Synthesis and physical chemical properties of 2-amino-4-(trifluoromethoxy)butanoic acid-a CF3O-containing analogue of natural lipophilic amino acids

Article abstract of DOI:10.1039/c6ob02436j

2-Amino-2-(trifluoromethoxy)butanoic acid (O-trifluoromethyl homoserine) was synthesized as a racemate and in both enantiomeric forms. The measured pK_a and log D values establish the compound as a promising analogue of natural aliphatic amino acids.

Full text of DOI:10.1039/c6ob02436j

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G. Logvinenko, N. A. Tolmachova, R. N. Morev, M. A. Kliachyna, F. Clausen, C. G. Daniliuc and G. Haufe,
Org. Biomol. Chem., 2016, DOI: 10.1039/C6OB02436J.
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DOI: 10.1039/C6OB02436J
Organic & Biomolecular Chemistry
ARTICLE
Synthesis and physical chemical properties of 2-amino-4-
(trifluoromethoxy)butanoic acid – CF3O-containing analogue of
Received 00th January 20xx,
Accepted 00th January 20xx
natural lipophilic amino acids.
Ivan S. Kondratov,*a,b Ivan G. Logvinenko,a,b Natalyia A. Tolmachova,a,b Roman N. Morev,a Maria A.
DOI: 10.1039/x0xx00000x
Kliachyna,a Florian Clausen,c Constantin G. Daniliucc and Günter Haufe*c,d
www.rsc.org/
2-Amino-2-(trifluoromethoxy)butanoic acid (O-trifluoromethyl also incorporated into different peptides to replace
homoserine) was synthesized as racemate and in both methionine [8] and exhibited significant activity as anti-
a
enantiomeric forms. Measured pKa and logD values establish the infective agent [9].
compound as promising analogue of natural aliphatic amino acids. Properties of the CF3O-group make it also attractive for
introduction into α-amino acid’s side chain. Thus, according to
Fluorinated amino acids are
a
remarkable class of
literature data the lipophilicity of the CF3O-group in aromatic
systems is comparable to that of CF3- and CF3S-groups [10,11].
Moreover, it is worth mentioning that the CF3O substituent is
thermally stable and chemically resistant towards acids and
bases, reducing and oxidizing agents, and organometallic
species [12]. The electronic properties of this substituent are
determined by the fact that n-electron pairs of the oxygen are
delocalized into the σ*-orbitals of the adjacent C-F bonds [10].
Different approaches to CF3O-containing compounds (mostly
aromatic) were developed [10]. Recent achievements to
introduce a CF3O-group into aliphatic position involve the
oxidative trifluoromethylation of alcohols using Ruppert-
Prakash reagent [13], the nucleophilic trifluoromethoxylation
using various generators of trifluoromethoxide [14] and
trifluoromethoxylation promoted by transition metals [15].
Nevertheless, compounds bearing a CF3O-group in aliphatic or
alicyclic positions are still rather rare. This might be due to the
limited number of synthetic methods for direct incorporation
of this group and by the low accessibility of CF3O-containing
building blocks. For instance, almost no data are available for
CF3O-containing α-amino acids except the recently reported
syntheses of several protected derivatives by Qing et al. [13].
This communication presents a straightforward synthesis and
physical chemical data of 2-amino-4-trifluoromethoxy-
organofluorine compounds, which attract widespread
attention of researchers in various fields such as medicinal
chemistry and enzymology [1,2]. These compounds as well as
their derivatives exhibit a broad spectrum of biological
activities [3] and the corresponding F-18 labelled isotopomers
are applied for PET-imaging [4]. They are also useful building
blocks for synthesis of biologically active peptidomimetics and
model peptides [5]. For instance, Koksch et al. incorporated
different α-amino acids of general structure
1 containing
fluoroalkyl chains into peptides as analogues of valine, leucine,
and isoleucine (Fig. 1). Structural and functional upgrading of
peptides and proteins was demonstrated [6].
Fig. 1 Compounds 1-3 as fluorinated analogues of lipophilic aminoacids.
Another lipophilic amino acid, trifluoromethionine (2) [7], was
butanoic acid (O-trifluoromethyl homoserine,
3) as an
analogue of lipophilic natural amino acids. Retrosynthesis
implies alkylation of a protected glycine derivative with the
CF3O-substituted triflate 4 (Scheme 1).
a.Enamine Ltd, Chervonotkatska St 78, Kyiv, 02094, Ukraine.
b.Institute of Bioorganic Chemistry and Petrochemistry, National Academy of
Sciences of Ukraine, Murmanska Str. 1, Kyiv, 02660, Ukraine
c. Organisch-Chemisches Institut, Universität Münster, Corrensstraße 40, Münster
48149, Germany.
d.Cells-in-Motion Cluster of Excellence, Universität Münster, Waldeyerstraße 15,
48149 Münster, Germany.
†
Electronic Supplementary Information (ESI) available: Synthetic procedures,
characterization data and copies of NMR spectra of new compounds are given in
the Electronic Supplementary Information. See DOI: 10.1039/x0xx00000x
Scheme 1 Retrosynthesis of compound 3 starting from triflate 4.
Org. Biomol. Chem., 2016, 00, 1-3 | 1
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Triflate
[16] from diethylene glycol (
adapted this approach for multigram synthesis and obtained proceeded diastereoselectively to give (+)-14 and (
31g of compound (29% yield over three steps, Scheme 2).
67 and 60% de, respectively (by 19F NMR and GC). In both
cases the major isomers (+)-14 and ( )-14 were separated
4
has been previously synthesized by Wakselman et al. including some syntheses of fluorine containingVaiemw AinrtiocleaOcnildinse
) in three steps via and
. We [21]. Alkylation of the enantiomers 1D3OwI: 1it0h.10t3h9e/C6tOriBfl0a2t4e36J
)-14 with
5
6
7
4

