DAST mediated preparation of β-fluoro-α-aminophosphonates

Article abstract of DOI:10.1016/j.jfluchem.2012.03.016

Herein, we report a new and convenient method for the synthesis of β-fluoro-α-aminophosphonates starting from naturally occurring l-amino acids. A key step in the synthetic protocol involves nucleophilic fluorination of N,N-dibenzylated-β-amino alcohols with diethylaminosulfur trifluoride (DAST).

Full text of DOI:10.1016/j.jfluchem.2012.03.016

Journal of Fluorine Chemistry 139 (2012) 23–27
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
DAST mediated preparation of
b-fluoro-a-aminophosphonates
*
´
Marcin Kazmierczak, Henryk Koroniak
Faculty of Chemistry, Adam Mickiewicz University, Grunwaldzka 6, 60-780 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 report a new and convenient method for the synthesis of
b-fluoro-a-aminophosphonates
Received 10 February 2012
Received in revised form 18 March 2012
Accepted 21 March 2012
Available online 6 April 2012
starting from naturally occurring -amino acids. A key step in the synthetic protocol involves
L
nucleophilic fluorination of N,N-dibenzylated-
b
-amino alcohols with diethylaminosulfur trifluoride
(DAST).
ß 2012 Elsevier B.V. All rights reserved.
Keywords:
Fluorination
DAST
Phosphonates
Aminophophonates
Aziridinium ion
1. Introduction
Nucleophilic fluorination is one of the common methods of
introduction of a fluorine atom into organic compounds [6]. It
should be noted that fluorine-containing reagents are usually poor
nucleophiles. Fluoride itself is the smallest anion which can form
strong hydrogen bonds, however, its solvation can dramatically
decrease its nucleophilicity by the formation of stable solvation
shells [2]. One of the most common procedures to introduce
fluorine atom to phosphonate system is the replacement of
hydroxyl group with fluorine. The common and quite useful
reagent (stable and commercially available) which can be used is
DAST (diethylaminosulfur trifluoride) [7]. However, mechanism of
Organophosphorus compounds are important substrates in
biochemical processes. They are potent bioactive molecules used
as agrochemicals and pharmaceuticals, as well as effective enzyme
inhibitors [1]. It is also known, that the introduction of fluorine
atom(s) into organic molecules may change their chemical,
physical and biological properties [2]. These fundamental observa-
tions are the conceptual base for studies on new organophospho-
rus–fluorine containing compounds. For example, it has been
shown that fluorinated aminophosphonates are useful inhibitors
of many enzymes [3]. Cytotoxic and antibacterial activities has
been reported for some of the fluorine-containing aminopho-
sphonates [4]. To the best of our knowledge, there are only a few
fluorination with DAST in case of
depends of the phosphonate system [8].
a-hydroxyphosphonates
In this paper we would like to report, neighbouring group
participation during DAST-mediated fluorination of series of
examples of synthesis of
b-fluorinated a-aminoalkylphospho-
nates, which have been found to be an inhibitor of alanine
racemase (Scheme 1) [5].
simple b-amino-a-hydroxyphosphonates. We believe, this is the
first example of direct access to various
sphonates.
b-fluoro-a-aminopho-
2. Results and discussion
Our synthetic strategy was to synthesize series of N-protected
a
-hydroxyphosphonates (Scheme 2) and next, modify the mole-
cule via introduction a fluorine atom into this system. As starting
material a series of simple alkyl and aryl -amino acids had been
chosen. At first -amino acids 1a–e (1a- Glycine, 1b- -Alanine, 1c-
-Leucine, 1d- -Phenylalanine, 1e- -Phenylglycine) were trans-
a
Scheme 1.
a
L
L
L
D
formed into N,N-dibenzylamino alcohols 2a–e in two step
procedure with good yields. First benzylation with BnBr in
presence of K2CO3 in water at 80 8C and next reduction of obtained
* Corresponding author. Tel.: +48 618291303; fax: +48 618291505.
E-mail address: koroniak@amu.edu.pl (H. Koroniak).
0022-1139/$ – see front matter ß 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2012.03.016

´
24
M. Kazmierczak, H. Koroniak / Journal of Fluorine Chemistry 139 (2012) 23–27
Scheme 2.
esters by LiAlH4 in Et2O at room temperature yielded aminoalco-
hols 2a–e [9]. Conversion of compounds 2a–e to corresponding
aldehydes 3a–e was carried out using the Swern oxidation under
standard conditions in CH2Cl2 at À78 8C (oxalyl chloride, DMSO,
Et3N).
