Synthesis of cis -5-trifluoromethylproline from l -glutamic acid

Article abstract of DOI:10.1055/s-0033-1340553

The diastereoselective synthesis of cis-5-trifluoromethylproline (5-Tfm-Pro) from l-glutamic acid is described. 5-Tfm-Pro could be obtained through a seven-step linear sequence. Trifluoromethylation of the glutamic-derived ester or aldehyde and subsequent reduction of the cyclic imine are the key steps in the synthesis. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1340553

LETTER
▌569
lSetyternthesis of cis-5-Trifluoromethylproline from L-Glutamic Acid
Synthesis of cis-5-Trifluoromethylproline
Stéphanie Ortial,a,b Rajesh Dave,1 Zohra Benfodda,a,b David Bénimélis,a,b Patrick Meffre*a,b
a
Institut des Biomolécules Max Mousseron (IBMM), UMR CNRS 5247, Université de Montpellier I & II, Place Eugène Bataillon,
34095 Montpellier Cedex 5, France
b
UNIVERSITE DE NIMES, Laboratoire de Chimie BioOrganique (LCBO), Place G. Péri, 30021 Nîmes Cedex 1, France
Fax +33(4)66364587; E-mail: patrick.meffre@unimes.fr
Received: 03.11.2013; Accepted after revision: 09.12.2013
Boc-4-trifluoromethylproline from 4-hydroxyproline
methyl ester involving a stereoselective substrate-directed
reduction using Crabtree’s catalyst.16 5-Trifluoromethylp-
rolines have attracted less attention. In 2010, Brigaud et
Abstract: The diastereoselective synthesis of cis-5-trifluorometh-
ylproline (5-Tfm-Pro) from L-glutamic acid is described. 5-Tfm-Pro
could be obtained through a seven-step linear sequence. Trifluoro-
methylation of the glutamic-derived ester or aldehyde and subse-
quent reduction of the cyclic imine are the key steps in the synthesis. al. reported the synthesis of 5-trifluoromethyl-1,3-oxa-
zolidines as pseudoprolines17 from the condensation reac-
Key words: amino acids, cis-5-trifluoromethylproline, fluorine,
tion of serine derivatives and trifluoroacetaldehyde ethyl
hemiacetal and their incorporation into peptides.18 More
recently, 5-trifluoromethylated polyhydroxypyrrolidines
were synthesized from the respective nitrone using Rup-
pert’s reagent and TBAF as tetrasubstituted proline deriv-
atives.19 The first diastereopure 5-trifluoromethylproline
(Figure 1) has been prepared 20 in 17% overall yield from
a trifluoromethyl enone and ethyl isocyanoacetate. In this
strategy, 5-Tfm-Pro was obtained after reduction of the
corresponding pyrrole, using H2, Pd/C, therefore leading
to the mixture of both cis enantiomers.
diastereoselective synthesis, imine, reduction
The conformation of peptides is known to influence their
biological properties. The increased rigidity of peptidomi-
metics containing constrained amino acids has been cor-
related with an enhanced activity toward biological
targets.2 It has been demonstrated that the introduction of
cyclic amino acids such as proline into peptides helps con-
trolling the cis/trans conformations of the amide bond,
leading to a modification of the peptide global conforma-
tion.3 On the other hand, there is a growing interest in flu-
orinated amino acids because of their various biomedical
applications.4 The presence of fluorine atoms in molecular
and supramolecular structures confers onto them different
physical and biological properties compared to the natural
parents, such as greater hydrophobicity, thermal stability
and increased protein–ligand interactions.5
HO2C
CF3
N
H
Figure 1 rac-cis-5-Trifluoromethyl proline (cis-5-Tfm-Pro)
The synthesis of the enantiopure or enantioenriched cis-5-
trifluoromethyl-L-proline remains challenging. We report
herein the synthesis of the cis-5-Tfm-Pro from naturally
occurring L-glutamic acid. Our strategy is based on the
chemoselective trifluoromethylation and selective reduc-
tion of a cyclic trifluoromethyl imine (Scheme 1).
