Chiral fluoroacetic acid: Synthesis of (R)- and (S)-[2H 1]-fluoroacetate in high enantiopurity

Article abstract of DOI:10.1016/j.tetasy.2013.05.001

A two-step synthesis of (R)- and (S)-[²H₁]- fluoroacetate (sodium salts) in high enantioselectivity is reported. The synthesis is the development of a previous one in which the enantioselectivity has been increased from ～38% ee to >95% ee. The improvement in enantioselectivity applied Bio's methodology, which involved a deoxyfluorination reaction with DAST on either enantiomer of [²H₁]-benzyl alcohol, adding TMS-morpholine to the reaction. The additive promotes an S _N2 inversion process, and suppresses a competing non-stereospecific S_N1 reaction course, and as a result significantly improves the stereointegrity of the C-F bond formation. The intermediate [²H ₁]-benzyl alcohols, [²H₁]-benzyl fluorides and the product [²H₁]-fluoroacetates as their hexyl esters were separately assayed for their stereochemical integrity, using the Courtieu method. This method involved measuring their ²H NMR spectra in a chiral matrix of poly-γ-benzyl l-glutamate. The chiral assay demonstrated that there was no significant loss in stereointegrity during the deoxyfluorination reaction and showed that the enantiomers of [ ²H₁]-fluoroacetate were generated with high enantiomeric purity (95% ee).

Full text of DOI:10.1016/j.tetasy.2013.05.001

Tetrahedron: Asymmetry 24 (2013) 719–723
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Chiral fluoroacetic acid: synthesis of (R)- and (S)-[2H1]-fluoroacetate
in high enantiopurity
Rudy D. P. Wadoux a, Xiaowei Lin a,b, Neil S. Keddie a, David O’Hagan a,
⇑
a School of Chemistry and Centre for Biomolecular Sciences, University of St. Andrews, St. Andrews, Fife KY16 9ST, UK
b Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Ling Ling Road 345, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
A two-step synthesis of (R)- and (S)-[2H1]-fluoroacetate (sodium salts) in high enantioselectivity is
reported. The synthesis is the development of a previous one in which the enantioselectivity has been
increased from ꢀ38% ee to >95% ee. The improvement in enantioselectivity applied Bio’s methodology,
which involved a deoxyfluorination reaction with DAST on either enantiomer of [2H1]-benzyl alcohol,
adding TMS-morpholine to the reaction. The additive promotes an SN2 inversion process, and suppresses
a competing non-stereospecific SN1 reaction course, and as a result significantly improves the stereoin-
tegrity of the C–F bond formation. The intermediate [2H1]-benzyl alcohols, [2H1]-benzyl fluorides and
the product [2H1]-fluoroacetates as their hexyl esters were separately assayed for their stereochemical
integrity, using the Courtieu method. This method involved measuring their 2H NMR spectra in a
Article history:
Received 3 April 2013
Accepted 1 May 2013
Available online 6 June 2013
chiral matrix of poly-c-benzyl L-glutamate. The chiral assay demonstrated that there was no significant
loss in stereointegrity during the deoxyfluorination reaction and showed that the enantiomers of
[2H1]-fluoroacetate were generated with high enantiomeric purity (95% ee).
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
Two previous routes for the preparation of chiral fluoroac-
Fluoroacetate, as its co-enzyme-A ester (FAcCoA), is the sub-
strate for a number of acetylCoA (AcCoA) utilising condensation
enzymes that mediate carbon–carbon bond forming reactions.1 In
such reactions of FAcCoA, the enzymes can be expected to mediate
a diastereotopic deprotonation at C-2, the fluoromethylene group.
The cryptic stereochemistry of such a process can be evaluated if
(R)-1a or (S)-1b [2H1]-fluoroacetate is prepared and then converted
into the corresponding [2H1]-FAcCoA by either a chemical or enzy-
matic conversion. Most notably, citrate synthase2 generates a sin-
gle stereoisomer of fluorocitrate when FAcCoA is used as a
substrate. Malate synthase is also known to utilise FAcCoA as an
alternative substrate, although the reaction is less stereospecific.3
We have also assayed the absolute configuration of chiral fluoroac-
etate generated in the fermentations of Streptomyces cattleya to as-
sess the stereochemistry of biological fluorination during the
biosynthesis of fluoroacetate in this organism.4
etate have been reported on. The first, which was accom-
plished in high enantiopurity, was described by Gartz
et al.,5 over six steps, where the asymmetry was introduced
using a Sharpless epoxidation and the enantiomeric excess of
the [2H1]-fluoroacetates was determined by circular dichroism
spectroscopy.