Aldehydes 3a–e after extraction and evaporation of solvents
were sufficiently pure to allow to be used directly to introduce C–P
bond in Pudovik reaction [10]. Lithium diethyl phosphite 4 was
generated in situ from diethyl phosphate/LiHMDS and added to a
solution of aldehydes 3a–e in dry THF at À30 8C. After purification
a mixture of chromatographically inseparable diastereoisomers of
19F NNR analysis of the crude products showed, that apart
from -fluorides 6b-d, we have found -fluorinated derivatives
b
a
as impurities which can be removed by the column chromatog-
raphy. We would suggest that the mechanism of this nucleo-
philic fluorination, after the activation of hydroxyl group,
involves formation of an aziridinium ion as the key step of the
synthesis (Scheme 5). A similar mechanism has been recently
proposed by O’Hagan et al. during fluorination of N,N-dibenzyl-
b
-amino alcohols with Deoxo-Fluor1 or DAST [11]. Dolence and
Roylance in their work also showed opening aziridinium ring by
a fluoride-ion [12].
b
-amino-
a
-hydroxyphosphonates 5a–d has been obtained in
Diastereoselectivity of this reaction was determined on the
bases of the 31P NMR as well as 19F NMR spectra. 31P{/H} NMR
analysis showed different P–F coupling constants between each of
diatereoisomer: 6b 3JP–F = 19.5 Hz, 3JP–F = 7.9 Hz, for compound 6c
modest yield.
Diastereoselectivity (Table 1) of this reaction can be explained
by the Felkin–Ahn model (Scheme 3), and was determined after
analysis of the 31P NMR spectra. The absolute configuration at
carbon C1 of compounds 5a–d was deduced from the known
stereochemical outcome of the nucleophilic additions to 2-(N,N-
dibenzyloamino)aldehydes [9].
3
3
3
3JP–F = 14.7 Hz, JP–F = 9.6 Hz and for 6d JP–F = 15.5 Hz, JP–
F = 9.4 Hz which can be easily understood by the Karplus dihedral
angle relationship (Table 2) [13].
In the case of fluorination of compound 5a using identical
protocol unexpectedly has been observed different regiochemistry.
From the complex reaction mixture we were able to isolated major
product the
a
-fluoride 6a, 31P{/H} NMR showed large P–F coupling
2
2
constants JP–F = 84.7 Hz, JP–F = 76.5 Hz, what unambiguously
indicates the fluorine atom is placed at
a-position to the
phosphorous. Regiochemistry of this reaction might be the
consequence of lower stability of the aziridinium ion.
In conclusion we have demonstrated simple procedure to
obtain a few
b-fluoro-a-aminophosphonates. Those compounds
can be used as convenient precursors for the new class of building
blocks in the preparation of medicinally important analogs.
Scheme 3.
3. Experimental
In the case of compound 5c we obtained, almost quantitatively
the anti diastereoisomer as it was anticipated. Unfortunately, the
3.1. General methods
Pudovik reaction failed for 5e derivative. Prepared
b-amino-a-
hydroxyphosphonates were then treated with DAST in CH2Cl2 at
À78 8C (Scheme 4).
1H NMR, 13C NMR, 19F NMR and 31P NMR spectra were
performed on Varian GEMINI 300 (300 MHz) and Varian 400
Table 1
Pudovik reaction.
Table 2
DAST-mediated fluorination.
Compound
R
d.r.
Yield %
Compound
R
d.r.
Yield %
5a
5b
5c
5d
H
–
52
48
44
50
Me
i-Pr
Bn
80:20
90:10
85:15
6b
6c
6d
Me
i-Pr
Bn
80:20
90:10
85:15
55
41
60

´
M. Kazmierczak, H. Koroniak / Journal of Fluorine Chemistry 139 (2012) 23–27
25
Scheme 4.
Scheme 5.
(400 MHz) spectrometers. Chemical shifts of 1H NMR were
expressed in parts per million downfield from tetramethylsilane
ethyl acetate 85:15, v/v). This methodology provided benzyl 2-
(dibenzylamino) derivatives as a colorless oil.