Numerous trifluoromethylprolines have already been syn-
thesized. 2-Trifluoromethylprolines were obtained in
their enantiopure forms from chiral oxazolidines6 or chiral
allylmorpholinones7 using ethyl trifluoropyruvate as a tri-
fluoromethylated partner and coupled to other amino ac-
ids to give peptides.8,9 Gulevich et al. also published the
preparation of dipeptides containing a 2-trifluoromethyl-
proline residue.10 Surprisingly, no synthesis of simple
3-trifluoromethylproline has been reported. Fully substi-
tuted derivatives have been prepared via Cu(I)-catalyzed
1,3-dipolar cycloaddition of azomethine ylides with triflu-
orocrotonates or trifluoromethyl-substituted nitro-
alkenes.11-13 N-Protected-4 trifluoromethylproline was
O
O
HO
OH
HO2C
CF3
HO2C
CF3
N
N
H
NH2
L-glutamic acid
rac-cis-5-Tfm-Pro
Scheme 1 Retrosynthesis
synthesized from Garner’s aldehyde14 and in a more effi- The synthesis of cyclic imine 6 is described in Scheme 2.
cient way from L-hydroxyproline.15 In this work, the tri- Boc-Glu(OMe)-OMe 1 is commercially available or can
fluoromethylation of the corresponding ketone with be prepared quantitatively from L-glutamic acid in a one-
Ruppert’s reagent and tetra-n-butylammonium fluoride pot two-step process by esterification of the carboxylic
(TBAF) was used to introduce the trifluoromethyl group. acid followed by protection of the amino group with di-
Similarly, Del Valle et al. reported the synthesis of N- tert-butyl dicarbonate (Boc2O). Enhanced selectivity for
the less sterically hindered methyl ester toward various
transformations could be achieved by the addition of a
second tert-butyloxycarbonyl group onto the amino func-
tion.
SYNLETT 2014, 25, 0569–0573
Advanced online publication: 14.01.2014
DOI: 10.1055/s-0033-1340553; Art ID: ST-2013-D1028-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

570
S. Ortial et al.
LETTER
O
O
O
O
O
O
O
O
a
b
d
HO
OH
MeO
OMe
MeO
OMe
MeO
NH2
NBoc2
NHBoc
NBoc2
1
3
2
c
e
O
O
O
HO
H
g or h
f
HO2C
CF3
MeO
CF3
MeO
CF3
N
NBoc2
NBoc2
6
5
4
Scheme 2 Reagents and conditions: (a) TMSCl, MeOH, r.t., 48 h then Boc2O, TEA, r.t., 24 h; (b) Boc2O, DMAP, MeCN, r.t., 16 h, 92% (2
steps); (c) CF3SiMe3, cat. TBAF, toluene, –78 °C to r.t., 16 h then TBAF, 0 °C to r.t., 15 min, 65%; (d) DIBAL-H, Et2O, −78 °C, 15 min, 84%;
(e) CF3SiMe3, TBAF, neat, 0 °C to r.t., 4 h, 95%; (f) Dess–Martin periodinane, CH2Cl2, r.t., 4 h, 79%; (g) 4 M HCl, THF, r.t., 30 min then 1 M
NaOH, r.t., 2 h, then Dowex 50WX8, 69%; (h) 6 M HCl, 60 °C, 24 h then Dowex 50WX8, 59%.