We have previously reported the preparation of chiral [2H1]-
fluoroacetate 1,4 which involved the deoxyfluorination of enanti-
omers of [7-2H1]-benzylalcohol 2 to generate the corresponding
chiral [7-2H1]-benzylfluorides 3 with predominant inversion of
configuration. However, there was a substantial loss in stereoin-
tegrity, because reactions with DAST, even at low temperatures,
are compromised by a significant SN1 character during the substi-
tution reaction. Recently a method has emerged, which sup-
presses the SN1 character of these benzylic deoxofluorination
reactions. This was first reported in 2008 by Bio et al.,6 when it
was demonstrated that the addition of TMS-morpholine to reac-
tions of Deoxofluor™ with benzyl alcohols, led to benzylfluoride
products with very high inversion integrity. The reaction has been
applied to other benzylic alcohols.7 Herein we apply Bio’s modifi-
cation to significantly improve the stereospecificity of our earlier
synthesis of chiral fluoroacetates, and demonstrate that samples
of (R)-1a and (S)-1b [2H1]-fluoroacetate (sodium salts) can be
prepared with high enantiopurity (>95% ee).
O
O
H
D
H
D
O
Na
O
Na
F
F
2
2
1a
1b
(S)-[ H1]-fluoroacetate
(R)-[ H1]-fluoroacetate
⇑
Corresponding author. Tel.: +44 1334 467176; fax: +44 1334 463808.
E-mail address: do1@st-andrews.ac.uk (D. O’Hagan).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.05.001

720
R. D. P. Wadoux et al. / Tetrahedron: Asymmetry 24 (2013) 719–723
Figure 1. 2H NMR
c
-PBG assay illustrating the stereointegrity of [7-2H1]-benzyl alcohols prepared by Yamada and Noyori’s methodology.8 (a) 2H NMR of racemic [7-2H1]-
benzyl alcohol derived from non-asymmetric reduction; (b) 2H NMR of (S)-2a; (c) 2H NMR of (R)-2b.
Figure 2. 2H NMR
c
-PBG assay illustrating the stereointegrity of [7-2H1]-benzylfluorides 3. (a) 2H NMR of a control reaction in the absence of TMS-morpholine; (b) 2H NMR of
(R)-3a; (c) 2H NMR of (S)-3b.

R. D. P. Wadoux et al. / Tetrahedron: Asymmetry 24 (2013) 719–723
721
O
O
D
iii
iv
D
H
D
H
v
HO
Na
O
O
H
D
i
F
F
H
F
4a
[2H1]-(R)- 1a
2a
3a
H
O
benzaldehyde
ii
O
O
iii
iv
H
H
D
v
H
D
HO
O
Na
D
O
H
F
D
F
F
4b
[2H1]-(S)- 1b
2b
3b
Scheme 1. The synthesis of hexyl (R)- and (S)-[1-2H1]-fluoroacetates (R)-4a and (S)-4b. Reagents and conditions: (i) [2H2]-formic acid, Et3N, RuCl(p-cymene)[(R,R)-Ts-DPEN],
MeCN, 95%; (ii) [2H2]-formic acid, Et3N, RuCl(p-cymene)[(S,S)-Ts-DPEN], MeCN, 99%; (iii) DAST, TMS-morpholine, DCM, 35–36%; (iv) RuCl3ꢁH2O, NaIO4, MeCN, H2O, CCl4,
17–20%; (v) EDCI, HOBt, hexan-1-ol, DCM, 41–66%.
fluoroacetates (R)-4a and (S)-4b for the 2H NMR assay. The resultant
2. Results and discussion
2H NMR assays for each enantiomer and an add-mixed sample
are shown in Figure 3. It is clear from the 2H NMR assay that the
stereointegrity of the hexyl [2H1]-fluoroacetates is high; thus it
was concluded that the (R)-4a and (S)-4b [2H1]-fluoroacetate
(sodium salts) were prepared in high enantiopurity.