(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 CDCl3. 1H, 13C NMR chemical shifts are
reported for the major diastereoisomer only. Low-resolution and
high resolution mass spectra were recorded by electron impact
(MS-EI) techniques using AMD-402 spectrometer. 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 per-
formed using a cooling bath (liquid N2/hexane or CO2/isopropa-
nol). 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. DAST was obtained from
Aldrich.
d = 0) in CDCl3. Chemical shifts of
3.2.2. Reduction
d
Benzyl 2-(dibenzylamino) derivatives (3.92 mmol, 1 equiv.)
were added to a stirred suspension of lithium aluminum hydride
(11.75 mmol, 3 equiv.) in Et2O (15 ml) under argon atmosphere at
0 8C. After 15 min cooling bath was removed and mixtures were
stirred overnight and cooled again to 0 8C. Mixtures has been
worked-up by careful dropwise addition of 0.5 mL of H2O, 1 mL of
15% KOH and 1.5 mL of H2O. Aluminum salts were removed by
filtration, and the filtrates were concentrated under reduced
pressure. Crude products were purified by flash chromatography
(hexane/ethyl acetate 70:30, v/v).
d
d
2a: Colorless oil 1H NMR (403 MHz, CDCl3)
d = 7.39–7.14 (m, 10
H, Ar), 3.61 (s, 2H, Bn), 3.58–3.54 (t, J = 5,30 Hz 2H, CH2H2OH),
2.67–2.63 (t, J = 5.40 Hz, 2H, CH2H2OH). The NMR data were in
good agreement with the reported data from an alternative
synthesis [14].
2b: 1H NMR (300 MHz, CDCl3)
d = 7.43–7.17 (m, 10 H, Ar), 3.82
(d, J = 13.3 Hz, 2H, NCHaHbPh), 3.51–3.35 (m, 1H, CHCHaHbOH),
3.35 (d, J = 13.3 Hz, 2H, NCHaHbPh), 3.38–3.28 (m, 1H, CHCHa
HbOH), 3.22–3.08 (s, 1H, OH) 3.05–2.91 (m, 1H, CHCH2OH), 0.98 (d,
J = 6.7 Hz, 3H, CH3). The NMR data were in good agreement with
the reported data from an alternative synthesis [15].
3.2. General procedures
2c: Colorless oil 1H NMR (403 MHz, CDCl3)
d = 7.42–7.16 (m,
10H, Ar), 3.80 (d, J = 13.3 Hz, 2H, NCHaHbPh), 3.51–3.40 (m, 2H,
CH2OH), 3.36 (d, J = 13.3 Hz, 2H, NCHaHbPh), 3.23 (s, 1H, OH), 2.84
(tq, J = 10.2, 5.0, 2.6 Hz, 1H, (CH3)2CH), 1.56–1.46 (m, 1H,
CHCH2OH), 1.21–1.12 (m, 2H, (CH3)2CHCH2), 0.92 (d, J = 6.1 Hz,
3H, CH3), 0.85 (d, J = 6.0 Hz, 3H, CH3). The NMR data were in good
agreement with the reported data from an alternative synthesis
[15].
3.2.1. Benzylation
Amino acids 1a–e (5.6 mmol, 1 equiv.) were added to a
solution of potassium carbonate (12.35 mmol, 2.2 equiv.) in H2O
(20 mL) at room temperature. After 15 min benzyl bromide
(22.45 mmol, 4 equiv.) was added, and suspension was heated to
80 8C. After 18 h mixture was cooled to room temperature and
products were extracted with CH2Cl2 (3 Â 20 mL). The combined
organic phases were washed with 25 mL of saturated solution of
NaCl, dried over MgSO4, filtered and concentrated. The crude
products were purified using flash chromatography (hexane/
2d: White solid NMR (300 MHz, CDCl3)
d = 7.49–7.03 (m, 15H,
Ar), 3.93 (d, J = 13.3 Hz, 2H, NCHaHbPh), 3.50 (dd, J = 16.5, 6.1 Hz,
1H, CHaHbOH), 3.49 (d, J = 13.3, 2H, NCHaHbPh), 3.35 (s, 1H, OH),
3.20–2.96 (m, 3H, CHaHbOH, CHCH2OH, CHCHaHbPh), 2.43 (dd,

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M. Kazmierczak, H. Koroniak / Journal of Fluorine Chemistry 139 (2012) 23–27
26
J = 12.9, 9.4 Hz, 1H, CHCHaHbPh). The NMR data were in good
agreement with the reported data from an alternative synthesis
[16].