Thus, the reaction of secondary amine 1 with Boc2O in ine 6 must be stored in a dry environment as a solid to
acetonitrile using N,N-dimethylaminopyridine (DMAP)21 avoid any isomerization or hydration (Scheme 3). In an-
gave the fully protected intermediate 2 in 92% yield from hydrous organic solvents, 6 slowly isomerized irrevers-
L-glutamic acid after purification by flash chromatogra- ibly leading to the loss of chirality at C-2. This
phy. Introduction of the trifluoromethyl group was less observation was not completely unexpected since Solo-
simple. Our initial strategy was the direct trifluoromethyl- shonok had described the [1,3]-proton shift reaction of
ation of the ester with Ruppert’s reagent (CF3SiMe3) and fluorinated imines under thermal or basic conditions.28 In
a catalytic amount of TBAF as described by Olah.22 Al- our case, the isomerization occurred at room temperature
though the selective trifluoromethylation of the γ-methyl under neutral conditions due to the conjugation of 6′. Wa-
ester group could be achieved in 65% yield (20% of start- ter adds non-selectively to the double bond of 6 giving a
ing material was recovered) on a 2-gram scale, this reac- mixture of both diastereomeric acetals and the opened
tion was difficult to reproduce in our hands.23 Therefore, form. Methanol and ethanol also add slowly to the double
we decided to use a more reliable strategy to prepare the bond of the imine.
trifluoromethyl ketone 5, involving the nucleophilic tri-
Considering the lack of stability and the high polarity of
fluoromethylation of the aldehyde 3. The latter was syn-
6, finding a suitable solvent for its reduction to 5-trifluo-
thesized through the selective reduction of 2 with
romethylproline was problematic. We turned our attention
to N,N-dimethylformamide since it dissolves the imine 6
and does not react with the double bond. Three methods
were assessed to reduce 6 selectively and the results are
diisobutylaluminium hydride (DIBAL-H) at −78 °C in di-
ethyl ether in good yield (84%).24 Trifluoromethylation of
the resulting aldehyde was conducted with an excess of
Ruppert’s reagent in the presence of a stoichiometric
depicted in Table 1. Firstly, classical hydrogenation using
amount of TBAF at 0 °C on the neat substrate following a
palladium on carbon under mild conditions afforded the
recently published method.25 After five hours at room
amine 7 in quantitative yield after 16 hours.29 The relative
configuration of 7 could not be definitively proven by
temperature, the carbinol 4 was obtained in excellent yield
(95%) and used without any further purification. Dess–
NOE experiments. The correlation between the protons on
Martin oxidation of 4 led to the corresponding trifluoro-
C-2 and C-5 is known to be weak and in this case, those
methyl ketone 5 in 79% yield. This three-step sequence
protons are too close in the 1H NMR spectrum of 7 (ca. 0.1
was reproduced on various scales (0.5 g to 3 g) and re-
ppm) to give an interpretable result in a NOE experiment,
mains competitive with the direct trifluoromethylation of
appearing as a single multiplet when 7 is the hydrochlo-
ride salt. Kondratov et al. also reported such an issue (see
ref. 20 and references therein). Therefore, the cis configu-
ration of 7 was deduced by analogy with hydrogenation
ester 2 with a similar overall yield (63%). The key cyclic
imine 6 was obtained after cleavage of the tert-butoxycar-
bonyl groups and saponification of the methyl ester. Un-
der classical conditions, saponification of methyl ester
results of similar compounds.
containing amino acids can lead to epimerization.26
This consideration was also supported by the fact that hy-
Therefore, we chose to deprotect the tert-butoxycarbonyl
groups using 4 M HCl in THF before removing the methyl
ester under basic aqueous conditions (Scheme 2, path g).
Similarly, the fully deprotected amino acid could be pre-
drogen addition on the less hindered face of the imine is
favored.30 We were also interested in isolating the trans-
5-Tfm-Pro as the major isomer. Thus, cyclic imine 6 was
reacted with sodium triacetoxyborohydride in methanol31
pared using strongly acidic conditions and heating (6 M
at room temperature to produce a complex mixture of
HCl, 60 °C, Scheme 2, path h). The neutral amino group
amine 7 and acetals because of the addition of methanol
onto the double bond. Only 50% conversion was observed
was then regenerated using an acidic resin, spontaneously
giving the cyclic imine 6 in 69% and 59% yields, respec-
tively after removal of the water in vacuo.27 The cyclic im-
Synlett 2014, 25, 569–573
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of cis-5-Trifluoromethylproline
571
Scheme 3 Cyclic imine 6 behavior in water and organic solvents. 19F NMR spectrum A (DMSO-d6): (a) t = 0, no 6′, (b) t = 7 h, 6% 6′, (c) t =
48 h, 35% of 6′, (d) t = 8 d, 72% of 6′; 19F NMR spectrum B: (a) in DMSO-d6, (b) in DMSO-d6 + D2O, (c) in D2O.
