Synthesis of fluorinated piperidine and azepane β-amino acid derivatives

Article abstract of DOI:10.1016/j.tet.2016.10.005

A convenient and robust stereocontrolled procedure has been developed for the synthesis of novel trifluoromethyl-containing piperidine and azepane β-amino ester stereoisomers. The synthesis started from readily available unsaturated bicyclic β-lactams and

Full text of DOI:10.1016/j.tet.2016.10.005

Accepted Manuscript
Synthesis of fluorinated piperidine and azepane β-Amino acid derivatives
Renáta Anita Ábrahámi, Loránd Kiss, Pablo Barrio, Ferenc Fülöp
PII:
S0040-4020(16)31015-8
10.1016/j.tet.2016.10.005
TET 28146
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 21 July 2016
Revised Date: 22 September 2016
Accepted Date: 4 October 2016
Please cite this article as: Ábrahámi RA, Kiss L, Barrio P, Fülöp F, Synthesis of fluorinated piperidine
and azepane β-Amino acid derivatives, Tetrahedron (2016), doi: 10.1016/j.tet.2016.10.005.
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ACCEPTED MANUSCRIPT
Synthesis of Fluorinated Piperidine and Azepane β-Amino Acid Derivatives
Renáta Anita Ábrahámi1, Loránd Kiss1, Pablo Barrio3, Ferenc Fülöp1,2*
1Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Eötvös u. 6,
Hungary
2MTA-SZTE Stereochemistry Research Group, Hungarian Academy of Sciences, H-6720
Szeged, Eötvös u. 6, Hungary
3Universidad de Valencia, Facultad de Farmàcia, Departamento de Química
Orgánica, Av. Vicente Andrés Estellés, s/n 46100, Valencia, Spain
Graphical abstract:
Abstract:
A convenient and robust stereocontrolled procedure has been developed for the synthesis
of novel trifluoromethyl-containing piperidine and azepane β-amino ester stereoisomers. The
synthesis started from readily available unsaturated bicyclic β-lactams and was based on
oxidative cleavage of the ring C=C double bond followed by ring closure of the diformyl
intermediates in the presence of 2,2,2-trifluoroethylamine hydrochloride through reductive
amination. The synthetic procedure has efficiently been extended towards the synthesis of
mono- and difluorinated analogs.
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Keywords: stereocontrol, fluorine, azaheterocycle, amino acid, reductive amination, ring
closing
Introduction
N-Heterocyclic β-amino acids constitute an important class of derivatives in
pharmaceutical and organic chemistry with high biological potential. For example, several
piperidine, pyrrolidine or N-bridged β-amino acid derivatives exhibit antiviral or antibacterial
activities (Figure 1, 1-3).1
Figure 1. Some N-heterocyclic β-amino acids with biological relevance.
Fluorinated molecules have gained increasing attention in the area of pharmaceuticals
and agrochemicals over the past decade.2 Among a significant number of fluorinated
biomolecules, a series of fluorine-containing acyclic α- and β-amino acids exhibit antitumoral or
antibiotic properties.3 Molecules containing the β-fluorinated or β-trifluorinated amine units are
important scaffolds in medicinal chemistry or agrochemistry.2a,4 Thus, fluorine-containing
pyrrolidines and piperidines, which are present in drugs such as MK-0657, MK-0731 and
neceprevir, are of great interest in medicinal chemistry.5 Fluorine-containing azepanes, in turn,
are relatively less reported in the literature. However, because of the important role of various
functionalized counterparts in pharmaceutical design, they may receive increasing attention in
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the future.6 Fluorine-containing tetrahydroisoquinoline derivatives, N-bridged bicyclic scaffolds
and other N-fluoroalkylated molecular entities are known to have high biologically relevance.7
β-Fluoramine or trifluoroamine motifs are also present in various fluorine-containing amino acid
derivatives of biological importance (Figure 2).8
Figure 2. Related molecules with fluoroamine or trifluoroamine element.
Fluorinated saturated N-heterocycles are of special interest, since introduction of fluorine into
the structure of an azaheterocycle may increase lipophilicity and metabolic stability. In
additition, fluorine substitution may reduce basicity thereby providing better bioavailability to a
certain molecule.
Results and Discussion
Taking into consideration the high biorelevance of saturated N-heterocycles, β-amino
acids and organofluorine scaffolds, our present aim was to combine these molecular structures.
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The actual work has been directed towards the stereocontrolled access of novel fluorine-
containing six- or seven membered N-heterocyclic β-amino acid derivatives.
The synthetic concept included the use of a commercially available reagent, containing
the trifluoromethyl group, and was based on the oxidative ring cleavage of unsaturated cyclic β-
amino esters, followed through ring closure by reductive amination resulting in ring expansion
of the diformyl intermediates.9
First, unsaturated bicyclic β-lactam (±)-9 was transformed to dihydroxylated cis amino
esters (±)-10 and (±)-11 by lactam ring opening with ethanolysis followed by N-protection and
cis-dihydroxylation.10 The products subjected to oxidative ring cleavage in the presence of
NaIO4 in THF/H2O gave the corresponding open chain diformyl amino esters (±)-14 and (±)-15.
These unstable dialdehyde derivatives were further used in the next step without isolation. Upon
treatment with the commercially available 2,2,2-trifluoroethylamine hydrochloride in EtOH, in
the presence of NaHCO3 and NaBH3CN, ring closure involving reductive amination took place.
(Scheme 1).
Since the stereocenters at C-1 and C-2 of amino esters (±)-10 and (±)-11 were not
affected during the ring expansion procedure, the configuration of the chiral centers in (±)-18
and (±)-19 are predetermined by the structure of the starting materials (also assigned on the
basis of NMR analysis). Consequently, the cis amino ester afforded the corresponding
piperidine derivative with the carboxylate and carbamate/amide functions in a cis relative
arrangement. Analogously, dihydroxylated amino esters (±)-12 and (±)-13 (derived from lactam
(±)-9 by ring opening, epimerization at C-1 and cis-dihydroxylation)10 with the ester and the N-
protected group in a trans relationship were submitted to oxidative ring opening with NaIO4.
