as protease resistant, biologically active ligands.
To harness the full potential of such compounds, however,
detailed predictive insight into their propensity to adopt well-
defined secondary structures is highly desirable. In this work
we present an investigation of the effects of thioamides and/or
fluorides in peptoid monomer model systems using chemical
synthesis, NMR spectroscopy, and X-ray crystallography. We
find that the steric environment surrounding the tertiary amide
bonds is the key promoter of conformational preference, and X-ray crystallographic interrogation of our model systems did not
suggest the presence of stabilizing n → π* interactions unless the carbonyls were altered electronically by α-halogenation or
thioamide formation. In addition to the function as an investigative tool, these two types of modification may thus be utilized as
stabilizers of secondary structure in future oligomer designs, such as the cis-amide-based polypeptoid helices that resemble the
polyproline type-I helix.
Chart 1. Generic Structures of the Backbone Architectures
of Peptides, Peptoids (α-peptoids), β3-Peptides (β2- and
disubstituted β-peptides are not shown), and β-Peptoids
INTRODUCTION
■
Development of biopharmaceutical drugs and their approval by
governing agencies such as the Food and Drug Administration
in the United States has flourished immensely in recent years.1
Monoclonal antibodies, proteins, and naturally occurring
peptides often exhibit highly potent and selective activities
with possible therapeutic benefit, but they are inherently
susceptible to proteolytic degradation, which causes a reduction
in half-life and efficacy and hence increases the required dosage.
For these reasons, the ability to mimic or modify natural
peptide-based compounds has become highly desirable, and
one of the many approaches pursued in the area of
peptidomimetics entails modification of the peptide backbone
architecture to achieve resistance to proteases.2 Two prominent
examples of abiotic designs that exhibit high stability are the β-
peptides3 and peptoids4 (Chart 1), and both of these have
received considerable attention during the last two decades.
Both designs have been investigated as homooligomeric
constructs as well as in hybrid backbones containing canonical
α-amino acids or other residues,2c−e and recently β-amino acids
have been site-specifically incorporated in a therapeutic
polypeptide to increase pharmacokinetic properties in vivo,
demonstrating improvement of biopharmaceuticals through
backbone modification.5
report in 1992,7 these compounds have been studied in
numerous contexts including antimicrobials,8 antifouling
agents,9 nanomaterials,10 and ligands for protein−protein
interactions.11 Still, limited success has been achieved in design
and characterization of secondary structures by high-resolution
X-ray diffraction structure determination12,13 or NMR spec-
troscopy,14,15 except for macrocyclic constructs in which the
inherently flexible peptoid backbones are locked into well-
Access to structurally diverse peptoids through chemical
Received: January 8, 2015
synthesis is inexpensive and highly efficient,6 and since the first
© XXXX American Chemical Society
A
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a
Scheme 1. Synthesis of Peptoid Model Compounds Under Investigation
a
Reagents and conditions: (a) For aromatic side chains H2N−R (2 equiv), Et3N (2 equiv), THF, 16 h and for aliphatic side chains H2N−R (3
equiv), Et3N (2 equiv), EtOAc, 0 °C → rt, 16 h; (b) Ac2O (2 equiv) or AcCl (2 equiv), Et3N (2 equiv), CH2Cl2, 0 °C → rt, 16 h; (c) trifluoroacetic
anhydride (2 equiv), pyridine (2 equiv), DMF, 0 °C → rt, 2−16 h; (d) 5,5-dimethyl-2-sulfido-1,3,2-dioxaphosphinan-2-yl ethanedithioate (9; 1.1
equiv), pyridine (1.1 equiv) CH2Cl2, rt, 1 h; (e) Lawesson’s reagent (1.5 equiv), THF, reflux, 2 h. Nonstandard abbreviations for N-alkyl side chains
are used as follows: spe = (S)-1-phenylethyl,14 s1npe = (S)-1-(1-naphthyl)ethyl,18 bnz = benzhydryl.
a
Table 1. Rotamer Equilibrium Constants (Kcis/trans) in Selected Solvents and Associated Differences in Free Energy (ΔG, in
b
kcal mol1
)
a
b
c
Determined by integration of 1H NMR spectra of 12 mM compound solutions at ambient temperature. ΔG = −RT × ln (Kcis/trans). Not soluble.
d
e
Low solubility resulting in <12 mM NMR sample concentration. Synthesis of the thioacetylated version of the hindered tert-butyl-containing
compound was not successful in our hands and was left out of the study.
defined conformations.16 Compared to peptides and β-
peptides, peptoids lack the ability to stabilize folding through
intramolecular hydrogen-bond networks and are also endowed
with an additional degree of flexibility due to the low energy
barrier between cis and trans amide conformations of tertiary
amide bonds (Chart 1), as observed for proline residues in
native proteins.
direct this equilibrium toward either the cis or the trans
conformation.17−19 Due to interest in a backbone design called
β-peptoids20 (Chart 1), we reported a similar study of the effect
of side chain structure in this system and furthermore included
thioamide and trifluoroacetyl modifications21 inspired by model
studies22,23 of proline behavior.24 Thionation and fluorination
permutations may report on the nature of putative stereo-
electronic interactions and may also stabilize desired cis−trans
equilibria of tertiary amide bonds. A recent study provided
Control of the cis−trans isomerization in peptoids has been
demonstrated by introduction of certain N-alkyl side chains that
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detailed insight into the effect of thioacetylation in a range of
structurally diverse tertiary amides containing peptoid-derived
side chains,25 and the effect on rotamer preference of tertiary
amides has been investigated by altering the acyl moiety as well,
including halogenation of the α-position of the acyl group.26
However, C-terminal amide groups were not included in these
studies, which prohibited interrogation of putative carbonyl−
carbonyl interactions. In the present work, we thus disclose the
first systematic investigation of the effects of thioamidation
and/or haloacetylation on cis−trans isomerism in α-peptoid
model systems by using NMR spectroscopy and X-ray
crystallography.
Figure 1. Example of a HOESY spectrum recorded in CD3OD
(compound 4a) applied for signal assignment. Highlighted signals
correspond to correlations involving the fluorine atoms. In blue boxes
are shown the correlations with the side chain methine, methyl, and
aromatic protons in the trans conformation. In magenta, correlation to
the backbone methylene protons confirms the cis conformation.
RESULTS
■
Design and Synthesis. An initial compound collection was
designed to mimic the environment of a single peptoid residue
within an oligomer in a minimalistic manner. The C-termini
were therefore chosen to be dimethylamides, and the amide
bonds to be probed for cis−trans isomerism were based on
acetyl (3), trifluoroacetyl (4), or thioacetyl (5 prepared using
reagent 927) as outlined in Scheme 1. To examine putative
carbonyl−carbonyl interactions in both N → C and C → N
directions, we also included thioamides in the C-termini (7 and
8). These series were prepared from common intermediates
2a−e by thionation using Lawesson’s reagent28 to give 6a−e,
which were subsequently acylated (Scheme 1). Previous studies
of rotamer isomerism in proline model systems have primarily
focused on identifying the nature of trans carbonyl−carbonyl
interactions in the N → C direction (COi···COi+1)22,23
due to the stabilizing effect on protein folding.29 However,
since the two available X-ray crystal structures of oligomeric
peptoids revealed helical arrangements similar to the all-cis
polyproline type-I helix,12,13 we found it relevant to include
strongly cis-directing side chains such as (S)-1-(1-naphthyl)-
ethyl (s1npe; b) and tert-butyl (e) in our series. The full matrix
of compounds was prepared according to Scheme 1, except
compound 5e, for which several strategies failed to deliver the
target compound, presumably due to steric congestion.
increase in Kcis/trans in all solvents, albeit to a lesser extent.
Interestingly, when comparing spe and bnz groups in β-peptoid
model systems, similar Kcis/trans values were observed.21 This
indicates that the increased population of the cis conformation
in bnz-containing α-peptoids is due to steric rather than
electronic effects. Moreover, when we replaced the phenyl
groups of 3c with methyl groups (3d) we observed a change of
preference to the trans rotamer, which supports the notion that
the main driving force is of a steric nature. Finally, introduction
of the bulky tert-butyl N-alkyl group (3e) gave exclusively the
cis conformation (Kcis/trans > 20) at our level of detection, which
is also in agreement with previously published data.19
Introduction of a trifluoroacetyl group should make the
carbonyl carbon more electron deficient due to the inductive
effect of the fluorines. It is furthermore known that the fluorine
lone pairs can donate electron density into the π* orbital of the
adjacent carbonyl group if ideally positioned.31 On the other
hand, the trifluoromethyl group resembles an isobutyl group in
size,23 giving rise to simultaneous steric and electronic effects
that may complicate the interpretation of the driving forces
behind the conformational changes. Since compound 4b
showed an increase in Kcis/trans value compared to 3b, while
compounds 4a, 4c, and 4d showed a decrease, we indeed
suspect that there are differential forces at play depending on
the specific structures of the model systems.
1
Cis−Trans Equilibrium Constants Determined by H
NMR Spectroscopy. Measuring the cis−trans amide equili-
brium constants by NMR spectroscopy is straightforward as
integration of peaks from each conformation report quantita-
tively on their relative concentrations. Because previous
evaluation of thioamide-containing peptoids revealed significant
solvent effects on cis−trans equilibria,21 it was decided to
record NMR spectra in four different deuterated solvents of
varying polarities (Table 1). Rotating frame Overhauser effect
Raines and co-workers studied carbonyl−carbonyl inter-
actions in proline model systems by substituting oxygen atoms
with sulfur to increase the nucleophilicity of the putative
carbonyl donor.22 Inspired by these studies, we investigated
both N- and C-terminal thioamide-containing model systems
individually. The thioacetylated compounds 5a−e displayed
roughly the same trends as their acetylated counterparts (3a−
e). This indicates that there are negligible contributions from
the n → π* interaction in the N → C direction in this series.
The C-terminal thioamide series (7a−e), on the other hand,
displayed slightly higher Kcis/trans values compared to the C-
terminal oxoamide series as well as the (O,O)-series (3), except
for the s1npe-containing compounds 5b and 7b, where the
trend was opposite (Table 1). The latter would agree with a
stabilizing effect between the sulfur and a C(sp2)−H on the
naphthyl ring in 5b as previously indicated for β-peptoids.21
spectroscopy (ROESY) and H−19F heteronuclear Overhauser
effect spectroscopy (HOESY) experiments were performed in
order to assign the signals to the correct conformations (Figure
1).
1
First, compound 3a containing the (S)-1-phenylethyl (spe)
side chain, a well-studied moiety with respect to the folding
behavior of peptoids,14,30 showed data that were fully in
agreement with previously published studies.18 Furthermore,
the more sterically demanding s1npe-containing side chain in
compound 3b showed trends that were in accordance with
previously reported data obtained for similar compounds based
on both peptoids18 and β-peptoids.21 There was a significant
preference for the cis conformation in all four solvents,
increasing in the order CDCl3 < D2O < CD3OD < CD3CN.
Increasing the bulk of the N-alkyl side chain relative to spe by
introduction of a benzhydryl (bnz) group (3c) also led to an
1
The difference in H NMR chemical shifts of the aromatic
hydrogen atom in proximity to the carbonyl in the 3b−8b
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Table 2. Torsion Angles and Distances in Crystal Structures
a
b
c
d
Measured from the methine proton in the N-alkyl side chains. CS···CO direction. CO...CS direction. Pyramidalization away from
donor carbonyl. Measurements from the X-ray diffraction crystal structure of a peptoid pentamer reported by Barron and co-workers.12 The sign of
e
χ-angles in achiral compounds 3c−8c were assigned according to the crystallized form of the compounds.
Figure 2. X-ray diffraction crystal structures of s1npe-containing compounds 3b (A), 5b (B), and 7b (C). Stick representations showing the CO/
Si+1···CiO/S distance in green and distances between N-terminal carbonyls and their two closest hydrogen atoms in magenta. Atom-coloring
scheme: gray, carbon; white, hydrogen; red, oxygen; blue, nitrogen; and yellow, sulfur. Hydrogen atoms in methyl and methylene groups have been
removed for clarity.
series supports the existence of such an interaction (Supporting
Information Figure S1).
provided further insight into the various features affecting
conformational preference (vide infra).
Finally, the series containing a combination of N-terminal
trifluoroacetylation and C-terminal thionation (8a−e) exhibited
similar Kcis/trans values as found for trifluoroacetylated
compounds (4a−e), thus, exhibiting lower overall resemblance
to the other C-terminal thioamide series (7a−e), which
qualitatively may indicate a stronger cis-directing effect of the
sterically demanding trifluoroacetyl group compared to the
effect of the thioamide donor capability in a C → N terminal
carbonyl−carbonyl interaction.