after 20 hours and the cis/trans ratio was not favorable intermediate. 1H NMR and 13C NMR spectroscopy
(Table 1).
showed the disappearance of the proton at C-2 and mass
spectrometry using negative electrospray ionization, indi-
cated a major peak at m/z = 180.00 ([M − H]−, 80%).
Table 1 Synthesis of 5-Tfm-Pro through Reduction of the Imine 6
To assess the enantiopurity of 7, the more convenient to
handle methyl ester was prepared. Reaction with trimeth-
ylsilyl diazomethane in methanol afforded the desired
compound, and only the major isomer 9 was isolated after
chromatography (50% yield, Scheme 4). Unfortunately,
chiral chromatography showed that a racemic mixture of
9 had been obtained. If partial isomerization can occur
during the reduction step (reaction time is 16 h), this can-
not explain the extensive racemization observed. Lubell et
al. reported such racemization during the deprotection and
cyclization of their iminium intermediate under acidic
conditions in the synthesis of 5-tert-butylproline.30c Fur-
ther investigations must be conducted to ascertain if the
deprotection of trifluoromethylated ketone 5 using 4 or 6
M HCl led to the racemization of the steoreogenic center.
HO2C
CF3
N
H
( )-7
reduction
or
HO2C
CF3
N
6
O
CF3
N
CHO
8
Reagents
Conversion (%) Product (cis/trans)a
H2, Pd/C, DMF
100
50
7 (87:13)
7 (67:33)
8
NaBH(OAc)3, MeOH
(R)-TRIP, ethidine, DMF
100
a The cis/trans ratio was assessed using 19F NMR.
TMSCHN2, MeOH
HO2C
CF3
MeO2C
CF3
N
H
N
H
r.t., 2 h
Finally, the chiral phosphoric acid–Hantzsch ester system
was also examined for catalytic transfer hydrogenation
of imine 6.32 At room temperature, in the presence of
(R)-TRIP (CAS# 791616-63-2) and ethidine (CAS#
1143-23-1) no reaction occurred, so the mixture was heat-
ed at 50 °C for 48 hours, to ensure complete conversion of
the starting material. At such a temperature, the cyclic im-
ine 6 isomerizes (Scheme 3) to give the more stable
α,β-unsaturated compound. Further heating led to the pro-
posed formation of 2-oxo-5-(trifluoromethyl)pyrrolidine-
1-carbaldehyde (8) through addition of DMF onto the
C-2 position followed by the decarbonylation of the cyclic
( )-7
( )-9
Scheme 4 Synthesis of cis-5-Tfm-Pro methyl ester
In summary, we report herein the diastereoselective syn-
thesis of cis-5-Tfm-Pro from L-glutamic acid in 40%
overall yield. Developing a related strategy avoiding
strongly acidic or basic conditions during the synthesis of
5-Tfm-Pro is currently being investigated to afford the en-
antiopure compound. Finally, incorporation of cis-5-Tfm-
Pro into peptides to study its influence on the conforma-
tion of the peptide will be examined.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 569–573

572
S. Ortial et al.
LETTER
(18) (a) Chaume, G.; Feytens, D.; Chassaing, G.; Lavielle, S.;
Acknowledgment
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We thank Marion Jean for chiral HPLC separations (ISM2-UMR
7313, Aix-Marseille Université).
