Enantiopure 5-CF3-Proline: Synthesis, Incorporation in Peptides, and Tuning of the Peptide Bond Geometry

Article abstract of DOI:10.1021/acs.orglett.0c03880

The straightforward synthesis of enantiopure 5-(R)-and 5-(S)-trifluoromethylproline is reported. The key steps are a Ruppert-Prakash reagent addition on l-pyroglutamic esters followed by an elimination reaction and a selective reduction. The solution-phase and solid-phase incorporation of this unprotected enantiopure fluorinated amino acid in a short peptide chain was demonstrated. Compared to proline, the CF3 group provides a decrease of the trans to cis amide bond isomerization energy and an increase of the cis conformer population.

Full text of DOI:10.1021/acs.orglett.0c03880

pubs.acs.org/OrgLett
Letter
Enantiopure 5‑CF3−Proline: Synthesis, Incorporation in Peptides,
and Tuning of the Peptide Bond Geometry
́
̀
́
Clement A. Sanchez, Charlene Gadais, Gregory Chaume, Sylvaine Girard, Evelyne Chelain,*
and Thierry Brigaud*
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ABSTRACT: The straightforward synthesis of enantiopure 5-(R)-and 5-(S)-trifluoromethylproline is reported. The key steps are a
Ruppert-Prakash reagent addition on L-pyroglutamic esters followed by an elimination reaction and a selective reduction. The
solution-phase and solid-phase incorporation of this unprotected enantiopure fluorinated amino acid in a short peptide chain was
demonstrated. Compared to proline, the CF3 group provides a decrease of the trans to cis amide bond isomerization energy and an
increase of the cis conformer population.
The synthesis of 5-(R)- and 5-(S)-CF3-proline was planned
via a short multistep procedure involving the addition of the
Ruppert-Prakash reagent (CF3SiMe3) on a properly protected
pyroglutamic acid followed by an elimination reaction and a
selective reduction (Scheme 2). To obtain enantiopure proline
derivatives, the challenge was to avoid the isomerization of the
intermediate trifluoromethylated imine leading to a complete
racemization of the C2 center (Scheme 1).12
The Ruppert-Prakash reagent addition on an amide
functional group, except Weinreb amides, is known to be a
difficult reaction.14 However, cyclic imides have been reported
to be electrophilic enough to react with trifluoromethyltrime-
thylsilane under fluoride catalysis to give the corresponding
aminoacetal.15 Therefore, we hypothesized that the amide
function of a pyroglutamic ester bearing a tert-butyloxycar-
bonyl (Boc) electron-withdrawing protecting group would
undergo a trifluoromethylation reaction. The N-Boc-protected
pyroglutamic methyl and benzyl esters 1 and 2 were prepared
as starting material according to literature procedures (Scheme
3).16,17
t is now widely recognized that the incorporation of fluorine
Iatoms is a successful strategy for the discovery of new
bioactive compounds.1 Fluorinated peptides are very promis-
ing compounds because of their specific chemical and
biophysical properties.2 The incorporation of fluorinated
amino acids provides a modulation of the peptide’s metabolic
stability3 and hydrophobicity.4 Moreover, the 19F atom can be
a useful probe for 19F NMR analysis in biological media.5 For
all these reasons the synthesis of non-natural fluorinated amino
acids is a field of research in full expansion.6 Because of their
cyclic structure, substituted prolines and proline analogues are
playing a crucial role in the peptide backbone conformation
and biological properties by the control of the trans/cis
isomerization of the peptidyl-prolyl amide bond.7 Several
substituted analogues of proline incorporating a trifluorometh-
yl group in positions 2, 3, and 4 have been reported in the
literature.8 However, to control the trans/cis isomerization, the
incorporation of a trifluoromethyl group in position 5 is clearly
the most strategic position. In Scheme 1 are presented several
strategies reported in the literature for the synthesis of racemic
cis-5-CF3-proline.9−12 Although we already reported the
syntheses of enantiopure cis- and trans-5-CF3-prolines, these
syntheses were long and required several tedious diastereomers
separations.13 We present herein a straightforward synthesis of
enantiopure 5-CF3-proline, a methodological study of its
unreported incorporation in a peptide chain in solution or by
solid-phase peptide synthesis (SPPS), as well as a thermody-
namic study of the trans/cis isomerization of the amide bond.
Received: November 23, 2020
Published: December 28, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03880
© 2020 American Chemical Society
Org. Lett. 2021, 23, 382−387
382