The resulting unstable diformyl intermediates (±)-16 and (±)-17 again, without isolation, were
reacted with 2,2,2-trifluoroethylamine and NaBH3CN to afford trans trifluoromethylated
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piperidine amino esters (±)-20 and (±)-21 (Scheme 1). Amino esters (±)-20 and (±)-21 could be
accessed on an alternative pathway by epimerization at C-4 of (±)-18 and (±)-19 with NaOEt in
EtOH with the involvement of the active methine group.
Scheme 1.
The synthetic approach described above was applied towards the synthesis of
trifluoromethylated azepane 2-aminocarboxylates. First, cis and trans 2-aminocyclohex-4-
enecarboxylates (±)-23 and (±)-24 (derived from bicyclic β-lactam (±)-22 by azetidinone ring
opening with ethanolysis, Z-protection and epimerization)11 were oxidized with NMO/OsO4
affording the corresponding vicinal diol derivatives (±)-25 and (±)-26 (for similar
transformations see, ref. 11c-d). Next, these dihydroxylated esters were converted to cis and
trans amino esters (±)-27 and (±)-28 with an azepane ring, which contain the ring N-atom at
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three C-atom distance from the carbamate group (Scheme 2). The corresponding
transformations involved oxidative ring cleavage and stereocontrolled ring enlargement through
reductive amination with 2,2,2-trifluoroethylamine and NaBH3CN.
Scheme 2.
The synthetic procedure was further extended for the preparation of novel
trifluoromethylated azepane derivatives, by starting from bicyclic β-lactam (±)-29, a
regioisomer of (±)-22. Lactam (±)-29 was converted through lactam ring opening by ethanolysis
followed by N-Z protection to (±)-30 and, finally, epimerization to derivative (±)-31.11 Alkene
bond dihydroxylation of (±)-30 and (±)-31 with NMO and OsO4 provided vicinal diols (±)-32
and (±)-33 (see also ref. 11). Both dihydroxylated amino ester stereoisomers were subjected to
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NaIO4 mediated oxidative ring opening followed by reductive ring closing with
trifluoroethylamine resulting in cis and trans azepane amino esters (±)-34 and (±)-35
(regioisomers of (±)-27 and (±)-28). In these products, the ring N-atom is located at a two C-
atom distance from the carbamate group (Scheme 3).
Scheme 3.
Taking into consideration the high physiological relevance of N-bridged bicyclic amino
acid derivatives (eg., cocaine, anatoxin-a analogs 3, etc.), our next aim was the extension of the
above described synthetic protocol to the preparation of trifluoromethylated N-bicyclic systems.
Thus, the readily available diexo-norbornene β-amino ester (±)-369b was first transformed by N-
Z protection to (±)-37 and then dihydroxylation was carried out to form diol derivative (±)-38
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(see also ref. 9b). Oxidative ring opening of (±)-38 followed by reductive amination with
trifluoroethylamine and NaBH3CN gave N-bicyclic amino ester (±)-39 (Scheme 4).
Scheme 4.
The synthesis of the new stereoisomeric N-bridged bicyclic β-amino ester containing the
trifluoromethyl group could also be accomplished, by starting from the diendo-norbornene
amino ester (±)-40.9b Following the synthetic approach used as for the diexo isomer, N-Z-
protection of (±)-40, dihydroxylation, oxidative ring opening and ring enlargement via reductive
amination with trifluoroethylamine led to compound (±)-43, a stereoisomer of (±)-39 (Scheme
5).
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Scheme 5.
The synthetic method, based on oxidative carbocyclic ring opening followed by
reductive ring closing presented here, could be readily extended to access novel fluorine-
containing N-heterocyclic β-amino acid derivatives by variation of the fluorine-containing
building element. An example consists of the reductive amination either with 2-
fluoroethanamine or 2,2-difluoroethanamine. Thus, dialdehyde (±)-15 (derived from lactam (±)-
9) on treatment with these commercially available fluoroamines in the presence of NaHCO3 and
NaBH3CN delivered the corresponding monofluorinated and difluorinatedpiperidine β-amino
esters (±)-40 and (±)-41 (Scheme 6).
Scheme 6.
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Conclusions
A convenient and efficient stereocontrolled procedure has been developed for the
synthesis of novel trifluoromethyl-containing piperidine and azepane β-amino ester
stereoisomers. The protocol is based on the C=C bond oxidative ring cleavage of cyclic β-amino
acids, followed by reductive ring closure of diformyl intermediates in the presence of
commercially available fluoramine building element 2,2,2-trifluoroethylamine. Since the
stereocenters of the starting carbocyclic β-amino acid derivatives are not affected during the
synthetic procedure, they will predetermine the configuration of the chiral centers in the
products. The synthetic approach has been readily extended towards novel trifluoromethyl N-
bridged scaffolds and mono- or difluorinated piperidine β-amino acid derivatives.
Experimental
General procedure for the Z-protection of amino esters
To a solution of amino ester hydrochloride (8 mmol) in THF (30 mL), Et3N (5 mL) was added at
0 °C, followed by the addition of Z-Cl (1 equiv, a 50% solution in toluene). The mixture was
stirred for 10 h at 20 °C and then diluted with EtOAc (80 mL). The organic layer was washed
with H2O (3 x 40 mL), dried (Na2SO4) and then concentrated under reduced pressure. The crude
product was purified by column chromatography on silica gel (n-hexane/EtOAc 4:1), affording
the protected amino ester.
General procedure for epimerization of the cis-amino esters
To a solution of cis N-protected amino ester (3mmol) in EtOH (30 mL), EtONa (1.5 equiv) was
added at 0 °C and the mixture was stirred at 20 °C for 18 h. After the addition of H2O (70 mL),
the mixture was extracted with CH2Cl2 (3 x 30 mL), the organic layer dried over Na2SO4 and
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concentrated under vacuo. The crude material was purified by column chromatography on silica
gel (n-hexane/EtOAc 4:1) to give the trans isomer.