X-ray Crystallography. A number of the model com-
pounds were obtained in diffraction quality crystal forms, and
their high-resolution solid-state structures were solved by
single-crystal X-ray diffraction structure determination. Crystal
structures can provide useful, atomic resolution information
about potential interactions that may stabilize certain cis−trans
The attenuated hydrogen-bond acceptor capability of the
trifluoroacetyl group correlates with an upfield shift of this
proton (Supporting Information Figure S1). On the other
hand, the thioacetyl group gave rise to a slight downfield shift as
previously rationalized by NBO calculations of similar β-
peptoids to arise from increased orbital overlap.21 Furthermore,
Kcis/trans values of 3a−e determined in CDCl3 were generally
higher than those of both 5a−e and 7a−e and were lower or
similar when recorded in CD3OD and CD3CN, except for 7b in
CD3CN. Overall, the extent of solvent effects between
compound series results in difficulty in deriving truly general
trends regarding the Kcis/trans values across all compounds in all
solvents (Table 1). Fortunately, however, a number of model
compounds were crystallized in X-ray diffraction quality, which
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Figure 3. X-ray diffraction crystal structures of bnz-containing compounds (A) 3c, (B) 4c, (C) 5c, (D) 7c, and (E) 8c, as well as compound 8c
shown in partial space-filling representation (F). Stick representations showing the CO/Si+1···CiO/S distances in green and the CSi···Ci+1

O distance in yellow. Atom-coloring scheme: gray, carbon; white, hydrogen; red, oxygen; blue, nitrogen; cyan, fluorine; and yellow, sulfur. Hydrogen
atoms in methyl and methylene groups have been removed for clarity.
amide bond conformations; in particular, the angle between
interacting carbonyls as well as the acceptor carbonyl
pyramidalization can report on the probability of possible n
→ π* interactions.32
Three X-ray diffraction structures of s1npe-containing
compounds were solved, and all showed a cis amide
conformation consistent with the obtained Kcis/trans values in
solution (Figure 1).
trajectory angles closer to the Burgi−Dunitz angle and also
̈
showed significantly increased pyramidalization (Table 2).
This correlates with an improved acceptor character of the
trifluoroacetyl group compared to acetyl. Interestingly, ω angles
of the trifluoroacetylated model compounds deviated signifi-
cantly from planarity compared to their acetylated analogues,
which indicates a steric influence of the trifluoromethyl group
in the cis conformation as well. Thus, common for the four
crystal structures that exhibit cis conformation (Figure 3A, B,
D, and E) is packing of the backbone with one of the phenyl
rings of the bnz group, which reduces its flexibility and ability to
point away from the bulk of the trifluoromethyl group in
compounds 4c and 8c (see, Figure 3F for example).
Furthermore, the distribution of steric bulk across the two
side chains in bnz results in altered χ angles in all examples
where increased bulk (fluorination and/or thionation) is
introduced into the backbone (Table 2). Finally, in agreement
with the presence of n → π* interactions with C → N
directionality, the C-terminal thioamide-containing compounds
exhibited angles closer to 107° and stronger pyramidalization
than their C-terminal oxoamide analogues (Table 2).
The distances between the C-terminal carbonyl heteroatoms
and the carbon of the N-terminal carbonyls were consistent
with an orbital overlap in all cases, but the angles were 14−19°
higher than the optimal Burgi−Dunitz trajectory of 107°, and
̈
the degree of pyramidalization (Δ) was relatively low (Table 2)
compared to values found in proline model systems.32 In
agreement with our previous studies,21 the distance between
the hydrogen atom in the 8 position of the naphthyl group and
the thiocarbonyl in compound 5b (Figure 2B) was consistent
with an aromatic C−H···Samide interaction. This potential
interaction is also observed in the two other compounds
(Figure 2A and 2C). Notably, the longer interaction distances
of the sulfur of 0.2−0.3 Å compared to oxygen is in agreement
with the larger van der Waals radius (1.80 and 1.52 Å,
respectively). The close proximity of the side chain methine
hydrogen and the carbonyl in the crystal structures are also
consistent with the chemical shifts in 1H NMR discussed above.
Gratifyingly, we were also able to obtain X-ray diffraction
quality crystals of the entire bnz series, 3c−8c (Figure 3A−E).
Compounds 3c, 4c, 7c, and 8c crystallized in the cis
conformation, while the X-ray diffraction crystal structure of
5c was in the trans conformation. Comparing the acetylated
compounds (3c and 7c) with their trifluoroacetylated analogues
(4c and 8c), the trifluoroacetylated compounds displayed
The trans amide conformation of compound 5c showed
distances indicating possible carbonyl−carbonyl interactions in
both N → C and C → N directions, which could help explain
its preferred crystallization in this conformation. However,
inspection of the geometry in this crystal structure revealed
trajectory angles and pyramidalization in poor agreement with n
→ π* interactions (Table 2). Nevertheless, since 5c was
crystallized by vapor diffusion from chloroform it could be
reasoned that the trans conformation in the crystal is due to its
conformational preference in this solvent as indicated by the
NMR analyses above (Table 1).
E
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Figure 4. (A) Chemical structures of dihaloacetylated monomers. (B) Kcis/trans values determined by 1H NMR. “All cis” refers to ratios above 20. (C)
X-ray diffraction crystal structures of compounds 10, 11, and 12. (D) Newman projection showing the τ angle. Atom-coloring scheme: gray, carbon;
white, hydrogen; red, oxygen; blue, nitrogen; cyan, fluorine; green, chlorine; and yellow, sulfur. Hydrogen atoms in methyl and methylene groups
have been removed for clarity.
Table 3. Torsion Angles and Distances in Crystal Structures of Compounds 10−14
torsion angles
a
compd
ϕ
ψ
ω
χ
τ
trajectory, θ
distance, d (Å)
pyramidalization, Δ (Å)
10
11
12
13
14
74.5°
75.3°
−80.3°
83.7°
151.2°
152.9°
−156.9°
144.2°
4.8°
10.2°
−18.2°
−5.4°
−7.0°
−34.8°
47.9°
−24.8°
−12.6°
−176.1°
−152.5°
133.9°
−139.8°
140.9°
132.4°
128.5°
115.9°
133.3°
122.5°
2.99
2.95
3.21
3.11
3.29
0.010
0.024
0.033
0.030
0.033
−84.5°
−142.9°
−13.6°
a
Measured from the methine proton in the N-alkyl side chains. The sign of the χ angle of achiral compounds 10−12 was assigned according to the
single-crystal X-ray diffraction structures.
We also acquired two crystal structures with the spe side
chain (4a and 8a), which both crystallized in the trans
conformation as would be expected based on their Kcis/trans
values. Notably, even though compound 8a contains the
donor−acceptor pair identified above to be most likely to
engage in an n → π* interaction, the trajectory angle and
pyramidalization do not indicate the presence of a particularly
strong interaction (Table 2; please consult the Supporting
Information Figure S2 for ORTEP illustrations of these
structures).
Dihalogenated Acyl Compounds (10−15). To further
investigate stereoelectronic versus steric effects in haloacety-
lated compounds, we prepared a selection of dihaloacetylated
peptoid model compounds shown in Figure 4A. In a study by
Raines and co-workers,23,33 the donor capability of the carbonyl
in mono-, di-, and trifluoroacetyl groups was investigated,
whereas the acceptor capacity is under scrutiny here. We chose
benzhydryl (10−12) and s1npe (13 and 14) as side chains and
also included compound 15 with an isopropyl side chain to test
if these backbone modifications would be able to shift the
preference from trans to cis conformation.
4c and 10). This strongly suggests a predominant steric effect
of the two chlorine atoms since the inductive potency should
be lower than that of fluorine and should therefore give rise to
lower Kcis/trans
.
The steric effect is further supported by the X-ray diffraction
crystal structure of 11 where the CH of the dichloromethyl
group is close to antiperiplanar in relation to the carbonyl (τ
angle in Table 3), pointing the chlorines away from the
backbone (Figure 4C). This will also disfavor the donation of
chlorine lone pairs into the π* orbital of the adjacent carbonyl
to attenuate its acceptor capacity for possible carbonyl−
carbonyl n → π* interactions.31,33,34 The same was observed in
both crystal structures of difluoroacetylated compounds 10 and
12 (Figure 4C and Table 3). Compound 12 exhibited the
highest degree of pyramidalization as well as a trajectory angle
that was closer to 107° than the other two compounds, thus
adhering to the same trend as observed for 4c vs 8c.
Compounds 13 and 14 also exhibited increased Kcis/trans
values in all solvents compared to their trifluoroacetylated
homologues 3b and 7b, respectively (Figure 4B). Although the
backbone would not be as rotationally restricted as in the
benzhydryl case discussed above, this observation correlates
with favorable accommodation of the difluoromethyl group
compared to the trifluoromethyl group toward the backbone
face. Interestingly, however, the ϕ and ψ angles of compound
13 showed opposite signs compared to all other s1npe-
Interestingly, the difluoroacetylated compounds (10 and 12−
15) all showed higher Kcis/trans values than their trifluoroacety-
lated counterparts (Figure 4B). When introducing the
dichloroacetyl group, preference for the cis conformation was
even more pronounced than difluoro- or trifluoroacetyl (11 vs
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containing compounds, thus giving rise to a packing of the
backbone similar to that observed in the benzhydryl-containing
compounds (Figure 5A). Furthermore, compound 14 contains
structures of trifluoroacetylated compounds (4c and 8c)
obtained in the cis conformation showed clear evidence of
steric effects as the amides were twisted out of the planarity
preferred for amide bonds. In addition, the data obtained for
dihaloacetylated model systems (10, 11, and 12) support the
argument of steric congestion between the backbone and the
haloacetyl group by displaying higher Kcis/trans values. This could
be explained by conformations where the single hydrogen of
the dihalomethyl groups faces the backbone, which is indeed
the case in the crystal structures of 10−12 where the
dihaloacetyl groups adopt near antiperiplanar conformations.
The data thus suggest that when the steric environment allows
for it, carbonyl−carbonyl interactions can be optimized to affect
conformational space.
The steric effect of the side chain in response to
i
trifluoroacetylation becomes less prominent in the spe and Pr
Figure 5. X-ray diffraction crystal structures of difluoroacetylated
compounds 13 and 14. Stick representations showing the CO/
Si+1···CiO distance in green and distances between N-terminal
carbonyls and their two closest hydrogen atoms in magenta. Atom-
coloring scheme: gray, carbon; white, hydrogen; red, oxygen; blue,
nitrogen; cyan, fluorine; green, chlorine; and yellow, sulfur. Hydrogen
atoms in methyl and methylene groups have been removed for clarity.
series, where the cis−trans equilibrium is significantly shifted
toward the trans conformation. Interestingly, the difluoroacety-
lated compound 15 displays opposite conformational prefer-
ence than its trifluoroacetylated analog (8d) in MeOH and
MeCN. Since there is no steric argument for a cis preference of
15, this also supports that, when sterically allowed, stereo-
electronic effects in the form of the carbonyl−carbonyl
interactions may affect conformational preference in peptoids.
On the basis of the qualitative relationship between the
strength of a potential n → π* interaction and the degree of
pyramidalization of the carbonyl acceptor, the crystal structures
of the bnz series provide insight into the stereoelectronic effects
of our various modifications. Improving the carbonyl acceptor
by trifluorination (4c) significantly enhances the character of a
putative n → π* interaction, while enhanced carbonyl donor
capacity in a thioamide (7c) results in an improved trajectory
angle but modest pyramidalization. Combination of the two
modifications (8c), however, gives rise to a trajectory close to
both haloacetylation and C-terminal thioamide, which is
indicated above to promote a carbonyl−carbonyl n → π*
interaction in the C → N direction. The increase in Kcis/trans
observed for 14 compared to 13 is also in agreement with such
an interaction. The X-ray diffraction crystal structures revealed
carbonyl−carbonyl distances in agreement with orbital overlap
and pyramidalization indicative of n → π* interaction in the C
→ N direction in both cases. However, the angles in compound
13 and 14 differed by 26° and 15° from the ideal Burgi−Dunitz
̈
trajectory, respectively.
Finally, compound 15 revealed an increased fraction of cis
i
conformation in comparison to the entire Pr series (3d−8d).
the Burgi−Dunitz angle as well as the highest degree of
̈
Trifluoroacetylation (4d and 8d) resulted in a slight decrease in
Kcis/trans values, while difluoroacetylation furnished an increase
in Kcis/trans, which again is in agreement with favorable
accommodation of the less hindered difluoromethyl group
toward the backbone in the cis conformation. Moreover, a
carbonyl−carbonyl interaction as observed for compound 12
may add to the stabilization of this conformation, but we do not
have X-ray diffraction data to support this.
acceptor pyramidalization observed in all our X-ray diffraction
crystal structures.