4

from the minor ones with >95% de by column chromatography
(1% Et3N in EtOAc/cyclohexane, 1:6) contaminated with the
starting ketones (
)-12 40 and 20%, respectively) due to the close Rf-values.
Hydrolysis with 6N HCl was executed starting from these
mixtures. As in the case of compound , the hydrolysis of (+)-
14 and ( )-14 proceeded smoothly giving the amino acid
hydrochlorides (+)- and ( )- with 13% and 36% overall yields,
)- or (+)-2-hydroxy-3-pinanone (+)-12 and
(
(


9

3
 3
Scheme 2 Synthesis of triflate 4.
respectively (>95% ee). Again we did not observe any products
of CF3O-group decomposition.
The absolute configuration of compound (+)-
by X-ray analysis (Fig. 2) [22]: as all natural lipophilic (+)-amino
acids it has (S)-(or )-configuration. According to the X-ray, the
crystal contains a 1:1 mixture of the hydrochloride and the
betaine form. The CO2H and CO2— groups do interact through a
hydrogen bond. Another remarkable property is the folded
conformation of the chain containing the CF3O-group, which
has a gauche-orientation with regard to the C1-C2-bond.
3 was confirmed
The racemic amino acid
acetyl diethyl malonate (
butoxide as the base to give
hydrolysed with subsequent decarboxylation by refluxing with
6N HCl to give the target amino acid in 65% yield (Scheme 3).
Remarkably, the CF3O-group tolerated these harsh conditions:
not any by-products resulting from CF3O-group decomposition
were observed.
3
was prepared by alkylation of N-
) with using potassium tert-
(88% yield), which was easily
L
8
4
9
3
Scheme 3 Synthesis of racemc amino acid 3.
For asymmetric synthesis of enantiomers (+)- and (
tert-butylesters (+)-13 and )-13 were prepared from
enantiomeric α-pinenes via (+)-(R,R,R)-2-hydroxy-3-pinanone
((+)-12 and )-(S,S,S)-2-hydroxy-3-pinanone (( )-12),
)-3, imino
(
)
(

respectively, following a known protocol [17] (Scheme 4).
These auxiliaries were used for the first time by Yamada et al.
for asymmetric synthesis of α-amino acids [18]. Later many
other groups utilized these imino esters for different
diastereoselective alkylations and aldol-type reactions [19,20]
Fig.2 Crystal structure of compound (+)-3a [22]. Thermal ellipsoids are
shown at 30% probability
Scheme 4 Synthesis the enantiopure CF3O-containing amino acids (+)- and (-)-3.
2 | Org. Biomol. Chem., 2016, 00, 1-3
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DOI: 10.1039/C6OB02436J
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ARTICLE
With amino acid
3 in hand, its pKa values as well as pKa values
of some natural [23] and non-natural lipophilic amino acids
16a-g were measured for comparison (see Table 1).
Remarkably the pKa values of compound
3 are close to those
of valine and leucine but quite different from most of the
other measured amino acids. The data show that the CF3O-
group has minor impact on the pKa values in comparison with
MeS-, MeO- and CF3-groups in the same distance from the
functional groups (Table 1, entries 2, 5 and 8).
Scheme 5. Synthesis of N-tosyl amino acids 15, 17a-g (see Table 1 for R).
Table 1 Measured pKa values of amino acids 3, 16a-g [23] and logD values
for N-tosyl derivatives 15, 17a-g.
Furthermore, we compared the lipophilicity of N-tosyl
derivatives of amino acids
3 and 16a-g in order to estimate the
impact of the CF3O-group. Effect of fluorine on lipophilicity is
extremely important for drug discovery and was extensively
studied during the past decade [11,24,25]. Recently,
lipophilicity of CF3O-containing aromatics was investigated
[10,11], while no investigation for CF3O-containing aliphatic
molecules was found in the literature. Since amino acids
themselves are not suitable for logD measurements because of
their ionic character [25,26], we investigated N-tosyl
derivatives 15 and 17a-g [27-29] (Scheme 5, Table 1).
The measured LogD value of N-tosyl amino acid 15 (entry 1) is
similar to methionine derivative 17a (entry 2) while tosylates
of valine 17b and leucine 17c (entries 3,4) are more
hydrophilic. Comparison of 15 with the non-fluorinated
analogue 17d demonstrates remarkable increase of LogD value
(∆LogD = 1.36), which is in agreement with observed ∆LogP in
case of replacement of CH3O- by CF3O-group in aromatic
compounds [11]. It is also interesting to compare compound
15 with known fluorinated amino acids 17e-g. The parent
amino acids were previously used as “surrogates” of valine,
leucine and isoleucine [6,25]. As expected difluoro- and
trifluoroethyl glycine derivatives 17e,f (entries 6,7) are less
lipophilic than 15. On the other hand the trifluoropropyl
glycine derivative 17g (entry 8) has almost the same lipohilicity
value as amino acid 15. Only minor differences in lipophilicity
therefore arise from the replacement of CF3- with CF3O-group.
In summary, the first unprotected aliphatic CF3O-containing
N-tosyl
amino
acid
Starting
Entry amino
acid
pKa values
of amino
acids 3, 16
logD
of 15
17
R
,
(yield)
1
2
3
4
5
6
7
8
3
(CH2)2OCF3 9.70/2.40 15 (73)
-0.10
16a
16b
16c
16d
16e
16f
16g
(CH2)2SMe
i-Pr
9.24/2.20 17a (67) -0.33
9.72/2.26 17b (87) -1.18
9.69/2.27 17c (77)
8.88/2.10 17d (54) -1.46
9.48/2.21 17e (51) -1.18
8.05/2.33 17f (66)
i-Bu
-0.71
(CH2)2OMe
CH2CHF2
CH2CF3
-1.12
(CH2)2CF3
8.86/2.21 17g (72) -0.12
Experimental section
General
Solvents were purified according to standard procedures.
Starting materials including (+) and (-)-α-pinenes (+)-11 and (-)-
11 and amino acids 16a-g were purchased from Acros, Sigma-
Aldrich, Merck and Enamine at the highest commercial quality
and were used without further purification. Melting points are
uncorrected. NMR spectra were recorded on Bruker Avance
DRX at 500 MHz (1H), 128 MHz (13C) and 470 MHz (19F) at 25
°C. TMS (for H and 13C NMR) and CCl3F (for 19F NMR) were
used as internal standards. Mass spectra (ESI-MS) were
measured on a MicroTof Bruker Daltonics. The progress of
1
amino acid
3 has been synthesised both as racemate and pure
enantiomers. The absolute configuration of (+)-enantiomer
was confirmed by X-ray analysis which also demonstrates an
unusually folded conformation of the lipophilic chain. The pKa
value is close to those of natural neutral amino acids and logD
measurements of N-tosyl derivatives demonstrate remarkable
lipophilicity similar to that of methionine and trifluoropropyl
reactions was monitored by TLC-plates (silica gel 60 F254
,
Merck). Column chromatography was carried out on silica gel
60 (Merck, particle size 0.040–0.063 mm). Elemental analyses
are correct within the limits of ± 0.3% for C, H, and N.
glycine derivatives 17a and 17g. Therefore amino acid
3 is a
X-Ray diffraction
promising building block for incorporation into peptides
replacing natural lipophilic amino acids.
Data sets for the compound (+)-3a were collected with a D8
Venture CMOS diffractometer. Programs used: data collection:
APEX2 V2014.5-0 [30]; cell refinement: SAINT V8.34A [30];
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data reduction: SAINT V8.34A [30]; absorption correction, the temperature did not exceed 25 °C. LiberationVioewf AhryticdleroOgnleinne
SADABS V2014/2 [30]; structure solution SHELXT-2014 [31]; gas was controlled by bubble counterD. OWI: 1h0e.1n03t9h/Ce6OaBd0d2i4ti3o6nJ
structure refinement SHELXL-2014 [31]. R-values are given for completed stirring at r.t. was continued for 3 h. Then the
observed reflections, and wR2 values are given for all mixture was cooled to 0 °C and carbon disulfide (143.5 g, 1.88
reflections. The hydrogen atom positions H1C (between the mol) was added dropwise under stirring. After 1 h, another
O3A and O3B atoms) and the hydrogen atom positions at N1A portion of carbon disulfide (143.5 g, 1.88 mol) was added. The
and N1B atoms were refined freely, but with N-H distance mixture was stirred at r.t. overnight, cooled to 0 °C and
restraints (N1A: DFIX and U-fixed value; N1B: U-fixed value).
iodomethane (401.1 g, 2.83 mol) was added dropwise. The
mixture was stirred at r.t. for 2 h, then cooled to 0 °C and
carefully treated with water (100 mL) and then with ice-water
Measurement of pKa values
The measurements were based on the technical protocols for mixture (1 L). The formed precipitate was filtered off, washed
pKa measurement provided by Pion, Inc. and Sirius Analytical, with water (2 × 150 mL), hexanes (2 × 150 mL) and dried giving
Inc. Acquisition and analysis of the data were performed using the pure target compound
6 as pale yellow solid. Yield: 181.2 g
SmartLogger II 1.0.14 software (Beckman Coulter). The (69%). M.p. 61-62 °C (Lit. [16]: 62.5-62.9 °C).
recording pH-meter (Beckman Coulter pHi510) was calibrated
before the measurements using calibration standards with pH 1-(Trifluoromethoxy)-2-[2-(trifluoromethoxy)ethoxy]ethane
1.68 and 10.01. Data analysis was done using GraphPad Prism (7). Under an argon atmosphere a mixture of 1,3-dibromo-5,5-
5.01, and Excel 2010 software.
pKa values of compounds and 16a-g were determined by pH- dichloromethane (1 L) was cooled to –78 °C in a 2 L Teflon
metric method based on potentiometric acid-base titration at reactor, equipped with overhead stirrer and bubble counter.
25 °C. The compounds were dissolved in acidified (HCl) Then pyridine 9HF (152.5 mL) was added via a polyethylene
solution of NaCl (150 mM, pH 1.9) and slowly titrated with 75 syringe followed by a solution of compound (40.0 g, 0.14
dimethylhydantoin
(DBH,
219.6 g,
0.77 mol)
in
3

