Access to Constrained Fluoropseudopeptides via Ring-Closing Metathesis of Fluoroalkenes

Article abstract of DOI:10.1021/acs.orglett.6b01631

Bis-alkene substrates, containing one fluoroalkene and linked by an amide moiety, have been designed and synthesized to be subjected to ring-closing metathesis reactions. The substitution of fluoroalkene by a phenyl group enhanced the reactivity, and the

Full text of DOI:10.1021/acs.orglett.6b01631

Letter
pubs.acs.org/OrgLett
Access to Constrained Fluoropseudopeptides via Ring-Closing
Metathesis of Fluoroalkenes
David Guerin,† Isabelle Dez,† Annie-Claude Gaumont,† Xavier Pannecoucke,‡
́
and Samuel Couve-Bonnaire*,‡
†Normandie Universite,
́
ENSICAEN, Unicaen, CNRS, LCMT, 14000 Caen, France
‡Normandie Universite,
́
INSA Rouen, UNIROUEN, CNRS, COBRA, 76000 Rouen, France
S
* Supporting Information
ABSTRACT: Bis-alkene substrates, containing one fluoroal-
kene and linked by an amide moiety, have been designed and
synthesized to be subjected to ring-closing metathesis
reactions. The substitution of fluoroalkene by a phenyl
group enhanced the reactivity, and the resulting fluorinated
lactams were obtained in high yields except when a hindered
alkyl group was present in the molecule. The cycles were then subjected to ring opening in order to develop a new route to
constrained fluoropseudopeptides bearing a fluoroalkene as a peptide bond mimic.
eptides are ubiquitous molecules for the living world.1
of neuropeptide 26RFa by a fluoropseudodipeptide containing
PThey have countless biological roles and generate a lot of
a fluoroalkene as peptide bond mimic increased by a factor 5
interest for academic and industrial researchers.2 Nevertheless,
the half-life of the molecule in human serum (compound B,
their use as therapeutic agents is still limited by a few factors,
Scheme 1, eq 1).5b Another feature of the fluoroalkene is the
possible design of transoid or cisoid conformers in order to
undertake structural studies as proposed by Otaka and Fujii
concerning a pepdide transporter PEPT1.6 In their elegant
paper, they reported the sole stereoselective synthesis of cisoid
pseudopeptide bearing a fluoroalkene as peptide bond mimic.
Their strategy was based on (i) cyclization, (ii) defluorination,
and (iii) ring-opening reactions to afford exclusively the cisoid
conformer (Scheme 1, eq 2). An elegant alternative to the
formation of fluoroalkene pseudopeptides as exclusive cisoid
conformer would be the use of ring-closing metathesis (RCM)
reaction as a crucial step as in the synthesis sequence depicted
in the following retrosynthesis Scheme 2. The RCM reaction to
design peptidomimetics bearing an alkene as peptide bond
for example, low cellular uptake and fast metabolization in vivo.
To overcome these drawbacks, peptidomimetics have been
developed.3 Among them, pseudopeptides (replacement of
scissile peptide bond by isoelectronic and isosteric moiety)
have emerged as an interesting solution to increase the half-life
of compounds. Numerous peptide bond mimics have been
reported. Among them, we are particularly interested in the
fluoroalkene moiety, which is an effective peptide bond mimic4
already known for its tendency to stabilize peptide from
enzymatic degradation.5
Indeed, in a study concerning dipeptidyl peptidase inhibitors,
Welch showed a half-time multiplied by 11 for a fluoroalkene
chemical with respect to the amide bond (compound A,
Scheme 1, eq 1).5a In the same way, we showed that the
replacement of the first dipeptide of the terminal heptapeptide
Scheme 2. Retrosynthesis of Fluoroalkene Pseudopeptides
Scheme 1. Comparison of Fluoroalkene Resistance (eq 1)
and the Single Way Described To Reach the Cisoid
Conformer for Fluoropseudopeptide (eq 2)
Received: June 6, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01631
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Access to Bis-alkenes 3 from Chiral Substrates 4
yield (%)
a
a
a
entry
R
compd
6
7
3
b
1
2
3
6
7
4
5
8
H
a
b
c
d
e
f
(S)-Me
(R)-Me
(S)-Ph
(R)-Ph
(S)-iPr
(R)-iPr
rac-Bn
quant
quant
quant
quant
quant
quant
quant
64
51
70
69
66
58
98
82
74
97
93
54
37
78
g
h
a
b
Yield based on isolated product after flash chromatography. Compound a was synthesized according to previous report.11,12
Table 2. Ring-Closing Metathesis
a
b
,c
entry
substrate
R
catalyst loading (mol %)
temp (°C)
side products (%)
yield (%)
1
2
3
4
5
8a
8a
8b
8b
3a
H
H
H
H
H
4
2
1
2
2
120
120
80
7
1
0
0
0
88
46
100
70
100
70
100 (99)
6
7
3b
3c
(S)-Me
(R)-Me
2
2
70
70
0
0
100 (95)
100 (91)
8
3d
(S)-Ph
(S)-Ph
(S)-Ph
rac-Ph
2
2
2
2
70
70
60
70
0
95 (94)
100 (98)
69
9
3d
0
10
11
3d
10
0
3d+3e
100 (93)
12
13
14
3f
3f
3f
(S)-iPr
(S)-iPr
(S)-iPr
2
4
4
80
100
120
major
major
major
0
0
0
15
16
3h
3h
rac-Bn
rac-Bn
2
4
80
0
20
120
0
100 (84)
a
b
Side products (%) refer to numerous undesired and uncharacterized compounds produced during the RCM process. Yields were determined by
c
1H NMR spectroscopy using 2,4-dinitrofluorobenzene as internal standard. Yield based on isolated product after flash chromatography are shown in
parentheses.
