Preparation and characterization of α-fluorinated-γ-aminophosphonates

Article abstract of DOI:10.1016/j.jfluchem.2014.06.008

Herein we would like to present a synthetic approach to series of α-fluorinated-γ-aminophosphonates, which were prepared by hydrogenolysis of (E)-α-fluorovinylphosphonates. The reaction conditions of hydrogenolysis in the presence of palladium on carbon h

Full text of DOI:10.1016/j.jfluchem.2014.06.008

Journal of Fluorine Chemistry 167 (2014) 128–134
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Preparation and characterization of
aminophosphonates
a-fluorinated-g-
*
´
Marcin Kazmierczak , Maciej Kubicki, Henryk Koroniak
Faculty of Chemistry, Adam Mickiewicz University in Poznan, Umultowska 89B, 61-614 Poznan´, Poland
A R T I C L E I N F O
A B S T R A C T
Article history:
Herein we would like to present a synthetic approach to series of
a-fluorinated-g-aminophosphonates,
Received 17 April 2014
Received in revised form 1 June 2014
Accepted 8 June 2014
which were prepared by hydrogenolysis of (E)- -fluorovinylphosphonates. The reaction conditions of
a
hydrogenolysis in the presence of palladium on carbon has been optimized. After conversion of
aminophosphonates to their oxalte salts, the absolute configuration of the main diastereoisomer has
Available online 13 June 2014
been determined by X-ray analysis.
a-Fluorinated-g-aminophosphonates can be used as convenient
precursors (‘‘building blocks’’) in the preparation of medicinally important analogues. As an example
Keywords:
preparation of dipeptide analogues of
a
-fluorinated-
g-aminophosphonates was described.
Fluorination
ß 2014 Elsevier B.V. All rights reserved.
Fluorine
Horner–Wadsworth–Emmons
HWE reaction
Fluorinated aminophophonates
Aminophosphonates
1. Introduction
2. Results and discussion
Aminophosphonates and aminophosphonic acids are important
substrates in the study of biochemical processes. They have found
a wide range of applications as enzyme inhibitors, agrochemicals
and pharmaceuticals in the areas of biological and medicinal
chemistry [1]. Due to the unique properties of fluorine atom, such
as high electronegativity and electron density, its presence in
aminophosphonates moiety can influence chemical reactivity,
biological and metabolic stability, chemical bonding ability and
solubility [2]. Recently, special interest has been focused on
synthesis of fluorinated aminophosphonates due to their promis-
ing applications in bioorganic chemistry [3,4]. Many of these
compounds exhibit antitumor, antibacterial and antifungal activi-
ties [5–9].
The first step in the synthesis of a-fluorinated-g-aminopho-
sphonates was a electrophilic fluorination of tetraethyl methyle-
nebisphosphonate with Selectfluor, leading to tetraethyl
fluoromethylenebisphosphonate 1, according to the Prestwich
procedure [13]. Carbonyl compounds 2a–f were prepared from
amino acids (a- -alanine, b- -valine, c- -leucine, d- -isoleucine, e-
phenylalanine, f-
a
L
-
-
L
L
L
L
D
-phenylglycine) in a three step procedure [16].
N,N-dibenzylamino aldehydes 2a–f were then treated with
lithiated carbanion generated by addition of n-BuLi to tetraethyl
fluoromethylenebisphosphonate 1 at ꢀ78 8C in dry THF. The HWE
olefination afforded (E)-a-fluorovinylphosphonates 3a–f exclu-
sively with good yields. Stereochemistry of compounds 3a–f was
confirmed by spectroscopic analysis [17,18]; e.g. 3e gave a doublet
2
3
The Horner–Wadsworth–Emmons (HWE) olefination reaction of
aldehydes or ketones with tetraalkyl fluoromethylenebisphospho-
of doublets at ꢀ125.74 ppm (dd, JF–P = 105.4, JF–H = 40.1 Hz) in
19F NMR spectra. The observed 3JF–H = 40.1 Hz coupling constant is
consistent to the coupling across the double bond between trans
oriented hydrogen and fluorine atoms. Furthermore, analysis of the
olefinic proton signal, appearing in the 1H NMR spectra as a
doublet of doublets of doublets also confirmed the stereochemistry
of the obtained products. For the derivative 3e this signal occurred
nate is one of the synthetic method to get access to
aminophosphonates via -fluorovinylphosphonates[10–15]. Herein
we would like to present synthetic approach to series of
fluorinated- -aminophosphonates,as wellastheirapplication in the
synthesis of dipeptide analogues.
a-fluorinated
a
a-
g
3
3
3
at 6.13 ppm (ddd, JH–F = 40.1, JH–H = 10.2, JH–P 8.0 Hz). In this
case 8.0 Hz coupling constant corresponds to Z relationship
between the phosphorous and the olefinic hydrogen atom attached
to the double bond (Scheme 1).
*
Corresponding author. Tel.: +48 618291225/+48 618291525.
E-mail address: marcin.kazmierczak@amu.edu.pl (M. Kaz´mierczak).
http://dx.doi.org/10.1016/j.jfluchem.2014.06.008
0022-1139/ß 2014 Elsevier B.V. All rights reserved.

´
M. Kazmierczak et al. / Journal of Fluorine Chemistry 167 (2014) 128–134
129
Table 1
(EtO)2(O)P
F
R
a)
(EtO)2(O)P
P(O)(OEt)2
Optimization of reaction conditions for the formation of 4a–e from 3a–f.
O
NBn2
NBn2
F
Entry Hydrogenation conditions
R
Cat.
v/v (%)
Solvent
Temperature
Time
(1)
(2a-f)
(3a-f)
1
2
3
4
5
6
7
8
10% Pd/C
5
EtOH
EtOH
EtOH
MeOH
AcOEt
AcOEt
TFE
RT
3 days
3 days
3 days
3 days
3 days
3 days
3 days
3 h
10% Pd(OH)2/C
20% Pd(OH)2/C
20% Pd(OH)2/C
10% Pd/C
5
RT
a: R=CH 3
b: R=CH(CH 3)2
c: R=CH 2CH(CH3)2
5
RT
5
RT
5
RT
d: R=CH(CH 3)CH2CH3
e: R=CH 2Ph
20% Pd(OH)2/C
10% Pd/C
5
RT
20
20
RT
10% Pd/C
THF
50 8C
f: R=Ph( ent.)
(a) n-BuLi, THF, -78°C
present the chemical shifts in 19F and 31P{/1H} NMR spectra, and
the ratio of diastereoisomers present in the mixture. The
hydrogenation was also successfully accomplished by Beier
approach (Table 1, entry 8), but with lower yield [20].
To determine the absolute configuration of the alpha carbon
atom with respect to the fluorine atom of 4a–e, we decided to
convert the amines into their corresponding oxalate salts (Table 3)
[21]. The reaction was conducted by addition of the anhydrous
oxalic acid in dry solvent to a vigorously mixed solution of amines
4a–e in a suitable media. For the compounds 4b–e the reactions
were carried out in anhydrous diethyl ether but for amine 4a –
Scheme 1. Synthesis of (E)-fluorovinylphosphonates 3a–f.
