Evaluation of in-batch and in-flow synthetic strategies towards the stereoselective synthesis of a fluorinated analogue of retro-thiorphan

Article abstract of DOI:10.3390/molecules24122260

A stereoselective synthetic strategy for the preparation of trifluoromethylamine mimics of retro-thiorphan, involving a diastereoselective, metal-free catalytic step, has been studied in batch and afforded the target molecule in good yields and high diast

Full text of DOI:10.3390/molecules24122260

molecules
Article
Evaluation of In-Batch and In-Flow Synthetic
Strategies towards the Stereoselective Synthesis of a
Fluorinated Analogue of Retro-Thiorphan
Margherita Pirola 1 , Alessandra Puglisi 1, Laura Raimondi 1, Alessandra Forni 2 and
Maurizio Benaglia 1,
*
1
Dipartimento di Chimica, Università degli Studi di Milano, Via Golgi 19, 20133 Milano, Italy;
margherita.pirola@unimi.it (M.P.); alessandra.puglisi@unimi.it (A.P.); lauramaria.raimondi@unimi.it (L.R.)
Istituto di Scienze e Tecnologie Molecolari–ISTM-CNR, Via Golgi 19, 20133 Milano, Italy;
alessandra.forni@istm.cnr.it
2
*
Correspondence: Maurizio.benaglia@unimi.it; Tel.: +39-2-5031-4171
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 8 May 2019; Accepted: 12 June 2019; Published: 18 June 2019
Abstract: A stereoselective synthetic strategy for the preparation of trifluoromethylamine mimics of
retro-thiorphan, involving a diastereoselective, metal-free catalytic step, has been studied in batch
and afforded the target molecule in good yields and high diastereoselectivity. A crucial point of the
synthetic sequence was the catalytic reduction of a fluorinated enamine with trichlorosilane as reducing
agent in the presence of a chiral Lewis base. The absolute configuration of the key intermediate
was unambiguously assigned by X-ray analysis. The synthesis was also investigated exploiting
continuous flow reactions; that is, an advanced intermediate of the target molecule was synthesized
in only two in-flow synthetic modules, avoiding isolation and purifications of intermediates, leading
to the isolation of the target chiral fluorinated amine in up to an 87:13 diastereoisomeric ratio.
Keywords:
fluorinated derivatives; flow chemistry; organocatalysis; stereoselective
synthesis; reduction
1. Introduction
The unique properties of fluorine, a small and highly electronegative atom, are widely employed in
medicinal chemistry to tune different aspects of the molecular properties of drugs, or drug candidates [
The introduction of fluorinated groups or fluorine atoms in specific positions of a molecule allows
to modulate its physical chemistry, potency and pharmacokinetics [ ]. In case of chiral compounds,
1].
2
the need to control the absolute stereochemistry of the target molecule adds a further synthetic challenge
and calls for the development of novel efficient, possibly green, enantioselective catalytic methods of
wide general applicability [3].
The incorporation of a trifluoromethyl group has found application also in peptides and proteins,
in an attempt to improve the biological activity and modify the metabolic properties [
interest is the replacement of a peptide or amide bond [CONH] with trifluoroethylamine units,
to provide the so called [CH(CF3)NH] isosteres [ ]. In this context, Zanda and co-workers
4]. Of particular
ψ
5–7
provided a synthesis of trifluoromethylamine mimics of retro-thiorphan A (Figure 1), which was tested
as an inhibitor of metalloproteinase NEP (neutral endopeptidase) [8].
Molecules 2019, 24, 2260; doi:10.3390/molecules24122260
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Figure 1. Retro-thiorphan peptide mimetic and its fluorinated analogue.
None of the two known procedures for the synthesis of this fluorinated compound was completely
satisfactory: The first strategy gives a diastereomerically pure compound, but the procedure proved
to be not completely reliable; the second synthetic approach, although more solid and reproducible,
did not lead to the isolation of single diastereoisomers [
needed to realize a truly efficient diastereoselective synthesis of this target compound. Following our
recent studies on the synthesis of chiral fluorinated molecules [ 12], the key step of our approach
8]. Thus, a new, more practical strategy is
9–
towards the synthesis of the fluorinated analogue of retro-thiorphan would be a diastereoselective
reduction with a proper HSiCl3/Lewis base combination (Scheme 1).
Scheme 1. Retrosynthetic approach to A.
The employment of trichlorosilane in the presence of catalytic amounts of a chiral Lewis base
is a well-established methodology to perform enantioselective reduction of carbon–nitrogen double
bonds of α,β-unsaturated compounds [13,14], and represents a metal-free approach for the synthesis
of pharmaceutically relevant compounds.
2. Results and Discussion
The synthetic strategy involves the preparation of the enamine
5
, starting from commercially
available enantiomerically pure amino alcohol
1, which needs to be protected at the hydroxyl moiety.
2.1. Synthetic Strategy: In Batch Optimization
We first reacted the N-Boc-protected amino alcohol
N,N-dimethylformamide (DMF), to give the corresponding allylated compound
Then, N-Boc-protected amine was de-protected with trifluoroacetic acid in dichlorometane (1:1).
After a basic cleavage of the ammonium salt, product was obtained in 95% yield [15]. Different
attempts for enamine formation were performed on ethyl 4,4,4-trifluoroacetate, to form enamine
2
with allylbromide and KO-tBu in
3
in 99% yield.
3
4
5.
Obtained results proved that a catalytic amount of acid and ethanol as solvent are the best conditions
for this condensation to afford the desired key intermediate as the 98/2 E/Z ratio (Scheme 2).