6
mM sodium hydroxide solution, while recording pH of the mol) in dichloromethane (100 mL). The cooling bath was
solution as a function of NaOH volume used during the removed and the reaction mixture was stirred at r.t. for 3 h.
titration (construction of the titration curve). Titration of The mixture was poured into ice water (1 L), the organic layer
acidified NaCl solution in absence of any compounds is used was separated and the aqueous phase was extracted with
for blank plotting. The titration assembly was based on dichloromethane (2 × 150 mL). Combined organic layers were
Graseby MS16A Hourly Rate Syringe Driver (Smiths Medical) washed successively with a cold 37% solution of sodium
and a system of tubing and syringes.
bisulfite (400 mL), water (400 mL) and brine (400 mL) and
Buffering capacity was calculated in each point of titration dried with Na2SO4. Then the mixture was concentrated under
curve as the ratio of the NaOH flow (constant) to the pH rise reduced pressure giving 34.5 g of the crude product
velocity. The pKa value was determined from resulting plot of was used for the next step without purification.
buffering capacity versus pH as the maximum of buffering
7, which
capacity.
2-(Trifluoromethoxy)ethyl trifluoromethanesulfonate (4).
mixture of triflic anhydride (85 mL), triflic acid (3 mL) and
crude compound (34.5 g) was stirred at 60 °C under an argon
A
LogD measurements
7
The logD values of 15 and 17a-g were measured using a atmosphere for 2 days. After full conversion (the reaction was
miniaturized shake-flask method. Compounds were dissolved monitored by NMR), the mixture was concentrated under
in the previously mutually saturated mixture containing 990 μL reduced pressure and the residue was diluted with
of phosphate-buffered saline (PBS, pH 7.4) and 100 μL of n- dichloromethane (150 mL), carefully washed with ice water (50
octanol, followed by mixing on a rotator for 1 hour at 30 rpm. mL), brine (50 mL) and dried with Na2SO4. The solution was
Equilibrium distribution of each compound between the concentrated under reduced pressure and the residue was
phases was determined using LC-MS (Shimadzu VP HPLC distilled (b.p. 62-65 °C/20 mbar) giving compound
4 as
system, API3000 mass-detector, AB Sciex). Analyte colourless liquid, which was used for the next step without
concentrations were measured in both phases, in duplicates.
additional purification. Yield: 31 g (42% over 2 steps).
Spectral data of compounds 4, 6 and
literature data [16]
7 coincide with the
Synthesis of compound 4 (optimized procedure)
The synthesis was carried out based on a literature approach
[16] modified for multigram synthesis.
Synthesis of racemic 2-amino-4-(trifluoromethoxy)butanoic
acid (3)
S,S'-Dimethyl O,O'-[oxybis(ethane-2,1-diyl)]dicarbonodithio-
ate (6). A suspension of sodium hydride (60% oil, 113.0 g, 2.83 Diethyl 2-acetamido-2-[2-(trifluoromethoxy)ethyl]malonate
mol) in dry THF (600 mL) in a three-necked 2 L round- (9). To a solution of potassium tert-butoxide (13.4 g, 0.12 mol)
bottomed flask equipped with a magnetic stir bar, with a in THF (200 mL) diethyl 2-acetamidomalonate (21.7 g, 0.1 mol)
bubble counter, thermometer and dropping funnel was cooled was added portion-wise under vigorous stirring at 0-5 °C. After
to 5-10 °C. Then diethylene glycol
5 (100.0 g, 0.942 mol) in THF 30 min a solution of compound 4 (28.8 g, 0.11 mmol) in THF
(100 mL) was added dropwise under vigorous stirring so that (200 mL) was added dropwise and the mixture was left stirring
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at ambient temperature for 6 h. The mixture was poured into °C for 2 h and left stirring at r.t. overnight. Then the mixture
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water (800 mL), extracted with EtOAc (3 × 300 mL), washed was quenched with brine. The aqueousDpOhI:a1s0e.10w39a/sC6eOxBtr0a2c4t3e6dJ
with brine and dried with MgSO4. The mixture was with EtOAc (3 × 20 mL) and the combined organic layers were
concentrated under reduced pressure and the residue was dried with MgSO4. The solution was concentrated under
purified by column chromatography (EtOAc/c-hex, 2:1, Rf = reduced pressure to give 5.37 g of a crude product. According
0.45) giving compound
9 62% of major
as colourless oil. Yield: 31.9 g (88%). to GC and 19F NMR the mixture contained
1H NMR (300 MHz, CDCl3) δ 1.26 (t, J = 7.1 Hz, 6H), 2.07 (s, 3H), diastereomer (+)-14 (estimated de 67%) which was isolated by
2.80 (t, J = 5.7 Hz, 2H), 4.01 (t, J = 5.7 Hz, 2H), 4.24 (q, J = 7.1 column chromatography (eluent: 1% Et3N in EtOAc/c-hexane,
Hz, 4H), 6.96 (br. s, 1H); 13C NMR (75 MHz, CDCl3) δ 13.8, 22.9, 1:6, Rf = 0.65) giving 1.34 g of a mixture of diastereomerically
31.3, 62.9, 64.0, 70.6, 121.2 (q, J = 256.1 Hz), 167.5, 169.7; 19F pure (+)-14 (de >95% by GC and 19F NMR) and
38% of
NMR (283 MHz, CDCl3) δ –61.91 (s); HRMS (ESI-MS) calcd for compound (+)-12 (by GC and 1H NMR) as a pale yellow oil.
[M+Na+] C12H18F3NNaO6 352.0978, found 352.0997; anal calcd NMR data are provided without signals of compound (+)-12. 1H
for C12H18F3NO6 (329.27): C 43.77, H 5.51, N 4.25, found C NMR (600 MHz, CDCl3) δ 0.65 (s, 3H), 1.07 (s, 3H), 1.27 (s, 9H),
43.42, H 5.77, N 4.02%.
1.51 (s, 3H), 1.65–1.69 (m, 1H), 1.75 (d, J = 10.5 Hz, 1H), 2.01-
2.06 (m, 1H, dt, J1 = 18.1 Hz, J2 = 2.9 Hz, 1H), 2.06 (t, J = 6.0 Hz,
rac-2-Amino-4-(trifluoromethoxy)butanoic acid hydrochloride 1H), 2.14–2.21 (m, 2H), 2.25 (dt, J1 = 18.1 Hz, J2 = 2.9 Hz, 1H),
(3). A mixture of compound
9 (3.2 g, 9.7 mmol) and 6N HCl (30 2.45 (dd, J1 = 18.1 Hz, J2 = 2.0 Hz, 1H), 2.79 (bs, 1H), 3.68–3.75
mL) was stirred under reflux for 5 h. Then the mixture was (m, 2H), 4.17 (dd, J1 = 10.2 Hz, J2 = 3.9 Hz); 13C NMR (151 MHz,
cooled and extracted with EtOAc (3 × 30 mL). The aqueous CDCl3) δ = 22.1, 26.9, 27.5, 28.1, 28.3, 33.1, 37.8, 38.3, 42.6,
layer was concentrated under reduced pressure and the 50.2, 58.44, 64.2 (q, J = 3.1 Hz), 76.1, 80.8, 121.9 (q, J = 254.0
residue was crystallized from acetonitrile giving compound
3
.
Hz), 169.3, 180.6; 19F NMR (578 MHz, CDCl3) δ –60.60 (s).
Yield: 1.41 g (65%). Colourless solid, m.p. 190-191 °C. H NMR HRMS (ESI-MS) calcd for [M+Na+] C19H30F3NNaO4 416.2019,
1
+
(300 MHz, CD3OD) δ 2.12–2.45 (m, 2H), 3.93 (t, J = 6.2 Hz, 1H), found 416.2015.
4.20–4.35 (m, 2H); 13C NMR (75 MHz, CD3OD) δ 31.2, 51.6,
66.3, 122.9 (q, J = 255 Hz), 171.9; 19F NMR (283 MHz, CD3OD) δ tert-Butyl
2-[(E)-((1S,2S,5S)-2-hydroxy-2,6,6-
–60.71 (s). HRMS (ESI-MS) calcd for [M+H+] C5H9F3NO3 trimethylbicyclo[3.1.1]heptan-3-ylidene)amino]acetate (