General procedure for dihydroxylation of N-protected amino esters
To a solution of N-protected β-amino ester (5mmol) and NMO (1.2 equiv) in acetone (30 mL),
0.3 mL of 2% OsO4 solution in t-BuOH was added, and the resulting mixture was stirred for 3 h
at room temperature. After completion of the reaction, 90 mL of saturated aqueous Na2SO3
solution was added and the reaction mixture was extracted with CH2Cl2 (3 x 30 mL). The
combined organic layers were dried over Na2SO4, filtered and evaporated under reduced
pressure. The crude product was purified by means of column chromatography on silica gel (n-
hexane/EtOAc 1:4).
General procedure for the synthesis of fluorine-containing N-heterocyclic amino esters by
oxidative ring cleavage followed by ring closure via reductive amination
To a stirred solution of amino ester (2mmol) NaIO4 (1.5 equiv) was added in THF/H2O (25
mL/2 mL). After stirring for 1 h at 20 °C under an Ar atmosphere, H2O was added (40 mL). The
mixture was then extracted with CH2Cl2 (3 × 20 mL), the combined organic layers were dried
over Na2SO4 and the resulting solution containing the dialdehyde derivative was evaporated and
the crude product was immediately used for the next reaction without purification. Fluorine-
containing ethylamine hydrochloride (2 mmol), NaHCO3 (2 equiv) were added to the solution of
the dialdehyde in EtOH (20 mL) and the mixture was stirred at 20 °C for 10 min. Next
NaCNBH3 (2mmol) and AcOH (2 drops) were added and stirring was continued for another 4 h
at 20 °C. The reaction mixture was diluted with H2O (20 mL) and extracted with CH2Cl2 (3 × 20
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mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced
pressure. The residue was purified by column chromatography on silica gel (n-hexane/EtOAc).
Ethyl (1R*,2S*)-2-(((benzyloxy)carbonyl)amino)cyclohex-3-enecarboxylate (±)-30
1
White solid; yield: 66% (980 mg); mp = 56-58 °C; (Rf= 0.36, n-hexane/EtOAc 4:1). H NMR
(DMSO, 400 MHz) δ = 1.08 (t, 3H, CH3, J = 8.1 Hz), 1.62-2.03 (m, 4H, CH2), 2.63-2.71 (m,
1H, H-1), 3.92-3.99 (m, 2H, OCH2), 4.41-4.48 (m, 1H, H-2), 4.96-5.03 (m, 2H, OCH2), 5.54-
13
5.60 (m, 1H, H-4), 5.77-5.82 (m, 1H, H-3), 7.29-7.40 (m, 6H, Ar-H and N-H). C NMR (100
MHz, DMSO): δ = 14.8, 19.9, 24.9, 44.5, 46.6, 60.5, 66.0, 127.1, 128.5, 128.6, 129.1, 130.5,
136.0, 156.3, 173.3. Anal. Calcd for C17H21NO4: C 67.31, H 6.98, N 4.62; found: C 67.01, H
6.61, N 4.29.
Ethyl (1S*,2S*)-2-(((benzyloxy)carbonyl)amino)cyclohex-3-enecarboxylate (±)-31
1
White solid; yield: 63% (1.46 g).; mp = 52-54 °C; (Rf= 0.33, n-hexane/EtOAc 4:1). H NMR
(DMSO, 400 MHz) δ = 1.18 (t, 3H, CH3, J = 8.0 Hz), 1.61-1.70 (m, 1H, CH2), 1.83-1.90 (m,
1H, CH2), 1.98-2.04 (m, 2H, CH2), 2.47-2.52 (m, 1H, H-1), 3.97-4.04 (m, 2H, OCH2), 4.31-4.39
(m, 1H, H-2), 5.01 (s, ,2H, OCH2), 5.48-5.02 (m, 1H, H-4), 5.73-5.77 (m, 1H, H-3), 7.72-7.86
13
(m, 5H, Ar-H), 7.94 (brs, 1H, N-H). C NMR (100 MHz, DMSO): δ = 14.9, 24.2, 25.1, 45.8,
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49.4, 60.8, 66.1, 128.5, 128.6, 128.8, 128.9, 129.2, 138.0, 156.5, 174.4. Anal. Calcd for
C17H21NO4: C 67.31, H 6.98, N 4.62; found: C 67.02, H 6.64, N 4.92.
Ethyl
(1R*,2R*,3S*,4S*)-3-(((benzyloxy)carbonyl)amino)bicyclo[2.2.1]hept-5-ene-2-car-
boxylate (±)-37
1
White solid; yield: 77% (1.94 g); mp 89-90 °C; (Rf = 0.6, n-hexane/EtOAc 4:1). H NMR
(CDCl3, 400 MHz) δ = 1.23 (t, 3H, CH3, J = 7.2 Hz), 1.60-1.66 (m, 1H, CH2), 1.96-2.01 (m, 1H,
CH2), 2.65-2.70 (m, 1H, H-2), 2.21-2.25 (m, 1H, H-4), 2.99-3.02 (m, 1H, H-1), 3.99-4.18 (m,
3H, OCH2 and H-3), 5.08 (s, 2H, OCH2), 5.50 (brs, 1H, N-H), 6.20-6.27 (m, 2H, H-5 and H-6),
13
7.38-7.48 (m, 5H, Ar-H). C NMR (100 MHz, DMSO): δ = 14.8, 44.8, 45.9, 48.0, 48.2, 54.5,
60.6, 66.2, 128.7, 129.0, 137.7, 137.8, 139.8, 139.9, 156.6, 173.5. Anal. Calcd for C18H21NO4: C
68.55, H 6.71, N 4.44; found: C 68.23, H 6.90, N 4.18.