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Scheme 2. Synthetic strategy for enamine preparation.
2.2. Catalytic Tests
We further investigated the catalytic reduction of fluorinated enamine
reducing agent in the presence of a Lewis base (Scheme 3).
5
with trichlorosilane as
Scheme 3. Diastereoselective catalytic reduction of enamine.
First, the addition of N,N-dimethylformamide (DMF) as achiral Lewis Base was performed,
to evaluate the simple diastereoselectivity exerted by the stereocenter of the phenylalaninol residue.
The reaction afforded product
6 in 22% yield and a 67:34 diastereomeric ratio (d.r.) (Scheme 3 and
Table 1).
Table 1. Diastereoselective catalytic reductions.
T (◦C)
d.r.
Yield (%) 2
1
Entry
Lewis Base
Cat. eq
1 3
2
3
4
5
DMF
Cat. I
Cat. II
Cat. ent-I
Cat. ent-I
Cat. ent-I
Cat. ent-I
5
0
67:34
34:66
81:19
83:17
95:5
95:5
96:4
3
22
40
38
70
60
53
37
0.2
0.2
0.2
0.2
0.1
0.1
0 to rt
0 to rt
0 to rt
-10
-10
-20
6
7
Calculated by 19F-NMR on the crude mixture. Isolated yield. Reaction time 48 h.
1
2
Then catalyst
I
, derived from the chiral scaffold of ( )-(1R,2S)-ephedrine [16], was tested;
−
the reduction yield was improved, but the other diastereoisomer was preferentially obtained,
thus proving to be a mismatch couple with the chiral substrate (Table 1). Therefore, we decided to test
catalyst II, known to lead to the formation of the opposite enantiomer of catalyst
presence of fluorinated substrates [ ]. Indeed, catalyst II showed to be a matching combination with
enamine and gave slightly better results than DMF, improving both yield and the diastereomeric ratio.
I when used in the
9
5