In summary, we systematically investigated the conforma-
tional preference in an array of structurally diverse α-peptoid
(N-alkylglycine) model systems using NMR spectroscopy as
well as X-ray crystallography of more than a dozen of the model
compounds. Collectively, our data show no evidence for a
general stabilizing effect of trans amide bonds by n → π*
interactions in peptoids, which, compared to proline
systems,22,23,29 may arise from the increased flexibility of the
acyclic peptoids under investigation herein. Nevertheless, we
see strong evidence for the ability to promote such interactions
in the C → N direction in cis-configured peptoids by altering
the electronic properties of the donor and acceptor carbonyls,
respectively. Whereas compelling evidence for an n → π*aryl
interaction between a carbonyl lone pair and a positively
charged triazolium side chain has been reported for peptoids,19
the present work provides the first demonstration of subtle
backbone modifications (α-fluorination and thioamidation)
that may stabilize certain peptoid conformations. On the basis
of the complete body of data, we therefore propose a model for
the factors affecting conformational space in peptoids that is
first and foremost dependent on sterics but may include
stabilizing effects of carbonyl−carbonyl interactions in elec-
tronically altered systems.
DISCUSSION
■
Overall, the observed changes in Kcis/trans values in response to
structural changes in our model system series demonstrate that
a complex combination of interactions work in concert to
determine conformational preference of the molecules. In
general, the steric demand of the side chain appears to be the
prime determinant of conformational preference. Not surpris-
ingly, the bulky s1npe side chain repels the sterically demanding
methyl or halomethyl groups, giving rise to high Kcis/trans values,
albeit with subtle effects of altering carbonyls by thioamide
substitution. However, the less bulky bnz side chain, which
more readily adopts both conformations in a solvent-dependent
manner, allowed for a more detailed inspection of the effect of
the electronic properties of the carbonyl groups (3c−8c and
10−12). In particular, the X-ray diffraction structures of the N-
terminally haloacetylated model systems with a C-terminal
thioamide, which should provide a strong acceptor−donor pair,
showed pyramidalization and trajectory angles in agreement
with n → π* interactions. The X-ray diffraction crystal
Thioamide substitution has been shown to affect the
equilibrium between α- and 310-helices in peptides,35 and we
thus envision that the insights provided herein may be utilized
G
DOI: 10.1021/acs.joc.5b00048
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(m, 1H), 7.74 (d, J = 7.5 Hz, 2H), 7.53−7.40 (m, 3H), 4.65 (q, J = 6.5
Hz, 1H), 3.35 (d, J = 16.1 Hz, 1H), 3.24 (d, J = 16.1 Hz, 1H), 2.93 (s,
3H), 2.69 (s, 3H), 2.62 (s, 1H), 1.53 (d, J = 6.5 Hz, 3H). 13C NMR
(101 MHz, CDCl3) δ 171.2, 140.7, 134.0, 131.4, 128.9, 127.2, 125.8,
125.8, 125.3, 123.0, 53.8, 48.6, 35.8, 35.5, 24.2. UPLC-MS gradient B,
tR = 1.08 min, m/z 257.2 ([M + H]+, C16H21N2O+ calcd 257.2).
[α]589.3: −11° (c = 0.14, 293 K, MeOH).
2-(Benzhydrylamino)-N,N-dimethylacetamide (2c). Yield: 1.05 g
(66%) as amorphous substance. VLC eluent: hexane−EtOAc−EtOH
(70:28:2). 1H NMR (400 MHz, CDCl3) δ 7.47−7.41 (m, 4H), 7.32−
7.28 (m, 4H), 7.24−7.18 (m, 2H), 4.89 (s, 1H), 3.39 (s, 2H), 3.08 (s,
1H), 2.96 (s, 3H), 2.81 (s, 3H). 13C NMR (101 MHz, CDCl3) δ
170.8, 143.3, 128.7, 127.6, 127.3, 67.3, 48.7, 36.1, 35.7. UPLC-MS
gradient B, tR = 1.05 min, m/z 269.2 ([M + H]+, C17H21N2O+ calcd
269.2).
General Procedure for Synthesis of Compounds 2d−e. 2-
Bromo-N,N-dimethylacetamide (1 equiv) was dissolved in EtOAc to
give a 0.5 M solution, and Et3N (2 equiv) was added. The solution was
cooled to 0 °C before addition of the desired primary amine (4 equiv,
1.5 M in EtOAc). The reaction mixture was allowed to reach rt and
stirred overnight. The solvent was removed in vacuo, and the crude
material was taken up in CH2Cl2−water (1:1). The aqueous phase was
extracted with CH2Cl2 (3×), and the combined organic layers were
washed with water (2×) and brine, dried (Na2SO4), filtered, and
concentrated in vacuo. The products were elaborated without further
purification.
for stabilization of peptoid secondary structures, such as those
resembling polyproline type-I helix.
EXPERIMENTAL SECTION
■
General. All chemicals were analytical grade and used without
further purification. All reactions were performed in dry solvents and
under argon atmosphere. Dichloromethane, N,N-dimethylformamide
(DMF), tetrahydrofuran (THF), and toluene were retrieved from a
solvent purification system, and EtOAc was dried over molecular
sieves (4 Å). Vacuum liquid chromatography (VLC) purification was
performed on silica gel 60 (particle size 0.015−0.040 μm). UPLC−MS
analyses were performed using an ultra-high-performance liquid
chromatography system. A gradient with eluent I (0.1% HCOOH in
water) and eluent II (0.1% HCOOH in MeCN) rising linearly from
0% to 95% of II during t = 0.00−2.50 min was applied at a flow rate of
0.6 mL/min (gradient A) or during t = 0.00−5.20 min (gradient B).
Compounds, which were not obtained in sufficient purity by VLC,
were purified by preparative HPLC performed on a 250 mm × 20 mm,
C18 column (5 μm, 100 Å) using a diode array UV detector. A
gradient C with eluent III [95:5:0.1, water−MeCN−trifluoroacetic
acid (TFA)] and eluent IV (0.1% TFA in MeCN) rising linearly from
0% to 95% of IV during t = 5−45 min was applied at a flow rate of 20
mL/min. All final compounds were determined by analytical HPLC
analysis to be >95% pure on a 150 mm × 4.6 mm, C18 column (3 μm)
using a multiwavelength UV detector. The gradient consisted of eluent
III (95:5:0.1, water−MeCN−TFA) and eluent IV (0.1% TFA in
MeCN) rising linearly from 0% to 95% of IV during t = 2−20 min at a
flow rate of 1 mL/min (gradient D; data not shown). NMR chemical
shifts are reported in ppm relative to deuterated solvent peaks as
internal standards (δH, D2O 4.79 ppm; δH, CD3OD 3.31 ppm; δH,
CD3CN 1.94 ppm; δH, CDCl3 7.26 ppm; δC, CDCl3 77.16 ppm).
Coupling constants (J) are given in hertz (Hz). Multiplicities of NMR
signals are reported as follows: s, singlet; br s, broad singlet; d, doublet;
t, triplet; q, quartet; sept, septet; m, multiplet. Signals in the NMR data
marked with an asterisk correspond to peaks assigned to the minor
rotamer conformation and (*) denotes peaks where both rotamers
overlap. The HRMS spectra were recorded using either matrix-assisted
laser desorption/ionization (MALDI) or electrospray ionization (ESI)
as indicated for each compound with Fourier transform ion cyclotron
resonance (FT-ICR) as mass analyzer.
2-(Isopropylamino)-N,N-dimethylacetamide (2d). Yield: 612 mg
(47%) as oil, which solidified upon storage at −18 °C.
2-(tert-Butylamino)-N,N-dimethylacetamide (2e). Yield: 1.44 g
(76%) as oil, which solidified upon storage at −18 °C.
General Procedure for Synthesis of Compounds 6a−e.
Lawesson’s reagent (1.5 equiv) was suspended in THF (0.15 M)
and heated to reflux. Then, 2a−e in THF (2 M) was added, and
stirring was continued under reflux for 1 h. The reaction mixture was
cooled to rt, and the solvent was removed in vacuo. Most thionation
byproducts were removed by VLC to give the crude product, which
was used without further purification.
(S)-N,N-Dimethyl-2-((1-phenylethyl)amino)ethanethioamide
(6a). Crude amount: 402 mg as oil. VLC eluent: CH2Cl2−MeOH−
NH4OHaq (100:0:0−95:4.5:0.5). UPLC-MS gradient B, tR = 1.05 min,
m/z 223.1 ([M + H]+, C17H21N2S+ calcd 223.1).
(S)-N,N-Dimethyl-2-((1-(naphthalen-1-yl)ethyl)amino)-
ethanethioamide (6b). Crude amount: 363 mg as oil. VLC eluent:
CH2Cl2−MeOH−NH4OHaq (98:1.8:0.2). UPLC-MS gradient B, tR =
1.22 min, m/z 273.2 ([M + H]+, C16H21N2S+ calcd 273.1).
2-(Benzhydrylamino)-N,N-dimethylethanethioamide (6c). Crude
amount: 114 mg as oil. VLC eluent: hexane−EtOAc−EtOH (90:9:1−
60:36:4). UPLC-MS gradient B, tR = 1.30 min, m/z 285.2 ([M + H]+,
C17H21N2S+ calcd 285.1).
2-(Isopropylamino)-N,N-dimethylethanethioamide (6d). Crude
amount: 580 mg as amorphous substance. VLC eluent: CH2Cl2−
MeOH−NH4OHaq (100:0:0−90:9:1). UPLC-MS gradient B, tR = 0.40
min, m/z 161.1 ([M + H]+, C7H17N2S+ calcd 161.1).
2-Bromo-N,N-dimethylacetamide (1). Bromoacetyl bromide
(7.32 mL, 84 mmol) was dissolved in CH2Cl2 (80 mL), and
dimethylammonium chloride (5.7 g, 70 mmol) was added. The
suspension was cooled to 0 °C, and a solution of triethylamine (Et3N)
(22.3 mL, 160 mmol) in CH2Cl2 (20 mL) was added dropwise over 15
min. The reaction was stirred overnight, where the temperature
reached room temperature (rt). The mixture was washed with 10% w/
v aq. citric acid (100 mL) and saturated aqueous NaHCO3 (100 mL),
and the organic phase was dried (MgSO4), filtered, and concentrated
in vacuo. The crude product was purified by VLC (60% EtOAc in
hexane) to give 1 as a yellow oil (5.09 g, 44%).
General Procedure for Synthesis of Compounds 2a−c. 2-
Bromo-N,N-dimethylacetamide (1 equiv) was dissolved in THF to
give a 0.4 M solution, and the desired primary amine (2 equiv) was
added at 0 °C. Then, Et3N (2 equiv, 1 M in THF) was added by
syringe, and the reaction was stirred at rt overnight. The formed
precipitate was filtered off, and the organic solvent was removed in
vacuo. The resulting crude products were purified by VLC.
2-(tert-Butylamino)-N,N-dimethylethanethioamide (6e). Crude
amount: 240 mg as amorphous substance. VLC eluent: CH2Cl2−
MeOH−NH4OHaq (100:0:0−90:9:1). UPLC-MS gradient B, tR = 0.26
min, m/z 175.1 ([M + H]+, C7H17N2S+ calcd 175.1).
General Procedure for Acetylation. Acetic anhydride or acetyl
chloride (3 equiv) was added dropwise at 0 °C to a solution of
secondary amine (2 or 6; 1 equiv) and pyridine (2 equiv) in CH2Cl2
to give a 0.4 M solution with respect to the amine. The reaction
mixture was then stirred at rt for 16 h, after which it was poured into
saturated aqueous NaHCO3 and extracted with EtOAc (3×). The
combined organic phases were dried (NaSO4), filtered, and
concentrated in vacuo. The crude products were purified by VLC.
(S)-N,N-Dimethyl-2-(N-(1-phenylethyl)acetamido)acetamide
(3a). Crude amount: 91 mg (60%) as oil. VLC eluent: 0−1.75%
MeOH in CH2Cl2. 1H NMR (400 MHz, CDCl3) δ 7.40−7.28 (m, 5H,
Ar-H), 6.11*/5.19 (2 × q, J = 7.1 Hz, 1H, NCHCH3), 4.39/3.35 (2 ×
d, J = 16.0 Hz, 2H, COCH2), 3.84*/3.65* (2 × d, J = 17.7 Hz, 2H,
(S)-N,N-Dimethyl-2-((1-phenylethyl)amino)acetamide (2a). Yield:
1
1.74 g (79%) as oil. VLC eluent: 5% EtOH in EtOAc. H NMR (400
MHz, CDCl3) δ 7.36−7.27 (m, 4H), 7.25−7.17 (m, 1H), 3.76 (q, J =
6.4 Hz, 1H), 3.23 (s, 2H), 2.92 (s, 3H), 2.79 (s, 3H), 2.55 (s, 1H),
1.38 (d, J = 6.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 171.1, 145.2,
128.5, 127.1, 126.9, 58.4, 48.4, 36.0, 35.6, 24.8. UPLC-MS gradient B,
tR = 0.75 min, m/z 207.2 ([M + H]+, C12H19N2O+ calcd 207.2).
[α]589.3: −73° (c = 0.11, 293 K, MeOH).