)-13
188.0529, found 188.0526; anal calcd for C5H9ClF3NO3 was obtained by reported procedure from tert-butyl glycine
(223.58): C 26.86, H 4.06, N 6.26, found C 26.98, H 3.95, N ester (generated from tert-butyl glycine ester hydrochloride
6.12%.
(3.36 g, 20 mmol) and triethylamine (2.8 mL, 20 mmol), (+)-
(1S,2S,5S)-2-hydroxy-3-pinanone (-)-12 (2.24 g, 13.3 mmol) and
Synthesis of enantiopure 2-amino-4-(trifluoromethoxy)buta- BF3Et2O (250 μL) by refluxing in toluene (60 mL) [20]. The
noic acid 3
obtained crude product (-)-13 (4.05 g, 76% purity by GC) was
used for alkylation without purification. HRMS (ESI-MS) calcd
(+)-(1R,2R,5R)-2-hydroxy-3-pinanone (+)-12 and (-)-(1S,2S,5S)- for [M+Na+] C16H27NNaO3+ 304.1883, found 304.1890.
2-hydroxy-3-pinanone (-)-12 were obtained from commercially
available (+)- or (-)-α-pinenes by a described procedure [17] in (R)-tert-Butyl
57% and 49% yields, respectively. trimethylbicyclo[3.1.1]-heptan-3-ylidene)amino]-4-
(trifluoromethoxy)butanoate (-)-14. According to the
tert-Butyl 2-[(E)-((1R,2R,5R)-2-hydroxy-2,6,6-trimethylbicyclo- procedure given above, alkylation of (-)-13 (3.04 g, 10.7 mmol)
[3.1.1]heptan-3-ylidene)amino]acetate (+)-13 was obtained with triflate (2.37 g, 9.0 mmol) in the presence of 2M LDA in
by reported procedure from tert-butyl glycine ester THF (13.5 mL, 27.0 mmol), gave 5.71 g of the crude product (-)-
(generated from tert-butyl glycine ester hydrochloride (3.36 g, 14. GC and 19F NMR showed that the mixture contained
67%
2-[(E)-((1S,2S,5S)-2-hydroxy-2,6,6-
4
a