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Letter
Scheme 1. Previous Syntheses of Racemic and Enantiopure
5-CF3-Proline in the Literature
Scheme 4. Synthesis of Enantiopure 5-(R)- and 5-(S)-CF3-
Proline
providing the expected imines occurred at the same step by
treatment of the diastereomeric mixtures of 3 and 4 with
trifluoroacetic acid (TFA). After neutralization of the TFA
ammonium salts, the imine 5 was obtained in 86% yield, and
the imine 6 was obtained in 66% yield in enantiopure form. In
contrast to what has been observed by Meffre et al.12 for
carboxylic acids in these conditions no epimerization reaction
of the C2 chiral center occurred through a C5 to C2 imine/
imine equilibrium for the esters (Scheme 1). The imines 5 and
6 were then hydrogenated under Pd/C catalysis to provide the
corresponding enantiopure 5-(R)-CF3-proline methyl ester
(R)-7 and 5-(R)-CF3-proline (R)-8 in 50% and 96% yields,
respectively (Scheme 4). The hydrogenation reaction was
completely diastereoselective occurring on the less-hindered
face of the imine and provided the cis isomers. The
enantiomeric purity of (R)-7 and (R)-8 was confirmed by
analytical chiral high-performance liquid chromatography
(HPLC) (see the Supporting Information). To obtain the
trans isomer the hydride reduction of the imine 6 was
investigated. The best results were obtained with NaBH3CN
giving the trans 5-CF3-proline benzyl ester (S)-9 in 30%
isolated yield and the cis 5-CF3-proline benzyl ester (R)-9 in
45% yield after column chromatography. Finally the
debenzylation of (S)-9 and (R)-9 by a palladium-catalyzed
hydrogenolysis provided the trans 5-CF3-proline (S)-8 and the
cis 5-CF3-proline (R)-8 in 96% yield (Scheme 4).
Scheme 2. Strategic Pathway for the Synthesis of
Enantiopure 5-(R) and 5-(S)-CF3-Proline
Scheme 3. Synthesis of the Pyroglutamic Acid Derivative
Starting Materials
To investigate the incorporation of the 5-CF3-proline in
peptides in solution or by SPPS, a preliminary methodological
study of the peptide coupling reactions at its N- and C-
terminal positions was undertaken. According to our previous
experience on the peptide coupling of α-CF3 amino acids4c18
and fluoroalkylated pseudoprolines19 the coupling at the N-
terminal position is likely to be very difficult because of the
strong electron-withdrawing effect of the fluorine atoms.
Indeed typical protocols using Hydroxybenzotriazole
(HOBt)/1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
(EDCI), hexafluorophosphate azabenzotriazole tetramethyl
uronium (HATU)/N,N-diisopropylethylamine (DIPEA), or
isobutylchloroformate (IBCF)/N-methylmorpholine (NMM)
reagents failed to achieve the N-coupling reaction with Boc-
Ala-OH, while the activation of the fluorenylmethoxycarbonyl
As expected the trifluoromethylation reaction of the N-Boc
amides 1 and 2 by CF3SiMe3 promoted by cesium fluoride
proceeded in good yields to provide the fluorinated silylated
aminoacetal 3 and 4 as a 79:21 and 74:26 diastereomeric
mixture, respectively (Scheme 4). Notice that the choice of
cesium fluoride was crucial in order to obtain the O-silylated
aminoacetal as the final product. When tetra-n-butylammo-
nium fluoride (TBAF) was used as the reaction promoter, the
nonsilylated trifluoromethylated hemiaminal was only obtained
in a low yield. As the separation of each diastereomer of 3 and
4 was not needed for the elimination reaction, the next steps
were performed on the diastereomeric mixtures. The removal
of the Boc protecting group and the elimination reaction
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(Fmoc)-protected amino acids as their acid chlorides were
successful.18 Therefore, the N-coupling reaction on (R)-8
could be achieved in very good yield to give the dipeptide 10
provided that the most electrophilic Fmoc-protected valine
amino acid chloride was used (Scheme 5). It is remarkable to
cis amide bond isomerization (Figure 1). Since the pioneer
investigations of Lubell et al.21 the synthesis of δ-substituted
Scheme 5. Incorporation of 5-(R)-CF3-Proline in a Peptide
Chain
Figure 1. Peptidyl bond isomerization of CF3−Pro, CF3−ΨPro, and
CF2H−ΨPro.
prolines and proline surrogates have been designed for the
control of the trans/cis peptide bond conformation. In the
fluorinated series we developed the synthesis of CF3-
pseudoprolines19 and CF2H-pseudoprolines22 from serine
and fluorinated aldehydes as stable proline surrogates (Figure
1).
Our main observations with these compounds were the
increased cis amide bond content and an unexpected decrease
of the trans to cis amide bond isomerization energy.22,23 We
report herein the thermodynamic study of the N-acetyl-5-CF3-
proline methylamide 13, which is considered as a tripeptide
model (Table 1). As already observed both in the non-
Table 1. Thermodynamic Properties of 13 and 14
Compared to Their Non-Fluorinated Proline Analogues
Determined by NMR in D2O
note that it is not necessary to protect the carboxylic acid
functional group of the fluorinated amino acid for the peptide
coupling reaction at its N-terminal position. As a result it saves
one protecting group removal step to perform the following
coupling at the C-terminal position. The dipeptide 10 was then
submitted to a coupling reaction with H2N-Ala-OtBu to afford
the corresponding tripeptide 11 in 56% yield (Scheme 5). This
class of tripeptide building block has been properly