CH3), 0.51 (d, J = 6.5 Hz, 3H, CH3). 13C NMR (75 MHz, CDCl3)
2
d
= 140.02, 129.15, 128.03, 126.80, 65.94 (d, JC–P = 153.5 Hz),
3
3
62.44 (d, JC–P = 7.2 Hz), 54.97 (d, JC–P = 6.3 Hz), 54.26, 52.99,
34.93, 23.98, 23.86, 21.15, 16.47 (d, JC–P = 5.2 Hz), 16.40 (d, JC–
4
4
3.2.3. Oxidation
P = 5.4 Hz). 31P NMR (163 MHz, CDCl3) major diastereoisomer
DMSO (3.92 mmol, 2 equiv.) was added dropwise to a stirred
solution of oxalyl chloride (2.35 mmol, 1.2 equiv.) in CH2Cl2
(15 mL) under argon at À78 8C and the reaction mixture was
stirred for 5 min. Then a solution of 2-(dibenzylamino)alcohols 2a–
d (1.96 mmol, 1 equiv.) in CH2Cl2 (1 mL) were added. After 30 min
of stirring at À78 8C triethylamine (7.8 mmol, 4 equiv.) was added,
and mixtures were allowed to warm to room temperature over
30 min. The reaction mixtures were then diluted with H2O (30 mL)
and CH2Cl2 (30 mL) and the layers were separated. The organic
layers were washed with 1% HCl (10 mL), H2O (10 mL), 5% NaHCO3
(10 mL) and brine (10 mL), dried over MgSO4, filtrated and
concentrated under reduced pressure. The resulting crude 2-
(dibenzylamino)aldehydes 3a–d were used without additional
purification.
d
= 24.32 (s), minor diastereoisomer
[M+H]+.
5d: White solid 1H NMR (403 MHz, CDCl3)
d = 23.64 (s); MS m/z: 420
d
= 7.47–7.03 (m,
15H, Ar), 4.35 (ddd, J = 10.4, 7.2, 1.8 Hz, 1H, CHOH), 4.22–3.95 (m,
4H, OCH2CH3), 3.88 (d, J = 14.2 Hz, 2H, NCHaHbPh), 3.58 (d,
J = 14.1 Hz, 2H, NCHaHbPh), 3.42–3.33 (m, 1H, PhCH2CH), 3.24
(dd, J = 7.2, 3.9 Hz, 1H, PhCHaCHb), 3.09 (dd, J = 7.2, 4.8 Hz, 1H,
PhCHaCHb), 1.30–1.20 (m, 6H, OCH2CH3). 13C NMR (75 MHz, CDCl3)
d
= 140.27, 139.52, 129.65, 128.55, 127.88, 127.82, 126.52, 125.66,
2
3
3
65.64 (d, JC–P = 154.1 Hz), 62.90 (d, JC–P = 7.1 Hz), 62.24 (d, JC–
P = 7.4 Hz), 59.29 (d, 4JC–P = 6.2 Hz), 54.01, 32.23, 16.40, 16.33. 31P
NMR (163 MHz, CDCl3) major diastereoisomer
d = 24.23 (s), minor
diastereoisomer
d
= 23.42 (s); MS m/z: 468 [M+H]+.
3.2.5. Fluorination
3.2.4. Pudovik reaction
To a stirred solution of DAST (1.05 mmol, 1.5 equiv.) in 3 mL of
CH2Cl2 under an atmosphere of argon at À78 8C a solutions of 5a–d
compounds (1 mmol, 1 equiv.) in 0.5 mL of CH2Cl2 were added. The
mixtures were stirred at À78 8C for 1 h, followed by 1 h at room
temperature. Solutions were poured into a stirred mixture of
saturated NaHCO3 and ice chips, extracted to CH2Cl2 (3 Â 10 mL),
dried over MgSO4, filtered, concentrated under reduced pressure
and purified using flash chromatography (hexane/ethyl acetate
50:50, v/v).