mimic (Ψ[CHCH]) in replacement of a peptidic bond has
previous reports by Grubbs9 and then by Dorta,10 indicating
the beneficial effect of a substitution pattern on alkene partner,
we applied with success this “modification of substrates”
strategy to the fluoroalkenes, allowing us to reach an
unprecedented TON as well as success under milder
experimental conditions (60−80 °C) than usual.11 Herein, we
report the synthesis of constrained pseudopeptides bearing a
fluoroalkene as peptide bond mimic via a crucial RCM reaction
step.
already been described7 as, for example, in the pioneering and
elegant work reported by Guibe
́
et al.7a and more recently by
Lamaty et al. to generate cyclic pseudopeptides by cyclization−
cleavage using RCM.7e
However, among the thousands of reports dealing with the
metathesis reaction, fewer than 10 publications have reported a
RCM process involving reluctant fluoroalkenes, and none of
them deals with peptide chemistry.8 Recently, based on
B
DOI: 10.1021/acs.orglett.6b01631
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Organic Letters
Letter
tert-Butanesulfinylimine 5, prepared via a four-step synthesis
sequence already reported,11,12 was subjected to organometallic
addition to afford chiral sulfinamides 4. We used (R)-tert-
butanesulfinamide auxiliary in order to obtain the major
diastereomer with a newly created stereogenic center in (S)
configuration, as found in native peptides, through addition of
Grignard reagents.13 Each diastereoisomer was isolated and
engaged in the next steps (Table 1). Deprotection of the tert-
butanesulfinamide was quantitative, whatever the substrate was.
Then we introduced a p-methoxybenzyl (PMB) group on the
amine moiety with moderate to excellent yields. Finally, we
created the amide bond with 3-butenoic acid, using T3P as
coupling reagent, in very good yields excepted for the more
sterically hindered 4f/4g, bearing an isopropyl group as the side
chain. It has to be noted that other protecting groups of amine
(FMOC, BOC, and even the chiral Ellman’s auxiliary) were
assessed without any success (see the Supporting Informa-
tion).12
provide full conversion of 3h and very good (84%) yield of
cycle 2h (Table 2, entries 15 and 16).
These results seem to indicate that the efficiency of the RCM
reaction with our specific substrates 3 are conditioned by the
steric hindrance of the side chain bearing an alkyl or an aryl
substituent. Worthy of note is that we have to take into account
that substrates 3 contain an amide moiety, which should make
the substrate primarily under a transoid form, whereas for an
effective cyclization, the cisoid one is required.14 This was
confirmed by NOESY and ROESY NMR experiments, pointing
out that when the main form was the most stable transoid form
in the media the more difficult was the RCM reaction (Table
3).
Table 3. Influence of Transoid/Cisoid Amide Configuration
on the RCM Reaction
The bis-alkenes 3 were subjected to the RCM reaction in
order to synthesize the six-membered ring precursors of
constrained pseudopeptides. It has to be noted that several
ruthenium precatalysts have been tested and the M2 catalyst
proved to be the most efficient with our fluorinated
substrates.11 Main results for RCM reaction are given in
Table 2. The beneficial role of the phenyl substituent on the
fluoroalkene moiety is shown by comparing the first entries of
Table 2. Indeed, whereas 4 mol % of M2 catalyst at 120 °C was
necessary for substrate 8a to provide a good yield in cycle 2′
with small amounts of side products (Table 2, entries 1 and 2),
the use of phenyl-substituted bis-olefin 8b allowed us to
decrease the catalyst loading as well as the reaction temper-
ature. As a matter of fact, quantitative yield in the desired cycle
2′ was achieved with only 1 mol % of catalyst at 80 °C (Table
2, entry 3) or with 2 mol % of catalyst at 70 °C (Table 2, entry
4). The replacement of the benzyl group on nitrogen by a PMB
group had no impact, and cycle 2a was obtained in quantitative
yield (Table 2, entry 5). Pleasingly, the substrates 3b and 3c,
bearing a methyl group as R group on the side chain, were
converted quantitatively, furnishing excellent (95% and 91%)
isolated yields in cycles 2b and 2c, respectively (Table 2, entries
6 and 7). The RCM reaction did not seem to be influenced by
the steric hindrance of the methyl group, so the results may be
theoretically equivalent with a phenyl group. The experimenta-
tion confirmed this hypothesis; cycle 2d was synthesized in
excellent yield with 2 mol % of catalyst at 70 °C. The reaction
was carried out on a 0.1 mmol (Table 2, entry 8) or 0.5 mmol
scale (Table 2, entry 9) of substrate 3d without loss of
efficiency, furnishing 94% and 98% yields of 2d, respectively.