Ethyl
(1R*,2S*,3R*,4S*)-3-(((benzyloxy)carbonyl)amino)bicyclo[2.2.1]hept-5-ene-2-car-
boxylate (±)-41
1
Colourless oil; yield: 74% (2.3 g); (Rf = 0.65, n-hexane/EtOAc 4:1). H NMR (DMSO, 400
MHz) δ = 1.22 (t, 3H, CH3, J = 7.1 Hz), 1.33-1.38 (m, 1H, CH2), 1.50-1.55 (m, 1H, CH2), 3.13-
3.18 (m, 2H, H-1 and H-4), 3.21-3.25 (m, 1H, H-2), 4.01-4.13 (m, 2H, OCH2), 4.56-4.61 (m,
1H, H-3), 5.10 (s, 2H, OCH2), 5.42 (brs, 1H, N-H), 6.22-6.26 (m, 1H, H-6), 6.44-6.49 (m, 1H,
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13
H-5), 7.29-7.37 (m, 5H, Ar-H). C NMR (100 MHz, DMSO): δ = 14.8, 41.0, 46.2, 47.5, 49.5,
55.0, 60.5, 66.2, 128.6, 128.7, 129.1, 133.9, 137.9, 138.9, 156.5, 172.3. MS: (ESI) m/z = 316.1
(M+1). Anal. Calcd for C18H21NO4: C 68.55, H 6.71, N 4.44; found: C 68.20, H 6.39, N 4.16.
Ethyl
(1R*,2R*,3S*,4R*)-2-(((benzyloxy)carbonyl)amino)-3,4-dihydroxycyclohexane-
carboxylate (±)-32
White solid; yield: 72% (740 mg); mp = 130-132 °C; (Rf= 0.42, n-hexane/EtOAc 1:4). 1H NMR
(DMSO, 400 MHz) δ =1.10 (t, 3H, CH3, J = 7.9 Hz), 1.39-1.54 (m, 3H, CH2), 1.62-1.74 (m, 1H,
CH2), 2.74-2.79 (m, 1H, H-1), 3.51-3.55 (m, 1H, H-4), 3.59-3.63 (m, 1H, H-3), 3.92-4.03 (m,
2H, OCH2), 4.23-4.29 (m, 1H, H-2), 4.33 (brs, 1H, O-H), 4.84 (brs, 1H, O-H), 4.96-5.04 (m,
13
2H, OCH2), 7.19 (brs, 1H, N-H), 7.26-7.41 (m, 5H, Ar-H). C NMR (100 MHz, DMSO): δ =
14.7, 21.4, 27.7, 41.0, 54.3, 60.2, 66.1, 67.2, 71.9, 128.1, 128.5, 128.6, 137.9, 156.6, 173.9.
Anal. Calcd for C17H23NO6: C 60.52, H 6.87, N 4.15; found: C 60.18, H 6.48, N 3.85.
Ethyl
(1S*,2R*,3S*,4R*)-2-(((benzyloxy)carbonyl)amino)-3,4-dihydroxycyclohexane-
carboxylate (±)-33
White solid; yield: 58% (850 mg); mp = 102-103 °C (Rf= 0.31, n-hexane/EtOAc 1:4). 1H NMR
(DMSO, 400 MHz) δ = 1.08 (t, 3H, CH3, J = 7.9 Hz), 1.29-1.36 (m, 1H, CH2), 1.41-1.49 (m,
1H, CH2), 1.58-1.64 (m, 1H, CH2), 1.72-1.79 (m, 1H, CH2), 2.37-2.43 (m, 1H, H-1), 3.18-3.24
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(m, 1H. H-4), 3.78-3.85 (m, 2H, H-2 and H-3), 3.96-4.08 (m, 2H, OCH2), 4.23 (brs, 1H, O-H),
4.49 (brs, 1H, O-H), 4.97-5.02 (m, 2H, OCH2), 7.00 (brs, 1H, N-H), 7.32-7.48 (m, 5H, Ar-H).
13C NMR (100 MHz, DMSO): δ = 14.8, 23.0, 30.4, 48.6, 53.2, 60.5, 65.7, 69.3, 73.9, 128.4,
128.5, 129.1, 138.3, 156.7, 173.9. Anal. Calcd for C17H23NO6: C 60.52, H 6.87, N 4.15; found:
C 60.16, H 7.22, N 3.81.
Ethyl
(1R*,2S*,4S*,5R*)-2-(((benzyloxy)carbonyl)amino)-4,5-dihydroxycyclohexane-
carboxylate (±)-25
1
White solid; yield: 78% (1.05 g); mp = 83-85 °C (Rf= 0.33, n-hexane/EtOAc 1:4). H NMR
(DMSO, 400 MHz) δ = 1.03 (t, 3H, CH3, J = 7.9 Hz), 1.51-1.57 (m, 1H, CH2), 1.59-1.72 (m,
2H, CH2), 1.77-1.86 (m, 1H, CH2), 2.76-2.84 (m, 1H, H-1), 3.59-3.70 (m, 2H, H-4 and H-5),
3.89-4.01 (m, 2H, OCH2), 4.08-4.14 (m, 1H, H-2), 4.30 (brs, 2H, 2x O-H), 4.96-5.04 (m, 2H,
OCH2), 7.33-7.48 (m, 6H, Ar-H, and N-H). 13C NMR (100 MHz, DMSO): δ = 14.8, 29.3, 34.9,
48.4, 60.5, 66.0, 66.9, 68.2, 69.9, 128.5, 128.6, 129.2, 138.1, 156.5, 173.6. Anal. Calcd for
C17H23NO6: C 60.52, H 6.87, N 4.15; found: C 60.15, H 6.51, N 4.41.
Ethyl
(1S*,2S*,4S*,5R*)-2-(((benzyloxy)carbonyl)amino)-4,5-dihydroxycyclohexane-
carboxylate (±)-26
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White solid; yield: 57% (750 mg); mp = 102-104 °C (Rf= 0.30, n-hexane/EtOAc 1:4). 1H NMR
(DMSO, 400 MHz) δ = 1.09 (t, 3H, CH3, J = 7.9 Hz), 1.45-1.62 (m, 3H, CH2), 1.71-1.78 (m,
1H, H-1), 2.57-2.65 (m, 1H, H-1), 3.42-3.50 (m, 1H, H-5), 3.55-3.58 (m, 1H, H-4), 3.62-3.69
(m, 1H, H-2), 3.89-4.03 (m, 2H, OCH2), 4.46 (brs, 1H, O-H), 4.53 (brs, 1H, O-H), 4.98 (s, 2H,
OCH2), 7.73-7.88 (m, 6H, Ar-H and N-H).13C NMR (100 MHz, DMSO): δ = 14.8, 33.5, 35.6,
46.8, 50.5, 61.5. 66.6. 67.5, 70.1, 128.5, 128.6, 129.1, 138.2, 156.1, 174.8.Anal. Calcd for
C17H23NO6: C 60.52, H 6.87, N 4.15; found: C 60.18, H 7.20, N 3.88.