The synthesis of the enantiomers of chiral [2H1]-fluoroacetate
started from enantiomerically enriched samples of [7-2H1]-benzyl
alcohol 2. Each enantiomer was prepared in high enantiomeric
purity following a method previously described by Yamada and
Noyori.8 This was achieved by the direct catalytic reduction of
benzaldehyde using [2H2]-formic acid as the deuterium source to
generate (S)-2a using the RuCl(p-cymene)[(R,R)-Ts-DPEN] catalyst
and (R)-2b from the corresponding (S,S) catalyst. In this manner,
both enantiomers were obtained with high enantiomeric purity
3. Conclusion
In conclusion, an efficient two step synthesis of sodium [2H1]-
fluoroacetates (R)-1a and (S)-1b has been demonstrated utilising
the Bio modification for benzylic deoxofluorination reactions with
DAST. This synthesis is a significant improvement on that reported
by us with the enantiomeric purity of the resultant chiral [2H1]-
fluoroactetates being increased from 38% ee to >95% ee, making
this preparation much more useful for future stereochemical
studies on the fluoroacetate of FAcCoA processing enzymes. The
approach offers an alternative and shorter route to the methodol-
ogy reported by Gartz et al.5
as determined using Courtieu’s 2H NMR method in a poly-
c-ben-
zyl-L-glutamate (c-PBG): chloroform matrix, as previously de-
scribed.9 The resultant 2H NMR spectra for (R)-2b and (S)-2a, as
well as a racemic mixture of 2, are presented in Figure 1.
Treatment of the chiral benzyl alcohols (S)-2a and (R)-2b with
DAST adding TMS-morpholine (3.1 equiv),7 generated the corre-
sponding benzyl fluorides (R)-3a and (S)-3b, respectively, in 35–
36% yield. The benzyl fluorides were then subjected to a stereo-
chemical assay using Courtieu’s 2H NMR method in a
c-PBG matrix
as previously described.9 The high stereointegrity of the products is
evident from the resultant 2H NMR spectra as illustrated in
Figure 2b and c. The result of the control reaction in the absence
of TMS-morpholine is also shown in Figure 2a, demonstrating the
importance of the additive in maintaining the stereointegrity of
the deoxyfluorination reaction. The benzyl fluorides were then
subjected to aryl ring oxidation under conditions previously de-
scribed by Sharpless (RuCl3, NaIO4).10 This generated chiral fluoro-
acetates (R)-1a and (S)-1b. Caution! Fluoroacetate is highly toxic.11
Purification of the [2H1]-fluoroacetates required that the products
were acidified to pH 1 and lyophilised to afford the free (R)- and
(S)-[2H1]-fluoroacetic acids in an aqueous solution. Careful pH
adjustment of this solution with dilute sodium hydroxide to pH
3.5, followed by freeze drying, afforded the sodium fluoroacetate
salts (R)-4a and (S)-4b as amorphous powders. It proved important
to control the pH at the final freeze drying stage and prevent it
going above pH 3.5. If neutralisation and freeze drying were carried
out at a more basic pH (>pH 3.5), then trace amounts of sodium
formate and sodium acetate (from EtOAc) were also retained.
Therefore, it was advantageous to tension the pH between the
pKa’s of these acids and fluoroacetate (pKa 2.5).
4. Experimental
4.1. General
1H NMR spectra were recorded at 400 MHz or 500 MHz, on Bru-
ker Avance II or Avance III spectrometers, using CDCl3 as reference
and as internal deuterium lock. Chemical shifts are given as d in
units of parts per million (ppm) relative to tetramethylsilane.
13C NMR spectra were recorded at 100 MHz or 126 MHz using
the DEPT Q pulse sequence with proton decoupling. 19F NMR spec-
tra were recorded at 376 MHz either with proton coupling or using
broadband proton decoupling and internal deuterium lock. Flash
column chromatography was carried out using Merck Geduran
Silica Gel 60 (240–400 mesh), under
a positive pressure of
compressed air. Anhydrous solvents (CH2Cl2, Et2O) were eluted
from a MBraun GmbH MB SPS-800 solvent purification system
and anhydrous acetonitrile was obtained by distillation from
CaH2. Benzaldehyde was washed successively with Na2CO3
solution (10% w/v), saturated Na2SO4 solution and brine, and dried
over MgSO4 prior to use.