(S)-N,N-Dimethyl-2-((1-(naphthalen-1-yl)ethyl)amino)acetamide
(2b). Yield: 1.26 g (82%) as oil. VLC eluent: 1−5% EtOH in EtOAc.
1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 7.5 Hz, 1H), 7.88−7.82
H
DOI: 10.1021/acs.joc.5b00048
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
COCH2), 2.96/2.94/2.90*/2.86* (4 × s, 6H, N(CH3)2), 2.26/2.08*
(2 × s, 3H, COCH3), 1.66/1.44* (2 × d, J = 7.1 Hz, 3H, NCHCH3).
13C NMR (101 MHz, CDCl3) δ 171.9*, 171.1, 168.1, 168.0*, 141.2,
140.9*, 128.9, 128.5*, 127.8, 127.7*, 127.5*, 126.6, 56.5, 51.0*, 45.3*,
43.9, 36.6, 36.3*, 36.1*, 36.0, 22.2*, 21.8, 18.4, 16.1*. UPLC-MS
COCH2), 3.45*/3.39/3.29*/2.93 (4 × s, 6H, N(CH3)2), 2.15/2.12*
(2 × s, 3H, COCH3), 1.84*/1.66 (2 × d, J = 7.0 Hz, 3H, NCHCH3).
13C NMR (101 MHz, CDCl3) δ 199.7*, 198.9, 172.4*, 172.2, 139.1*,
136.8, 134.0, 134.0*, 132.1, 130.4*, 129.3*, 129.0, 128.7, 128.5*,
127.0, 126.9*, 126.2, 126.1*, 125.7*, 124.9, 124.8, 124.3, 123.4*,
122.3*, 54.5*, 51.9, 51.3*, 49.1, 45.5(*), 41.1*, 40.4, 23.3, 22.4*, 20.8*,
17.8. UPLC-MS gradient B, tR = 1.89 min, m/z 315.1 ([M + H]+,
C18H23N2OS+ calcd 315.2). [α]589.3: −69° (c = 0.17, 293 K, CHCl3).
HRMS (ESI) m/z calcd for [M + Na]+, C18H22N2NaOS+ 337.1345;
found 337.1346.
N-Benzhydryl-N-(2-(dimethylamino)-2-thioxoethyl)acetamide
(7c). Yield: 44 mg (43%) as colorless solid, obtained over two steps
from 2c. Mp: 174−176 °C. VLC eluent: 0−1.25% MeOH in CH2Cl2.
1H NMR (400 MHz, CDCl3) δ 7.33−7.18 (m, 10H, Ar-H), 6.87*/
6.42 (2 × s, 1H, NCH(C6H5)2), 4.48/4.32* (2 × s, 2H, CSCH2),
3.25/3.14*/3.03/2.84* (4 × s, 6H, N(CH3)2), 2.31*/2.03 (2 × s, 3H,
COCH3). 13C NMR (101 MHz, CDCl3) δ 198.2, 197.7*, 172.9,
172.8*, 139.8*, 139.7, 129.5*, 129.2, 128.6, 128.2*, 128.0, 127.4*,
66.6, 62.6*, 53.2*, 52.6, 45.1(*), 40.8, 40.2*, 23.8*, 23.5. UPLC-MS
gradient B, tR = 1.90 min, m/z 327.2 ([M + H]+, C19H23N2OS+ calcd
327.2). HRMS (ESI) m/z calcd for [M + Na]+, C19H22N2NaOS+
349.1345; found 349.1346.
+
gradient B, tR = 1.44 min, m/z 249.2 ([M + H]+, C14H20N2O2 calcd
249.2). [α]589.3: −29° (c = 0.13, 293 K, CHCl3). HRMS (MALDI) m/
+
z calcd for [M + Na]+, C14H20N2NaO2 271.1417; found 271.1422.
(S)-N,N-Dimethyl-2-(N-(1-(naphthalen-1-yl)ethyl)acetamido)-
acetamide (3b). Yield: 143 mg (70%) as colorless solid. Mp: 153−155
°C. VLC eluent: 0−1% MeOH in CH2Cl2. 1H NMR (400 MHz,
CDCl3) δ 8.07−7.43 (m, 7H, Ar-H), 6.70/5.79* (2 × q, J = 6.9 Hz,
1H, NCHCH3), 4.46*/3.35* (2 × d, J = 16.0 Hz, 2H, COCH2), 3.65/
3.52 (2 × d, J = 17.8 Hz, 2H, COCH2), 2.91*/2.87*/2.82/2.67 (4 × s,
6H, N(CH3)2), 2.32*/2.05 (2 × s, 3H, COCH3), 1.80*/1.58 (2 × d, J
= 7.0 Hz, 3H, NCHCH3). 13C NMR (101 MHz, CDCl3) δ 171.5,
171.4*, 168.5*, 168.0, 137.0*, 136.5, 134.1*, 134.0, 132.2, 131.1*,
129.3*, 129.0, 128.9*, 128.6, 127.0*, 127.0, 126.2, 126.1*, 125.5*,
124.9, 124.8, 124.4, 124.2*, 122.7*, 54.1*, 48.4, 44.8, 44.1*, 36.7*,
36.3, 36.0, 22.3, 21.8*, 19.6*, 16.7. UPLC-MS gradient B, tR = 1.65
min, m/z 299.2 ([M + H]+, C18H24N2O2+ calcd 299.2). [α]589.3: −88°
(c = 0.16, 293 K, CHCl3). HRMS (MALDI) m/z calcd for [M + Na]+,
+
C18H22N2NaO2 321.1573; found 321.1578.
N-(2-(Dimethylamino)-2-thioxoethyl)-N-isopropylacetamide
2-(N-Benzhydrylacetamido)-N,N-dimethylacetamide (3c). Yield:
(7d). Yield: 43 mg (23%) as oil, obtained over two steps from 2d. VLC
1
1
182 mg (90%) as oil. VLC eluent: 0−1.5% MeOH in CH2Cl2. H
eluent: 0−2% MeOH in CH2Cl2. H NMR (400 MHz, CDCl3) δ
NMR (400 MHz, CDCl3) δ 7.36−7.18 (m, 10H, Ar-H), 7.09*/6.30 (2
× s, 1H, NCH(C6H5)2), 4.07/4.04* (2 × s, 2H, COCH2), 2.74/2.73/
2.61*/2.57* (4 × s, 6H, N(CH3)2), 2.21*/2.12 (2 × s, 3H, COCH3).
13C NMR (101 MHz, CDCl3) δ 172.4*, 172.3, 167.3, 167.1*, 139.4(*),
129.2(*), 129.0(*), 128.6(*), 128.3(*), 128.0, 127.5*, 66.4, 61.4*, 46.8*,
45.6, 36.2, 35.7*, 22.5(*). UPLC-MS gradient B, tR = 1.82 min, m/z
4.72*/4.12 (2 × sept, J = 6.8 Hz, 1H, NCH(CH3)2), 4.26/4.09* (2 ×
s, 2H, CSCH2), 3.49*/3.44/3.34*/3.32 (4 × s, 6H, N(CH3)2), 2.16/
2.01* (2 × s, 3H, COCH3), 1.24/1.08* (2 × d, J = 6.8 Hz, 6H,
NCH(CH3)2). 13C NMR (101 MHz, CDCl3) δ 199.4, 199.0*, 172.0*,
170.6, 51.4*, 49.9, 49.2, 45.9*, 45.6*, 45.4, 41.3, 40.6*, 23.3*, 22.0,
21.4, 20.4*. UPLC-MS gradient B, tR = 1.13 min, m/z 203.1 ([M +
H]+, C9H19N2OS+ calcd 203.1). HRMS (ESI) m/z calcd for [M +
Na]+, C9H18N2NaOS+ 225.1032; found 225.1035.
N-(tert-Butyl)-N-(2-(dimethylamino)-2-thioxoethyl)acetamide
(7e). Yield: 9 mg (2%) as oil, obtained over two steps from 2e. VLC
eluent: 0−40% EtOAc in hexane. 1H NMR (400 MHz, CDCl3) δ 4.27
(s, 2H, CSCH2), 3.53/3.34 (2 × s, 6H, N(CH3)2), 2.07 (s, 3H,
COCH3), 1.47 (s, 9H, NC(CH3)3). 13C NMR (101 MHz, CDCl3) δ
200.2, 172.4, 57.8, 54.3, 45.7, 40.5, 29.0, 25.7. UPLC-MS gradient B, tR
= 1.39 min, m/z 217.2 ([M + H]+, C10H21N2OS+ calcd 217.1). HRMS
(ESI) m/z calcd for [M + Na]+, C10H20N2NaOS+ 239.1189; found
239.1191.
+
311.2 ([M + H]+, C19H23N2O2 calcd 311.2). HRMS (MALDI) m/z
calcd for [M + Na]+, C19H22N2NaO2+ m/z 333.1573; found 333.1579.
2-(N-Isopropylacetamido)-N,N-dimethylacetamide (3d). Yield:
1
118 mg (57%) as oil. VLC eluent: 0−2.25% MeOH in CH2Cl2. H
NMR (400 MHz, CDCl3) δ 4.85*/4.09 (2 × sept, J = 6.8 Hz, 1H,
NCH(CH3)2), 3.93/3.91* (2 × s, 2H, COCH2), 3.04(*)/2.97*/2.93
(4 × s, 6H, N(CH3)2), 2.15/1.95* (2 × s, 3H, COCH3), 1.17/1.03*
(2 × d, J = 6.8 Hz, 6H, NCH(CH3)2). 13C NMR (101 MHz, CDCl3) δ
171.3*, 170.3, 168.4, 168.2*, 49.3, 44.6*, 44.2*, 41.6, 36.6, 36.4*,
36.2*, 36.0, 22.3*, 21.6, 21.2, 20.1*. HRMS (ESI) m/z calcd for [M +
+
Na]+, C9H18N2NaO2 209.1260; found 209.1261.
General Procedure for Di- and Trifluoroacetylation. Di- or
trifluoroacetic anhydride (3 equiv) was added dropwise to a solution of
secondary amine (2 or 6; 1 equiv) and Et3N (3 equiv) in CH2Cl2 (to
give a 0.4 M solution with respect to the amine) at 0 °C. The reaction
mixture was then stirred for 2−18 h (monitored by TLC) at rt, poured
into saturated aqueous NaHCO3, and extracted with EtOAc (3×). The
combined organic phases were dried (NaSO4), filtered, and
concentrated in vacuo. The crude products were purified by VLC.
(S)-N-(2-(Dimethylamino)-2-oxoethyl)-2,2,2-trifluoro-N-(1-
phenylethyl)acetamide (4a). Yield: 162 mg (79%) as oil. VLC eluent:
2-(N-(tert-Butyl)acetamido)-N,N-dimethylacetamide (3e). Yield:
99 mg (49%) as oil. VLC eluent: 0−1.25% MeOH in CH2Cl2. H
1
NMR (400 MHz, CDCl3) δ 4.09 (s, 2H, COCH2), 3.01/2.97 (2 × s,
6H, N(CH3)2), 1.98 (s, 3H, COCH3), 1.41 (s, 9H, NC(CH3)3). 13C
NMR (101 MHz, CDCl3) δ 171.9, 169.0, 57.2, 47.8, 36.4, 36.1, 28.7,
25.2. UPLC-MS gradient B, tR = 1.09 min, m/z 201.1 ([M + H]+,
C10H21N2O2S+ calcd 201.2). HRMS (ESI) m/z calcd for [M + Na]+,
+
C10H20N2NaO2 223.1417; found 223.1421.
(S)-N-(2-(Dimethylamino)-2-thioxoethyl)-N-(1-phenylethyl)-
acetamide (7a). Yield: 82 mg (78%) as oil, obtained over two steps
from 2a. VLC eluent: 20−80% EtOAc in hexane. 1H NMR (400 MHz,
CDCl3) δ 7.30−7.16 (m, 5H, Ar-H), 6.01*/5.23 (2 × q, J = 6.9 Hz,
1H, CHCH3), 4.74/3.84 (2 × d, J = 16.1 Hz, 2H, CSCH2), 4.06*/
3.91*(2 × d, J = 16.1 Hz, 2H, CSCH2), 3.43(*)/3.28/3.12* (4 × s, 6H,
N(CH3)2), 2.16(*) (2 × s, 3H, COCH3), 1.72/1.50* (2 × d, J = 7.0
Hz, 3H, NCHCH3). 13C NMR (101 MHz, CDCl3) δ 199.0, 198.6*,
172.6*, 171.8, 142.1, 141.3*, 128.9, 128.5*, 127.8*, 127.6, 126.3, 57.0,
52.4*, 52.3*, 51.4, 45.5*, 45.4, 41.2, 40.6*, 23.2*, 22.5, 19.6, 17.09*.
UPLC-MS gradient B, tR = 1.57 min, m/z 265.2 ([M + H]+,
C14H21N2OS+ calcd 265.1). [α]589.3: −11° (c = 0.14, 293 K, CHCl3).