Ethyl (1S*,2R*,3S*,4R*,5R*,6S*)-3-(((benzyloxy)carbonyl)amino)-5,6-dihydroxybicyclo-
[2.2.1]heptane-2-carboxylate (±)-38
1
White solid; yield: 79% (1.53 g); mp 85-87 °C; (Rf = 0.4, n-hexane/EtOAc 1:4). H NMR
(DMSO, 400 MHz) δ = 1.11 (t, 3H, CH3, J = 7.1 Hz), 1.62-1.66 (m, 1H, CH2), 1.75-1.80 (m,
2H, CH2 and H-4), 2.18-2.21 (m, 1H, H-1), 2.52-2.56 (m, 1H, H-2), 3.51-3.60 (m, 2H, H-5 and
H-6), 3.83-3.94 (m, 3H, OCH2 and H-3), 4.59 (brs, 2H, O-H), 5.00 (s, 2H, OCH2), 7.23 (brs, 1H,
N-H), 7.32-7.45 (m, 5H, Ar-H). 13C NMR (100 MHz, DMSO): δ = 14.8, 30.0, 46.3, 49.3, 49.8,
53.5, 60.4, 66.2, 71.9, 72.5, 128.6, 128.7, 129.2, 137.9, 156.4, 172.1. MS: (ESI) m/z = 350.2
(M+1). Anal. Calcd for C18H23NO6: C 61.88, H 6.64, N 4.01; found: C 61.56, H 6.31, N 3.75.
Ethyl (1S*,2S*,3R*,4R*,5R*,6S*)-3-(((benzyloxy)carbonyl)amino)-5,6-dihydroxybicyclo-
[2.2.1]heptane-2-carboxylate (±)-42
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1
Colourless oil; yield: 80% (1.24 g); (Rf = 0.45, n-hexane/EtOAc 1:4). H NMR (DMSO, 400
MHz) δ = 1.15 (t, 3H, CH3, J = 7.1 Hz), 1.16-1.22 (m, 1H, CH2), 1.73-1.77 (m, 1H, CH2), 2.18-
2.21 (m, 1H, H-4), 2.22-2.25 (m, 1H, H-1), 2.98-3.03 (m, 1H, H-2), 3.98-4.09 (m, 4H, OCH2,
H-5 and H-6), 4.11-4.16 (m, 1H, H-3), 4.51 (brs, 1H, O-H), 4.58 (brs, 1H, O-H), 5.01 (m, 2H,
OCH2), 7.09 (brs, 1H, N-H), 7.35-7.44 (m, 5H, Ar-H). 13C NMR (100 MHz, DMSO): δ = 14.8,
31.6, 44.5, 47.7, 49.0, 50.7, 60.7, 66.3, 68.1, 69.4, 128.6, 128.7, 129.2, 137.9, 156.7, 172.4. MS:
(ESI) m/z = 350.2 (M+1). Anal. Calcd for C18H23NO6: C 61.88, H 6.64, N 4.01; found: C 61.56,
H 6.31, N 3.75.
Ethyl
(3R*,4R*)-3-(((benzyloxy)carbonyl)amino)-1-(2,2,2-trifluoroethyl)piperidine-4-
carboxylate (±)-18
Brown oil; yield: 33% (225 mg, two steps). (Rf= 0.43, n-hexane/EtOAc 3:1); 1H NMR (DMSO,
400 MHz) δ = 1.09 (t, 3H, CH3, J = 7.9 Hz), 1.52-1.59 (m, 1H, CH2), 1.98-2.08 (m, 1H, CH2),
2.41-2.50 (m, 1H, H-4), 2.55-2.63 (m, 2H, NCH2), 2.81-2.88 (m, 2H, NCH2), 3.12-3.20 (m, 2H,
NCH2CF3), 3.93-4.02 (m, 2H, OCH2), 4.10-4.17 (m, 1H, H-3), 4.99-5.10 (m, 2H, OCH2), 6.88
13
(brs, 1H, N-H), 7.28-7.46 (m, 5H, Ar-H). C NMR (100 MHz, DMSO): δ = 14.8, 23.9, 43.3,
48.6, 52.3, 57.5 (q, 2JC,F= 28.6 Hz, CCF3), 57.8, 60.3, 66.1, 126.5 (1JC,F = 284.3 Hz, CF3), 128.3,
128.5, 131.2, 138.0, 156, 3, 172.8.19F NMR (100 MHz, DMSO): δ = -67.3. MS: (ESI) m/z =
17

ACCEPTED MANUSCRIPT
389.6 (M+1). IR (KBr): νmax 1150, 1520, 1710, 2900, 3450. Anal. Calcd for C18H23F3N2O4: C
55.67, H 5.97, N 7.21; found: C 55.30, H 6.32, N 6.89.
Ethyl
(3R*,4S*)-3-(((benzyloxy)carbonyl)amino)-1-(2,2,2-trifluoroethyl)piperidine-4-
carboxylate (±)-20
White soli; yield: 39% (302 mg, two steps); mp = 88-89 °C. (Rf= 0.33, n-hexane/EtOAc 3:1); 1H
NMR (DMSO, 400 MHz) δ = 1.12 (t, 3H, CH3, J = 7.9 Hz), 1.51-1.57 (m, 1H, CH2), 1.72-1.79
(m, 1H, CH2), 2.17-2.24 (m, 1H, H-4), 2.26-2.31 (m, 2H, NCH2), 2.87-2.97 (m, 2H, NCH2),
3.10-3.19 (m, 2H, NCH2), 3.62-3.69 (m, 1H, H-3), 3.96-4.08 (m, 2H, OCH2), 4.99 (s, 2H,
OCH2), 7.32-7.48 (m, 6H, Ar-H and N-H). 13C NMR (100 MHz, DMSO): δ = 14.8, 28.7, 46.9,
2
50.0, 52.6, 57.0 (q, JC,F= 29.2 Hz, CCF3),, 58.4, 60.8, 66.1, 127.7 (1JC,F = 275.5 Hz, CF3),,
128.5, 128.6, 129.2, 137.9, 156.2, 173.8.19F NMR (100 MHz, DMSO): δ = -67.8. MS: (ESI) m/z
= 389.7 (M+1). IR (KBr): νmax 1160, 1510, 1710, 2950, 3300. Anal. Calcd for C18H23F3N2O4: C
55.67, H 5.97, N 7.21; found: C 55.31, H 5.69, N 6.87.
