Synthesis of optically active α-(nonafluoro-tert-butoxy)carboxylic acids

Article abstract of DOI:10.1016/j.tetlet.2013.01.072

Three novel α-(nonafluoro-tert-butoxy)carboxylic esters were synthesized by two methods: the Mitsunobu reaction of optically active (S)-α-hydroxycarboxylic esters and the Williamson synthesis starting from the corresponding O-mesyl derivatives. Both procedures from ethyl (S)-lactate resulted in the formation of a fluorous optically active (R)-lactic acid ester derivative, while the reactions from methyl (S)-mandelate took place with racemization. The proposed mechanism of this racemization is described. The conversion of methyl (S)-phenyllactate under Mitsunobu conditions was also stereospecific, but the reaction of its O-mesyl derivative yielded a mixture of substitution and elimination products. The optical purity of the α-(nonafluoro-tert-butoxy)carboxylic acids prepared by the hydrolysis of the above esters was determined by ¹H NMR spectroscopy.

Full text of DOI:10.1016/j.tetlet.2013.01.072

Tetrahedron Letters 54 (2013) 1730–1733
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of optically active
a
-(nonafluoro-tert-butoxy)carboxylic acids
⇑
Tamás Csóka, Anikó Nemes, Dénes Szabó
Institute of Chemistry, Eötvös Loránd University, PO Box 32, H-1518, Budapest 112, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Three novel
obu reaction of optically active (S)-
a
-(nonafluoro-tert-butoxy)carboxylic esters were synthesized by two methods: the Mitsun-
Received 18 October 2012
Revised 9 January 2013
Accepted 17 January 2013
Available online 25 January 2013
a
-hydroxycarboxylic esters and the Williamson synthesis starting
from the corresponding O-mesyl derivatives. Both procedures from ethyl (S)-lactate resulted in the for-
mation of a fluorous optically active (R)-lactic acid ester derivative, while the reactions from methyl
(S)-mandelate took place with racemization. The proposed mechanism of this racemization is described.
The conversion of methyl (S)-phenyllactate under Mitsunobu conditions was also stereospecific, but the
reaction of its O-mesyl derivative yielded a mixture of substitution and elimination products. The optical
Keywords:
Nonafluoro-tert-butoxy
Fluorous tag
Chiral carboxylic acid
Mitsunobu reaction
purity of the
a-(nonafluoro-tert-butoxy)carboxylic acids prepared by the hydrolysis of the above esters
was determined by 1H NMR spectroscopy.
Ó 2013 Elsevier Ltd. All rights reserved.
Fluorine-containing organic compounds are important materi-
als based on their interesting physico-chemical properties1 and
potential applicability as biologically active substances.2 In most
cases, these molecules contain a single fluorine atom, a CF3 group
or an n-perfluoroalkyl chain (CnF2n+1, n = 4, 6, 8, 10). Several
compounds have been synthesized with a nonafluoro-tert-butoxy
moiety. This branched fluorous tag was used for the synthesis of
fluorous ethers 1,3 amines 2 and 3,4 imidazolium salts,4a alcohols,5
triflates,6 azodicarboxylate 47 and other aromatic and heteroaro-
matic compounds.8 Highly branched molecules with OC(CF3)3
groups have been prepared as imaging agents for 19F MRI and for
the synthesis of fluorous macromolecules.9
remarkably stable and tolerant towards numerous reagents and
conditions. This moiety can be inserted in a molecule by two ba-
sic methods: classic nucleophilic substitution (Williamson syn-
thesis) or via Mitsunobu reaction.3,11 The nucleophilic reagent in
the substitution reaction is the sodium salt of nonafluoro-
tert-butanol, which can be easily prepared from commercially
available fluorous alcohol with NaOH in aqueous solution. The
Mitsunobu synthesis is also a useful tool for the alkylation of nona-
fluoro-tert-butanol due to its relatively strong acidity (pKa = 5.4).12
In these cases the reactions with alcohols using the Ph3P/diisopro-
pyl azodicarboxylate (DIAD) reagent pair resulted in the expected
ethers in good yields. Starting from an optically active reagent,
the Mitsunobu reaction usually takes place with inversion of the
configuration of the stereogenic centre.11
(CF3)3C
(CF3)3C
NH2
O
CnF2n+1
O
The present study is related to the synthesis of novel, optically
active, ‘CF3-rich’ carboxylic acids, derived from commercially
available ethyl (S)-lactate, methyl (S)-mandelate and methyl
(S)-phenyllactate, by substitution of their hydroxyl group with a
perfluoro-tert-butoxy moiety (see compounds 5–7).