20.0 mmol) and triethylamine (2.8 mL, 20.0 mmol), (+)- of major diastereomer (-)-14 (estimated de 60%), which was
(1R,2R,5R)-2-hydroxy-3-pinanone (+)-12 (2.24 g, 13.3 mmol) isolated by column chromatography (eluent: 1% Et3N in
and BF3
obtained crude product (
for alkylation. HRMS (ESI-MS) calcd for [M+Na+] C16H27NNaO3 and

Et2O (250 μL) by refluxing in toluene (60 mL) [20]. The EtOAc/c-hexane, 1:6, Rf = 0.65) to give 2.33 g of a mixture of

4.0 g, 75% purity by GC) was used diastereomerically pure (-)-14 (de >95% by GC and 19F NMR)
+
1

20% of compound (-)-12 (by GC and H NMR) as a pale
304.1883, found 304.1891.
yellow oil. NMR spectra of compounds (+)-14 and (-)-14 are
+
identical. HRMS (ESI-MS) calcd for [M+Na+] C19H30F3NNaO4
(S)-tert-Butyl
2-[(E)-((1R,2R,5R)-2-hydroxy-2,6,6- 416.2019, found 416.2013.
trimethylbicyclo[3.1.1]-heptan-3-ylidene)amino]-4-
(trifluoromethoxy)-butanoate (+)-14. A 2 M solution of LDA in (S)-2-Amino-4-(trifluoromethoxy)butanoic
THF (11.1 mL, 22.2 mmol) was put into flask under argon Obtained product (+)-14 (0.90 g, containing
acid
(+)-3.
40% of

atmosphere and cooled to –78 °C. Then the crude product (+)- compound (+)-12) was dissolved in dioxane (10 mL). Then 6N
13 (2.50 g, 8.8 mmol) was added dropwise via syringe and the HCl (20 mL) was added and the mixture was refluxed for 3 h.
mixture was stirred for 90 min. Then triflate
4 (2.50 g, 9.5 Then the mixture was cooled to r.t. and extracted with EtOAc
mmol) was added and the reaction mixture was stirred at –78 (3 × 20 mL). The aqueous layer was concentrated under
This journal is © The Royal Society of Chemistry 20xx
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reduced pressure and the residue was crystallized from 326.0497; anal calcd for C12H17NO4S2 (303.40): C 47.50, H 5.65,
View Article Online
DOI: 10.1039/C6OB02436J
acetonitrile (20 mL) giving compound (+)-3 as colourless solid. N 4.62%; found C 47.28, H 5.60, N 4.79%.
Yield: 0.21 mg (13 % over 3 steps from compound (+)-12).
20
Colourless solid, mp 184-185 °C, [α]D = +8.8 (H2O). NMR (S)-3-Methyl-2-(4-methylphenylsulfonamido)butanoic
acid
spectra are identical with those for the racemic compound
3
.
17b was obtained by general procedure starting from L-valine
HRMS (ESI-MS) calcd for [M+H+] C5H9F3NO3 188.0529, found (117 mg, 1 mmol), tosyl chloride (210 mg, 1.1 mmol) and
188.0525.
NaOH (88 mg, 2.2 mmol). Yield: 236 mg (87%). Colourless solid,
m.p. 143-145 °C. NMR spectra coincide with the literature data
(R)-2-Amino-4-(trifluoromethoxy)butanoic acid (-)-3 was [27].
obtained by the same procedure as compound (+)- from
product (-)-14 (2.10 g, containing 20% of compound (-)-12) in (S)-4-Methyl-2-(4-methylphenylsulfonamido)pentanoic acid
dioxane (20 mL) and 6N HCl (35 mL). Yield: 0.91 g (36% over 3 17c was obtained by general procedure starting from L-leucine
steps from compound (-)-12). Colourless solid, mp 182-184 °C. (131 mg, 1 mmol), tosyl chloride (210 mg, 1.1 mmol) and
[α]D = –9.3 (H2O). NMR spectra are identical with those for NaOH (88 mg, 2.2 mmol). Yield: 219 mg (77%). Colourless solid,
3