Direct 2H NMR analysis by the Courtieu method of sodium
(R)-1a and (S)-1b fluoroacetates was not possible, as the salts are
4.1.1. 2H NMR chiral analysis
Poly-c-benzyl-
L
-glutamate
(c-PBG) (120 mg), the analyte
insoluble in the c-PBG NMR polymer matrix. Thus, the sodium flu-
(40 mg) and chloroform (800 mg) were successively added into a
pre-weighed 5 mm NMR tube. The NMR tube was sealed with a
PTFE pressure cap (Wilmad 521-pc) and left to stand for 1 h. When
oroacetates were individually converted into their hexyl esters 44b
as illustrated in Scheme 1. This gave suitable samples of derivatised

722
R. D. P. Wadoux et al. / Tetrahedron: Asymmetry 24 (2013) 719–723
Figure 3. 2H NMR
c
-PBG assay illustrating the stereointegrity of hexyl [2H1]-fluoroacetates 4. (a) 2H NMR of an add-mixture of both enantiomers 4a and 4b; (b) 2H NMR of
(R)-4a; (c) 2H NMR of (S)-4b.
the
c-PBG was completely dissolved, the NMR tube was placed in a
DPEN] as the catalyst, affording (R)-[7-2H1]-benzyl alcohol 2b
plastic outer tube and the entire was spun manually with a cord to
achieve a centrifugal force to draw the gel from one end of the tube
to the other. The tube was inverted and this manual centrifugation
was repeated 40 times. The sample was then left to stand for a fur-
ther 2 h to equilibrate, prior to recording the 2H NMR spectrum.
(5.13 g, 99%) as a colourless oil. The enantiomeric excess was
determined to be 96% ee by c-PBG-NMR assay.
4.3. (R)-[7-2H1]-benzyl fluoride 3a
At first, N-(Trimethylsilyl)morpholine (23.1 mL, 20.7 g,
130.1 mmol, 3.1 equiv) was added dropwise at ꢃ78 °C to a solution
of diethylaminosulfur trifluoride (15.7 mL, 21.0 g, 130.3 mmol,
3.1 equiv) in CH2Cl2 (50 mL) and the reaction was stirred for
2.5 h, warming to room temperature. The solution was then cooled
to ꢃ78 °C, and a solution of (S)-[7-2H1]-benzyl alcohol 2a (4.5 g,
41.3 mmol, 1 equiv) in CH2Cl2 (130 mL) was added slowly via can-
nula. The resulting solution was stirred at room temperature for
18 h. The reaction was quenched by slowly pouring the solution
onto an ice-cold saturated aqueous NaHCO3 solution (300 mL).
The layers were separated, and the aqueous was re-extracted into
CH2Cl2. The organics were dried and concentrated. The light brown
residue was purified by short path distillation to afford (R)-[7-2H1]-
benzyl fluoride 3a as a colourless oil (1.70 g, 36%): bp (60–62 °C,
72 mbar); 1H NMR (CDCl3, 400 MHz) dH 7.39 (5H, br s, Ar H), 5.37
(1H, dt, JHF 47.8, JHD 1.6, Ph-CDHF); 13C NMR (CDCl3, 100 MHz) dC
136.1 (d, JCF 17.0 Ar C-1), 128.8 (d, JCF 6.0, Ar C-2,6), 128.6
(Ar C-4), 127.6 (d, JCF 3.3, Ar C-3,5), 84.3 (dt, JCF 165.2, JCD 23.3,
Ph-CDHF); 19F NMR (CDCl3, 376 MHz) dF ꢃ207.7 (dt, JFH 47.7, JFD
7.4, Ph-CDHF); m/z (EI) 111 (M, 44%), 110 (MꢃH, 100).
The enantiomeric excess was determined to be 96% ee by
4.2. (S)-[7-2H1]-benzyl alcohol 2a
A
solution of RuCl(p-cymene)[(R,R)-Ts-DPEN] (117 mg,
0.18 mmol, 0.5 mol%), [2H2]-formic acid (1.74 g, 1.47 mL,
37.8 mmol, 1 equiv) and triethylamine (3.97 g, 5.30 mL,
36.8 mmol, 1 equiv) in acetonitrile (37 mL) was stirred at room
temperature for 10 min. Freshly washed benzaldehyde (3.94 g,
3.75 mL, 36.8 mmol, 1 equiv) was then added and the reaction
mixture was stirred for 14 h at room temperature. The reaction
was diluted with water (40 mL) and extracted into Et2O
(3 ꢂ 20 mL). The organics were dried and concentrated. Purifica-
tion over silica, eluting with petroleum ether and Et2O (80:20),
gave (S)-[7-2H1]-benzyl alcohol 2a (3.78 g, 95%) as a colourless
oil: m/z (EI) 109 (M, 100%), 108 (MꢃH, 66), 80 (88), 78 (Ph, 38),
77 (Ph–H, 38); mmax (thin film)/cmꢃ1 3333, 3087, 3063, 3030,
2900, 1495, 1452, 1205, 1043, 1023, 722 and 698; 1H NMR (CDCl3,
400 MHz) dH 7.38–7.26 (5H, m, Ar–H), 4.68 (1H, d, JHD 1.9,
Ph–CDH–OH), 1.75 (1H, s, Ph–CDH–OH); 13C NMR (CDCl3,
100 MHz) dC 141.0 (Ar C-1), 128.7 (2 ꢂ Ar CH), 127.8 (Ar CH),
127.1 (2 ꢂ Ar CH), 65.2 (t, JCD 21.0, Ph–CDH–OH). The enantiomeric
c-PBG-NMR assay.
excess was determined to be 96% ee by c-PBG-NMR assay.