The next step in the synthesis was simultaneous hydrogenation
of the double bond and removal of benzyl protecting groups
(Scheme 2). First, 3a derivative was chosen as a model substrate to
optimize the reaction conditions (solvent, catalyst, catalyst
concentration, temperature). The reaction has been carried out
under hydrogen atmosphere, in various conditions (Table 1, entry
1–6). Unfortunately, we did not observe formation of the expected
products. Next, we have decided to adapt the methodology of
hydrogenation proposed by Whittaker, using trifluoroethanol
(TFE) as a solvent [19]. Comparing to Whittaker method we
increased the amount of the catalyst to 20% (v/v) and extended the
reaction time to 3 days (Table 1, entry 7). Under such conditions,
other (E)-fluorovinylphosphonates were also hydrogenated. After
the reaction was completed the catalyst was filtered off and the
crude products 4a–e were purified using flash chromatography.
The hydrogenation of diethyl (R,E)-(3-(dibenzylamino)-1-fluoro-
3-phenylprop-1-en-1-yl)phosphonate 3f resulted in a very com-
plicated mixture of products, which was confirmed by the 19F NMR
and 31P{/1H} NMR analysis. We assume, that this is due to the fact
that all phenyl groups of the molecule 3f are located at the benzylic
position on the nitrogen atom and are removed during the
hydrogenation reaction.
poorly soluble in ether
– tetrahydrofuran was used. The
precipitation of salts 5a–e proceeded immediately, however the
reaction mixtures were left in a freezer overnight. The next day the
oxalates 5a–e were filtered off to give a white crystalline solid with
a quantitative yield.
Unfortunately, the crystals were not suitable for X-ray
diffraction studies, moreover we have tried recrystallization of
the oxalate salts 5a–e from acetone and water. Only the
recrystallization of 5e from hot water provided a single crystals
suitable for X-ray analysis. The analysis confirmed the structure of
the resulting compound 5e. The crystals of a hydrate turned out to
contain only (1S,3S)-diastereoisomer (Fig. 1)1, supported by Flack
parameter value of 0.024(35). The O1-P1-C31-C32-C33-C34 chain
is in all-trans conformation (torsion angles 1658–1778), but phenyl
substituent is almost perpendicular to the chain plane, the dihedral
angle between these two planes is almost 788. In the crystal
structure the network of relatively strong O–Hꢁ ꢁ ꢁO and N–Hꢁ ꢁ ꢁO
intermolecular hydrogen bonds, involving also water molecules,
connect all the components of the crystal into three dimensional
structure (Fig. 2).
The aminophosphonates with unprotected amino group 4a–e
were isolated as a mixture of two diastereoisomers, which were
characterized by NMR spectroscopy. High diastereoselectivity of
the reduction of double bond is due to the fact that hydrogenation
takes place mainly from the least hindered face. In Table 2 we
We assume, on the basis of comparison of the signals intensity
in the 19F and 31P{/1H} NMR spectra of derivatives 4a–e with those
from 5a–e, that after the hydrogenation reaction in each case the
absolute configuration of alpha carbon atom with respect to the
fluorine atom is also 1S for the main diastereoisomer.
The aminophosphonates 4a–e also were converted into their
dipeptide analogues 6a–e in reaction with N-tert-butoxycarbonyl-
L-phenylalanine in presence of N-hydroxybenzotriazole (HOBt)
and N,N0-dicyclohexylcarbodiimide (DCC) as coupling reagents
(Scheme 3) [22]. The above mentioned synthesis of compounds
6a–e is an example how to incorporate fluorinated aminopho-
sphonate moieties into peptide chain.
In conclusion, we have demonstrated stereoselective synthesis
of (E)-a-fluorovinylphosphonates. These compounds were con-
verted to
a-fluorinated-g-aminophosphonates. We were able to
1
Crystallographic data (excluding structure factors) for the structural analysis
has been deposited with the Cambridge Crystallographic Data Centre, No. CCDC—
995090. Copies of this information may be obtained free of charge from: The
Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK. Fax: +44(1223)336-033, e-
mail: deposit@ccdc.cam.ac.uk or www.ccdc.cam.ac.uk.
Scheme 2. Synthesis of
a-fluorinated-g-aminophosphonates 4a–e.

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M. Kazmierczak et al. / Journal of Fluorine Chemistry 167 (2014) 128–134
130
Table 2
NMR data and diastereomeric ratio of compounds 4a–e.
19F NMR (ppm)
31P{/1H} NMR (ppm)
d.r.
Yield (%)
4a
4b
4c
4d
4e
ꢀ208.54 (dddd), ꢀ211.22 (dddd)a
18.61 (d),a17.79 (d)
19.85 (d),a18.60 (d)
18.95 (d),a17.97 (d)
19.84 (d),a18.56 (d)
18.62 (d),a17.71 (d)
90:10
85:15
80:20
80:20
90:10
87
72
69
77
82
ꢀ206.48 (dddd), ꢀ211.88 (dddd)a
ꢀ206.76 to –207.63 (m), ꢀ211.57 (dddd)a
ꢀ206.08 (dddd), ꢀ211.97 (dddd)a
ꢀ208.87 to – 209.86 (m), ꢀ211.48 (dddd)a
a
Signal of the main distereoisomer.
Table 3
Synthesis of oxalate salts 5a–e.
.
Fig. 2. The fragment of crystal packing as seen approximately along b—direction;
thin blue lines denote the hydrogen bonds. (For interpretation of the references to
colour in this figure legend, the reader is referred to the web version of this article.)
3. Experimental
(a) (COOH)2, Et2O or THF
3.1. General methods
19F NMR (ppm)
31P{/1H} NMR (ppm)
d.r.
1H NMR, 13C NMR, 19F NMR and 31P NMR spectra were
performed on Varian GEMINI 300 (300 MHz), Varian 400
(400 MHz), Bruker Avance 400 (400 MHz) or Bruker Avance 600
(600 MHz) spectrometers. Chemical shifts of 1H NMR were
expressed in parts per million downfield from tetramethylsilane
5a
5b
5c
ꢀ209.25 (dddd), ꢀ210.37 (dddd)a
ꢀ209.66 (dddd), ꢀ211.88 (dddd)a
ꢀ209.51 to ꢀ210.22 (m), ꢀ210.62
(dddd)a
ꢀ209.15 (dddd) ꢀ212.16 (dddd)a
ꢀ209.78 to ꢀ210.36 (m), ꢀ210.41
to ꢀ211.15 (m)a
18.41 (d),a18.19 (d)
18.46 (d),a17.99 (d)
18.38 (d),a18.02 (d)
90:10
85:15
80:20
5d
5e
20.48 (d),a19.96 (d)
18.06 (d),a17.78 (d)
80:20
90:10
(TMS) as an internal standard (
13C NMR were expressed in parts per million downfield from CDCl3
as an internal standard (
= 77.0). Chemical shifts of 19F NMR were
expressed in parts per million upfiled from CFCl3 as an internal
standard (
= 0) in CDCl3. Chemical shifts of 31P NMR were
expressed in parts per million downfield from 85% H3PO4 as an
external standard (
= 0) in H2O. 1H, 13C NMR chemical shifts are
d = 0) in CDCl3. Chemical shifts of
a
Signal of the main distereoisomer.
d
d
determine the absolute configuration of the main diastereoisomer
by converting them to the oxalate salts. Moreover -fluorinated-g-
a
d
aminophosphonates can be used as convenient precursors for the
new class of building blocks in the preparation of medicinally
important analogues.
reported for the major diastereoisomer only. Mass spectra were
recorded by electron impact (MS-EI) techniques using AMD-402 or
Bruker 320-MS spectrometer. X-ray diffraction data were collected
at room temperature by the
v-scan technique on Agilent
Technologies four-circle SuperNova (Atlas detector) with mirror-
˚
monochromatized Cu K
a radiation (l = 1.54178 A). The data were
(EtO)2(O)P
F
Ph
(EtO)2(O)P
F
H
N
a)
NH2
NHt-Boc
R
O
R
(4a-e)
(6a-e)
a: R=CH3
b: R=CH(CH 3)2
c: R=CH2CH(CH3)2
d:
R=CH(CH 3)CH2CH3
e: R=CH2Ph
(a) N-t-Boc-Phe, DCC, HOBt, DMF, CH2Cl2
Fig. 1. Molecular structure of compound (1S,3S)-5e (ORTEP image).