20
the racemic compound
3
.
m.p. 113-115 °C. NMR spectra coincide with the literature data
HRMS (ESI-MS) calcd for [M+H+] C5H9F3NO3 188.0529, found [28].
188.0526.
4-Methoxy-2-(4-methylphenylsulfonamido)butanoic acid 17d
Synthesis of N-tosyl amino acids 15, 17a-g. General was obtained by general procedure starting from rac-2-amino-
procedure.
4-methoxybutanoic acid 16d (132 mg, 1 mmol), tosyl chloride
(210 mg, 1.1 mmol) and NaOH (88 mg, 2.2 mmol). Yield: 155
mg (54%). Colourless solid, m.p. 106-108 °C. 1H NMR (400
MHz, DMSO-d6) δ 1.47–1.97 (m, 2H), 2.37 (s, 3H), 3.05 (s, 3H),
3.11–3.32 (m, 2H), 3.70–3.85 (m, 1H), 7.37 (d, J = 8.0 Hz, 2H),
7.66 (d, J = 8.0 Hz, 2H), 8.02 (br s, 1H); 13C NMR (128 MHz,
DMSO-d6) δ 21.5, 32.7, 53.2, 58.3, 68.1, 127.0, 130.0, 139.0,
143.6, 173.5; HRMS (ESI-MS) calcd for [M+Na+] C12H17NNaO5S+:
310.0720, found 310.0708; anal calcd for C12H17NO5S (287.33):
C 50.16, H 5.96, N, 4.87%; found C 50.03, H 6.02, N 4.98%.
To a solution of the amino acid or the corresponding
hydrochloride (1 mmol) in H2O (5 mL) were added NaOH (88
mg, 2.2 mmol or 132 mg, 3.3 mmol in the case of
hydrochlorides) and TosCl (210 mg, 1.1 mmol). The reaction
mixture was stirred at r.t. overnight. Then the solution was
acidified with 1 M aqueous HCl until pH 1 and extracted with
EtOAc (3 × 10 mL). The combined organic phases were washed
with brine, dried over Na2SO4, filtered and concentrated under
reduced pressure. The residue was purified by crystallization
from MeOH/water.
4,4-Difluoro-2-(4-methylphenylsulfonamido)butanoic acid 17e
was obtained by general procedure starting from rac-2-amino-
4,4-difluorobutanoic acid 16e (139 mg, 1 mmol), tosyl chloride
(210 mg, 1.1 mmol) and NaOH (88 mg, 2.2 mmol). Yield: 150
mg (51%). Colourless solid, m.p. 134-136 °C. 1H NMR (400
MHz, DMSO-d6) δ 1.94–2.27 (m, 2H), 2.36 (s, 3H), 3.75–3.87
(m, 1H), 5.97 (tt, J1 = 56.0, J2 = 4.0 Hz, 1H), 7.36 (d, 2H, J = 8.1
Hz), 7.65 (d, 2H, J = 8.1 Hz), 8.20 (br s, 1H); 13C NMR (128 MHz,
DMSO-d6) δ 21.4, 37.0 (t, J = 21.8 Hz), 51.3 (t, J = 5.0 Hz), 116.1
(t, J = 238.5 Hz), 127.0, 130.0, 138.3, 143.2, 171.7; 19F NMR
(376 MHz, DMSO-d6) δ –116.78-–116.78 (m); HRMS (ESI-MS)
calcd for [M+Na+] C11H13F2NNaO4S+ 316.0426; found 316.0433;
anal calcd for C11H13F2NO4S (293.29): C 45.05, H 4.47, N 4.78%;
found C 44.89, H 4.58, N 4.92%.
rac-2-(4-Methylphenylsulfonamido)-4-(trifluoromethoxy)-
butanoic acid 15 was obtained by general procedure starting
from rac-
3 (223 mg, 1 mmol), tosyl chloride (210 mg, 1.1
mmol) and NaOH (133 mg, 3.3 mmol). Yield: 249 mg (73%).
1
Colourless solid, m.p. 129-131 °C. H NMR (400 MHz, DMSO-
d6) δ 1.32–2.06 (m, 2H), 2.36 (s, 3H), 3.74–3.84 (m, 1H), 3.92–
4.04 (m, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H),
8.16 (d, J = 8.4 Hz, 1H), 12.23–13.10 (br s, 1H); 13C NMR (128
MHz, DMSO-d6) δ 20.9, 31.1, 51.9, 64.1 (q, J = 3.5 Hz), 121.0 (q,
J = 254.0 Hz), 126.4, 129.3, 138.0, 142.5, 172; 19F NMR (376
MHz, DMSO-d6) δ –58.71 (s); HRMS (ESI-MS) calcd for [M+Na+]
C12H14F3NNaO5S+ 364.0437, found 364.0428; anal calcd for
C12H14F3NO5S (341.30): C 42.23, H 4.13, N 4.10, found C 42.01,
H 4.28, N 3.97%.
4,4,4-Trifluoro-2-(4-methylphenylsulfonamido)butanoic acid
17f was obtained by general procedure starting from rac-2-
amino-4,4,4-trifluorobutanoic acid 16f (157 mg, 1 mmol), tosyl
chloride (210 mg, 1.1 mmol) and NaOH (88 mg, 2.2 mmol).
(S)-2-(4-Methylphenylsulfonamido)-4-(methylthio)butanoic
acid 17a was obtained by general procedure starting from L-
methionine (150 mg, 1 mmol), tosyl chloride (210 mg, 1.1
mmol) and NaOH (88 mg, 2.2 mmol). Yield: 203 mg (67%).
1
Yield: 205 mg (66%). Colourless solid, mp 168-170 °C. H NMR
(400 MHz, DMSO-d6) δ 2.44 (s, 3H), 2.48–2.64 (m, 1H), 2.68–
2.84 (m, 1H), 3.98–4.08 (m, 1H), 7.43 (d, J = 8.1 Hz, 2H), 7.72
(d, J = 8.1 Hz, 2H), 8.33 (br s, 1H); 13C NMR (128 MHz, DMSO-
d6) δ =20.9, 35.5 (q, J = 28.0 Hz), 50.4, 125.6 (q, J = 276.7 Hz),
126.5, 129.3, 138.0, 142.6, 170.4; 19F NMR (376 MHz, DMSO-
d6) δ –63.04 (t, J = 10.5 Hz); HRMS (ESI-MS) calcd for [M+Na+]
C11H12F3NNaO4S+ 334.0331; found 334.0341; anal calcd for
1