orthogonally protected to be used in SPPS for longer peptides
synthesis. Notice that the peptide coupling reaction at the N-
terminal position of the trans isomer (S)-9 with Fmoc-Val-Cl
failed, and then it was not possible to incorporate the trans 5-
CF3-proline (S)-8 in a peptide chain. Despite the deactivation
of its amino group, we decided to investigate the ability of the
free amino acid 5-(R)-CF3-proline (R)-8 to be directly
incorporated in a peptide chain by SPPS. The unprotected
5-CF3-proline (R)-8 was successfully submitted to the peptide
coupling reaction with a valine loaded on a Wang resin under
classical SPPS conditions (HATU/DIPEA). As we already
observed in the solution phase, the weakly nucleophilic amino
group of the fluorinated amino acid did not require any
protecting group, and the reaction proceeded in a good yield.
More interestingly the most difficult coupling reaction at the
N-terminal position of the 5-CF3-proline could also be
achieved on the resin by using the amino acid chloride
Fmoc-Phe-Cl prepared in advance. This is one of the very rare
examples of peptide coupling of an amino acid chloride by
SPPS.20 After the removal of the Fmoc protecting group and
removal from the resin the tripeptide 12 was obtained in 82%
yield (Scheme 5).
AcProNHMe
13
AcProOMe4b
14
a
c
cis/trans
ΔG‡
24:7624
20.4021
19.83
0.57
b
35:65
17.48
17.07
0.41
17:83
21.03
20.08
0.95
28:72
b
b
b
c
18.22
17.58
0.64
trans−cis
cis−trans
c
ΔG‡
ΔG°trans−cis
a
Populations (%). All energies are given in kilocalories per mole.
c
These values are consistent with ref 4b in the racemic series.
fluorinated24 and in the fluorinated CF3- and CF2H-
pseudoproline series,22,23 the cis/trans amide bond ratio can
be affected by an intramolecular H bond between the C-
terminal amide NH and the carbonyl of the N-terminal acetyl
group. To evaluate the impact of this H bond on the
conformational behavior, we also considered the proline
methyl ester 14. The cis/trans ratio of the N-acetyl-CF3-
proline amide 13 and the N-acetyl-CF3-proline methyl ester 14
1
was determined by H and 19F NMR integration. For that
purpose, we first assigned each conformer by comparing the
13C chemical shifts of the cis and the trans isomers according to
Lubell et al.21 The δ carbon for the trans isomer appears
downfield relative to that of the cis isomer. By comparison with
the literature data of their non-fluorinated analogues Ac-Pro-
NHMe and Ac-Pro-OMe, we observed an increased ratio (ca.
11%) of the cis conformer for the 5-CF3-proline derivatives 13
and 14 (Table 1).24,4b In D2O an increase of the cis amide
bond ratio of the methylamide 13 could be explained by the
Prolines bearing a sterically demanding substituent at the δ-
position are very interesting tools for the control of the trans to
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breaking of the intramolecular H bond stabilizing the trans
amide bond conformation. The increased trans amide
conformation for the methyl ester 14 could be explained by
a stronger polar n → π* interaction between the oxygen atom
lone pair of the acetate and the carbonyl of the methylester.25
The energy barriers for the cis-trans bond isomerization of
Sylvaine Girard − CNRS, BioCIS, CY Cergy Paris Université,
95000 Cergy Pontoise, France; CNRS, BioCIS, Université
Paris-Saclay, 92290 Châtenay-Malabry, France
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03880
1
13 and 14 was studied by H NMR analysis in water. The
Notes
coalescence temperatures were determined to estimate the
rotational barriers for the cis-trans isomerization. The results
are reported in Table 1 and compared with those reported for
proline. Notice that the values of the cis/trans ratio and energy
barriers for 14 are consistent with those reported in the
racemic series.4b Interestingly, as observed with fluorinated
pseudoprolines,23a the energy barriers for the trans to cis amide
bond isomerization of CF3-proline derivatives 13 and 14 is ca.
2.9 kcal·mol−1 lower than for the corresponding proline
analogues.
In conclusion we report a straightforward synthesis of
enantiopure 5-(R)- and 5-(S)-trifluoromethylproline in four
steps from commercially available pyroglutamic acid. Despite
the low nucleophilicity of the amino group due to the electron-
withdrawing trifluoromethyl group, we demonstrated that the
5-(R)-trifluoromethylproline could be incorporated in a
peptide chain in both solution phase and SPPS. Because of
the decrease of the trans to cis amide bond isomerization, these
5-trifluoromethylprolines will constitute powerful tools for the
tuning of the peptide bond geometry and then the
conformation of peptides.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank N. Vanthuyne and M. Jean (Aix-Marseille
■
́
́
Universite, Institut des Sciences Moleculaires de Marseille)
for chiral HPLC separations and the Agence Nationale de la
Recherche for funding (ANR F-LAIR, ANR CH2PROBE).
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03880.
Details of the experimental procedures, analytical data of
all new compounds, NMR spectra copies, determination
of the rotational barriers for cis-trans isomerization
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́
Clement A. Sanchez − CNRS, BioCIS, CY Cergy Paris
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̀
Charlene Gadais − CNRS, BioCIS, CY Cergy Paris Université,
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