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We then decided to synthetize the opposite enantiomer of catalyst
I, starting from (+)-(1S,2R)-ephedrine,
which proved to be a very active catalyst; that is, at a lower temperature, the d.r. was improved up
to 95:5.
In order to confirm the hypothesized (S,S) absolute configuration of the key intermediate
the chiral amine was treated with an equimolar amount of HCl in diethyl ether, to afford the
corresponding hydrochloride salt /HCl. Slow crystallization from an Et2O/Hexane mixture afforded
6,
6
light yellow crystals. X-ray analysis allowed to unambiguously determine the absolute configuration
of the product to be (S,S), as reported in Figure 2.
Bn
Cl
O
O
NH2
F3C
OEt
6/HCl
Figure 2. X-ray determined structure of chiral intermediate (S,S) 6/HCl.
2.3. Derivatization
After the reduction, product
the presence of PPh3 in EtOH, to give the amino-alcohol 7 in 65% yield (Scheme 4).
6
was deprotected, using a Pd(OAc)2/SiO2 catalyzed procedure in
Bn
NH
Bn
NH
MsCl, Et3N
O
HO
Pd(OAc)2 ,PPh3 ,SiO2
EtOH reflux, 24h
CH2Cl2, r.t., 24 h
COOEt
COOEt
F3C
F3C
6
7
65%
Bn
NH
Bn
CH3COSK
Cl
H3COCS
NH
DMF, r.t., 24h
COOEt
COOEt
F3C
F3C
40%
8
9
99%
Scheme 4. Derivatization of the fluorinated amine to the direct precursor 9 of the target product.
Then, compound
7 was reacted with methanesulfonyl chloride to give the corresponding chloride
8
in 99% yield, via mesylation followed by the formation of an aziridinium cationic ring, opened by

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the chloride anion. Intermediate
8
was used as crude and reacted with potassium thioacetate to afford
in 40% yield product 9, the direct precursor of the final analogue [8].
2.4. Continuous Flow Strategy
Considering the rising interest for the in-flow preparation of active pharmaceutical ingredients
(API’s) [17–19], based on these results and with the aim to further accelerate the reaction, we explored
the possibility of developing a continuous flow method for the preparation of the target compound.
We started with the Boc-protection of phenylalaninol, performed under the same condition as in batch,
with a phase separator at the end of the coil reactor. All continuous flow reactions were performed
in a polytetrafluoroethylene (PTFE) coil reactor (0.58 mm internal diameter ID, and different lengths
depending on the desired reactor volume—see Supporting Information). We were able to obtain
the desired product with complete conversion, just by evaporating the solvent of the organic phase
(Scheme 5).
Scheme 5. Protection of phenylalaninol performed under continuous flow in a biphasic mixture.
With the aim of developing a multistep continuous synthesis, without isolation of intermediates,
since dichloromethane is not compatible with the use of potassium tert-butoxide due to possible
carbene formation, we decided to switch to tetrahydrofurane (THF) as solvent for the first step. Using a
more polar solvent an external base was not needed, and the desired Boc-protected aminoalcohol could
be obtained in just 5 min of residence time at room temperature (Scheme 6).
Scheme 6. Continuous flow protection of phenylalaninol.
Then we tested the second step under continuous flow, and we were pleased to see that in only
10 min of residence time, the desired product
3 was obtained in 72% conversion (Scheme 7). We
could not further optimize this reaction, due to solubility problems of by-products formed during
the reaction.

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Scheme 7. Protection of the hydroxyl moiety as allyl ether performed under continuous flow.
Unfortunately, when the two steps were combined in a single continuous flow system (Scheme 8),
low conversion was observed for the second reaction, probably due to the influence of by-products
formed in the first transformation.
Scheme 8. Multi-step continuous flow protection of phenylalaninol.
Therefore, we decided to start from commercially available Boc-protected phenylalaninol 2 and
synthesize the O-allyl protected phenyl alaninol ether. After the in-flow allylation, the reaction outcome
was poured directly into a biphasic mixture of dichloromethane and aqueous HCl (20%), where it was
stirred for 45 min. After an aqueous basic work-up, the desired product
as a completely de-protected compound (Scheme 9).
4 was obtained with 75% yield,
Scheme 9. Continuous flow hydroxyl moiety protection and Boc de-protection.
In order to develop a continuous flow strategy for the synthesis of enamine
the partner of our amine, choosing commercially available fluorinated alkyne 10
5
, we decided to change
20]. The reaction
[
occurred with complete conversion in just 10 min of residence time, in dichloromethane, the same
solvent of the subsequent diastereoselective reduction (Scheme 10). Then we looked at the catalytic
enamine reduction mediated by trichlorosilane.