Scheme 3. Synthesis of dipeptide analogues 6a–e.

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M. Kazmierczak et al. / Journal of Fluorine Chemistry 167 (2014) 128–134
131
corrected for Lorentz-polarization and absorption effects [23].
13C NMR (101 MHz, CDCl3)
d
150.56 (dd, J = 276.4, 232.8 Hz, CFP),
Accurate unit-cell parameters were determined by a least-squares
fit of 3423 reflections of highest intensity, chosen from the whole
experiment. The structures were solved with SIR92 [24] and
refined with the full-matrix least-squares procedure on F2 by
SHELXL97 [25]. All non-hydrogen atoms were refined anisotropi-
cally, hydrogen atoms involved in strong hydrogen bonds were
located in difference Fourier maps and isotropically refined, all
other H atoms were placed in the calculated positions, and refined
as ‘riding model’ with the isotropic displacement parameters set at
1.2 (1.5 for methyl groups) times the Ueq value for appropriate non-
hydrogen atom. Reagent grade chemicals were used Solvents were
dried by refluxing with sodium metal-benzophenone (THF), with
CaCl2 (CH2Cl2), NaH (Et2O) and distilled under argon atmosphere.
All moisture sensitive reactions were carried out under argon
atmosphere using oven-dried glassware. Reaction temperatures
below 0 8C were performed using a cooling bath (liquid N2/hexane
or CO2/isopropanol). TLC was performed on Merck Kieselgel 60-
F254 with EtOAc/hexane as developing systems, and products
were detected by inspection under UV light (254 nm) and with a
solution of potassium permanganate. Merck Kieselgel 60 (230–
400 mesh) was used for column chromatography. Selectfluor was
obtained from Aldrich.
139.61, 128.46, 128.11, 126.84, 125.57 (dd, J = 25.7, 6.3 Hz), 63.06
(d, J = 6.4 Hz), 63.04 (d, J = 4.7 Hz), 53.92, 48.50 (dd, J = 10.3,
1.9 Hz), 18.16, 16.27 (d, J = 6.1 Hz), 16.15 (d, J = 6.2 Hz). 19F NMR
(379 MHz, CDCl3)
d
ꢀ127.02 (dd, J = 105.1, 41.0 Hz, 1F). 31P{/1H}
NMR (121 MHz, CDCl3)
d 4.86 (d, J = 105.1 Hz, 1P).
3b: Yield: 68%, pale yellow oil, 1H NMR (300 MHz, CDCl3)
d
7.45–7.19 (m, 10H, Ar), 6.00 (ddd, J = 40.9, 10.7, 8.1 Hz, 1H, CHCFP),
4.35–4.08 (m, 4H, 2ꢂ OCH2CH3), 3.86 (d, J = 13.6 Hz, 2H,
NCHaHbPh), 3.26–3.16 (m, 1H, CHNBn2), 3.21 (d, J = 13.7 Hz, 2H,
NCHaHbPh), 1.87 (qd, J = 13.1, 6.6 Hz, 3H, CH(CH3)2), 1.47 (td,
J = 7.1, 0.5 Hz, 3H, OCH2CH3), 1.37 (td, J = 7.1, 0.5 Hz, 3H, OCH2CH3),
1.08 (d, J = 6.5 Hz, 3H, CH3), 0.77 (d, J = 6.6 Hz, 3H, CH3). 13C NMR
(101 MHz, CDCl3)
d 151.67 (dd, J = 275.5, 231.2 Hz, CFP), 139.36,
128.64, 128.04, 126.81, 123.57 (dd, J = 25.7, 7.5 Hz), 63.06 (d,
J = 5.4 Hz), 62.96 (d, J = 5.3 Hz), 59.51 (d, J = 9.5 Hz), 54.05, 29.10,
20.03, 19.98, 16.30 (d, J = 6.1 Hz), 16.11 (d, J = 6.1 Hz). 19F NMR
(282 MHz, CDCl3)
NMR (121 MHz, CDCl3)
d
ꢀ126.32 (dd, J = 106.8, 40.9 Hz, 1F). 31P{/1H}
d 4.88 (d, J = 106.8 Hz, 1P).
3c: Yield: 60%, pale yellow oil, 1H NMR (300 MHz, CDCl3)
d
7.38–7.19 (10H, Ar), 6.02 (ddd, J = 40.9, 10.1, 8.0 Hz, 1H, CHCFP),
4.33–4.09 (m, 4H, 2ꢂ OCH2CH3), 3.83 (d, J = 13.6 Hz, 2H, NCH2Ph),
3.79–3.75 (m, 1H, CHNBn2), 3.26 (d, J = 13.6 Hz, 2H, NCH2Ph), 1.82–
1.59 (m, 2H, (CH3)2CHCHa,CHb), 1.46 (td, J = 7.1, 0.5 Hz, 3H,
OCH2CH3), 1.37 (td, J = 7.1, 0.6 Hz, 3H, OCH2CH3), 1.26 (dt,
J = 13.8, 4.9 Hz, 1H, (CH3)2CHCHaCHb), 0.79 (d, J = 6.6 Hz, 3H,
3.2. General procedures
3.2.1. Tetraethyl fluoromethylenebisphosphonate 1
CH3), 0.65 (d, J = 6.5 Hz, 3H, CH3). 13C NMR (101 MHz, CDCl3)
d
1H NMR (403 MHz, CDCl3)
d
5.03 (dtd, J = 45.9, 13.6, 0.9 Hz, 1H,
150.86 (dd, J = 275.8, 232.1 Hz, CFP), 139.37, 128.59, 127.95,
126.77, 124.36 (dd, J = 25.5, 7.0 Hz), 62.97 (d, J = 3.6 Hz), 62.92 (d,
J = 3.7 Hz), 53.91, 50.52 (d, J = 9.7 Hz), 41.67, 24.35, 22.62, 21.85,
16.19 (d, J = 6.1 Hz), 16.04 (d, J = 6.1 Hz). 19F NMR (282 MHz,
CHF), 4.36–4.23 (m, 8H, 4ꢂ OCH2CH3), 1.39 (td, J = 7.0, 0.9 Hz, 12H,
4ꢂ OCH2CH3). 19F NMR (379 MHz, CDCl3)
d
ꢀ228.32 (dt, JF–
P,H = 63.3, 45.9 Hz, 1F). 31P{/1H} NMR (163 MHz, CDCl3)
d 11.07 (d,
JP–F = 63.3 Hz, 2P).
Tetraethyl fluoromethylenebisphosphonate 1 was prepared
according to the Prestwich procedure [13].
CDCl3)
d
ꢀ126.87 (dd, J = 106.1, 40.9 Hz, 1F). 31P{/1H} NMR
(121 MHz, CDCl3) d 4.85 (d, J = 106.2 Hz, 1P).