HRMS (ESI) m/z calcd for [M + Na]+, C14H20N2NaOS+ 287.1189;
found 287.1190.
1
0−2% MeOH in CH2Cl2. H NMR (400 MHz, CDCl3) δ 7.42−7.31
(m, 5H, Ar-H), 5.84*/5.40 (2 × q, J = 6.9 Hz, 1H, NCHCH3), 4.13/
3.36 (2 × d, J = 16.0 Hz, 2H, COCH2), 4.05*/3.72* (2 × d, J = 18.0
Hz, 2H, COCH2), 2.92(*)/2.89/2.80* (4 × s, 6H, N(CH3)2), 1.68/
1.57* (2 × d, J = 7.0 Hz, 3H, NCHCH3).13C NMR (101 MHz,
CDCl3) δ 167.0*, 165.9, 157.3 (q, J = 36.4 Hz), 139.0*, 138.6, 129.0,
128.9*, 128.4, 128.3*, 127.9*, 127.3, 116.9 (q, J = 288.2 Hz), 55.5 (q,
J = 3.0 Hz), 55.0*, 45.2*, 44.6, 36.6, 36.2 (2C)*, 36.0, 17.3, 16.1*.
UPLC-MS gradient B, tR = 1.81 min, m/z 303.2 ([M + H]+,
C14H18F3N2O2+ calcd 303.1). [α]589.3: −38° (c = 0.16, 293 K, CHCl3).
HRMS (ESI) m/z calcd for [M + Na]+, C14H17F3N2NaO2+ 325.1134;
found 325.1137.
(S)-N-(2-(Dimethylamino)-2-thioxoethyl)-N-(1-(naphthylen-1-yl)-
ethyl)acetamide (7b). Yield: 222 mg (64%) as colorless solid,
obtained over two steps from 2b. Mp: 123−125 °C. VLC eluent: 0−
75% EtOAc in hexane. 1H NMR (400 MHz, CDCl3) δ 8.07−7.39 (m,
7H, Ar-H), 6.72/5.91* (2 × q, J = 7.0 Hz, 1H, NCHCH3), 4.97*/
3.93* (2 × d, J = 16.2 Hz, 2H, CSCH2), 3.84/3.78 (2 × d, 2H,
(S)-N-(2-(Dimethylamino)-2-oxoethyl)-2,2,2-trifluoro-N-(1-(naph-
thalen-1-yl)ethyl)acetamide (4b). Yield: 77 mg (75%) as colorless
1
solid. Mp: 113−115 °C. VLC eluent: 0−40% EtOAc in hexane. H
NMR (400 MHz, CDCl3) δ 7.90−7.47 (m, 7H, Ar-H), 6.52/6.04* (2
× q, J = 6.7 Hz, 1H, NCHCH3), 4.19*/3.41* (2 × d, J = 16.0 Hz, 2H,
COCH2), 3.89/3.52 (2 × d, J = 18.0 Hz, 2H, COCH2), 2.90*/2.88/
I
DOI: 10.1021/acs.joc.5b00048
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
2.80*/2.64 (4 × s, 6H, N(CH3)2), 1.90*/1.72 (2 × d, J = 6.8 Hz, 3H,
NCHCH3).13C NMR (101 MHz, CDCl3) δ 167.1(*), 158.5 (q, J =
36.4 Hz), 134.2, 134.1*, 131.9*, 131.3*, 129.8, 129.3*, 129.0, 127.4,
127.3*, 126.5, 126.3*, 125.7, 125.3*, 125.2*, 125.0, 123.3, 116.7 (q, J
= 289.9 Hz), 53.7*, 51.8, 45.3*, 44.7 (q, J = 3.4 Hz), 36.6*, 36.2,
19.7*, 16.4. UPLC-MS gradient B, tR = 2.12 min, m/z 353.2 ([M +
N-Benzhydryl-N-(2-(dimethylamino)-2-thioxoethyl)acetamide
(8c). Yield: 66 mg (49%) as colorless solid, obtained over two steps
from 2c. Mp: 194−196 °C. VLC eluent: 0−25% EtOAc in hexane. 1H
NMR (400 MHz, CDCl3) δ 7.33−7.20 (m, 10H, Ar-H), 6.64*/6.57 (2
× s, 1H, NCH(C6H5)2), 4.47*/4.40 (2 × s, 2H, CSCH2), 3.21/3.17*/
3.05*2.76 (4 × s, 6H, N(CH3)3). 13C NMR (101 MHz, CDCl3) δ
197.0, 193.9*, 159.3 (q, J = 35.7 Hz), 158.5* (q, J = 34.3 Hz), 138.4,
137.8*, 129.3*, 129.3, 128.7*, 128.5, 128.5, 128.4*, 128.0, 116.7* (q, J
= 288.9 Hz), 116.5 (q, J = 289.5 Hz), 65.5, 65.0* (q, J = 3.0 Hz), 52.9
(q, J = 3.0 Hz), 51.5*, 45.3, 45.0*, 40.5*, 40.2. UPLC-MS gradient B,
tR = 2.32 min, m/z 381.1 ([M + H]+, C19H20F3N2OS+ calcd 381.1).
HRMS (ESI) m/z calcd for [M + Na]+, C19H19F3N2NaOS+ 403.1062;
found 403.1064.
N-(2-(Dimethylamino)-2-thioxoethyl)-2,2,2-trifluoro-N-isopropy-
lacetamide (8d). Yield: 65 mg (14%) as oil, obtained over two steps
from 2d. VLC eluent: 0−30% EtOAc in hexane. 1H NMR (400 MHz,
CDCl3) δ 4.37/3.39* (2 × sept, J = 6.6 Hz, 1H, NCH(CH3)2), 4.27*/
4.23 (2 × s, 2H, CSCH2), 3.49*/3.37 (2 × s, 6H, N(CH3)2), 1.30(*)
(d, J = 6.6 Hz, 6H, NCH(CH3)2). 13C NMR (101 MHz, CDCl3) δ
196.2(*), 157.2 (q, J = 36.0 Hz), 116.7 (q, J = 288.2 Hz), 52.4*, 49.5
(q, J = 3.7 Hz), 49.2, 45.5, 41.2, 40.6*, 21.3, 19.7*. UPLC-MS gradient
B, tR = 1.76 min, m/z 257.1 ([M + H]+, C9H16F3N2OS+ calcd 257.1).
HRMS (ESI) m/z calcd for [M + Na]+, C9H15F3N2NaOS+ 279.0749;
found 279.0751.
+
H]+, C18H20F3N2O2 calcd 353.1). [α]589.3: −47° (c = 0.19, 293 K,
+
CHCl3). HRMS (ESI) m/z calcd for [M + Na]+, C18H19F3N2NaO2
375.1291; found 375.1292.
N-Benzhydryl-N-(2-(dimethylamino)-2-oxoethyl)-2,2,2-trifluoroa-
cetamide (4c). Yield: 76 mg (75%) as colorless solid. Mp: 137−139
°C. VLC eluent: 0−30% EtOAc in hexane. 1H NMR (400 MHz,
CDCl3) δ 7.36−7.22 (m, 10H, Ar-H), 6.78*/6.58 (2 × s, 1H,
NCH(C6H5)2), 4.18*/4.14 (2 × s, 2H, COCH2), 2.73*/2.66/2.56* (3
× s, 6H, N(CH3)2). 13C NMR (101 MHz, CDCl3) δ 166.2*, 164.5,
158.5 (q, J = 38.4 Hz), 137.9*, 137.7, 134.7, 129.7, 129.7*, 129.2,
128.9, 128.7, 128.5*, 128.4*, 128.2*, 128.1(*), 116.8* (q, J = 288.9
Hz), 116.6 (q, J = 289.9 Hz), 67.5*, 64.5, 46.7*, 45.9, 36.4*, 36.1*,
35.8, 35.8. UPLC-MS gradient B, tR = 2.09 min, m/z 365.2 ([M + H]+,
C19H20F3N2O2+ calcd 365.1). HRMS (ESI) m/z calcd for [M + Na]+,
+
C19H19F3N2NaO2 387.1291; found 387.1299.
N-(2-(Dimethylamino)-2-oxoethyl)-2,2,2-trifluoro-N-isopropyla-
cetamide (4d). Yield: 58 mg (54%) as oil. VLC eluent: 0−2.25%
1
MeOH in CH2Cl2. H NMR (400 MHz, CDCl3) δ 4.49*/4.33 (2 ×
sept, J = 6.6 Hz, 1H, NCH(CH3)2), 4.08*/4.00 (2 × s, 2H, COCH2),
3.06/3.02*/2.98*/2.97 (4 × s, 6H, N(CH3)2), 1.23/1.21* (2 × d, J =
6.8 Hz, 6H, NCH(CH3)2). 13C NMR (101 MHz, CDCl3) δ 167.1*,
166.1, 157.0 (q, J = 36.0 Hz), 116.7 (q, J = 287.9 Hz), 49.8*, 48.9 (q, J
= 3.7 Hz), 44.8*(q, J = 3.7 Hz), 42.6, 36.6, 36.3*, 36.2*, 36.1, 21.0,
N-(tert-Butyl)-N-(2-(dimethylamino)-2-thioxoethyl)-2,2,2-trifluor-
oacetamide (8e). Yield: 29 mg (5%) as oil, obtained over two steps
from 2e. VLC eluent: 0−45% EtOAc in hexane. 1H NMR (400 MHz,
CDCl3) δ 4.38 (s, 2H, CSCH2), 3.51/3.32 (2 × s, 6H, N(CH3)2), 1.52
(s, 9H, NC(CH3)3). 13C NMR (101 MHz, CDCl3) δ 198.8, 157.5 (q, J
= 34.3 Hz), 116.4 (q, J = 291.6 Hz), 61.1, 52.3 (q, J = 3.7 Hz), 45.6,
40.6, 27.9. UPLC-MS gradient B, tR = 1.92 min, m/z 271.2 ([M + H]+,
C10H18F3N2OS+ calcd 271.1). HRMS (ESI) m/z calcd for [M + Na]+,
C10H17F3N2NaOS+ 293.0906; found 293.0907.
+
19.4*. HRMS (ESI) m/z calcd for [M + Na]+, C9H15F3N2NaO2
263.0978; found 263.0983.
N-(tert-Butyl)-N-(2-(dimethylamino)-2-oxoethyl)-2,2,2-trifluoroa-
cetamide (4e). Yield: 24 mg (23%) as oil. VLC eluent: 0−40% EtOAc
1
in hexane. H NMR (400 MHz, CDCl3) δ 4.23 (s, 2H, COCH2),
N-Benzhydryl-N-(2-(dimethylamino)-2-oxoethyl)-2,2-difluoroace-
tamide (10). Yield: 46 mg (36%) as colorless solid. Mp: 159−161 °C.
VLC eluent: 0−100% of EtOAc in hexane. 1H NMR (400 MHz,
CDCl3) δ 7.38−7.18 (m, 6H, Ar−H), 7.04/6.59* (2 × s, 1H,
NCH(C6H5)2), 6.32/6.09* (2 × t, J = 53.5 Hz, 1H, COCF2H), 4.16/
4.11* (2 × s, 2H, COCH2), 2.77*/2.73*/2.62/2.52 (4 × s, 6H,
N(CH3)2). 13C (101 MHz, CDCl3) δ 166.8, 165.6*, 164.2 (t, J = 24.4
Hz), 137.9*, 137.8, 129.0, 128.9*, 128.7*, 128.5, 128.3*, 128.0, 109.3/
108.3* (2 × t, J = 246.5 Hz), 64.2*, 62.2, 45.7*, 44.7, 44.1, 37.7*,
36.4*, 36.2, 36.1*, 35.7. UPLC-MS gradient B, tR = 1.93 min, m/z
3.00/2.98 (2 × s, 6H, N(CH3)2), 1.48 (s, 9H, NC(CH3)3). 13C NMR
(101 MHz, CDCl3) δ 168.0, 157.2 (q, J = 34.3 Hz), 116.5 (q, J = 291.2
Hz), 60.3, 46.1 (q, J = 3.7 Hz), 36.4, 36.2, 27.6. UPLC-MS gradient B,
+
tR = 1.53 min, m/z 255.2 ([M + H]+, C10H18F3N2O2 calcd 255.1).
HRMS (ESI) m/z calcd for [M + Na]+, C10H17F3N2NaO2+ 277.1134;
found 277.1139.
(S)-N-(2-(Dimethylamino)-2-thioxoethyl)-2,2,2-trifluoro-N-(1-
phenylethyl)acetamide (8a). Yield: 35 mg (28%) as oil, obtained over
1
two steps from 2a. VLC eluent: 0−30% EtOAc in hexane. H NMR
+
347.2 ([M + H]+, C19H21F2N2O2 calcd 347.2). HRMS (ESI) m/z
(400 MHz, CDCl3) δ 7.41−7.30 (m, 5H, Ar-H), 5.61*/5.44 (2 × q, J
= 6.5 Hz, 1H, NCHCH3), 4.36/3.55 (2 × d, J = 16.2 Hz, 2H, CSCH2),
4.26*/4.20* (2 × d, J = 16.2 Hz, 2H, CSCH2), 3.43(*)/3.19/3.11* (4
× s, 6H, N(CH3)2), 1.79/1.67* (2 × d, J = 6.9 Hz, 3H, NCHCH3).