2
1 (n = 4, 6, 8,10)
O
O
H
(CF3)3C
N
(CF3)3C
O
O
N
2
These
a-(nonafluoro-tert-butoxy)carboxylic acids are potential
CH3
fluorous phase labelling reagents,13 chiral building blocks,4 resolv-
ing agents4c or chiral auxiliaries.14 The nonafluoro-tert-butoxy tag
is suitable for ‘light fluorous’ synthesis15 and/or fluorous solid
phase extraction (F-SPE).16
3
4
The nonafluoro-tert-butoxy group has
a
strong electron-
withdrawing effect and imparts significant steric hindrance on
the surrounding molecular environment. This group may elimi-
nate the problems associated with persistency and bioaccumula-
tion of materials as with long n-perfluoroalkyl chains,10 and it is
CF3
CF3
O
CF3
CF3
O
CF3
F3C CF3
F3C
CH3
F3C
O
COOH
COOH
COOH
⇑
7
6
Corresponding author. Tel.: +36 1372 2500; fax: +36 1372 2620.
E-mail address: szabod@elte.hu (D. Szabó).
5
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.072

T. Csóka et al. / Tetrahedron Letters 54 (2013) 1730–1733
1731
the poor nucleophilic perfluoro-tert-butanolate anion on the inter-
mediate phosphonium cation (S)-14 is not favourable, thus the
reaction occurs via an SN1 mechanism. The C–O bond cleaves in
the first step affording a relatively stable benzylic-type carbenium
ion 15 (Scheme 2). In the second step, attack of the nucleophilic
perfluoro-tert-butanolate anion on 15 results in the formation of
racemic 11.
CF3
CF3
CF3
CF3 CF3
CF3
OH
COOQ
O
O
(i)
(ii)
R
R
COOQ
R
COOH
67%
61%
(S)-8
R=CH3, Q=C2H5
(R)-5
(R)-9
We also tried to prepare our target compounds by Williamson
synthesis. First, the starting esters [(S)-8, (S)-10 and (S)-12] were
converted into the corresponding mesylates [(S)-16, (S)-17 and
(S)-18], and then reacted with sodium nonafluoro-tert-butano-
late.21 The results are summarized in Scheme 3. As expected, start-
ing from the O-mesyl derivative of ethyl (S)-lactate [(S)-16], the
reaction was stereospecific, yielding (R)-9.
77%
49%
60%
(S)-10
R=C6H5, Q=CH3
(RS)-6
(R)-7
(RS)-11
(R)-13
71%
(S)-12
On the other hand, our attempts to synthesize optically active 11
by this method also failed. The nucleophilic substitution of the mes-
ylate (S)-17 with sodium perfluoro-tert-butanolate gave the fluor-
ous ester 11 in racemic form. We assume that this transformation
also takes place by an SN1 mechanism involving the loss of a mesy-
late anion and intermediate 15 achiral cation (see Scheme 2).
When we started from (S)-18, 1H and 13C NMR spectroscopic
data showed that both substitution and parallel elimination took
place. Thus, after work-up, a mixture of racemic 13 and methyl cin-
namate (19) was obtained.
R=CH6H5CH2, Q=CH3
Scheme 1. Synthesis of -(nonafluoro-tert-butoxy)carboxylic acids 5–7. Reagents
a
and conditions: (i) (CF3)3COH, DIAD, PPh3, 0 °C to rt, 24 h; (ii) NaOH, MeOH–CH2Cl2,
rt, 24 h, then aq HCl.
The synthesis of fluorous acids 5–7 was accomplished in two
steps from the esters (S)-8, (S)-10 and (S)-12 (Scheme 1). The
Mitsunobu-type condensation reactions were carried out between
the a-hydroxy esters (S)-8, (S)-10 and (S)-12 and perfluoro-tert-butyl
alcohol in the presence of the redox-couple, triphenylphosphine
and diisopropyl azodicarboxylate (DIAD). Due to the fluorous char-
acter and the volatility of the esters 9, 11 and 13, they were easily
separated from the by-products using steam distillation. Thus the
reaction can be performed on multigram scale.17 In the second
step, these compounds were converted into the appropriate car-
boxylic acids 5–7 by treatment with NaOH in MeOH–CH2Cl2 sol-
vent mixture at room temperature.18,19 It is worth noting that, in
these cases, conventional methods for hydrolysis of carboxylic es-
ters in aqueous solution did not take place under acidic or basic
conditions.