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Scheme 10. Enamine formation under continuous flow.
Our group already demonstrated that HSiCl3-mediated diastereoselective imine reduction could
be efficiently performed in (micro)-mesoreactors under continuous flow conditions [21]. The reaction,
performed in the coil reactor (PTFE, 1.58 mm OD, 0.58 mm ID, and tubes connected using standard
HPLC connectors—see Supporting Information) afforded the expected product, although the reduction
step revealed to be slower than in batch, and required long residence times (Scheme 11). To increase
the yield, we heated up the reactor to 35 ◦C, obtaining up to 37% isolated yield, but with lower d.r.,
while cooling to room temperature, the yield was below 20%, with a 95:5 d.r. (see Supplementary
Materials for experimental details).
Scheme 11. Multistep continuous flow enamine formation and reduction.
3. Conclusions
In the present study, a highly stereoselective, metal-free strategy for the synthesis of a fluorinated
chiral amine, a direct precursor of a retro-thiorphan fluorinated analogue, was developed. After setting
up reaction conditions in batch, the synthesis was studied also under continuous flow conditions.
In particular, two synthetic modules were set up, avoiding isolation and purification of intermediates.
The desired product, an enantiomerically pure advanced precursor of the target molecule, was obtained
in modest to good yields and high diastereomeric ratios, both in batch and under continuous flow.
In particular, the batch synthetic strategy afforded the desired intermediate
steps with an overall yield of 31% and a d.r. of 95:5, starting from the commercially available
Boc-protected phenylalaninol , involving the stereoselective metal-free trichlorosilane-mediated
enamine reduction [22 27]. Under continuous flow conditions the same intermediate was obtained in
6 in four synthetic
2
–
6
only two synthetic modules (with the same number of synthetic steps), with an overall yield of 26% and
a d.r. of 83:17. Furthermore, the Boc-protection was studied both in batch and flow conditions giving
quantitative yield. The present work represents a further step towards the development of a multistep
continuous flow process for the synthesis of enantiomerically pure, fluorinated, pharmaceutically
relevant products.
4. Materials and Methods
Reactions were monitored by analytical thin-layer chromatography (TLC) using silica gel 60 F254
pre-coated glass plates (0.25 mm thickness) and visualized using UV light. Flash chromatography
was carried out on silica gel (230–400 mesh). Proton NMR spectra were recorded on spectrometers