3d: Yield: 45%, pale yellow oil, 1H NMR (300 MHz, CDCl3)
d
7.40–7.19 (m, 10H, Ar), 6.02 (ddd, J = 40.9, 10.7, 8.1 Hz, 1H, CHCFP),
4.36–4.07 (m, 4H, 2ꢂ OCH2CH3), 3.85 (d, J = 13.6 Hz, 2H,
NCHaHbPh), 3.34 (td, J = 10.8, 1.4 Hz, 1H, CHNBn2), 3.21 (dd,
J = 13.6, 1.2 Hz, 2H, NCHaHbPh), 2.06–1.98 (m, 1H, CHCH3), 1.75–
1.60 (m, 1H, CH3CHa), 1.47 (dt, J = 7.1, 0.4 Hz, 3H, OCH2CH3), 1.37
(dt, J = 7.1, 0.5 Hz, 3H, OCH2CH3), 1.17–1.01 (m, 1H, CH3CHb), 0.74
3.2.2. N,N-dibenzylamino aldehydes 2a–f
3.2.2.1. N,N-dibenzylamino alcohols were prepared from
a-amino
acids [16]. The NMR data of all the synthesized N,N-dibenzylamino
alcohols were in good agreement with the reported data from an
alternative synthesis [16,26,27].
(br. t, J = 7.0 Hz, 6H, 2ꢂCH3). 13C NMR (75 MHz, CDCl3)
d 151.65
(dd, J = 275.4, 231.3 Hz, CFP), 139.40, 128.81), 128.07, 126.86,
123.56 (dd, J = 25.7, 7.5 Hz), 63.06 (d, J = 5.6 Hz), 62.97 (d,
J = 5.4 Hz), 57.71 (d, J = 9.5 Hz), 54.21, 35.04, 25.10, 16.33 (d,
J = 6.1 Hz), 16.16 (d, J = 6.2 Hz), 15.91, 10.33. 19F NMR (282 MHz,
3.2.2.2. N,N-dibenzylamino alcohols were next converted to corre-
sponding N,N-dibenzylamino aldehydes 2a–f [16]. Carbonyl com-
pounds 2a–f after extraction and evaporation of solvents, were
sufficiently pure to be used directly in the HWE reaction.
CDCl3)
(121 MHz, CDCl3)
d
ꢀ126.57 (dd, J = 107.5, 40.8 Hz, 1F). 31P{/1H} NMR
d 4.97 (d, J = 107.5 Hz, 1P).
3e: Yield: 69%, pale yellow oil, 1H NMR (403 MHz, CDCl3)
d
3.2.3. Horner–Wadsworth–Emmons reaction
Lithium tetraethyl fluoromethylenebisphosphonate was pre-
pared by addition of n-BuLi (3 mmol, 1.3 equiv., 2 M in pentane) to
a stirred solution of tetraethyl fluoromethylenebisphosphonate 1
(2.3 mmol, 1.3 equiv.) in THF (1 mL) under an atmosphere of argon
at ꢀ78 8C. After 10 min N,N-dibenzylamino aldehydes 2a–f
(1.74 mmol, 1 equiv.) in THF (1 mL) were added dropwise into
the solution. Reaction mixtures were then slowly allowed to warm
to room temperature and stirred overnight. The reaction was
quenched by addition of saturated solution of NH4Cl (10 mL).
Crude products were extracted to AcOEt (3 ꢂ 10 mL), dried over
MgSO4, filtered, concentrated under reduced pressure and purified
using flash chromatography (n-hexane: AcOEt 95:5 ! 50:50).
7.33–7.17 (m, 13H, Ar), 7.04 (dd, J = 7.7, 1.7 Hz, 2H, Ar), 6.13 (ddd,
J = 40.1, 10.2, 8.0 Hz, 1H, CHCFP), 4.23 (dqd, J = 8.4, 7.1, 1.4 Hz, 2H,
OCH2CH3), 4.17–4.06 (m, 1H, PhCH2CHNBn2), 4.04–3.95 (m, 1H,
OCHaHb), 3.93 (d, J = 13.8 Hz, 2H, NCH2Ph), 3.82 (ddq, J = 10.1, 8.3,
7.1 Hz, 1H, OCHaHb), 3.37 (d, J = 13.8 Hz, 2H, NCH2Ph), 3.09 (dd,
J = 13.7, 7.3 Hz, 1H PhCHaHb), 2.83 (dd, J = 13.7, 8.4 Hz, 1H,
PhCHaHb), 1.44 (td, J = 7.1, 0.6 Hz, 3H, OCH2CH3), 1.24 (td, J = 7.1,
0.7 Hz, 3H, OCH2CH3). 13C NMR (151 MHz, CDCl3)
d 151.43 (dd,
J = 277.9, 229.6 Hz, CFP), 139.27, 138.10, 129.31, 128.55, 128.15,
128.11, 126.93, 126.20, 123.63 (dd, J = 25.8, 6.9 Hz), 63.18 (d,
J = 5.4 Hz), 62.97 (d, J = 5.0 Hz), 54.47 (d, J = 10.0 Hz), 54.16, 39.04,
16.31 (d, J = 6.1 Hz), 16.06 (d, J = 6.5 Hz). 19F NMR (379 MHz,
3a: Yield: 73%, pale yellow oil, 1H NMR (403 MHz, CDCl3)
d
CDCl3)
(121 MHz, CDCl3)
d
ꢀ125.74 (dd, J = 105.4, 40.1 Hz, 1F). 31P{/1H} NMR
7.38–7.20 (m, 10H, Ar), 6.05 (ddd, J = 41.0, 9.3, 8.1 Hz, 1H, CHCFP),
4.28–4.10 (m, 4H, 2ꢂ OCH2CH3), 3.89 (dqd, J = 9.0, 6.9, 2.1 Hz, 1H,
CH3CHNBn2), 3.79 (d, J = 13.8 Hz, 2H, OCH2CH3), 3.36 (d,
J = 13.8 Hz, 2H, OCH2CH3), 1.43 (td, J = 7.1, 0.5 Hz, 3H, OCH2CH3),
1.36 (td, J = 7.1, 0.6 Hz, 3H, OCH2CH3), 1.27 (d, J = 6.8 Hz, 3H, CH3).
d 4.55 (d, J = 105.4 Hz, 1P).
3f: Yield: 64%, pale yellow oil, 1H NMR (403 MHz, CDCl3)
d 7.51–
7.18 (m, 15H, Ar), 6.42 (ddd, J = 39.6, 10.1, 7.9 Hz, 1H, CHCFP), 4.97
(d, J = 10.2 Hz, 1H, CHNBn2), 4.33–4.12 (m, 4H, 2ꢂ OCH2CH3), 3.76
(d, J = 13.6 Hz, 2H, NCHaHbPh), 3.43 (d, J = 13.7 Hz, 2H, NCHaHbPh),

´
M. Kazmierczak et al. / Journal of Fluorine Chemistry 167 (2014) 128–134
132
1.45 (td, J = 7.1, 0.4 Hz, 3H, OCH2CH3), 1.34 (td, J = 7.1, 0.4 Hz, 3H,
OCH2CH3). 13C NMR (101 MHz, CDCl3)
152.28 (dd, J = 279.1,
diastereoisomer 18.62 (d, J = 74.4 Hz, 1P), minor diastereoisomer
17.71 (d, J = 74.6 Hz, 1P).
d
231.7 Hz, CFP), 139.77 (d, J = 1.6 Hz), 138.96, 128.57, 128.27,
128.13, 127.55, 127.34, 126.94, 121.97 (dd, J = 26.5, 5.4 Hz), 63.16
(d, J = 5.5 Hz), 63.14 (d, J = 5.6 Hz), 56.28 (dd, J = 10.3, 2.9 Hz),
53.78, 16.28 (d, J = 6.1 Hz), 16.10 (d, J = 6.1 Hz). 19F NMR (379 MHz,
3.2.5. Oxalate synthesis
A solution of derivatives 4a–e (1 equiv.) in anhydrous diethyl
ether or tetrahydrofuran were added dropwise to a vigorously
stirred solutions of oxalic acid (1 equiv.) in suitable solvent. The
mixtures were left overnight in a freezer. The next day, the
precipitates were filtered off to give a white solid.