The reactions of (S)-8 and (S)-12 with perfluoro-tert-butyl alco-
hol yielded optically active (R)-9 and (R)-13, respectively. It should
be noted that, presently, we have no firm experimental evidence
for the absolute configuration of compounds (R)-9 and (R)-13,
but it was assigned based on the known mechanism of the reac-
tion. This involves the formation of a key intermediate oxyphos-
phonium ion, which then transforms into the product on attack
of a nucleophilic reagent with the loss of triphenylphosphine oxide
and inversion of the stereogenic centre, that is, an SN2 mechanism.
At the same time, starting from methyl (S)-mandelate [(S)-10], we
obtained racemic fluorous ester (RS)-11. To the best of our knowl-
edge, Mitsunobu reactions leading to complete racemization have
not been investigated in detail.20 We presume that the attack of
The enantiomeric purity of the carboxylic acids 5–7 was deter-
mined by 1H NMR spectroscopy using commercially available (S)-
a-methylbenzylamine (optical purity P98%) as a chiral reagent.
In all cases the amine was used in 0.5, 1.0, 1.5, 2.0, 2.5 and
3.0 equiv amounts relative to the acid in CDCl3 at room tempera-
ture. The determination of the enantiomeric purity is based on
the signals belonging to the methine proton of the stereogenic cen-
tre. At room temperature this dynamic equlibrium of the salt for-
mation is faster than the time scale of the NMR measurements.
Thus the signals of the spectra represent an average value of the
chemical shifts, which are composed from the resonance frequen-
cies of the free acid and the carboxylate anion, as well as the free
and the protonated amine, according to their relative amounts. It
should be noted that in apolar solution there are two salt formation
equilibria between the racemic carboxylic acid [(R)-6, (S)-6] and
(S)-a-methylbenzyl amine. Experimental data showed that the dif-
ference in the chemical shifts of the methine protons between the
diastereomeric salt pairs was maximum when using one equiva-
lent of the chiral reagent. These values are given in Table 1.
In the salts of the (R)-lactic acid [(R)-5] and (R)-phenyllactic acid
[(R)-7] derivatives with (S)-a-methylbenzyl amine, there is one
CH–O and one CH–N methine signal due to the presence of only
one diastereomeric form in the solution. Accordingly, the methine
protons of the racemic carboxylic acid (RS)-6 gave two singlets
PPh3
O
O
CF3
F3C
C
O
CF3
OCH3
-OPPh3
14
(S)-
Mitsunobu intermediate
O
(CF3)3CO-
O
C
10
(S)-
C
MsCl
OCH3
(RS)-11
OCH3
OMs
C
15
O
-MsO-
OCH3
(S)-17
Scheme 2. Proposed mechanisms for the formation of (RS)-11 from intermediate (S)-14 and mesylate (S)-17.

1732
T. Csóka et al. / Tetrahedron Letters 54 (2013) 1730–1733
CF3
CF3
References and notes
CF3
OH
COOQ
OSO2Me
COOQ
(i)
(ii)
O
1. (a) dos Ramos, M. C.; Blas, F. J. Mol. Phys. 2010, 10, 1349–1365; (b) Morgado, P.;
Lewis, J. B.; Laginhas, C. M. C.; Martins, L. F. G.; McCabe, C.; Blas, F. J.; Filipe, E. J.
M. J. Phys. Chem. B 2011, 115, 15013–15023.
R
R
R
COOQ
78%
83%
88%
(S)-8
R=CH3, Q=C2H5
2. (a) Bégué, J.-P.; Bonnet-Delpon, D. Bioorganic and Medicinal Chemistry of
Fluorine; John Wiley & Sons, Inc.: Hoboken, New Jersey, 2008; (b) O’Hagan, D. J.
Fluorine Chem. 2010, 131, 1071–1081.
3. (a) Rábai, J.; Szabó, D.; Borbás, E. K.; Kövesdi, I.; Csámpai, A.; Gömöry, Á.;
Pashinnik, V. E.; Shermolovich, Y. G. J. Fluorine Chem. 2002, 114, 199–207; (b)
Szabó, D.; Bonto, A.-M.; Kövesdi, I.; Gömöry, Á.; Rábai, J. J. Fluorine Chem. 2005,
126, 641–652.