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(23) The level of drying of all reagents and solvents required for
this reaction might be the cause of the capricious nature of
this transformation as discussed by the authors (Note:
commercially available 1 M solution of TBAF in THF
usually contains 5% of H2O).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett. Included are
1
detailed experimental procedures and H NMR, 13C NMR, 19F
NMR and HRMS data.SuInpooigf
m
iortnartSuIonpgmoritrifato
n
References and Notes
(1) Present address: Calyx Chemicals & Pharmaceuticals Ltd,
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(27) Experimental Procedure for 6:
Using 4 M HCl–1 M NaOH: Compound 5 (1.2 mmol, 1
equiv) was dissolved in THF (10 mL) and a THF–12 M HCl
mixture (11 mL/9 mL) was added dropwise and the solution
was stirred at r.t. for 30 min. After concentration in vacuo,
MeOH (2.4 mL) and 1 M NaOH (3.36 mL) were added to the
crude product. The solution was stirred at r.t. for 2 h and
concentrated in vacuo. Purification over Dowex 50WX8,
eluting with H2O then 5% aq NH3 followed by purification
over RP 18 silica gel, eluting with H2O afforded the imine 6
as an off-white solid after complete removal of the H2O
(0.15 g, 0.83 mmol, 69%).
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S.; Sanchez-Rosello, M.; Aceña, J. L.; Soloshonok, V.;
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Using 6 M HCl: Compound 5 (0.84 mmol, 1 equiv) was
dissolved in 6 M HCl (3.5 mL). The solution was heated at
60 °C until reaction was complete (24 h) and the brown
mixture then washed with Et2O (2 ×) and concentrated in
vacuo. Purification following the procedure previously
described afforded 6 in 59% yield (0.09 g, 0.50 mmol). 1H
NMR (300 MHz, DMSO-d6): δ = 4.62 (m, 1 H), 2.76 (m, 2
H), 2.13 (m, 2 H). 13C NMR (75.45 MHz, DMSO-d6): δ =
173.3 (C), 164.3 (q, JCCF = 34.8 Hz, C), 120.5 (q, JCF = 273
Hz, C), 77.9 (CH), 33.5, 27.0 (CH2). 19F NMR (282.4 MHz,
DMSO-d6): δ = −68.8 (d, JHF = 2.8 Hz). [α]D20 6.1 (c = 1.0,
DMSO). HRMS (ESI−): m/z [M − H]− calcd for C6H5NO2F3:
180.0272; found: 180.0273.
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(29) Experimental Procedure for 7: The cyclic imine 6 (0.27
mmol, 1 equiv) was dissolved in anhyd DMF (2 mL) and
Pd/C was (10−15 wt%) added. The solution was degassed at
−78 °C for 5 min and the flask was filled with H2. After 16 h
at r.t., the reaction was complete. The solution was filtered
over a pad of Celite® and concentrated under high vacuum.
Purification over RP 18 silica gel eluting with H2O
containing a few drops of 12 M HCl afforded 5-Tfm-Pro as
its hydrochloride salt (0.061 g, 0.27 mmol, 100%). 1H NMR
(300 MHz, D2O): δ = 4.41 (m, 2 H), 2.05−2.42 (m, 4 H). 13
C
NMR (75.45 MHz, D2O): δ = 171.2 (C), 123.0 (q, JCF = 278
Hz, C), 61.5 (CH), 59.5 (q, JCCF = 33.7 Hz, C), 27.1, 23.7
(CH2). 19F NMR (282.4 MHz, D2O): δ = −72.3 (d, JHF = 7.06
Synlett 2014, 25, 569–573
© Georg Thieme Verlag Stuttgart · New York

LETTER
Hz, cis isomer), −73.0 (d, JHF = 7.34 Hz, trans isomer). MS
Synthesis of cis-5-Trifluoromethylproline
573
(31) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.;
(ESI−): m/z = 181.94 ([M − H]−). HRMS (ESI−): m/z [M −
H]− calcd for C6H7NO2F3: 182.0429; found: 182.0430.
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 569–573

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