CDCl3)
d
ꢀ125.32 (dd, J = 103.9, 39.5 Hz, 1F). 31P{/1H} NMR
(121 MHz, CDCl3)
d 4.19 (d, J = 104.1 Hz, 1P).
3.2.4. Hydrogenation reaction
5a: White solid 1H NMR (403 MHz, D2O, TMS in CDCl3 ext
) d
Derivatives 3a–f (1 equiv.) were dissolved in 5 mL of TFE and
then 10% Pd/C (20% v/v) was added. The solutions were stirred
under an atmosphere of hydrogen at room temperature for 3 days.
After this time the catalyst was filtered off, the solvent was
evaporated and the crude products were purified using flash
chromatography (CHCl3:MeOH 100:0 ! 50:50).
5.38–5.19 (m, 1H, CHFP), 4.34–4.24 (m, 4H, OCH2CH3), 3.77–3.68
(m, 1H, CHNH3+), 2.40–2.15 (m, 2H, CHFPCH2), 1.41 (d, J = 6.7 Hz,
3H, CH3), 1.37 (t, J = 7.1 Hz, 6H, 2ꢂ OCH2CH3). 13C NMR (101 MHz,
D2O, CDCl3 ext) d 165.64 (s, C(O)), 85.34 (dd, J = 175.8, 173.1 Hz,
CPF), 65.36 (d, J = 7.0 Hz), 65.15 (d, J = 6.8 Hz), 45.00 (d, J = 15.3 Hz),
33.71 (d, J = 19.6 Hz), 17.75, 15.74, 15.69. 19F NMR (121 MHz, D2O,
4a: Yield: 87%, colorless oil 1H NMR (300 MHz, CDCl3)
d
5.05
CFCl3 in CDCl3 ext
46.4, 44.3, 14.5 Hz, 1F), major diastereoisomer ꢀ210.37 (dddd,
J = 64.6, 46.3, 38.7, 18.8 Hz, 1F). 31P{/1H} NMR (121 MHz, D2O)
)
d
minor diastereoisomer ꢀ209.25 (dddd, J = 76.2,
(dddd, J = 47.2, 11.4, 3.4, 2.3 Hz, 1H, CHFP), 4.28–4.15 (m, 4H, 2ꢂ
OCH2CH3), 3.23–3.12 (m, 1H, NH2CH), 2.04 (tddd, J = 8.4, 6.0, 5.4,
3.0 Hz, 1H, CHFPCHaHb), 1.85–1.65 (m, 1H, CHFPCHaHb), 1.64
(s, 2H, NH2), 1.37 (t, J = 7.1 Hz, 6H, 2ꢂ OCH2CH3), 1.18
d
major diastereoisomer 18.41 (d, J = 76.2 Hz, 1P), minor diastereo-
isomer 18.19 (d, J = 76.3 Hz, 1P).
(d, J = 6.5 Hz, 3H, CH3). 19F NMR (282 MHz, CDCl3)
d
minor
5b: White solid 1H NMR (300 MHz, D2O, TMS in CDCl3 ext
) d
diastereoisomer ꢀ208.54 (dddd, J = 74.4, 47.3, 40.0, 16.6 Hz, 1F),
major diastereoisomer ꢀ211.22 (dddd, J = 74.6, 47.2, 43.5,
5.43–5.17 (m, 1H, CHFP), 4.41–4.21 (m, 4H, OCH2CH3), 3.57–3.36
(m, 1H, CHNH3+), 2.50–1.97 (m, 2H, CHFPCH2), 1.49–1.42 (m,
(CH3)2CH), 1.39 (t, J = 7.1 Hz, 6H, 2ꢂ OCH2CH3), 1.04 (t, J = 7.0 Hz,
14.8 Hz, 1F). 31P{/1H} NMR (121 MHz, CDCl3)
d major diastereo-
isomer 18.61 (d, J = 74.5 Hz, 1P), minor diastereoisomer 17.79
(d, J = 74.4 Hz, 1P).
6H, 2ꢂ CH3). 13C NMR (75 MHz, D2O, CDCl3 ext
) d 164.50 (s, C(O)),
85.25 (dd, J = 176.4, 173.0 Hz, CPF), 65.40 (d, J = 7.1 Hz), 65.20 (d,
J = 6.9 Hz), 53.49 (d, J = 12.4 Hz), 29.71, 29.44 (d, J = 19.5 Hz), 17.25,
17.06, 15.79, 15.72. 19F NMR (282 MHz, D2O, CFCl3 in CDCl3 ext
) d
4b: Yield: 72%, colorless oil 1H NMR (300 MHz, CDCl3)
d 5.28–
5.05 (m, 1H, CHFP), 4.33–4.10 (m, 4H, 2ꢂ OCH2CH3), 2.82–2.73 (m,
1H, NH2CH), 2.13–1.92 (m, 1H, CHFPCHaHb), 1.73–1.46 (m, 2H,
CHFPCHaHb, CH(CH3)2), 1.37 (t, J = 7.1 Hz, 6H, 2ꢂ OCH2CH3), 1.30
(s, 2H, NH2), 0.93 (d, J = 6.8 Hz, 3H, CH3), 0.89 (d, J = 6.8 Hz, 3H,
minor diastereoisomer ꢀ209.66 (dddd, J = 76.5, 45.2, 39.7, 15.1,
1F), major diastereoisomer ꢀ211.88 (dddd, J = 75.7, 45.9, 38.9,
18.0 Hz, 1F). 31P{/1H} NMR (121 MHz, D2O)
d major diastereo-
CH3). 19F NMR (282 MHz, CDCl3)
d
minor diastereoisomer ꢀ206.48
isomer 18.46 (d, J = 76.4 Hz, 1P), minor diastereoisomer 17.99 (d,
J = 77.1 Hz, 1P).
(dddd, J = 75.1, 46.9, 35.7, 18.3 Hz, 1F), major diastereoisomer
ꢀ211.88 (dddd, J = 74.8, 46.7, 44.6, 14.2 Hz, 1F). 31P{/1H} NMR
5c: White solid 1H NMR (403 MHz, D2O, TMS in CDCl3 ext
) d
(121 MHz, CDCl3)
d
major diastereoisomer 19.85 (d, J = 74.8 Hz,
5.42–5.23 (m, 1H, CHFP), 4.35–4.25 (4H, OCH2CH3), 3.76–3.60 (m,
1H, CHNH3+), 2.27 (m, 2H, CHFPCH2), 1.81–1.56 (m, 3H,
(CH3)2CHCH2), 1.38 (t, J = 7.0 Hz, 6H, 2ꢂ OCH2CH3), 0.96 (t,
1P), minor diastereoisomer 18.60 (d, J = 75.3 Hz, 1P).