Colourless solid, m.p. 77-79 °C. H NMR (400 MHz, DMSO-d6):
δ 1.66–1.86 (m, 2H), 1.93 (s, 3H), 2.25–2.45 (m, 5H), 3.77–3.84
(m, 1H), 7,36 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H), 8.04 (br
s, 1H), 12.79 (br s, 1H); 13C NMR (128 MHz, DMSO-d6) δ 14.8,
21.4, 29.7, 32.1, 54.9, 127.0, 129.9, 138.9, 142.9, 173.0; HRMS
+
(ESI-MS) calcd for [M+Na+] C12H17NNaO4S2 326.0491; found
6 | Org. Biomol. Chem., 2016, 00, 1-3
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1
J.-P. Bégué and D. Bonnet-Delpon, Bioorganic and Medicinal
C11H12F3NO4S (311.28): C 42.44, H 3.89, N 4.50%; found C
42.37, H 4.02, N 4.41%.
View Article Online
Chemistry of Fluorine; John Wiley &DOSoI:n10s,.10In39c/.C, 6HOoBb0o2k43e6nJ,
New Jersey, 2008, pp 365; Fluorine and Health. Molecular
Imaging, Biomedical Materials and Pharmaceuticals, (Eds.: A.
Tressaud, G. Haufe), Elsevier, Amsterdam, 2008, pp 553-778;
Fluorine in Medicinal Chemistry and Chemical Biology, (Ed. I.
Ojima), Wiley-Blackwell, 2009, pp 3-198; Fluorine in
Pharmaceutical and Medicinal Chemistry. From Biophysical
Aspects to Clinical Application, (Eds.: V. Gouverneur, K.
Müller,), Imperial College Press, London, 2012, pp 139-331.
For recent reviews and synthesis examples see: R. Smits, C. D.
Cadicamo, K. Burger and B. Koksch, Chem. Soc. Rev., 2008,
37, 1727; V. P. Kukhar, A. E. Sorochinsky and V. A.
5,5,5-Trifluoro-2-(4-methylphenylsulfonamido)pentanoic acid
17g was obtained by general procedure starting from rac-2-
amino-5,5,5-trifluoropentanoic acid 16g (171 mg, 1 mmol),
tosyl chloride (210 mg, 1.1 mmol) and NaOH (88 mg, 2.2
mmol). Yield: 234 mg (72%). Colourless solid, mp 137-139 °C.
1H NMR (400 MHz, DMSO-d6) δ 1.61–1.88 (m, 2H), 2.08–2.27
(m, 2H), 2.37 (s, 3H), 3.78–3.88 (m, 1H), 7.37 (d, J = 7.8 Hz, 2H),
7.87 (d, J = 7.8 Hz, 2H), 8.16 (br s), 12.27–13.34 (br s, 1H); 13C
NMR (128 MHz, DMSO-d6) δ 21.5, 25.2, 29.7 (q, J = 27.8 Hz),
54.8, 127.1, 127.8 (q, J = 235.0 Hz), 130.0, 138.9, 143.2, 172.5;
19F NMR (376 MHz, DMSO-d6) δ –64.55 (t, J = 11.5 Hz) ppm.
HRMS (ESI-MS) calcd for [M+Na+] C11H12F3NNaO4S+ 334.0331;
found 334.0341; anal calcd for: C12H14F3NO4S (325.30): C 44.31,
H 4.34, N 4.31%; found: C 44.19, H 4.28, N 4.50%.
2
Soloshonok, Future Med. Chem., 2009, 1, 793; Sorochinsky,
A. E. and V. A. Soloshonok, J. Fluorine Chem., 2010, 131, 127;
A. Tarui, K. Sato, M. Omote, I. Kumadaki and A. Ando, Adv.
Synth. Catal., 2010, 352, 2733; C. Czekelius and C. C.
Tzschucke, Synthesis, 2010, 543; X.-L. Qiu and F.-L. Qing, Eur.
J. Org. Chem., 2011, 3261; Y.-L. Liu, T.-D. Shi, F. Zhou, X.-L.
Zhao, X. Wang and J. Zhou Org. Lett., 2011, 13, 3826; K.
Mikami, S. Fustero, J. L. Sánchez-Roselló, M. Aceña, V. A.
Soloshonok and A. E. Sorochinsky, Synthesis, 2011, 3045; J. L.
Aceña, A. E. Sorochinsky and V. A. Soloshonok, Synthesis,
2012, 44, 1591; J. L. Aceña, A. E. Sorochinsky, H. Moriwaki, T.
Sato and V. A. Soloshonok, J. Fluorine Chem., 2013, 155, 21.
For some examples see: A. Nakazato, T. Kumagai, K.
Sakagami, R. Yoshikawa, Y. Suzuki, S. Chaki, H. Ito, T. Taguchi,
S. Nakanishi and S. Okuyama, J. Med. Chem., 2000, 43 (25),
4893; D. Alexeev, R. L. Baxter, D. J. Campopiano, O. Kerbarh,
L. Sawyer, N. Tomczyk, R. Watta and S. P. Webster, Org.
X-ray crystal structure of compound (+)-3
A
colourless needle-like specimen of C10H17ClF6N2O6,
3
dimensions 0.055 mm x 0.072 mm x 0.228 mm, was used for
the X-ray crystallographic analysis. The X-ray intensity data
were measured. A total of 923 frames were collected. The
total exposure time was 24.10 hours. The frames were
integrated with the Bruker SAINT software-package using a
wide-frame algorithm. The integration of the data using a
monoclinic unit cell yielded a total of 7433 reflections to a
maximum θ angle of 63.65° (0.86 Å resolution), of which 2417
were independent (average redundancy 3.075, completeness =
95.0%, Rint = 14.73%, Rsig = 13.43%) and 1807 (74.76%) were
greater than 2σ(F2). The final cell constants of a = 11.0208(8) Å,
b = 5.0952(4) Å, c = 14.7276(11) Å, β = 103.403(6)°, volume =
804.48(11) Å3, are based upon the refinement of the XYZ-