Lithium bis-(trimethylsilyl)amide was prepared by addition of
n-BuLi (3 mmol, 1.3 equiv., 2 M in pentane) to a stirred solution of
bis(trimethylsilyl)amine (2.3 mmol, 1.3 equiv.) in THF (1 mL)
under an atmosphere of argon at 0 8C. The solution was stirred
for additional 30 min. Reaction mixture was then added dropwise
to a stirred solution of diethyl phosphite (2.3 mmol, 1.3 equiv.) in
THF (2 mL) under an atmosphere of argon at À78 8C. After 10 min
the solution was allowed to warm to room temperature over
45 min and then cooled to À30 8C. 2-(dibenzylamino)aldehydes
3a–d (1.74 mmol, 1 equiv.) in THF (1 mL) were added dropwise
into the solution. After addition, reaction mixtures were slowly
allowed to warm to room temperature and stirred overnight,
quenched by addition of saturated solution of NH4Cl (10 mL).
Crude products were extracted to AcOEt (3 Â 10 mL), dried over
MgSO4, filtered, concentrated under reduced pressure and purified
using flash chromatography (chloroform/methanol 100:1, v/v).
6a: Yellow oil 19F NMR (379 MHz, CDCl3)
d
= À201.20 (dd,
= 15.02 (d,
J = 84.8, 44.8 Hz). 31P NMR (163 MHz, CDCl3)
J = 84.7 Hz).
d
6b: Pale yellow oil 1H NMR (403 MHz, CDCl3)
d 7.43–7.16 (m,
10H, Ar), 5.11–4.89 (m, 1H, CH3CHF), 4.24–3.86 (m, 8H, OCH2CH3,
NCH2Ph), 3.12–3.01 (m, 1H, CH3CHFCH), 1.44–1.30 (m, 6H,
OCH2CH3). 13C NMR (101 MHz, CDCl3)
d = 138.98, 129.08,
128.23, 127.15, 89.14 (dd, J = 169.3, 3.4 Hz, C–F), 61.51 (dd,
J = 7.2, 2.1 Hz), 61.35 (dd, J = 7.1, 0.9 Hz), 60.39 (dd, J = 134.9,
24.7 Hz, C–P), 55.65 (d, J = 1.2 Hz), 55.63 (d, J = 1.0 Hz), 19.87 (dd,
J = 22.9, 7.2 Hz), 16.52 (d, J = 3.3 Hz), 16.46 (d, J = 3.3 Hz). 19F NMR
5a: Colorless oil 1H NMR (300 MHz, CDCl3)
d = 7.41–7.22 (m,
10H, Ar), 4.17–3.94 (m, 6H, 2x OCH2CH3, CH2NBn2), 3.85 (d,
J = 13.2 Hz, 2H, NCHaHbPh), 3.48 (d, J = 13.4 Hz, 2H, NCHaHbPh),
3.01–2.76 (m, 1H, CHCH2NBn2), 1.28–1.22 (td, J = 7.05, 0.5 Hz, 3H,
OCH2CH3), 1.18 (td, J = 7.1, 0.5 Hz, 3H, OCH2CH3). 13C NMR
(282 MHz, CDCl3) minor diastereoisomer
d
= À176.55 to À177.20
(m, 1F), major diastereoisomer À177.81 to À178.41 (m, 1F). 31P
3
(75 MHz, CDCl3)
d
= 138.07, 128.87, 128.23, 127.00, 70.42 (d,
NMR (163 MHz, CDCl3) minor diastereoisomer
d
= 25.98 (d, JP–
2JC–P = 160.3 Hz), 63.06 (d, JC–P = 7.1 Hz), 62.78 (d, JC–P = 7.3 Hz),
F = 19.5 Hz), major diastereoisomer 25.56 (d, 3JP–F = 7.9 Hz). HRMS
3
3
3
4
57.83, 53.22 (d, JC–P = 4.0 Hz), 16.19 (d, JC–P = 2.2 Hz), 16.12 (d,
(EI) Calcd. for C21H29FNO3P [M]+: 393.18690; Found: 393.18579.
4JC–P = 1.9 Hz). 31P NMR (121 MHz, CDCl3)
d
= 23.43 (s); MS m/z:
6c: Pale yellow oil 1H NMR (403 MHz, CDCl3)
d = 7.45–7.11 (m,
378 [M+H]+.