4c: Yield: 69%, colorless oil 1H NMR (300 MHz, CDCl3)
d
5.13
(dddd, J = 47.1, 11.6, 3.1, 2.3 Hz, 1H, CHFP), 4.28–4.14 (m, 2ꢂ
OCH2CH3), 3.08–2.97 (m, 1H, NH2CH), 2.17–1.85 (m, 2H, CHFPCH2),
1.80–1.50 (m, 5H, (CH3)2CHCH2, NH2), 1.36 (t, J = 7.1 Hz, 6H, 2ꢂ
OCH2CH3), 0.91 (t, J = 6.6 Hz, 6H, (CH3)2). 19F NMR (282 MHz,
J = 6.0 Hz, 6H, (CH3)2). 13C NMR (101 MHz, D2O, CDCl3
) d
ext
164.34 (s, C(O)), 85.30 (dd, J = 174.7, 173.4 Hz, CPF), 65.38 (d,
J = 6.8 Hz), 65.18 (d, J = 6.8 Hz), 46.89 (d, J = 13.9 Hz), 40.58, 31.97
(d, J = 19.4 Hz), 23.86, 21.51, 21.32, 15.79, 15.74. 19F NMR
CDCl3)
diastereoisomer ꢀ211.57 (dddd, J = 74.6, 46.8, 44.4, 14.6 Hz, 1F).
31P{/1H} NMR (121 MHz, CDCl3)
major diastereoisomer 18.95 (d,
J = 74.7 Hz, 1P), minor diastereoisomer 17.97 (d, J = 74.9 Hz, 1P).
4d: Yield: 77%, colorless oil 1H NMR (300 MHz, CDCl3)
5.15
d
minor diastereoisomer ꢀ206.76 to ꢀ207.63 (m, 1F), major
(282 MHz, D2O, CFCl3 in CDCl3
) d minor diastereoisomer
ext
ꢀ209.51 to ꢀ210.22 (m, 1F), major diastereoisomer ꢀ210.62
d
(dddd, J = 77.2, 46.0, 41.0, 17.8 Hz, 1F). 31P{/1H} NMR (121 MHz,
D2O)
d major diastereoisomer 18.38 (d, J = 79.7 Hz, 1P), minor
d
diastereoisomer 18.02 (d, J = 76.9 Hz, 1P).
(ddt, J = 46.9, 11.6, 2.1 Hz, 1H, CHFP), 4.30–4.10 (m, 4H, 2ꢂ
OCH2CH3), 2.87 (dd, J = 11.0, 2.9 Hz, 1H, NH2CH), 2.13–1.87 (m, 1H,
CHFPCHaHb, 1H, CHCH3), 1.72–1.59 (m, 1H, CH3CHa), 1.57–1.45 (m,
1H, CHFPCHaHb), 1.38 (d, J = 7.1 Hz, 6H, 2ꢂ OCH2CH3), 1.30 (br.s,
NH2), 1.21–1.09 (m, 1H, CH3CHb), 0.91 (t, J = 7.2 Hz, 3H, CH3), 0.89
5d: White solid 1H NMR (300 MHz, D2O, TMS in CDCl3 ext
) d
5.42–5.11 (m, 1H, CHFP), 4.38–4.20 (m, 4H, 2ꢂ OCH2CH3), 3.63–
3.54 (m, 1H, CHNH3+), 2.39–2.03 (m, CHFPCHaHb, 1H, CHCH3),
1.94–1.78 (m, 1H, CH3CHa), 1.53–1.42 (m, CHFPCHaHb), 1.37 (t,
J = 7.0 Hz, 6H, 2ꢂ OCH2CH3), 1.31–1.23 (m, 1H, CH3CHb), 1.00–0.95
(t, J = 7.3 Hz, 3H, CH3), 0.92 (d, J = 7.0 Hz, 3H, CH3). 13C NMR
(d, J = 6.7 Hz, 3H, CH3). 19F NMR (282 MHz, CDCl3)
d minor
diastereoisomer ꢀ206.08 (dddd, J = 75.7, 47.1, 35.0, 18.4 Hz, 1F),
(101 MHz, D2O, CDCl3 ext) d 164.64 (s, C(O)), 85.16 (dd, J = 176.6,
major diastereoisomer ꢀ211.97 (dddd, J = 74.9, 46.9, 44.4, 14.3 Hz,
173.0 Hz), 65.36 (d, J = 7.0 Hz), 65.16 (d, J = 6.9 Hz), 51.51 (d,
J = 12.8 Hz), 36.40, 28.50 (d, J = 19.6 Hz), 24.80, 15.77, 15.72, 13.02,
10.60. 19F NMR (282 MHz, D2O, CFCl3 in CDCl3 ext))
d minor
1F). 31P{/1H} NMR (121 MHz, CDCl3)
d major diastereoisomer 19.84
(d, J = 74.9 Hz, 1P), minor diastereoisomer 18.56 (d, J = 75.4 Hz, 1P).
4e: Yield: 82%, colorless oil 1H NMR (403 MHz, CDCl3)
7.34–
d
diastereoisomer ꢀ209.15 (dddd, J = 76.2, 47.2, 33.5, 14.5, 1F),
7.15 (m, 5H, Ar), 5.14 (dddd, J = 47.1, 11.5, 3.0, 2.3 Hz, 1H, CHFP),
4.25–4.14 (m, 4H, 2ꢂ OCH2CH3), 3.29–3.21 (m, 1H, NH2CH), 2.86
(dd, J = 13.5, 4.8 Hz, 2H, NCHaHbPh), 2.55 (dd, J = 13.5, 8.6 Hz, 2H,
NCHaHbPh), 2.24–2.09 (m, 1H, CHFPCHaHb), 1.83–1.63 (m, 1H,
major diastereoisomer ꢀ212.16 (dddd, J = 76.5, 46.1, 37.9, 18.9 Hz,
1F). 31P{/1H} NMR (121 MHz, D2O)
d major diastereoisomer 20.48
(d, J = 77.1 Hz, 1P), minor diastereoisomer 19.96 (d, J = 78.5 Hz, 1P).
5e: White solid 1H NMR (300 MHz, D2O, TMS in CDCl3
)
ext
d
CHFPCHaHb), 1.54 (s, 2H, NH2), 1.37–1.32 (m, 6H, 2ꢂ OCH2CH3). 19
F
7.51–7.30 (m, 5H, Ar), 5.48–5.21 (m, 1H, CHFP), 4.31–4.16 (m, 4H,
OCH2CH3), 3.97–3.85 (m, 1H, CHNH3+), 3.10 (d, J = 7.3 Hz, 2H,
PhCH2), 2.48–2.08 (m, 2H, CHFPCH2), 1.41–1.23 (m, 1H). 13C NMR
NMR (379 MHz, CDCl3)
d
minor diastereoisomer ꢀ208.87 to
ꢀ209.86 (m, 1F), major diastereoisomer ꢀ211.48 (dddd, J = 74,5,
47.8, 44.1, 14.4 Hz). 31P{/1H} NMR (121 MHz, CDCl3)
d
major
(75 MHz, D2O, CDCl3 ext) d 165.50 (s, C(O)), 135.15, 129.46, 129.25,

´
M. Kazmierczak et al. / Journal of Fluorine Chemistry 167 (2014) 128–134
133
127.78, 85.20 (dd, J = 176.3, 173.2 Hz, CPF), 65.35 (d, J = 7.1 Hz),
65.15 (d, J = 6.9 Hz), 49.77 (d, J = 12.9 Hz), 37.85, 31.37 (d,
J = 19.5 Hz), 15.74, 15.67. 19F NMR (282 MHz, D2O, CFCl3 in CDCl3
4.10 (m, 5H, 2ꢂ OCH2CH3, CHNH), 3.08 (dd, J = 13.6, 7.4 Hz, 1H,
NCHaHbPh), 3.02 (dd, J = 13.8, 6.6 Hz, 1H, NCHaHbPh), 2.11–1.89
(m, 2H, CH2CHF), 1.79–1.51 (m, 3H, (CH3)2CHCH2), 1.41 (s, 9H,
C(CH3)3), 1.35 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.34 (t, J = 7.1 Hz, 3H,
OCH2CH3), 0.89 (d, J = 6.5 Hz, 3H, CH3), 0.86 (d, J = 6.6 Hz, 3H, CH3).