centroids of 2344 reflections above 20 σ(I) with 8.247° < 2θ <
136.3°. Data were corrected for absorption effects using the
multi-scan method (SADABS). The ratio of minimum to
maximum apparent transmission was 0.793. The calculated
minimum and maximum transmission coefficients (based on
crystal size) are 0.5420 and 0.8500. The structure was solved
and refined using the Bruker SHELXTL Software Package, using
the space group P21, with Z = 2 for the formula unit,
C10H17ClF6N2O6. The final anisotropic full-matrix least-squares
refinement on F2 with 248 variables converged at R1 = 9.18%,
for the observed data and wR2 = 16.90% for all data. The
goodness-of-fit was 1.191. The largest peak in the final
difference electron density synthesis was 0.466 e-/Å3 and the
largest hole was -0.548 e-/Å3 with an RMS deviation of 0.115 e-
/Å3. On the basis of the final model, the calculated density was
1.695 g/cm3 and F(000), 420 e-. Flack parameter: 0.12(4).
Biomol. Chem., 2006, 4, 1209; K. H. Mortell, D. J. Anderson, J.
J. Lynch, S. L. Nelson, K. Sarris, H. McDonald, R. Sabet, S.
Baker, P. Honore, C.-H. Lee, M. F. Jarvis and M.
Gopalakrishnan, Bioorg. Med. Chem. Lett., 2006, 16, 1138; N.
Gupta, H. Zhang and P. Liu, Pharmacol. Biochem. Behavior,
2012, 100, 464.
4
P. Laverman, O. C. Boerman, F. H. Corstens and W. J. Oyen,
Eur. J. Nucl. Med. Mol. Imag., 2002, 29, 681; J. McConathy,
W. Yu, N. Jarkas, W. Seo, D. M. Schuster and M. M.
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McConathy, Curr. Topics Med. Chem., 2013, 13, 871; S.
Suzuki, K. Kaira, Y. Ohshima, N. S. Ishioka, M. Sohda, T.
Yokobori, T. Miyazaki, N. Oriuchi, H. Tominaga, Y. Kanai, N.
Tsukamoto, T. Asao, Y. Tsushima, T. Higuchi, T. Oyama and H.
Kuwano, Brit. J. Cancer, 2014, 110, 1985.
5
6
N. C. Yoder and K. Kumar, Chem. Soc. Rev., 2002, 31, 335; H.-
P. Chiu, Y. Suzuki, D. Gullickson, R. Ahmad , B. Kokona, R.
Fairman and R. P. Cheng J. Am. Chem. Soc., 2006, 128
,
15556; H. Meng and K. Kumar, J. Am. Chem. Soc., 2007, 129
(50), 15615; M. Salwiczek, E. K. Nyakatura, U. I. M. Gerling; S.
Ye and B. Koksch, Chem. Soc. Rev., 2012, 41, 2135.
For recent publications see: (a) E. K. Nyakatura, O. Reimann,
T. Vagt, M. Salwiczek and B. Koksch, RSC Adv., 2013, 3, 6319;
U. I. M. Gerling, M. Salwiczek, C. D. Cadicamo, H. Erdbrink, C.
Czekelius, S. L. Grage, P. Wadhwani, A. S. Ulrich, M.
Behrends, G. Haufe and B. Koksch, Chem. Sci., 2014,
S. Ye, B. Loll, A. A. Berger, U. Mulow, C. Alings, M. C. Wahl
and B. Koksch Chem. Sci., 2015, , 5246.
5, 819.
6
7
8
For synthesis see: H. Yasui; T. Yamamoto, E. Tokunaga and N.
Shibata, J. Fluorine Chem., 2011, 132, 186 and references
therein; A. E. Sorochinsky, H. Ueki, H. L. Aceña, T. K. Ellis, H.
Moriwaki, T. Sato and V. A. Soloshonok, J. Fluorine Chem.,
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Notes and references
M. E. Houston Jr., L. Harvath and J. F. Honek, Bioorg. Med.
Chem. Lett., 1997, 7, 3007; H. Duewel, E. Daub, V. Robinson
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This work has been supported by the Deutsche
Forschungsgemeinschaft (Ha 2145/9-1; AOBJ: 560896). We also
thank Dr. S. Zozulya (Enamine Ltd, Kiev) for his support in
determination of LogD and pKa values.
This journal is © The Royal Society of Chemistry 20xx
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Honek, Biochemistry, 2001, 40, 13167. N. Budisa, O. Pipitone, 23 Measured pKa values of natural amino acids 16a-c are in
I. Siwanowicz, M. Rubini, P. P. Pal, T. A. Holak and M. L.
good accordance with the literatureDdOaI:t1a0:.10c3yV9siet/Cwei6AnOretiBcl0e(21O46n3ali6n)Je:
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10 For reviews on synthesis and properties of CF3O-containing 25 S. A. Samsonov, M. Salwiczek, G. Anders, B. Koksch and M. T.
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11 For recent data of CF3O-group impact on lipophilicity see: K.
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22 CCDC 1511242 contains the supplementary crystallographic
data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif
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