13C NMR (101 MHz, CDCl3) δ 195.7, 157.7 (q, J = 36.4 Hz), 138.9,
129.0, 128.8*, 128.4, 128.2*, 127.8*, 127.3, 116.9 (q, J = 287.3 Hz),
57.2*, 56.0 (q, J = 3.0 Hz), 52.5*, 51.2, 45.6*, 45.4, 41.0, 40.5*,
17.8(*). UPLC-MS gradient B, tR = 2.12 min, m/z 341.1 ([M + Na]+,
C14H17F3N2NaOS+ calcd 341.1). [α]589.3: −8° (c = 0.17, 293 K,
+
calcd for [M + Na]+, C19H20F2N2NaO2 369.1385; found 369.1387.
N-Benzhydryl-N-(2-(dimethylamino)-2-thioxoethyl)-2,2-difluor-
oacetamide (12). Yield: 57 mg (89%) as colorless solid. Mp: 192−194
1
°C. VLC eluent: 0−0.5% MeOH in CH2Cl2. H NMR (400 MHz,
CDCl3) δ 7.33−7.19 (m, 10H, Ar-H), 6.84/6.67* (2 × s, 1H,
NCH(C6H5)2), 6.56/5.87* (2 × t, J = 53.7 Hz, 1H, COCHF2), 4.45*/
4.38 (2 × s, 2H, CSCH2), 3.25*/3.14/3.09*/2.77 (4 × s, 6H,
N(CH3)2). 13C NMR (101 MHz, CDCl3) δ 196.8*, 196.7, 164.6 (q, J
= 26.6 Hz), 138.2, 138.1*, 129.4, 129.3*, 128.7*, 128.4(*), 128.0,
108.5 (t, J = 246.4 Hz), 65.2*, 63.1, 52.5*, 50.5, 45.3, 40.3. UPLC-MS
gradient B, tR = 2.13 min, m/z 363.2 ([M + H]+, C19H21F2N2OS+
calcd 363.1). HRMS (ESI) m/z calcd for [M + Na]+,
C19H20F2N2NaOS+ 385.1157; found 385.1162.
+
CHCl3). HRMS (ESI) m/z calcd for [M + Na] , C14H17F3N2NaOS+
341.0906; found 341.0908.
(S)-N-(2-(Dimethylamino)-2-thioxoethyl)-2,2,2-trifluoro-N-(1-
(naphthalen-1-yl)ethyl)acetamide (8b). Yield: 54 mg (40%) as
colorless solid, obtained over two steps from 2b. Mp: 50−61 °C. VLC
1
eluent: 0−25% EtOAc in hexane. H NMR (400 MHz, CDCl3) δ
(S)-N-(2-(Dimethylamino)-2-oxoethyl)-2,2-difluoro-N-(1-(naph-
thalen-1-yl)ethyl)acetamide (13). Yield: 75 mg (60%) as colorless
7.90−7.46 (m, 7H, Ar-H), 6.47/6.11* (2 × q, J = 6.7 Hz, 1H,
NCHCH3), 4.50*/3.77* (2 × d, J = 16.1 Hz, 2H, CSCH2), 4.07/3.88
(2 × d, J = 18.2 Hz, 2H, CSCH2), 3.42(*)/3.15/2.94 (4× s, 6H,
N(CH3)2), 1.99*/1.78 (2 × d, J = 6.9 HZ, 3H, NCHCH3).13C NMR
(101 MHz, CDCl3) δ 197.9, 196.2*, 159.3 (q, J = 35.7 Hz), 135.7*,
135.1, 134.1, 131.8*, 130.9*, 129.6, 129.3*, 129.0, 127.3, 127.3*,
126.5, 126.3*, 125.3, 125.2*, 125.0, 124.8*, 123.4, 122.5*, 116.7 (q, J
= 289.5 Hz) 54.1*, 52.9, 52.0*, 51.6, 45.7, 45.5*, 41.1*, 40.4, 20.3*,
17.5. UPLC-MS gradient B, tR = 2.36 min, m/z 369.3 ([M + H]+,
C18H20F3N2OS+ calcd 369.1). [α]589.3: −39° (c = 0.20, 293 K, CHCl3).
HRMS (ESI) m/z calcd for [M + Na]+, C18H19F3N2NaOS+ 391.1062;
found 391.1064.
1
solid. Mp: 123−125 °C. VLC eluent: 0−1% MeOH in CH2Cl2. H
NMR (400 MHz, CDCl3) δ 7.95−7.46 (m, 7H, Ar-H), 6.61 (q, J = 6.9
Hz, 1H, NCHCH3), 6.19 (t, J = 53.8 Hz, 1H, COCHF2), 3.83/3.64 (2
× d, J = 18.0 Hz, 2H, COCH2), 2.73/2.62 (2 × s, 6H, N(CH3)2), 1.63
(d, J = 6.9 Hz, 3H, CHCH3). 13C NMR (101 MHz, CDCl3) δ 167.4,
163.5 (t, J = 24.7 Hz), 134.6, 134.0, 132.0, 129.6, 128.6, 127.3, 126.6,
125.2, 124.8, 124.0, 108.6 (t, J = 248.0 Hz), 50.1, 42.8 (t, J = 3.0 Hz),
36.3, 36.0, 16.3. UPLC-MS gradient B, tR = 1.87 min, m/z 335.2 ([M +
+
H]+, C18H21F2N2O2 calcd 335.2). [α]589.3: −118° (c = 0.18, 293 K,
+
CHCl3). HRMS (ESI) m/z calcd for [M + Na]+, C18H20F2N2NaO2
357.1385; found 357.1387.
J
DOI: 10.1021/acs.joc.5b00048
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(S)-N-(2-(Dimethylamino)-2-thioxoethyl)-2,2-difluoro-N-(1-
(naphthalen-1-yl)ethyl)acetamide (14). Yield: 46 mg (79%) as
colorless solid. Mp: 127−129 °C. VLC eluent: 0−0.5% MeOH in
1
CH2Cl2. H NMR (400 MHz, CDCl3) δ 7.96−7.45 (m, 7H, Ar-H),
6.62 (q, J = 6.9 Hz, 1H, NCHCH3), 6.41 (t, J = 53.8 Hz, 1H,
COCHF2), 3.92 (d, J = 4.2 Hz, 2H, CSCH2), 3.35/2.94 (2 × s, 6H,
N(CH3)2), 1.66 (d, J = 7.0 Hz, 3H, CHCH3). 13C NMR (101 MHz,
CDCl3) δ 197.5, 164.0 (t, J = 25.8 Hz), 135.0, 134.1, 132.0, 129.6,
128.7, 127.3, 126.6, 125.1, 124.7, 124.0, 108.1 (t, J = 246.9 Hz), 50.5,
49.3, 49.2, 45.7, 40.6, 17.0. UPLC-MS gradient B, tR = 2.11 min, m/z
351.2 ([M + H]+, C18H21F2N2OS+ calcd 351.1). [α]589.3: −147° (c =
0.19, 293 K, CHCl3). HRMS (ESI) m/z calcd for [M + Na]+,
C18H20F2N2NaOS+ 373.1157; found 373.1160.
(S)-N,N-Dimethyl-2-(N-(1-phenylethyl)ethanethioamido)-
acetamide (5a). Yield: 87 mg (22%) as oil. VLC eluent: 0−80%
EtOAc in hexane. 1H NMR (400 MHz, CDCl3) δ 7.41−7.22 (m, 5H,
Ar-H), 7.30*/5.63 (2 × q, J = 6.9 Hz, 1H, NCHCH3), 5.02/3.70 (2 ×
d, J = 15.6 Hz, 2H COCH2), 4.13*/3.90* (2 × d, J = 15.6 Hz, 2H
COCH2), 3.00/2.95/2.88*/2.81* (4 × s, 6H, N(CH3)2), 2.86/2.64*
(2 × s, 3H, CSCH3), 1.76/1.53* (2 × d, J = 7.0 Hz, 3H, NCHCH3).
13C NMR (101 MHz, CDCl3) δ 203.2*, 201.0, 166.3, 166.0*, 139.5,
N-(2-(Dimethylamino)-2-thioxoethyl)-2,2-difluoro-N-isopropyla-
cetamide (15). Yield: 45 mg (16%) as oil. VLC eluent: 0−30% EtOAc
1
in heptane. H NMR (400 MHz, CDCl3) δ 6.21*/6.18 (2 × t, J = 54
Hz, 1H, COCF2H), 4.64*/4.40 (2 × sept, J = 6.7 Hz, 1H,
NCH(CH3)2), 4.27/4.24* (2 × s, 2H, COCH2), 3.52*/3.49/3.38*/
3.36 (4 × s, 6H, N(CH3)2), 1.31/1.16* (2 × d, J = 6.6 Hz, 6H,
NCH(CH3)2). 13C NMR (101 MHz, CDCl3) δ 197.8*, 197.0, 162.2
(t, J = 25.3 Hz), 110.3/108.2* (2 × t, J = 251.0 Hz), 49.1*, 49.1, 48.6
(t, J = 4.0 Hz), 47.7*, 45.7*, 45.4, 41.1, 40.6*, 21.3, 19.8*. UPLC-MS
gradient B, tR = 1.36 min, m/z 239.1 ([M + H]+, C9H17F2N2OS+ calcd
239.3). HRMS (ESI) m/z calcd for [M + Na]+, C9H16F2N2NaOS+
261.0844; found 261.0848.
139.3*, 129.2, 128.7*, 128.2, 128.1*, 127.8*, 126.6, 60.6, 59.0*, 50.7,
48.1*, 36.9, 36.5*, 36.1, 35.0*, 33.2*, 32.4, 17.8, 14.8*. UPLC-MS
gradient B, tR = 1.58 min, m/z 287.1 ([M + Na]+, C14H20N2NaOS
calcd 287.1). [α]589.3: −48° (c = 0.14, 293 K, CHCl3). HRMS (ESI)
m/z calcd for [M + Na]+, C14H20N2NaOS+ 287.1189; found 287.1191.
(S)-N,N-Dimethyl-2-(N-(1-(naphthalen-1-yl)ethyl)ethanethio-
amido)acetamide (5b). Yield: 75 mg (38%) as amorphous substance.
VLC eluent: 0−50% EtOAc in hexane. 1H NMR (400 MHz, CDCl3) δ
8.08−7.43 (m, 7H, Ar-H), 7.55/6.12* (2 × q, J = 6.9 Hz, 1H,
NCHCH3), 5.05*/3.75* (2 × d, J = 15.5 Hz, 2H, COCH2), 3.96/3.79
(2 × d, J = 15.5 Hz, 2H, COCH2), 2.96*/2.60 (2 × s, 3H, CSCH3),
2.94*/2.91*/2.75/2.62 (4 × s, 6H, N(CH3)2), 1.93*/1.70 (2 × d, J =
6.9 Hz, 3H, NCHCH3). 13C NMR (101 MHz, CDCl3) δ 202.0,
201.2*, 166.7*, 165.8, 135.8, 135.6*, 134.1*, 133.9, 132.4, 131.1*,
129.5, 129.5*, 129.4*, 128.5, 127.5*, 127.3, 126.5, 126.3*, 125.6*,
125.4, 125.0, 124.9, 124.5*, 122.3*, 58.5*, 57.2, 51.0*, 47.9, 36.9*,
36.3*, 36.1, 36.0, 33.2, 32.2*, 19.0*, 14.8. UPLC-MS gradient B, tR =
N-Benzhydryl-2,2-dichloro-N-(2-(dimethylamino)-2-oxoethyl)-
acetamide (11). Dichloroacetyl chloride (3 equiv) was added to a
solution of 2c (1 equiv) and Et3N (3 equiv) in CH2Cl2 (20 mL) at 0
°C. The reaction was stirred for 2 h. The reaction mixture was poured
into satd aq NaHCO3 (50 mL) and extracted with EtOAc (3 × 50
mL). The combined organic phases were dried (MgSO4), filtered, and
concentrated in vacuo. The product was isolated as a colorless solid,
after preparative HPLC (gradient C). Yield: 12 mg (9%). Mp: 122−
1
134 °C. H NMR (400 MHz, CDCl3) δ 7.38−7.18 (m, 10H, Ar−H),
1.93 min, m/z 315.2 ([M + H]+, C18H23N2OS+ calcd 315.2). [α]589.3
:
7.06/6.53* (2 × s, 1H, NCH(C6H5)2), 6.42/6.17* (2 × s, 1H,
COCCl2H), 4.12/4.07* (2 × s, 2H, COCH2), 2.77*/2.74*/2.62/2.48
(4 × s, 6H, N(CH3)2). 13C NMR (101 MHz, CDCl3) δ 166.62,
165.47, 138.01, 128.9, 128.8*, 128.4, 128.0*, 127.9, 127.3, 66.4, 62.5,
45.4, 36.2, 35.7. UPLC-MS gradient B, tR = 2.06 min, m/z 379.1 ([M +
H]+, C19H21Cl2N2O2+ calcd 379.1). HRMS (ESI) m/z calcd for [M +
−189° (c = 0.17, 293 K, CHCl3). HRMS (ESI) m/z calcd for [M +
Na]+, C18H22N2NaOS+: 337.1345; found 337.1347.