10H, Ar), 4.99–4.77 (m, 1H, i-PrCHF), 4.25–3.92 (m, 4H, OCH2CH3),
3.98 (d, J = 13.5 Hz, 2H, NCHaHbPh), 3.88 (d, J = 13.6 Hz,
NCHaHbPh), 3.10 (ddd, J = 18.0, 14.4, 6.6 Hz, 1H i-PrCHFCH),
1.73–1.62 (m, 1H, (CH3)2CH), 1.57 (ddd, J = 14.5, 8.8, 2.8 Hz, 1H,
(CH3)2CHCHaHb), 1.46 (ddd, J = 9.7, 8.2, 5.2 Hz, 1H,
(CH3)2CHCHaHb), 1.38 (t, J = 6.2 Hz, 3H, OCH2CH3), 1.34 (t,
J = 6.2 Hz, 3H, OCH2CH3), 0.90 (d, J = 6.5 Hz, 3H, CH3), 0.88 (d,
5b: Yellow solid 1H NMR (403 MHz, CDCl3)
d
= 7.44–7.12 (m,
10H, Ar), 4.20 (dd, J = 9.7, 2.5 Hz, 1H, CHOH), 4.16–3.91 (m, 4H,
OCH2CH3), 3.78 (d, J = 14.0 Hz, 2H, NCHaHbPh), 3.63 (d, J = 13.9 Hz,
2H, NCHaHbPh), 3.24 (dqd, J = 13.9, 7.0, 2.8 Hz, 1H, CH3CHNBn2),
2.88 (s, 1H, OH) 1.25 (dd, J = 14.8, 7.3 Hz, 6H, CH3CHNBn2,
OCH2CH3), 1.19 (t, J = 7.1 Hz, 3H, OCH2CH3). 13C NMR (75 MHz,
2
CDCl3)
d
= 140.12, 128.66, 128.07, 126.71, 69.40 (d, JC–
J = 6.6 Hz, 3H, CH3). 13C NMR (101 MHz, CDCl3)
d = 139.10, 129.20,
3
3
P = 155.0 Hz), 62.45 (d, JC–P = 10.4 Hz), 62.36 (d, JC–P = 10.4 Hz),
128.25, 127.20, 91.32 (dd, J = 171.5, 1.8 Hz, C–F), 61.57 (dd, J = 7.1,
2.3 Hz), 61.39 (dd, J = 7.3, 0.7 Hz), 59.76 (dd, J = 136.0, 24.5 Hz, C–
P), 55.75 (d, J = 0.8 Hz), 55.72 (d, J = 0.6 Hz), 42.30 (dd, J = 20.6,
5.8 Hz), 24.53 (dd, J = 2.6, 1.8 Hz), 23.29, 21.80, 16.63 (d, J = 6.0 Hz),
3
54.32, 52.97 (d, JC–P = 6.8 Hz), 16.35, 16.27, 9.75. 31P NMR
(163 MHz, CDCl3) major diastereoisomer
diastereoisomer
= 23.12 (s); MS m/z: 392 [M+H]+.
5c: Colorless oil 1H NMR (403 MHz, CDCl3)
= 7.42–7.12 (m,
d = 23.86 (s), minor
d
d
16.55 (d, J = 5.7 Hz). 19F NMR (379 MHz, CDCl3)
d
= À184.92 to
10H, Ar), 4.39 (dd, J = 11.5, 6.4 Hz, 1H, CHOH), 4.25–3.99 (m, 4H,
OCH2CH3), 3.88 (d, J = 13.7 Hz, 2H, NCHaHbPh), 3.49 (d, J = 13.7 Hz,
2H, NCHaHbPh), 3.11 (dddd, J = 12.0, 10.1, 4.0, 1.9 Hz, 1H,
(CH3)2CHCH2CH), 2.82 (m, J = 6.9, 3.9 Hz, 1H, (CH3)2CHCH2CH),
1.91 (tdd, J = 13.2, 6.8, 3.4 Hz, 1H, (CH3)2CHCHaHbCH), 1.74 (ddd,
J = 14.1, 10.1, 4.0 Hz, 1H, (CH3)2CHCHaHbCH), 1.32 (t, J = 7.1 Hz, 3H,
OCH2CH3), 1.25 (t, J = 7.1 Hz, 3H, OCH2CH3), 0.90 (d, J = 6.8 Hz, 3H,
À185.54 (m, 1F). 31P NMR (121 MHz, CDCl3) minor diastereo-
3
isomer
d
d
= 26.48 (d, JP–F = 14.7 Hz), major diastereoisomer
3
= 25.65 (d, JP–F = 9.6 Hz). HRMS (EI) Calcd. for C24H35FNO3P
[M]+: 435.23388; Found: 435.23266.