4.3.1. (S)-[7-2H1]-benzyl fluoride 3b
4.2.1. (R)-[7-2H1]-benzyl alcohol 2b
(S)-[7-2H1]-Benzyl fluoride 3b was prepared in a similar manner
from (R)-[7-2H1]-benzyl alcohol 2b (4.70 g), affording (S)-[7-2H1]-
The (R)-[7-2H1]-benzyl alcohol was prepared in a similar man-
ner to (S)-2a and on 5 g scale, using RuCl(p-cymene)[(S,S)-Ts-

R. D. P. Wadoux et al. / Tetrahedron: Asymmetry 24 (2013) 719–723
723
benzyl fluoride 3b (1.67 g, 35%) as a colourless oil. The enantio-
FDHC-COOC6H13), 4.21 (2H, t,
J
6.8, FDHC–COO–CH2–C5H11),
meric excess was determined to be 94% ee by
c
-PBG-NMR assay.
1.69–1.64 (2H, m, FDHC–COO–CH2–CH2–C4H9), 1.36–1.28 (6H, m,
FDHC–COO–C2H4–C3H6–CH3), 0.89 (3H, t,
J
6.9, CFDH–
4.4. Sodium (R)-[2-2H]-fluoroacetate 1a
COO–C5H10–CH3); 13C NMR (CDCl3, 100 MHz) dC 168.2 (d, JCF 21.2,
FDHC-COOC6H13), 77.5 (dt, JCF 179.9, JDC 23.2, FDHC-COOC6H13),
65.8, 31.5, 28.6, 25.6, 22.7, 14.0; 19F NMR (CDCl3, 376 MHz) dF
ꢃ230.8 (1F, dt, JFH 48.0, JFD 7.1, FDHC-COOC6H13). The enantiomeric
Caution! The generated fluoroacetate is highly toxic.11
The (R)-[7-2H1]-benzyl fluoride 3a (200 mg, 1.8 mmol,
1.0 equiv) was added to a stirred biphasic solution of ruthenium
chloride hydrate (6 mg, 0.03 mmol, 0.02 equiv) and sodium perio-
date (1.28 g, 6.0 mmol, 3.3 equiv) in a mixture of acetonitrile:
water: CCl4 (3.5 mL, 2:3:2) at room temperature. The reaction
was then stirred for 24 h, after which a further portion of ruthe-
nium chloride hydrate (6 mg, 0.03 mmol, 0.02 equiv) and sodium
periodate (1.28 g, 6.0 mmol, 3.3 equiv) was added and the mixture
stirred for a further 24 h. The reaction was then neutralised by the
addition of concentrated NaOH solution (0.1 mL, 30% w/v) and fil-
tered through Celite. The layers were separated, and the organic
was extracted with water (2 ꢂ 1 mL). The combined aqueous layers
were decolourised by treatment with activated charcoal (2 g), fil-
tered through Celite and acidified with dilute H2SO4 to pH 1. The
aqueous solution was lyophilised and the collected vacuum trans-
ferred solution was neutralised with dilute sodium hydroxide
(0.05 M) to pH 3.5 (measured by pH meter). Freeze drying afforded
sodium (R)-[2-2H1]-fluoroacetate 1a as an amorphous colourless
solid (31.4 mg, 17%): 1H NMR (D2O, 500 MHz) dH 4.65 (1H, dt, JFH
47.7, JDH 2.1, FDHC-COONa); 13C NMR (D2O, 126 MHz) dC 176.3
(d, JCF 19.0, FDHC-COONa), 78.9 (dt, JCF 177.5, JCD 23.4, FDHC-
COONa); 19F NMR (D2O, 376 MHz) dF ꢃ218.3 (1F, dt, JFH 47.7,
JFD 7.5, FDHC-COONa).
excess was determined to be 93% ee by c-PBG-NMR assay.