2-(N-Benzhydrylethanethioamido)-N,N-dimethylacetamide (5c).
Yield: 75 mg (15%) as amorphous substance. VLC eluent: 0−0.8%
MeOH in CH2Cl2. 1H NMR (400 MHz, CDCl3) δ 8.24*/6.66 (2 × s,
1H, NCH(C6H5)2), 7.38−7.18 (m, 10H, Ar-H), 4.72/4.34* (2 × s,
2H, COCH2), 2.79*/2.71 (2 × s, 3H, CSCH3), 2.78/2.74/2.57(*) (4
× s, 6H, N(CH3)2). 13C NMR (101 MHz, CDCl3) δ 204.5*, 203.6,
165.3, 165.1*, 138.3, 137.8*, 129.4*, 129.2, 128.9, 128.5, 128.4*,
128.0*, 70.4, 68.7*, 52.8, 49.8*, 36.5*, 36.3, 35.8*, 35.6, 33.6*, 33.4.
UPLC-MS gradient B, tR = 1.92 min, m/z 327.2 ([M + H]+,
C19H23N2OS+ calcd 327.2). HRMS (ESI) m/z calcd for [M + Na]+,
C19H22N2NaOS+: 349.1351; found 349.1346.
+
Na]+, C19H20Cl2N2NaO2 m/z 401.0794; found 401.0798.
Procedure for Synthesis of Thioacetylation Reagent 9. The
synthesis was adapted from the reported procedure by Doszczak and
Rachon.27 P2S5 (11.2 g, 25 mmol) was suspended in toluene (70 mL),
2,2-dimethylpropane-1,3-diol (10.4 g, 100 mmol) was added, and the
mixture was heated to 80 °C overnight. The reaction was cooled to rt
and filtered. The filtrate was concentrated, and the crude was
recrystallized from CCl4 (25 mL). After letting the compound
precipitate in the freezer (−18 °C) for 6 h, the solvent was removed by
filtration and the colorless crystals were dried in vacuo to give 16 (13.0
g, 66%). Compound 16 (1.98 g, 10 mmol) was dissolved in CH2Cl2
(30 mL), and acetyl chloride (710 μL, 10 mmol) was added at rt. The
mixture was cooled to 0 °C, and Et3N (1.4 mL, 10 mmol) was added
dropwise. The reaction was stirred at 0 °C for 15 min followed by 15
min at rt. The mixture was then filtered through a pad of silica gel, and
the filtrate was concentrated in vacuo to give 17 (1.75 g, 73%).
Compounds 16 (2.78 g, 14 mmol) and 17 (1.7 g, 7 mmol) were then
dissolved in toluene (50 mL) and heated to 90 °C for 2.5 h, at which
point the solution turned red. The solution was allowed to cool to rt,
and the solvent was removed in vacuo. The crude was dissolved in
CH2Cl2 (50 mL), washed with satd aq NaHCO3 and water. The
organic phase was dried (MgSO4), filtered, and concentrated in vacuo
to give 9 (1.52 g, 85%), which was used without further purification.
General Procedure for Thioacetylation. A solution of 2a−e (1
equiv) and pyridine (1 equiv) in CH2Cl2 (0.7 M) was added dropwise
to thioacetylation reagent 9 (0.9 equiv) in CH2Cl2 (0.2 M) at rt. After
stirring for 1 h the reaction mixture was washed with satd aq NaHCO3
and water. The organic phase was dried (MgSO4), filtered, and
concentrated in vacuo. The crude product was purified by VLC.
2-(N-Isopropylethanethioamido)-N,N-dimethylacetamide (5d).
1
Yield: 30 mg (6%) as oil. VLC eluent: 0−1% MeOH in CH2Cl2. H
NMR (400 MHz, CDCl3) δ 5.96*/4.56 (2 × sept, J = 6.8 Hz, 1H,
NCH(CH3)2), 4.51/4.19* (2 × s, 2H, COCH2), 3.12/3.07*/3.01*/
2.98 (4 × s, 6H, N(CH3)2), 2.75/2.55* (2 × s, 3H, CSCH3), 1.29/
1.15* (2 × d, J = 6.7 Hz, 6H, NCH(CH3)2). 13C NMR (101 MHz,
CDCl3) δ 199.9, 166.4, 53.7, 48.4, 36.9, 36.7*, 36.3*, 36.1, 31.9, 20.8,
19.3*. UPLC-MS gradient B, tR = 1.05 min, m/z 225.2 ([M + Na]+,
C9H19N2NaOS+ calcd 225.1). HRMS (ESI) m/z calcd for [M + Na]+,
C9H18N2NaOS+: 225.1032; found 225.1033.
NMR Spectroscopy. 1D and 2D NMR spectra were recorded at
1
298 K. Spectra were recorded at 400 MHz for H and 100 MHz for
13C. The correlation spectroscopy (COSY) spectra were recorded with
a relaxation delay of 1.5 s before each scan, a spectral width of 3 k × 3
k, collecting 4 FIDs and 1 k × 128 data points. The heteronuclear
single quantum coherence (HSQC) spectra were recorded with a
relaxation delay of 1.5 s before each scan, a spectral width of 4.8 k ×
16.6 k, collecting 4 FIDs and 1 k × 256 data points. Heteronuclear
multiple-bond correlation (HMBC) spectra were recorded with a
relaxation delay of 1.34 s before each scan, a spectral width of 3.5 k ×
22.3 k, collecting 32 FIDs and 2k × 256 data points. Rotating frame
Overhauser effect (ROESY) spectra were recorded with a relaxation
K
DOI: 10.1021/acs.joc.5b00048
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The Journal of Organic Chemistry
Article
delay of 2 s before each scan, a spectral width of 3.5 k × 3.5 k,
collecting 8 FIDs at 295 K, 1 k × 256 data points, and a mixing time of
100 ms. Heteronuclear Overhauser effect (HOESY) spectra36 were
recorded with a relaxation delay of 1.5 s before each scan, a spectral
width of 5 × 19 kHz, collecting 64 FIDs at 300 K, 2 k × 256 data
points, and a mixing time of 50 ms. The gradient augmented pulse
sequence was ‘hoesyetgp.2′.
Crystal Data from Single-Crystal Diffraction Studies for
Compound 10. C19H20F2N2O2, Mr = 346.37, orthorhombic, space
group Pna21, colorless, a = 11.35582(11) Å, b = 15.33727(14) Å, c =
9.60241(9) Å, T = 120 K, Z = 4, Rint = 0.0255, GOF = 1.033, R1[F0 >
4s(F0)] = 0.0301, wR2[all data] = 0.0799.
Crystal Data from Single-Crystal Diffraction Studies for
Compound 11. C19H20Cl2N2O2, Mr = 379.27, orthorhombic, space
group Pbca, colorless, a = 17.97160(18) Å, b = 10.96238(11) Å, c =
19.1950(2) Å, T = 120 K, Z = 8, Rint = 0.0362, GOF = 1.053, R1[F0 >
4s(F0)] = 0.0452, wR2[all data] = 0.1269.
Crystal Data from Single-Crystal Diffraction Studies for
Compound 12. C19H20F2N2OS, Mr = 362.43, orthorhombic, space
group P212121, colorless, a = 9.31801(6) Å, b = 10.65613(7) Å, c =
18.11473(12) Å, T = 120 K, Z = 4, Rint = 0.0392, GOF = 1.088, R1[F0
> 4s(F0)] = 0.0240, wR2[all data] = 0.0635.
Crystal Data from Single-Crystal Diffraction Studies for
Compound 13. C18H20F2N2O2, Mr = 334.36, triclinic, space group
P1, colorless, a = 7.3111(4) Å, b = 8.9012(5) Å, c = 14.1362(8) Å, T=
120 K, Z = 2, Rint = 0.0279, GOF = 1.011, R1[F0 > 4s(F0)] = 0.0522,
wR2[all data] = 0.1508.
Crystal Data from Single-Crystal Diffraction Studies for
Compound 14. C18H20F2N2OS, CHCl3, Mr = 469.79, orthorhombic,
space group P212121, colorless, a = 8.1156(6) Å, b = 19.8520(12) Å, c
= 12.9765(9) Å, T= 120 K, Z = 4, Rint = 0.0343, GOF = 1.101, R1[F0 >
4s(F0)] = 0.0609, wR2[all data] = 0.1851.
CIF files for the X-ray diffraction crystal structures have been
deposited at the Cambridge Crystallographic Data Centre (CCDC)
under accession codes 1041654−1041666.
X-ray Crystallography. All final compounds were subjected to
vapor diffusion crystallization with chloroform as solvent and pentane
as precipitant. Compounds unsuccessful to this method were
attempted crystallized by slow evaporation from solubility compatible
solvents (e.g., chloroform, EtOAc, CH2Cl2, or acetone). Compounds
7c and 10 were crystallized by slow evaporation from acetone and 12
by slow evaporation from chloroform. X-ray diffraction profile data
from ω scans were collected on using Cu Kα radiation. Data was
processed and scaled using the CrysAlisPro software [Version
1.171.36.28 (released Jan 02, 2013 CrysAlis171.NET)]. Details of
the data collection are found in the supplementary CIF files. All crystal
structures were solved using SHELXS and refined using SHELXL37,38
in the OLEX2 interface.38 Hydrogen atoms were observed and
included on ideal positions using riding coordinates.
Crystal Data from Single-Crystal Diffraction Studies for
Compound 3b. C22H22N2O2, Mr = 298.38, orthorhombic, space
group P212121, colorless, a = 9.37265(13) Å, b = 9.64096(14) Å, c =
17.45640(2) Å, T = 120 K, Z = 4, Rint = 0.0222, GOF = 1.052, R1[F0 >
4s(F0)] = 0.0337, wR2[all data] = 0.0876.
Crystal Data from Single-Crystal Diffraction Studies for
Compound 3c. C19H22N2O2, Mr = 310.39, orthorhombic, space
group Pna21, colorless, a = 10.88660(16) Å, b = 14.8755(2) Å, c =
10.23202(14) Å, T = 120 K, Z = 4, Rint = 0.0264, GOF = 1.024, R1[F0
> 4s(F0)] = 0.0323, wR2[all data] = 0.0865.
ASSOCIATED CONTENT
■
S
* Supporting Information
Crystal Data from Single-Crystal Diffraction Studies for
Compound 4a. C14H17F3N2O2, Mr = 302.30, hexagonal, space
group P61, colorless, a = 15.74885(18) Å, c = 11.05787(17) Å, T =
120 K, Z = 6, Rint = 0.0453, GOF = 1.090, R1[F0 > 4s(F0)] = 0.0756,
wR2[all data] = 0.2306.
Supplementary figures and tables and copies of H and 13C
1
NMR spectra; X-ray crystallographic data files (CIF). This
material is available free of charge via the Internet at http://
pubs.acs.org.
Crystal Data from Single-Crystal Diffraction Studies for
Compound 4c. C19H19F3N2O2, Mr = 364.36, orthorhombic, space
group P212121, colorless, a = 9.46505(10) Å, b = 10.52840(11) Å, c =
18.0621(2) Å, T = 120 K, Z = 4, Rint = 0.0235, GOF = 1.096, R1[F0 >
4s(F0)] = 0.0368, wR2[all data] = 0.0941.
Crystal Data from Single-Crystal Diffraction Studies for
Compound 5b. C18H22N2OS, Mr = 314.44, orthorhombic, space
group P212121, colorless, a = 9.42849(13) Å, b = 10.19836(14) Å, c =
17.3158(3) Å, T = 120 K, Z = 4, Rint = 0.0287, GOF = 1.053, R1[F0 >
4s(F0)] = 0.0339, wR2[all data] = 0.0908.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: cao@sund.ku.dk.
Present Address
§Christian A. Olsen: Center for Biopharmaceuticals and
Department of Drug Design & Pharmacology, University of
Copenhagen, Universitetsparken 2, DK-2100, Copenhagen,
Denmark.
Crystal Data from Single-Crystal Diffraction Studies for
Compound 5c. C H N OS, M = 326.45, triclinic, space group P1,
̅
19 22
2
r
Author Contributions
colorless, a = 8.6606(3) Å, b = 8.8909(2) Å, c = 11.7871(4) Å, T = 120
K, Z = 4, Rint = 0.0275, GOF = 1.087, R1[F0 > 4s(F0)] = 0.0391,
wR2[all data] = 0.1072.