Ethyl (3R*,4R*)-3-benzamido-1-(2,2,2-trifluoroethyl)piperidine-4-carboxylate (±)-19
White-yellowish solid; yield: 53% (389 mg, two steps); mp = 64-67 °C. (Rf= 0.32, n-
1
hexane/EtOAc 3:1); H NMR (DMSO, 400 MHz) δ = 1.10 (t, 3H, CH3, J = 8.1 Hz), 1.58-1.65
(m, 1H, CH2), 2.07-2.14 (m, 1H, CH2), 2.50-2.55 (m, 1H, H-4), 2.72-2,77 (m, 2H, NCH2), 2.88-
2.94 (m, 2H, NCH2), 3.97-4.08 (m, 2H, OCH2), 4.51-5.54 (m, 1H, H-3). 7.45-7.53 (m, 3H, Ar-
18

ACCEPTED MANUSCRIPT
H), 7.68-7.75 (m, 2H, Ar-H), 7.81 (brs, 1H, N-H). 13C NMR (100 MHz, DMSO): δ = 14.8, 25.2,
2
41.3, 45.8, 52.2, 57.7 (q, JC,F = 30.3 Hz, CCF3), 60.8, 125.6 (1JC,F = 281.5 Hz, CF3), 128.1,
128.4, 129.1, 132.0, 136.7, 166.9, 173.0.19F NMR (100 MHz, DMSO): δ = -67.6. MS: (ESI) m/z
= 359.5 (M+1). IR (KBr): νmax 1120, 1510, 1630, 1720, 2330, 3400. Anal. Calcd for
C17H21F3N2O3: C 56.98, H 5.91, N 7.82; found: C 56.67, H 5.60, N 7.49.
Ethyl (3R*,4S*)-3-benzamido-1-(2,2,2-trifluoroethyl)piperidine-4-carboxylate (±)-21
White solid; yield: 28% (203 mg, two steps); mp = 129-132 °C. (Rf= 0.30, n-hexane/EtOAc
1
3:1); H NMR (DMSO, 400 MHz) δ = 1.08 (t, 3H, CH3, J = 8.1 Hz), 1.59-1.66 (m, 1H, CH2),
1.88-1.96 (m, 1H, CH2), 2.39-2.44 (m, 2H, NCH2), 2.55-2.60 (m, 1H, H-4), 2.93-3.04 (m, 2H,
NCH2), 3.22-3.34 (m, 2H, NCH2), 3.94-4.04 (m, 2H, OCH2), 4.21-4.28 (m, 1H, H-3), 7.41-7.51
(m, 3H, Ar-H), 7.77-7.84 (m, 2H, Ar-H), 8.42 (brs, 1H, N-H). 13C NMR (100 MHz, DMSO): δ
2
=14.8, 28.6, 46.6, 48.7, 52.7, 52.2 (q, JC,F= 28.4 Hz, CCF3), 58.0, 60.8, 128.1, 129.1, 128.8
19
(1JC,F = 286.5 Hz, CF3), 132.1, 135.3, 166.7. 173.6. F NMR (100 MHz, DMSO): δ = -67.8.
MS: (ESI) m/z = 359.3 (M+1). IR (KBr): νmax 1130, 1510, 1650, 1720, 2340, 3400. Anal. Calcd
for C17H21F3N2O3: C 56.98, H 5.91, N 7.82; found: C 56.64, H 6.29, N 7.50.
Ethyl
(3R*,4R*)-3-(((benzyloxy)carbonyl)amino)-1-(2,2,2-trifluoroethyl)azepane-4-
carboxylate (±)-34
19

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1
Colorless oil; yield: 26% (188 mg, two steps). (Rf= 0.30, n-hexane/EtOAc 3:1); H NMR
(DMSO, 400 MHz) δ = 1.12 (t, 3H, CH3, J = 8.2 Hz), 1.46-1.52 (m, 1H, CH2), 1.70-1.85 (m,
3H, CH2), 2.64-2.73 (m, 2H, H-4 and NCH2), 2.81-2.87 (m, 1H, NCH2), 3.07-3.12 (m, 1H,
NCH2), 3.34-3.42 (m, 2H, NCH2), 3.86-3.98 (m, 2H, OCH2), 3.99-4.07 (m, 1H, NCH2), 4.18-
4.24 (m, 1H, H-3), 4.87-5.04 (m, 2H, OCH2), 6.99 (brs, 1H, N-H), 7.37-7.49 (m, 5H, Ar-H).13C
NMR (100 MHz, DMSO): δ = 14.8, 24.2, 28.4, 48.8, 52.1, 57.1, 58.4, (q, 2JC,F= 29.6 Hz, CCF3),
58.7, 60.5, 66.1, 127.5 (1JC,F = 278.5 Hz, CF3), 128.5, 128.6, 129.1, 134.2, 156.6, 173.9.19F
NMR (100 MHz, DMSO): δ = -69.6. MS: (ESI) m/z = 403.4 (M+1). IR (KBr): νmax 1140, 1290,
1530, 1715, 2320, 2950, 3300. Anal. Calcd for C19H25F3N2O4: C 56.71, H 6.26, N 6.96; found:
C 56.39, H 5.88, N 6.60.