)
d
minor diastereoisomer ꢀ209.78 to ꢀ210.36 (m, 1F), major
ext
diastereoisomer ꢀ210.41 to ꢀ211.15 (m, 1F). 31P{/1H} NMR
(121 MHz, D2O)
d
major diastereoisomer 18.06 (d, J = 76.4 Hz,
13C NMR (101 MHz, CDCl3)
d 170.85, 155.36, 136.60, 129.19,
1P), minor diastereoisomer 17.78 (d, J = 76.6 Hz, 1P). Crystal data:
(C14H24FNO3P)+ꢁ(C2HO4)ꢀꢁH2O, Mr = 411.36, monoclinic, P21,
128.55, 126.86, 85.51 (dd, J = 180.3, 171.3 Hz, CFP), 80.06, 63.21 (d,
J = 6.8 Hz), 62.73 (d, J = 6.8 Hz), 56.07, 43.80 (d, J = 18.0 Hz), 37.87,
35.62 (d, J = 19.8 Hz), 28.14, 24.58, 22.89, 21.91, 16.40 (d,
˚
˚
˚
b
a = 10.3025(4)A, b = 5.6308(2) A, c = 17.5579(6) A,
= 94.938(4)8,
3
V = 1014.78(6) A , Z = 2, dx = 1.35g cmꢀ3
,
F(0 0 0) = 436,
m
l
(Cu
(Cu
J = 4.6 Hz), 16.34 (d, J = 5.1 Hz). 19F NMR (282 MHz, CDCl3)
d minor
˚
K ) = 1.66 cmꢀ1
.
Agilent SuperNova diffractometer,
diastereoisomer ꢀ206.43 to ꢀ207.60 (m, 1F), major diastereo-
a
K ) = 1.54178 A, 4277 reflections collected, 2953 unique
isomer ꢀ209.31 to ꢀ210.67 (m, 1F). 19F{/1H} NMR (377 MHz,
˚
a
(Rint = 2.03%), final R = 3.98%, wR2 = 10.99%, S = 1.028, (Dr
)
CDCl3)
d
minor diastereoisomer ꢀ207.14 (d, J = 75.7 Hz, 1F), major
max/
ꢀ3
.
in final
D
F map: 0.36/ꢀ0.24e A
diastereoisomer ꢀ209.96 (d, J = 74.0 Hz, 1F). 31P{/1H} NMR
˚
min
(121 MHz, CDCl3)
d major diastereoisomer 18.53 (d, J = 74.1 Hz,
3.2.6. Dipeptide synthesis
1P), minor diastereoisomer 18.23 (d, J = 75.8 Hz, 1P). MS-EI
[M+] = 516 m/z.
To a cooled (0 8C) solution of derivatives 4a–e (1.05 equiv.) in
methylene chloride a solution of a blocked N-phenylalanine
(1 equiv.), HOBt (1.25 equiv.) in a 3:7 CH2Cl2/DMF and DCC
(1.25 equiv.) were added. Stirring was continued at this tempera-
ture for 30 min and then the solutions were stirred for 18 h at room
temperature. The DCU was filtered off, and the filtrates were
washed with cold solutions of 1 M NaOH, water, 1 M citric acid,
water, 1 M NaHCO3, water. The organic extracts were dried over
anhydrous MgSO4. Drying agent was filtered off and the solvent
was evaporated. The crude products were purified by flash
chromatography (n-hexane:AcOEt 50:50 ! 40:60).
6d: Yield: 58%, white solid, 1H NMR (600 MHz, CDCl3)
d 7.33–
7.20 (m, 5H, Ar), 5.90 (d, J = 9.6 Hz, 1H, NH), 5.05 (br. s, 1H, NH),
4.36 (dd, J = 47.7, 9.1 Hz, 1H, CHFP), 4.27 (dd, J = 14.8, 7.5 Hz, 1H,
CHNH), 4.22–4.13 (m, 4H, 2ꢂ OCH2CH3), 4.12–4.06 (m, 1H, CHNH),
3.09 (dd, J = 13.6, 8.0 Hz, 1H, NCHaHbPh), 3.04 (dd, J = 13.7, 6.5 Hz,
1H, NCHaHbPh), 2.06–1.90 (m, 2H, CH2CHF), 1.72–1.62 (m, 1H,
CHCH3), 1.57–1.49 (m, 1H, CH3CHaHb), 1.42 (s, 9H, C(CH3)3), 1.36 (t,
J = 7.1 Hz, 6H, 2ꢂ OCH2CH3), 1.10–1.00 (m, 1H, CH3CHaHb), 0.87 (t,
J = 7.3 Hz, 3H, CH3CHaHb), 0.81 (d, J = 6.8 Hz, 3H, CH3CH). 13C NMR
(101 MHz, CDCl3) d 171.03, 155.48, 136.72, 129.23, 128.66, 126.96,
6a: Yield: 84%, white solid, 1H NMR (300 MHz, CDCl3)
d
7.40–
85.42 (dd, J = 180.9, 171.1 Hz, CFP), 80.22, 63.33 (d, J = 6.9 Hz),
62.77 (d, J = 6.7 Hz), 56.25, 49.00 (d, J = 13.9 Hz), 38.51, 33.88,
31.65 (d, J = 20.6 Hz), 28.21, 24.90, 16.47 (d, J = 4.3 Hz), 16.41 (d,
7.02 (m, 5H, Ar), 6.05 (br.d, J = 8.7 Hz, 1H, NH), 5.12 (br.d, J = 5.3 Hz,
1H, NH), 4.51 (dd, J = 47.1, 10.5 Hz, 1H, CHFP), 4.34–3.97 (m, 6H, 2ꢂ
OCH2CH3, 2ꢂ CHNH), 3.04 (d, J = 7.0 Hz, 2H, CH2Ph), 2.04–1.66 (m,
2H, CH2CHF), 1.43–1.40 (s, 9H, C(CH3)3), 1.36 (t, J = 7.1 Hz, 6H, 2ꢂ
OCH2CH3), 1.15 (d, J = 6.7 Hz, 3H, CH3). 13C NMR (101 MHz, CDCl3)
J = 5.4 Hz), 14.78 (d, J = 4.1 Hz), 11.54. 19F NMR (379 MHz, CDCl3)
d
minor diastereoisomer ꢀ204.80 to ꢀ205.76 (m, 1F), major
diastereoisomer ꢀ209.97 to ꢀ211.01 (m, 1F). 19F{/1H} NMR
d
170.81, 155.30, 136.61, 129.21, 128.54, 126.86, 85.62 (dd,
(377 MHz, CDCl3)
d
minor diastereoisomer ꢀ205.48 (d,
J = 180.4, 171.4 Hz, CFP), 79.98, 63.27 (d, J = 6.9 Hz), 62.85 (d,
J = 6.8 Hz), 55.99, 41.91 (d, J = 15.7 Hz), 38.41, 36.37 (d, J = 19.8 Hz),
28.17, 20.87, 16.41 (d, J = 4.4 Hz), 16.35 (d, J = 4.5 Hz). 19F NMR
J = 76.1 Hz, 1F), major diastereoisomer ꢀ210.43 (d, J = 74.1 Hz,
1F). 31P{/1H} NMR (121 MHz, CDCl3)
d
major diastereoisomer 18.69
(d, J = 74.1 Hz, 1P), minor diastereoisomer 18.15 (d, J = 76.8 Hz, 1P).