#Jens Engel-Andreasen and Kathrine Wich contributed equally
to the experimental work.
Crystal Data from Single-Crystal Diffraction Studies for
Compound 7b. C18H22N2OS, Mr = 314.44, orthorhombic, space
group P212121, colorless, a = 9.53269(13) Å, b = 9.99519(13) Å, c =
17.7400(3) Å, T = 120 K, Z = 4, Rint = 0.0267, GOF = 1.042, R1[F0 >
4s(F0)] = 0.0318, wR2[all data] = 0.0824.
Crystal Data from Single-Crystal Diffraction Studies for
Compound 7c. C19H22N2OS, Mr = 326.45, monoclinic, space group
P21/c, colorless, a = 14.2453(4) Å, b = 6.3820(2) Å, c = 19.0726(6) Å,
T = 120 K, Z = 4, Rint = 0.0515, GOF = 1.292, R1[F0 > 4s(F0)] =
0.1146, wR2[all data] = 0.2848.
Crystal Data from Single-Crystal Diffraction Studies for
Compound 8a. C14H17F3N2OS, Mr = 318.36, orthorhombic, space
group P212121, colorless, a = 5.78072(13) Å, b = 9.29719(17) Å, c =
27.6640(5) Å, T = 120 K, Z = 4, Rint = 0.0656, GOF = 1.059, R1[F0 >
4s(F0)] = 0.0464, wR2[all data] = 0.1257.
Crystal Data from Single-Crystal Diffraction Studies for
Compound 8c. C19H19F3N2OS, Mr = 380.42, orthorhombic, space
group P212121, colorless, a = 9.42268(11) Å, b = 10.66811(13) Å, c =
18.2399(2) Å, T = 120 K, Z = 4, Rint = 0.0253, GOF = 1.025, R1[F0 >
4s(F0)] = 0.0297, wR2[all data] = 0.0794.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Charlotte H. Gotfredsen and Ms. Anne Hector
(DTU Chemistry) for assistance with NMR spectroscopy, Dr.
Niels T. Nyberg (University of Copenhagen) for setting up the
HOESY experiments, and Ms. Tina Gustafsson (DTU
Chemistry) for technical assistance with UPLC-MS. This
work was supported by the Danish Independent Research
Council/Natural Sciences (Steno Grant No. 10-080907;
C.A.O.), Lundbeck Foundation (Young Group Leader Fellow-
ship; C.A.O.), Carlsberg Foundation (equipment; C.A.O.), and
University of Copenhagen. The NMR equipment used at the
University of Copenhagen was purchased via a grant from the
Lundbeck Foundation (R77-A6742). We thank DTU Chem-
istry for a Ph.D. Fellowship to J.E.-A.
L
DOI: 10.1021/acs.joc.5b00048
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ChemBioChem 2010, 11, 1356−1360. (g) Olsen, C. A. Biopolymers
2011, 96, 561−566.
REFERENCES
■
(1) Rader, R. A. Nat. Biotechnol. 2008, 26, 743−751.
(21) Laursen, J. S.; Engel-Andreasen, J.; Fristrup, P.; Harris, P.;
Olsen, C. A. J. Am. Chem. Soc. 2013, 135, 2835−2844.
(22) (a) Choudhary, A.; Gandla, D.; Krow, G. R.; Raines, R. T. J. Am.
Chem. Soc. 2009, 131, 7244−7246. (b) Newberry, R. W.; VanVeller,
B.; Guzei, I. A.; Raines, R. T. J. Am. Chem. Soc. 2013, 135, 7843−7846.
(23) Choudhary, A.; Fry, C. G.; Raines, R. T. ARKIVOC 2010, 2010,
251−262.
(2) (a) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173−180.
(b) Goodman, C. M.; Choi, S.; Shandler, S.; DeGrado, W. F. Nat.
Chem. Biol. 2007, 3, 252−262. (c) Horne, W. S.; Gellman, S. H. Acc.
Chem. Res. 2008, 41, 1399−1408. (d) Olsen, C. A. ChemBioChem
2010, 11, 152−160. (e) Horne, W. S. Expert Opin. Drug Discovery
2011, 6, 1247−1262.
(3) (a) Seebach, D.; Beck, A. K.; Bierbaum, D. J. Chem. Biodivers.
2004, 1, 1111−1239. (b) Seebach, D.; Gardiner, J. Acc. Chem. Res.
2008, 41, 1366−1375. (c) Cheng, R. P.; Gellman, S. H.; DeGrado, W.
F. Chem. Rev. 2001, 101, 3219−3232.
(4) (a) Zuckermann, R. N.; Kodadek, T. Curr. Opin. Mol. Ther. 2009,
11, 299−307. (b) Zuckermann, R. N. Biopolymers 2011, 96, 545−555.
(5) Cheloha, R. W.; Maeda, A.; Dean, T.; Gardella, T. J.; Gellman, S.
H. Nat. Biotechnol. 2014, 32, 653−655.
(6) (a) Zuckermann, R. N.; Kerr, J. M.; Kent, S. B. H.; Moos, W. H. J.
Am. Chem. Soc. 1992, 114, 10646−10647. (b) Burkoth, T. S.;
Fafarman, A. T.; Charych, D. H.; Connolly, M. D.; Zuckermann, R. N.
J. Am. Chem. Soc. 2003, 125, 8841−8845.
(7) Simon, R. J.; Kania, R. S.; Zuckermann, R. N.; Huebner, V. D.;
Jewell, D. A.; Banville, S.; Ng, S.; Wang, L.; Rosenberg, S.; Marlowe, C.
K.; Spellmeyer, D. C.; Tan, R.; Frankel, A. D.; Santi, D. V.; Cohen, F.
E.; Bartlett, P. A. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 9367−9371.
(8) Patch, J. A.; Barron, A. E. J. Am. Chem. Soc. 2003, 125, 12092−
12093.
(24) (a) Pal, D.; Chakrabarti, P. J. Mol. Biol. 1999, 294, 271−288.
(b) Zondlo, N. J. Acc. Chem. Res. 2013, 46, 1039−49.
(25) Gorske, B. C.; Nelson, R. C.; Bowden, Z. S.; Kufe, T. A.; Childs,
A. M. J. Org. Chem. 2013, 78, 11172−11183.
(26) Bonacorso, H. G.; Caro, M. S. B.; Zanatta, N.; Martins, M. A. P.
Magn. Reson. Chem. 1993, 31, 451−454.
(27) Doszczak, L.; Rachon, J. J. Chem. Soc., Perkin Trans. 1 2002,
1271−1279.
(28) Scheibye, S.; Pedersen, B. S.; Lawesson, S. O. Bull. Soc. Chim.
Belg. 1978, 87, 229−238.
(29) Bartlett, G. J.; Choudhary, A.; Raines, R. T.; Woolfson, D. N.
Nat. Chem. Biol. 2010, 6, 615−620.
(30) Kirshenbaum, K.; Barron, A. E.; Goldsmith, R. A.; Armand, P.;
Bradley, E. K.; Truong, K. T. V.; Dill, K. A.; Cohen, F. E.;
Zuckermann, R. N. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 4303−4308.
(31) Olivato, P. R.; Guerrero, S. A.; Yreijo, M. H.; Rittner, R.;
Tormena, C. F. J. Mol. Struct. 2002, 607, 87−99.
(32) Bartlett, G. J.; Newberry, R. W.; VanVeller, B.; Raines, R. T.;
Woolfson, D. N. J. Am. Chem. Soc. 2013, 135, 18682−18688.
(33) Eisenstein, O.; Anh, N. T.; Jean, Y.; Devaquet, A.; Cantacuzen,
J.; Salem, L. Tetrahedron 1974, 30, 1717−1723.
(34) Basso, E. A.; Kaiser, C.; Rittner, R.; Lambert, J. B. J. Org. Chem.
1993, 58, 7865−7869.
(35) (a) Tran, T. T.; Zeng, J.; Treutlein, H.; Burgess, A. W. J. Am.
Chem. Soc. 2002, 124, 5222−5230. (b) Reiner, A.; Wildemann, D.;
Fischer, G.; Kiefhaber, T. J. Am. Chem. Soc. 2008, 130, 8079−8084.
(36) Yu, C.; Levy, G. C. J. Am. Chem. Soc. 1984, 106, 6533−6537.
(37) Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, 64, 112−122.
(38) Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A. K.;
Puschmann, H. J. Appl. Crystallogr. 2009, 42, 339−341.
(9) Statz, A. R.; Meagher, R. J.; Barron, A. E.; Messersmith, P. B. J.
Am. Chem. Soc. 2005, 127, 7972−7973.
(10) Nam, K. T.; Shelby, S. A.; Choi, P. H.; Marciel, A. B.; Chen, R.;
Tan, L.; Chu, T. K.; Mesch, R. A.; Lee, B. C.; Connolly, M. D.;
Kisielowski, C.; Zuckermann, R. N. Nat. Mater. 2010, 9, 454−460.
(11) (a) Nguyen, J. T.; Turck, C. W.; Cohen, F. E.; Zuckermann, R.
N.; Lim, W. A. Science 1998, 282, 2088−2092. (b) Hara, T.; Durell, S.
R.; Myers, M. C.; Appella, D. H. J. Am. Chem. Soc. 2006, 128, 1995−
2004. (c) Udugamasooriya, D. G.; Dineen, S. P.; Brekken, R. A.;
Kodadek, T. J. Am. Chem. Soc. 2008, 130, 5744−5752.
(12) Wu, C. W.; Kirshenbaum, K.; Sanborn, T. J.; Patch, J. A.; Huang,
K.; Dill, K. A.; Zuckermann, R. N.; Barron, A. E. J. Am. Chem. Soc.
2003, 125, 13525−13530.
(13) Stringer, J. R.; Crapster, J. A.; Guzei, I. A.; Blackwell, H. E. J. Am.
Chem. Soc. 2011, 133, 15559−15567.
(14) Armand, P.; Kirshenbaum, K.; Goldsmith, R. A.; Farr-Jones, S.;
Barron, A. E.; Truong, K. T. V.; Dill, K. A.; Mierke, D. F.; Cohen, F.
E.; Zuckermann, R. N.; Bradley, E. K. Proc. Natl. Acad. Sci. U.S.A. 1998,
95, 4309−4314.
(15) (a) Huang, K.; Wu, C. W.; Sanborn, T. J.; Patch, J. A.;
Kirshenbaum, K.; Zuckermann, R. N.; Barron, A. E.; Radhakrishnan, I.
J. Am. Chem. Soc. 2006, 128, 1733−1738. (b) Crapster, J. A.; Guzei, I.
A.; Blackwell, H. E. Angew. Chem., Int. Ed. 2013, 52, 5079−5084.
(16) Shin, S. B.; Yoo, B.; Todaro, L. J.; Kirshenbaum, K. J. Am. Chem.
Soc. 2007, 129, 3218−3225.
(17) (a) Sui, Q.; Borchardt, D.; Rabenstein, D. L. J. Am. Chem. Soc.
2007, 129, 12042−12048. (b) Gorske, B. C.; Bastian, B. L.; Geske, G.
D.; Blackwell, H. E. J. Am. Chem. Soc. 2007, 129, 8928−8929.
(18) Gorske, B. C.; Stringer, J. R.; Bastian, B. L.; Fowler, S. A.;
Blackwell, H. E. J. Am. Chem. Soc. 2009, 131, 16555−16567.
(19) Caumes, C.; Roy, O.; Faure, S.; Taillefumier, C. J. Am. Chem.
Soc. 2012, 134, 9553−9556.
(20) (a) Hamper, B. C.; Kolodziej, S. A.; Scates, A. M.; Smith, R. G.;
Cortez, E. J. Org. Chem. 1998, 63, 708−718. (b) Olsen, C. A.; Bonke,
G.; Vedel, L.; Adsersen, A.; Witt, M.; Franzyk, H.; Jaroszewski, J. W.
Org. Lett. 2007, 9, 1549−1552. (c) Vedel, L.; Bonke, G.; Foged, C.;
Ziegler, H.; Franzyk, H.; Jaroszewski, J. W.; Olsen, C. A.
ChemBioChem 2007, 8, 1781−1784. (d) Bonke, G.; Vedel, L.; Witt,
M.; Jaroszewski, J. W.; Olsen, C. A.; Franzyk, H. Synthesis 2008, 2381−
2390. (e) Foged, C.; Franzyk, H.; Bahrami, S.; Frokjaer, S.;
Jaroszewski, J. W.; Nielsen, H. M.; Olsen, C. A. Biochim. Biophys.
Acta: Biomembr. 2008, 1778, 2487−2495. (f) Olsen, C. A.; Ziegler, H.
L.; Nielsen, H. M.; Frimodt-Møller, N.; Jaroszewski, J. W.; Franzyk, H.
M
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