4.5.1. Hexyl (S)-[1-2H1]-fluoroacetate 4b
Hexyl (S)-[1-2H1]-fluoroacetate 4b was prepared on the same
scale from sodium (S)-[2-2H1]-fluoroacetate 1b, affording hexyl
(S)-[1-2H1]-fluoroacetate 4b (12.7 mg, 41%) as a colourless oil.
The enantiomeric excess was determined to be 95% ee by
NMR assay.
c-PBG-
Acknowledgements
We thank the ERC for an Advanced Investigator Award to DO’H
and we thank the EPSRC for a research Grant (EPSRC GR/EP/
HO22651/1) to support this work. XL thanks the University of
St. Andrews for financial support for a research visit to St. Andrews
University, where this work was carried out.
References
1. Frey, P. A.; Hegeman, A. D. ‘Enzyme Reaction Mechanisms’; Oxford University
Press: New York, 2007. Chapter 14.
2. (a) O’Hagan, D.; Rzepa, H. S. Chem. Commun. 1994, 2029–2030; (b) Marletta, M.
A.; Srere, P. A.; Walsh, C. Biochemistry 1981, 20, 3719–3723; (c) Dummel, R. J.;
Kun, E. J. Biol. Chem. 1969, 244, 2966–2969.
3. Keck, R.; Haas, H.; Rétey, J. FEBS Lett. 1980, 114, 287–290.
4. (a) Cadicamo, C.; Courtieu, J.; Deng, H.; Meddour, A.; O’Hagan, D. ChemBioChem
2004, 5, 685–690; (b) Goss, R. J.; O’Hagan, D.; Meddour, A.; Courtieu, J. J. Am.
Chem. Soc. 2003, 125, 379–387.
4.4.1. Sodium (S)-[2-2H1]-fluoroacetate 1b
Sodium (S)-[2-2H1]-fluoroacetate 1b was obtained in a similar
manner from (S)-[7-2H1]-benzyl fluoride 3b, affording sodium
(S)-fluoro[2-2H1]-acetate 1b as a colourless solid.
5. Gartz, D.; Reed, J.; Rétey, J. Helv. Chim. Acta 1996, 79, 1021–1025.
6. Bio, M. M.; Waters, M.; Javadi, G.; Sang, Z. J.; Zhang, F.; Thomas, D. Synthesis
2008, 891–896.
7. Bresciani, S.; O’Hagan, D. Tetrahedron Lett. 2010, 51, 5795–5797.
8. Yamada, I.; Noyori, R. Org. Lett. 2000, 2, 3425–3427.
9. (a) Tavasli, M.; Courtieu, J.; Goss, R. J. M.; Meddour, A.; O’Hagan, D. Chem.
Commun. 2002, 844–845; (b) Meddour, A.; Canlet, C.; Blanco, L.; Courtieu, J.
Angew. Chem., Int. Ed. 1999, 38, 2391–2393; (c) Lesot, P.; Merlet, D.;
Loewenstein, A.; Courtieu, J. Tetrahedron: Asymmetry 1998, 9, 1871–1881; (d)
Canet, I.; Courtieu, J.; Loewenstein, A.; Meddour, A.; Pechine, J. M. J. Am. Chem.
Soc. 1995, 117, 6520–6526.
10. Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org. Chem. 1981, 46,
3936–3938.
11. (a) Proudfoot, A. T.; Bradberry, S. M.; Vale, J. A. Toxicol. Rev. 2006, 25, 213–219;
(b) Peters, R. A.; Wakelin, R. W.; Buffa, P.; Thomas, L. C. Proc. R. Soc. B 1953, 140,
497–507.
4.5. Hexyl (R)-[1-2H1]-fluoroacetate 4a
At first, N-(3-dimethylaminopropyl)-N0-ethylcarbodiimide HCl
(78 mg, 0.40 mmol, 2 equiv), HOBt (54 mg, 0.40 mmol, 2 equiv)
and 1-hexanol (21 mg, 0.21 mmol, 1.05 equiv) were added to a sus-
pension of sodium (R)-[2-2H1]-fluoroacetate 1a (20 mg, 0.20 mmol,
1 equiv) in CH2Cl2 (4 mL) and the resulting mixture was stirred for
18 h. The reaction was then diluted with CH2Cl2 and washed with
water and brine. The organic layer was dried and concentrated and
the residue was purified over silica gel, eluting with CH2Cl2, to af-
ford hexyl (R)-[1-2H1]-fluoroacetate 4a as a colourless oil (20.5 mg,
66%): 1H NMR (CDCl3, 500 MHz) dH 4.54 (1H, dt, JFH 47.0, JDH 2.2,