MS-EI [M+] = 516 m/z.
(282 MHz, CDCl3)
d
minor diastereoisomer ꢀ207.50 to ꢀ208.56 (m,
1F), major diastereoisomer ꢀ209.23 to ꢀ210.11 (m, 1F). 19F{/1H}
6e: Yield: 79%, white solid, 1H NMR (403 MHz, CDCl3)
d 7.35–
NMR (377 MHz, CDCl3)
d
minor diastereoisomer ꢀ207.94 (d,
7.05 (m, 10H, Ar), 5.94 (br.d, J = 7.7 Hz, 1H, NH), 4.97 (br.s, 1H, NH),
4.82–4.62 (m, 1H, CHFP), 4.42–4.30 (m, 1H, CHNH), 4.29–4.20 (m,
1H, CHNH), 4.20–4.08 (m, 4H, 2ꢂ OCH2CH3), 2.99 (d, J = 7.1 Hz, 2H,
CH2Ph), 2.84 (dd, J = 13.6, 6.2 Hz, 1H, NCHaHbPh), 2.75 (dd, J = 13.7,
7.0 Hz, 1H, NCHaHbPh), 1.87–1.63 (m, 2H, CH2CHF), 1.40 (s, 9H,
C(CH3)3), 1.36–1.28 (m, 6H, 2ꢂ OCH2CH3). 13C NMR (101 MHz,
J = 74.8 Hz, 1F), major diastereoisomer ꢀ209.59 (d, J = 73.6 Hz, 1F).
31P{/1H} NMR (121 MHz, CDCl3)
d
major diastereoisomer 17.94 (d,
J = 73.6 Hz, 1P), minor diastereoisomer 17.30 (d, J = 74.8 Hz, 1P).
MS-EI [M + 1]+ = 475 m/z.
6b: Yield: 70%, white solid, 1H NMR (300 MHz, CDCl3)
d 7.30–
7.11 (m, 5H, Ar), 5.91 (d, J = 9.7 Hz, 1H, NH), 5.06 (d, J = 8.1 Hz, 1H,
NH), 4.41–4.29 (m, 1H, CHFP), 4.27–4.19 (m, 4H, 2ꢂ OCH2CH3),
4.17–4.05 (m, 4H), 4.00–3.91 (m, 1H, CHNH), 3.06 (dd, J = 13.6,
7.8 Hz, 1H, NCHaHbPh), 2.97 (dd, J = 13.5, 6.5 Hz, 1H, NCHaHbPh),
1.95–1.83 (m, 1H, CHFPCHaHb), 1.77–1.59 (m, 2H, CHFPCHaHb,
CH(CH3)2) 1.36 (s, 9H, C(CH3)3), 1.30 (t, J = 7.1 Hz, 6H, 2ꢂ
OCH2CH3), 0.79 (t, J = 7.0 Hz, 6H, 2ꢂ CH3). 13C NMR (75 MHz,
CDCl3) d 170.96, 155.23, 136.88, 129.32, 129.20, 128.62, 128.46,
128.32, 126.94, 126.64, 85.33 (dd, J = 180.7, 171.4 Hz, CFP), 80.11,
63.32 (d, J = 6.8 Hz), 62.81 (d, J = 6.8 Hz), 56.14, 46.58 (d,
J = 14.8 Hz), 40.71, 38.19, 33.77 (d, J = 20.0 Hz), 28.19, 16.39 (d,
J = 2.8 Hz), 16.34 (d, J = 3.0 Hz). 19F NMR (379 MHz, CDCl3)
d minor
diastereoisomer ꢀ206.12 to ꢀ207.02 (m, 1F), major diastereo-
isomer ꢀ209.79 to ꢀ210.64 (m, 1F). 19F{/1H} NMR (377 MHz,
CDCl3)
d
171.24, 155.46, 136.72, 129.20, 128.61, 126.92, 85.44
CDCl3)
d
minor diastereoisomer ꢀ205.04 (d, J = 72.8 Hz, 1F), major
(dd, J = 180.8, 171.3 Hz, CFP), 80.20, 63.30 (d, J = 6.6 Hz), 62.76 (d,
J = 6.8 Hz), 56.29, 49.93 (d, J = 13.7 Hz), 37.72, 33.88, 32.55 (d,
J = 20.5 Hz), 28.19, 18.85, 18.82, 16.44 (d, J = 3.6 Hz), 16.36 (d,
J = 3.8 Hz). 19F NMR (282 MHz, CDCl3)
diastereoisomer ꢀ210.15 (d, J = 73.4 Hz, 1F). 31P{/1H} NMR
(121 MHz, CDCl3)
d major diastereoisomer 18.27 (d, J = 73.7 Hz,
1P), minor diastereoisomer 17.83 (d, J = 75.9 Hz, 1P). MS-EI
[M + 1]+ = 551 m/z.
d minor diastereoisomer
ꢀ205.75 to ꢀ206.42 (m, 1F), major diastereoisomer ꢀ210.01 to
ꢀ211.03 (m, 1F). 19F{/1H} NMR (377 MHz, CDCl3)
d minor
Acknowledgments
diastereoisomer ꢀ206.06 (d, J = 77.2 Hz, 1F), major diastereo-
isomer ꢀ210.44 (d, J = 74.1 Hz, 1F). 31P{/1H} NMR (121 MHz,
CDCl3)
d
major diastereoisomer 18.67 (d, J = 74.1 Hz, 1P), minor
The research was supported by Wroclaw Research Centre EIT+
under the project ‘‘Biotechnologies and advanced medical tech-
nologies’’ – BioMed (POIG.01.01.02-02-003/08) financed from the
European Regional Development Fund (Operational Programme
Innovative Economy, 1.1.2).
diastereoisomer 18.15 (d, J = 76.8 Hz, 1P). MS-EI [M]+ = 502 m/z.
6c: Yield: 65%, white solid, 1H NMR (403 MHz, CDCl3)
7.33–
d
7.16 (m, 5H, Ar), 5.93 (d, J = 9.1 Hz, 1H, NH), 5.08 (s, 1H, NH), 4.48
(dd, J = 47.3, 10.4 Hz, 1H, CHFP), 4.31–4.25 (m, 1H, CHNH), 4.24–

´
134
M. Kazmierczak et al. / Journal of Fluorine Chemistry 167 (2014) 128–134
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