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operating at 300 MHz (Bruker Avance 300, Bruker BioSpin, Billerica, MA, USA). Proton chemical shifts
were reported in ppm ( ) with the solvent reference relative to tetramethylsilane (TMS) employed as the
internal standard (CDCl3,
= 7.26 ppm). 13C-NMR spectra were recorded on 300 MHz spectrometers
(Bruker Fourier 300) operating at 75 MHz, with complete proton decoupling. Carbon chemical shifts
were reported in ppm ( ) relative to TMS with the respective solvent resonance as the internal standard
(CDCl3,
= 77.0 ppm). 19F-NMR spectra were recorded on 300 MHz spectrometers (Bruker Fourier
300) operating at 282.1 MHz. Fluorine chemical shifts were reported in ppm ( ) relative to CF3Cl with
the respective solvent resonance as the internal standard (CDCl3, = 77.0 ppm). Mass spectra and
δ
δ
δ
δ
δ
δ
accurate mass analysis were carried out on a VG AUTOSPEC-M246 spectrometer (MasSpec Consulting
Inc.,Oakville, ON, Canada, double-focusing magnetic sector instrument with EBE geometry) equipped
with an EI source or with an LCQ Fleet ion trap mass spectrometer, ESI source, with acquisition in
positive ionization mode in the mass range of 50–2000 m/z. X-ray data were collected on a Bruker
Smart Apex CCD area detector (Bruker AXS Inc., Madison, WI, USA) equipped with a fine-focus sealed
tube operating at 50 kV and 30 mA, using graphite-monochromated Mo Kα radiation (λ = 0.71073 Å).
The fluidic device was realized by assembling coil-reactors, connected by T-junctions using standard
HPLC connectors. Coil-reactors consisted of PTFE tubing (diameter: 0.58 mm) coiled in a bundle.
Syringe pump: Chemix Fusion 100, equipped with two Hamilton gastight syringes.
Dry solvents were purchased and stored under nitrogen over molecular sieves (bottles with crown
caps). All chemicals were purchased from commercial suppliers and used without further purification
unless otherwise specified.
4.1. General Procedure for the Stereoselective Catalytic Reduction of Enamine 5 under Batch Conditions
Dry DMF or the appropriate catalytic chiral Lewis base in the reported amount (Table 1), and
a 0.1 M solution of enamine
5 (1 equiv.) in dry CH2Cl2 were introduced in a round bottomed flask
under nitrogen atmosphere. The mixture was cooled down to the indicated temperature and HSiCl3
(3.5 equiv.) was added to the reaction mixture. After the desired time, the reaction was quenched with
a 4 M solution of NaOH until basic pH was reached. The resulting mixture was extracted with CH2Cl2,
separated, and the organic phase dried over anhydrous Na2SO4. The solvent was removed under
reduced pressure and the residue purified by column chromatography (silica gel, hexanes/EtOAc =
98:2) to afford 6 as a colorless oil.
4.2. General Procedure for the Multistep Formation and Stereoselective Catalytic Reduction of Enamine 5 under
Flow Conditions
Two 2.5 mL Hamilton gastight syringes, one containing compound 10 (2 mL of a 0.8 M solution in
CH2Cl2, 1.03 equiv.) and the other compound
connected by a PEEK tee junction to a 250 L PTFE coil reactor. Both syringes fed the solutions at
L/min, giving a residence time of 10 min. The outcome of the reactor was connected to another tee
junction, fed by a 1 mL Hamilton gastight syringe, containing cat. ent-I (0.8 mL of 0.4 M solution in
CH2Cl2, 0.2 equiv.), feeding at 2.5 L/min. The outcome of this second tee was connected to another
tee junction, fed by a 5 mL Hamilton gastight syringe, containing HSiCl3 (3.3 mL of a 1.9 M solution
in CH2Cl2, 4 equiv.) with a flow rate of 10 L/min. The outcome of this third tee was connected to a
1000 L PTFE coil reactor, with a total flow rate of 24.5 L/min, and a subsequent residence time of
4 (2 mL of a 0.8 M solution in CH2Cl2, 1 equiv.) were
µ
6
µ
µ
µ
µ
µ
40 min. The outcome of the reactor was collected into a NaOH 4 M solution at 0 ◦C. After the first two
volumes were discharged, steady state conditions were reached. The conversion was reported as an
average of three reactors volume, separately collected, and confirmed as isolated yield.
Supplementary Materials: The supplementary materials are available online.
Author Contributions: Methodology and experimental work: M.P.; X-ray analysis and absolute configuration
determination A.F.; Validation: M.P. and A.P.; Data Curation: A.P. and L.R.; conceptualization and supervision: M.B.
Funding: This research was funded by European Union’s Horizon 2020 research and innovation programme
under the Marie Sklodowska Curie grant agreement number 812944 “TECHNOTRAIN”.

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Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of all of the prepared compounds are available from the authors.
2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
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