6d: Pale yellow oil 1H NMR (403 MHz, CDCl3)
d = 7.51–6.91 (m,
15H, Ar), 5.13–4.91 (m, 1H, PhCH2CHF), 4.24–3.92 (m, 4H,
OCH2CH3), 4.04 (d, J = 13.4 Hz, 2H, NCHaHbPh), 3.76 (d,

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M. Kazmierczak, H. Koroniak / Journal of Fluorine Chemistry 139 (2012) 23–27
27
Sokolov, N.V. Kovaleva, A.N. Razdol’skii, V.I. Fetisov, I.V. Martynov, Bioorgani-
cheskaia Khimiia 16 (1990) 1500–1508, Chem. Abstr. 114, 1991, 138643;
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Pharmaceutical and Chemistry Journal (Engl. Transl.) 26 (1992) 489–492;
(g) P. Van der Veken, K. Senten, I. Kertes´z, A. Haemers, K. Augustyns, Tetrahedron
Letters 44 (2003) 969–972;
(h) G.F. Makhaeva, V.V. Malygin, A.Y. Aksinenko, V.B. Sokolov, N.N. Strakhova,
A.N. Rasdolsky, R.J. Richardson, I.V. Martynov, Doklady. Biochemistry and Bio-
physics 400 (2005) 831–835;
J = 13.5 Hz, 2H, NCHaHbPh), 3.34 (ddd, J = 30.6, 14.3, 4.8 Hz, 1H,
PhCHaCHb), 3.21 (ddd, J = 19.4, 18.0, 5.8 Hz, 1H, PhCHaCHb), 2.79
(ddd, J = 16.2, 14.4, 8.4 Hz, 1H, PhCH2CHFCH), 1.34 (t, J = 6.4 Hz, 3H,
OCH2CH3), 1.31 (t, J = 6.4 Hz, 3H, OCH2CH3). 13C NMR (101 MHz,
CDCl3)
d = 138.91, 137.03 (dd, J = 4.6, 1.3 Hz), 129.35, 129.14,
128.51, 128.23, 127.13, 126.60, 92.70 (dd, J = 176.0, 1.8 Hz, C–F),
61.64 (dd, J = 7.0, 1.0 Hz), 61.50 (dd, J = 7.1, 1.8 Hz), 58.51 (dd,
J = 140.8, 24.1 Hz, C–P), 55.69 (d, J = 1.1 Hz), 55.65 (d, J = 1.0 Hz),
39.54 (dd, J = 21.6, 5.3 Hz), 16.53 (d, J = 6.1 Hz), 16.46 (d, J = 6.2 Hz).
(i) G.F. Makhaeva, A.Y. Aksinenko, V.B. Sokolov, I.I. Baskin, V.A. Palyulin, N.S.
Zefirov, N.D. Hein, J.W. Kampf, S.J. Wijeyesakere, R.J. Richardson, Chemico-Bio-
logical Interactions 187 (2010) 177–184.
19F NMR (379 MHz, CDCl3)
À182.61 (m, 1F), minor diastereoisomer À184.97 À185.51 (m, 1F).
d
= major diastereoisomer À182.14 to
[4] E. Pfund, T. Lequeux, S. Masson, M. Vazeux, A. Cordi, A. Pierre, V. Serre, G. Herve,
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31P NMR (121 MHz, CDCl3) minor diastereoisomer = 25.75 (d, 3JP–
d
F = 15.5 Hz), major diastereoisomer 24.50 (d, 3JP–F = 9.4 Hz). HRMS
(EI) Calcd. for C27H33FNO3P [M]+: 469.21820; Found: 469.21699.
Acknowledgments
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The research was supported by Wroclaw Research Centre EIT+
under the project, ‘‘Biotechnologies and advanced medical
technologies’’ – BioMed (POIG.01.01.02-02-003/08) financed from
the European Regional Development Fund (Operational Pro-
gramme Innovative Economy, 1.1.2).
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