Ethyl
(3R*,4S*)-3-(((benzyloxy)carbonyl)amino)-1-(2,2,2-trifluoroethyl)azepane-4-
carboxylate (±)-35
1
Colorless oil; yield: 22% (159 mg, two steps). (Rf= 0.33, n-hexane/EtOAc 3:1); H NMR
(DMSO, 400 MHz) δ = 1.19 (t, 3H, CH3, J = 8.2 Hz), 1.47-1.52 (m, 1H, CH2), 1.66-1.79 (m,
3H, CH2), 2.48-2.57 (m, 1H, H-4), 2.69-2.90 (m, 4H, NCH2), 3.38-3.44 (m, 2H, NCH2), 3.77-
3.82 (m, 1H, H-3), 3.98-4.07 (m, 2H, OCH2), 4.97-5.03 (m, 2H, OCH2), 7.17 (brs, 1H, N-H),
7.23-7.38 (m, 5H, Ar-H).13C NMR (100 MHz, DMSO): δ = 14.8, 27.0, 27.1, 51.4, 53.7, 54.4,
55.4 (q, 2JC,F= 28.3 Hz, CCF3), 58.4, 60.7, 66.0, 125.8 (q, 1JC,F = 280.5 Hz, CCF3),128.4, 128.5,
129.1, 138.0, 156.0, 174.9.19F NMR (100 MHz, DMSO): δ = -69.4. MS: (ESI) m/z = 403.5
20

ACCEPTED MANUSCRIPT
(M+1). IR (KBr): νmax 1160, 1285, 1510, 1710, 2320, 2950, 3300. Anal. Calcd for
C19H25F3N2O4: C 56.71, H 6.26, N 6.96; found: C 56.35, H 6.50, N 6.61.
Ethyl
(4R*,5S*)-5-(((benzyloxy)carbonyl)amino)-1-(2,2,2-trifluoroethyl)azepane-4-
carboxylate (±)-27
1
Colorless oil; yield: 21% (147 mg, two steps). (Rf= 0.30, n-hexane/EtOAc 3:1); H NMR
(DMSO, 400 MHz) δ = 1.20 (t, 3H, CH3, J = 8.2 Hz), 1.63-1.71 (m, 3H, CH2), 1.86-1.97 (m,
1H, CH2), 2.62-2.90 (m, 5H, H-5 and NCH2), 3.22-3.32 (m, 2H, NCH2), 3.97-4.04 (m, 2H,
OCH2), 4.10-4.17 (m, 1H, H-4), 4.97-5.03 (m, 2H, OCH2), 6.93 (brs, 1H, N-H), 7.30-7.47 (m,
13
5H, Ar-H). C NMR (100 MHz, DMSO): δ = 14.8, 26.7, 33.3, 47.6, 51.3, 51.7, 53.9, 57.6 (q,
2JC,F= 29.5 Hz, CCF3), 60.6, 66.1, 125.8 (q, 1JC,F = 279.5 Hz, CCF3), 128.2, 128.4, 129.2, 138.0,
156.1, 173.7. 19F NMR (100 MHz, DMSO): δ = -69.5. MS: (ESI) m/z = 403.4 (M+1). IR (KBr):
νmax 1110, 1290, 1500, 1720, 2320, 2950, 3450. Anal. Calcd for C19H25F3N2O4: C 56.71, H 6.26,
N 6.96; found: C 56.40, H 6.53, N 7.31.
Ethyl
(4S*,5S*)-5-(((benzyloxy)carbonyl)amino)-1-(2,2,2-trifluoroethyl)azepane-4-
carboxylate (±)-28
21

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White solid; yield: 29% (207 mg, two steps); mp = 37-40 °C. (Rf= 0.33, n-hexane/EtOAc 3:1);
1H NMR (DMSO, 400 MHz) δ = 1.16 (t, 3H, CH3, J = 8.2 Hz), 1.66-1.72 (m, 1H, CH2), 1.74-
1.83 (m, 3H, CH2), 2.54-2.60 (m, 1H, H-5), 2.69-2.74 (m, 2H, NCH2), 2.77-2.84 (m, 2H,
NCH2), 3.19-3.28 (m, 2H, NCH2), 3.83-3.90 (m, 1H, H-4), 3.98-4.08 (m, 2H, OCH2), 4.96-5.01
(m, 2H, OCH2), 7.30-7.46 (m, 6H, Ar-H and N-H).13C NMR (100 MHz, DMSO): δ = 14.8, 28.6,
2
1
34.8, 49.7, 51.7, 53.0, 53.8, 57.4 (q, JC,F= 29.4 Hz, CCF3), 60.6, 65.9, 125.8 (q, JC,F = 280.3
19
Hz, CCF3), 128.5, 128.6, 129.2, 138.1, 156.0, 174.6. F NMR (100 MHz, DMSO): δ = -69.0.
MS: (ESI) m/z = 403.4 (M+1). IR (KBr): νmax 1110, 1300, 1530, 1710, 2310, 2950, 3300. Anal.
Calcd for C19H25F3N2O4: C 56.71, H 6.26, N 6.96; found: C 57.02, H 6.52, N 6.63.
Ethyl
(1S*,5S*,6R*,7S*)-7-(((benzyloxy)carbonyl)amino)-3-(2,2,2-trifluoroethyl)-3-
azabicyclo[3.2.1]octane-6-carboxylate (±)-39
1
Colorless oil; yield: 42% (298 mg, two steps). (Rf= 0.33, n-hexane/EtOAc 4:1); H NMR
(DMSO, 400 MHz) δ = 1.08 (t, 3H, CH3, J = 8.1 Hz), 1.09-1.18 (m, 2H, CH2), 1.972.02 (m, 1H,
H-1), 2.20-2.25 (m, 1H, H-5), 2.33-2.38 (m, 1H, H-6), 2.59-2.64 (m, 1H, NCH2), 2.70-2.76 (m,
1H NCH2), 2.99-3.04 (m, 1H NCH2), 3.11-3.18 (m, 2H, NCH2), 3.79-3.99 (m, 3H, NCH2 and
13
OCH2), 4.23-4.28 (m, 1H, H-7), 4.99 (s, 2H, OCH2), 7.80-7.92 (m, 6H, Ar-H amd N-H). C
NMR (100 MHz, DMsO): δ = 14.8, 35.1, 39.8, 42.1, 53.6, 56.8, 57.0 (q, 2JC,F= 29.3 Hz, CCF3),
1
58.6, 59.2, 60.3, 66.1, 125.7, (q, JC,F = 276.4 Hz, CCF3), 128.5, 128.7, 129.4, 137.9, 156.2,
173.0.19F NMR (100 MHz, DMSO): δ = -68.1. MS: (ESI) m/z = 415.2 (M+1). IR (KBr): νmax
1180, 1530, 1720, 2940, 3410. Anal. Calcd for C20H25F3N2O4: C 57.96, H 6.08, N 6.76; found:
C 57.69, H 5.80, N 7.00.