4. (a) Nemes, A.; Tölgyesi, L.; Bodor, A.; Rábai, J.; Szabó, D. J. Fluorine Chem. 2010,
131, 1368–1376; (b) Szabó, D.; Mohl, J.; Bálint, A.-M.; Bodor, A.; Rábai, J. J.
Fluorine Chem. 2006, 127, 1496–1504; (c) Szabó, D.; Nemes, A.; Kövesdi, I.;
Farkas, V.; Hollósi, M.; Rábai, J. J. Fluorine Chem. 2006, 127, 1405–1414.
5. Jiang, Z.-X.; Yu, Y. B. Tetrahedron 2007, 63, 3982–3988.
62%
(S)-16
(S)-17
(S)-18
(R)-9
42%
(S)-10
R=C6H5, Q=CH3
(RS)-11
(RS)-13
(S)-12
+
R=C6H5CH2, Q=CH3
C6H5CH CHCOOMe
6. Jiang, Z.-X.; Yu, Y. B. Synthesis 2008, 215–220.
19
7. Chu, Q.; Henry, C.; Curran, D. P. Org. Lett. 2008, 10, 2453–2456.
8. Zhao, X.; Ng, W. Y.; Lau, K.-C.; Collis, A. E. C.; Horváth, I. T. Phys. Chem. Chem.
Phys. 2012, 14, 3909–3916.
9. (a) Jiang, Z.-X.; Liu, X.; Jeong, E.-K.; Yu, Y. B. Angew. Chem., Int. Ed. 2009, 48, 1–5;
(b) Yue, X.; Taraban, M. B.; Hyland, L. L.; Yu, Y. B. J. Org. Chem. 2012, 77, 8879–
8887.
Scheme 3. Preparation of mesylates (S)-16, (S)-17 and (S)-18 and their reactions
with sodium perfluoro-tert-butanolate. Reagents and conditions: (i) MsCl, Et3N,
CH2Cl2, 0 °C, 2 h; (ii) (CF3)3CONa, DMSO, 80 °C.
10. Prevedouros, K.; Cousins, I. T.; Buck, R. C.; Korzeniowsky, S. H. Environ. Sci.
Technol. 2006, 40, 32–44.
11. Kumara Swamy, K. C.; Bhuvan Kumar, N. N.; Balaraman, E.; Pavan Kumar, K. V.
P. Chem. Rev. 2009, 109, 2551–2651.
Table 1
The chemical shifts of the methine peaks of (R)-5, (RS)-6 and (R)-7 after treatment
with 1.0 equiv of (S)-a-methylbenzylamine in CDCl3
12. Knunyants, I. L.; Dyatkin, B. L. Izv. Akad. Nauk. SSR, Chem. Ser. 1964, 923–925.
13. Zhang, W. Chem. Rev. 2009, 109, 749–795.
14. (a) Hein, J. E.; Hultin, P. G. Synlett 2003, 635–638; (b) Hein, J. E.; Zimmerman, J.;
Sibi, M. P.; Hultin, P. G. Org. Lett 2005, 7, 2755–2758.
15. (a) Studer, A.; Curran, D. P. Tetrahedron 1997, 53, 6681–6696; (b) Curran, D. P.;
Luo, Z. J. Am. Chem. Soc. 1999, 121, 9069–9072.
16. (a) Zhang, W.; Curran, D. P. Tetrahedron 2006, 51, 11837–11865; (b) Yoshida, J.-
I.; Itami, K. Chem. Rev. 2002, 102, 3693–3716.
Compound
Dd
(ppm/
Hz)
RCH[OC(CF3)3]COOH
(S)-CH3CH(NH2)C6H5
d
Multiplicity Integral
d
Multiplicity Integral
(ppm)
(ppm)
(R)-5
(RS)-6
4.28
5.19
5.04
4.61
q
s
s
t
1.00
1.00
4.13
3.61
q
q
1.00
1.10
0
0.15/
37.5
0
(R)-7
1.00
3.95
q
1.16
17. General procedure for the synthesis of esters (R)-9, (RS)-11 and (R)-13 via
Mitsunobu synthesis
A mixture of the ester (S)-8, (S)-10 or (S)-12 (30 mmol) and Ph3P (11.8 g,
45 mmol) in Et2O (50 ml) was cooled to 0 °C, then a solution of nonafluoro-tert-
butyl alcohol (11.3 g, 48 mmol) in Et2O (30 ml) was added. DIAD (9.1 g,
45 mmol) in Et2O (30 ml) was added dropwise to the cold reaction mixture.