The reaction performed on a racemic mixture of 3d and 3e
gave also an excellent yield of cyclic compound. The reaction
carried out with more hindered substrates 3f bearing an
isopropyl group as side chain proved to be inefficient whatever
the catalyst loading or the temperature of the reaction (Table 2,
entries 12−14). Whereas a Thorpe−Ingold effect could have
been expected in this case, only side products were observed in
NMR experiments without any trace of the desired cycle 2f.
Other catalysts were tested, including bis-NHC catalyst, which
was highly stable at high temperature, but, unfortunately,
without success. Finally, the benzyl group, with a steric
hindrance intermediate between the methyl/phenyl and
isopropyl group, required higher temperature and catalyst
loading, compared to methyl and phenyl substituents, to
a
b,c
entry substrate
R
Y
T/C ratio
temp (°C) yield (%)
1
2
3
4
5
6
7
3a
3b
3d
3h
3f
H
PMB
PMB
PMB
PMB
PMB
H
50/50
73/27
74/26
78/22
87/13
100/0
100/0
70
70
100 (99)
Me
Ph
100 (95)
70
100 (98)
Bn
120
100 (84)
i-Pr
Ph
80 to 120
80 to 120
80 to 120
0
0
0
9e
9g
i-Pr
H
a
T/C: transoid/cisoid ratio was determined by NMR experiments.
b
Yields were determined by 1H NMR spectroscopy using 2,4-
c
dinitrofluorobenzene as internal standard. Yields based on isolated
product after flash chromatography are shown in parentheses.
These observations are in accordance with the fact that the
RCM reaction requires the cis configuration for which both
alkenes are ready to cyclize. Additional experiments and
molecular modeling will be reported in due course to support
this hypothesis.
Finally, with the cyclic precursors in hand, we envisioned
obtaining the fluoropseudopeptides by a two-step sequence
synthesis (Table 4). First, we carried out the PMB deprotection
of the nitrogen by treatment with CAN reagent in a mixture of
acetonitrile and water. The obtained yields are moderate to
good in secondary lactam 10. A final ring-opening step under
acidic conditions7e allowed us to quantitatively recover the
desired compounds 1 in hydrochoride salt form. These last
Table 4. Access to Fluoropseudopeptides
a
yield (%)
entry
substrate
R
10
1
1
2
3
2a
H
81
76
55
quantitative
quantitative
quantitative
2d
Ph
Ph
rac-2d
a
Yield based on isolated product after flash chromatography.
C
DOI: 10.1021/acs.orglett.6b01631
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(5) (a) Lin, J.; Toscano, P. J.; Welch, J. T. Proc. Natl. Acad. Sci. U. S.
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steps were carried out on substrates 2a and 2d, the latter being
the most sensitive molecule to racemization due to the benzylic
position, in order to prove the feasibility of the strategy. We
obtained Gly-[Ψ(E)CFCH]Gly and Gly-[Ψ(E)CFCH]-
PhGly as enantiopure fluoropseudopeptides.
It has to be noted that every single step of the synthesis was
performed on pure enantiomer as well as on racemic mixture
for all asymmetric substrate in order to control the possible
epimerization of the stereogenic center. Control analyses were
monitored by NMR and chiral HPLC experiments, and no
trace of racemization was observed during the synthesis12 for
any carried out step.
To conclude, we synthesized activated fluorinated bis-
alkenes, including asymmetric substrates. We successfully
carried out the RCM reaction with reluctant fluoroalkenes
bearing an amide linker, except for the substrate including a
sterically hindered isopropyl group as the side chain. Taking
into account the few reports on metathesis reaction with
fluoroalkenes, these results are highly relevant. Finally, some of
the synthesized lactams have been deprotected and opened to
furnish a novel path toward constrained cisoid fluoropseudo-
peptides bearing a fluoroalkene moiety as peptide bond mimic.
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̈
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01631.
Experimental procedures, characterization data, and
NMR spectra of new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: samuel.couve-bonnaire@insa-rouen.fr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was promoted by the Interregional Norman
Chemistry Network (CRUNCh). The “Reg
́
ions Basse−et
Haute−Normandie” are gratefully thanked for their financial
support. ENSICAEN and University of Caen, INSA Rouen,
Rouen University, CNRS, and Labex SynOrg (ANR-11-LABX-
0029) are also thanked for their support.
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D
DOI: 10.1021/acs.orglett.6b01631
Org. Lett. XXXX, XXX, XXX−XXX