22

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Ethyl
(1S*,5S*,6S*,7R*)-7-(((benzyloxy)carbonyl)amino)-3-(2,2,2-trifluoroethyl)-3-
azabicyclo[3.2.1]octane-6-carboxylate (±)-43
1
Colorless oil; yield: 78% (548 mg, two steps). (Rf= 0.33, n-hexane/EtOAc 4:1); H NMR
(DMSO, 400 MHz) δ = 1.14 (t, 3H, CH3, J = 8.1 Hz), 1.44-1.50 (m, 1H, CH2), 1.53-1.57 (m,
1H, CH2), 2.18-2.22 (m, 1H, H-1), 2.24-2.29 (m, 1H, H-6), 2.41-2.52 (m, 3H, H-6 and NCH2),
2.78-2.84 (m, 1H, NCH2), 3.04-3.12 (m, 3H, NCH2), 3.97-4.06 (m, 2H. OCH2), 4.40-4.48 (m,
13
1H, H-7), 5.02 (s, 2H, OCH2), 6.32 (brs, 1H, N-H), 7.30-7.47 (m, 5H, Ar-H). C NMR (100
MHz, DMSO): δ =14.7, 35.2, 37.7, 38.2, 47.1, 52.4, 56.2, 56.3, 56.7, (q, 2JC,F= 29.7 Hz, CCF3),
60.3, 66.5, 125.8 (q, 1JC,F = 279.4 Hz, CCF3), 128.2, 128.5, 129.1, 138.1, 156.7, 171.4.19F NMR
(100 MHz, DMSO): δ = -68.2. MS: (ESI) m/z = 415.4 (M+1). IR (KBr): νmax 1190, 1530, 1720,
2930, 3410. Anal. Calcd for C20H25F3N2O4: C 57.96, H 6.08, N 6.76; found: C 58.31, H 5.78, N
7.02.
Ethyl (3R*,4R*)-3-benzamido-1-(2-fluoroethyl)piperidine-4-carboxylate (±)-40
1
Colorless oil; yield: 53% (353 mg, two steps). (Rf= 0.20, n-hexane/EtOAc 3:1); H NMR
(DMSO, 400 MHz) δ =1.09 (t, 3H, CH3, J = 8.0 Hz), 1.60-1.66 (m, 1H, CH2), 2.04-2.10 (m, 1H,
CH2), 2.18-2.24 (m, 1H, H-4), 2.43-2.50 (m, 1H, NCH2), 2.59-2.70 (m, 3H, NCH2), 2.77-2.85
(m, 2H, NCH2), 3.91-4.04 (m, 2H, OCH2), 4.50-4.54 (m, 1H, H-3), 4.47-4.59 (dt, 2H, CH2F, 1J
23

ACCEPTED MANUSCRIPT
= 47.4 Hz, 2J = 5.45 Hz), 7.47-7.54 (m, 3H, Ar-H), 7.68-7.73 (m, 3H, Ar-H and N-H).13C NMR
2
(100 MHz, DMSO): δ = 14.8, 24.2, 41.0, 46.2, 52.4, 57.7, 58.1 (d, JC,F= 19.4 Hz, CCH2F),
2
60.7, 82.5 (d, JC,F = 164.8 Hz, CF2F), 128.1, 129.1, 132.0, 135.5, 166.8, 173.1.19F NMR (100
MHz, DMSO): δ = -217.1.MS: (ESI) m/z = 323.4 (M+1). IR (KBr): νmax 1310, 1520, 1680,
1720, 2990, 3480. Anal. Calcd for C17H23FN2O3: C 63.34, H 7.19, N 8.69; found: C 63.01, H
6.84, N 8.99.
Ethyl (3R*,4R*)-3-benzamido-1-(2,2-difluoroethyl)piperidine-4-carboxylate (±)-41
1
Colorless oil; yield: 68% (473 mg, two steps). (Rf= 0.22, n-hexane/EtOAc 2:1); H NMR
(DMSO, 400 MHz) δ = 1.08 (t, 3H, CH3, J = 8.1 Hz), 1.66-1.73 (m, 1H, CH2), 2.07-2.13 (m,
1H, CH2), 2.31-2.38 (m, 1H, H-4), 2.55-2.59 (m, 1H, NCH2), 2.70-2.97 (m, 5H, NCH2), 3.96-
1
2
4.04 (m, 2H, OCH2), 4.48-4.53 (m, 1H, H-3), 5.96-6.32 (tt, 1H, CHF2, J = 56.8 Hz, J = 4.9
Hz), 7.46-7.53 (m, 3H, Ar-H), 7.73-7.79 (m, 3H, Ar-H and N-H). 13C NMR (100 MHz, DMSO):
δ = 14.8, 24.3, 43.4, 47.0, 52.6, 58.0, 59.7 (t, 2JC,F= 26.4 Hz, CCF2), 61.1, 116.9 (t, 1JC,F = 264.8
19
Hz, CF2), 128.1, 128.9, 132.0, 135.6, 166.8, 173.0. F NMR (100 MHz, DMSO): δ = -118.6.
MS: (ESI) m/z = 341.3 (M+1). IR (KBr): νmax 1280, 1510, 1690, 1715, 2990, 3400. Anal. Calcd
for C17H22F2N2O3: C 59.99, H 6.51, N 8.23; found: C 59.63, H 6.12, N 7.89.
Acknowledgements
We are grateful to the Hungarian Research Foundation (OTKA K-115731) for financial support.
This paper was supported by the János Bolyai Research Scholarship to L. K. of the Hungarian
Academy of Sciences. The authors also thank Kitti Vasvári for experimental contribution.
24

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