The ice bath was removed and the mixture was stirred at room temperature for
24 h. The resulting precipitate was filtered, the filtrate evaporated and the
residue was steam distilled. The two-phase distillate was extracted with
CH2Cl2 (2 Â 25 ml) and the combined organic phases dried over MgSO4. The
obtained crude product was purified by distillation in vacuo.
Ethyl (R)-2-[1,1-bis(trifluoromethyl)-2,2,2-trifluoroethoxy]propionate [(R)-9]
with (S)-a-methylbenzyl amine, while the amine displays one CH–
N quartet. In this case the CH–N protons are distant from the ste-
reogenic centre of the carboxylic acid, thus they occur at similar
positions in both diastereomeric salts, that is, they give the same
signal in the spectra. On the other hand, the CH–O protons of
(R)-6 and (S)-6, which are directly attached to the stereogenic car-
bon atom, occupy different chemical surroundings in the diaste-
reomeric salts, therefore they have different chemical shifts.
Yield: 6.7 g (67%) colorless oil, bp: 70–72 °C (20 mmHg), [a]578 = +15 (c 2.0,
MeOH), 1H NMR (250 MHz, CDCl3) d (ppm): 1.30 (3H, t, 3JHH = 7.1 Hz, CH2CH3),
3
In conclusion, three new
a-(nonafluoro-tert-butoxy)carboxylic
1.56 (3H, d, JHH = 6.7 Hz, CH3CH), 4.25 (2H, dq, J1 = 4.65 Hz, J2 = 2.4 Hz,
3
CH2CH3), 4.71 (1H, q, JHH = 6.7 Hz, CH); 13C NMR (62.9 MHz, CDCl3) d (ppm):
acids were synthesized from commercially available ethyl (S)-lac-
tate, methyl (S)-mandelate and methyl (S)-phenyllactate. The
nonafluoro-tert-butoxy group was inserted in the molecules by
Williamson synthesis or via Mitsunobu reaction, on multigram
(signals missing for (CF3)3C), 14.3 (CH3CH2), 19.7 (CHCH3), 62.1 (CH2CH3), 74.5
(CH), 170.5 (CO); 19F NMR (235.4 MHz, CDCl3) d (ppm): À70.9 (CF3).
Methyl
(RS)-2-phenyl-2-[1,1-bis(trifluoromethyl)-2,2,2-trifluoroethoxy]acetate
[(RS)-11]
Yield: 5.6 g (49%) colorless oil, bp: 128–132 °C (20 mmHg), 1H NMR (250 MHz,
scale. The 1H NMR measurements with (S)-
demonstrated that (R)-
(R)- -(nonafluoro-tert-butoxy)phenyllactic acid were optically
a
-methylbenzylamine
CDCl3) d (ppm): 3.74 (3H, s, CH3), 5.55 (1H, s CH), 7.38–7.49 (5H, m, Ar); 13C
a-(nonafluoro-tert-butoxy)lactic acid and
NMR (62.9 MHz, CDCl3)
d (ppm): 53.1 (CH3), 79.0 (CH), 120.5 (CF3, q,
2JCF = 285 Hz), 126.9 (o-Ar), 129.2 (p-Ar), 129.8 (m-Ar), 135.7 (1C-Ar), 167.7
(CO); 19F NMR (235.4 MHz, CDCl3) d (ppm): À70.8 (CF3).
Methyl (R)-3-phenyl-2-[1,1-bis(trifluoromethyl)-2,2,2-trifluoroethoxy]propionate
[(R)-13]
a
pure compounds. Derivatization of methyl (S)-mandelate with
the nonafluoro-tert-butoxy group afforded a racemic product in
both cases. A reaction mechanism is proposed for the racemization.
Further work on the application of the above fluorous compounds
as building blocks, resolving agents and chiral shift reagents are
currently in progress in our laboratory.
Yield: 7.2 g (60%) colorless oil, bp: 144–146 °C (20 mmHg), [a]578 = +3 (c = 2.0,
3
MeOH), 1H NMR (250 MHz, CDCl3) d (ppm): 3.17 (2H, d, JHH = 6.1 Hz, CH2),
3
3.66 (3H, s, CH3), 4.82 (1H, t, JHH = 6.1 Hz, CH), 7.1–7.4 (5H, m, Ar); 13C NMR
(62.9 MHz, CDCl3) d (ppm): (signals missing for (CF3)3C), 40.3 (CH3), 52.5 (CH2),
78.8 (CH), 127.8 (p-Ar), 128.8 (m-Ar), 130.0 (o-Ar), 134.4 (1C-Ar), 169.5 (CO);
19F NMR (235.4 MHz, CDCl3) d (ppm): À70.7 (CF3).
18. Theodorou, V.; Skobridis, K.; Tzakos, A. G.; Ragoussis, V. Tetrahedron Lett. 2007,
48, 8230–8233.
Acknowledgements
19. General procedure for the synthesis of carboxylic acids (R)-5, (RS)-6 and (R)-7
A solution of NaOH (1.0 g, 25 mmol) in MeOH (35 ml) was added to a solution
of the ester (R)-9, (RS)-11 or (R)-13 (5 mmol) in CH2Cl2 (30 ml). The mixture
was stirred at room temperature for 24 h. The solvents were then removed in
vacuo and the residue was dissolved in H2O (20 ml). The aqueous solution was
acidified to pH 1 with concd HCl at 0 °C and the resulting white precipitate was
filtered and dried.
The authors thank Professors József Rábai, Dr. Eric J. Olson and
Dr. Ildikó Szabó for stimulating discussions.
Supplementary data
(R)-2-[1,1-Bis(trifluoromethyl)-2,2,2-trifluoroethoxy]propionic acid [(R)-5]
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.01.
072. These data include MOL files and InChiKeys of the most
important compounds described in this article.
Yield: 0.95 g (61%), mp: 45–49 °C,
[
a
]
578 = +17 (c = 2.0, MeOH), 1H NMR
3
(250 MHz, CDCl3)
d
(ppm): 1.64 (3H, JHH = 6.5 Hz, CH3), 4.77 (1H,
3JHH = 6.5 Hz, CH), 8.14 (1H, s, COOH); 13C NMR (62.9 MHz, CDCl3) d (ppm):
2
19.7 (CH3), 73.8 (CH), 120.5 (q, JCF = 290 Hz, CF3), 175.8 (COOH); 19F NMR
(235.4 MHz, CDCl3) d (ppm): À70.9 (CF3).

T. Csóka et al. / Tetrahedron Letters 54 (2013) 1730–1733
1733
3
(RS)-2-Phenyl-2-[1,1-bis(trifluoromethyl)-2,2,2-trifluoroethoxy]acetic acid [(RS)-6]
Yield: 1.41 g (77%), mp: 112–114 °C, 1H NMR (250 MHz, CDCl3) d (ppm): 5.54
(1H, s, CH), 7.26 (1H, s, COOH), 7.39–7.49 (5H, m, Ar); 13C NMR (62.9 MHz, CDCl3)
d (ppm): (signals missing for (CF3)3C), 78.4 (CH), 127.0 (o-Ar), 129.3 (p-Ar), 130.1
(m-Ar), 134.0 (1C-Ar), 137.2 (COOH); 19F NMR (235.4 MHz, CDCl3) d (ppm):
À70.7 (s, CF3).
3.13 (3H, s, SO2CH3), 4.23 (2H, q, JHH = 7.1 Hz, CH2CH3), 5.08 (1H, q,
3JHH = 7.0 Hz, CH); 13C NMR (62.9 MHz, CDCl3) d (ppm): 14.45 (CH3CH2), 18.7
(CHCH3), 39.52 (SO2CH3), 62.47 (CH3CH2), 74.70 (CH), 169.90 (CO).
Methyl (S)-2-(methanesulfonyloxy)-2-phenylethanoate [(S)-17]
Yield: 3.98 g (83%), mp: 113–114 °C, [a]
578 = +110 (c = 1.0, MeOH), 1H NMR
(250 MHz, CDCl3) d (ppm): 3.07 (3H, s, OCH3), 3.76 (3H, s, SO2CH3), 5.95 (1H, s,
CH), 7.4–7.6 (5H, m, Ar); 13C NMR (62.9 MHz, CDCl3) d (ppm): 39.9 (COOCH3),
53.5 (SO2CH3), 79.3 (CH), 128.2 (o-Ar), 129.5 (p-Ar), 130.4 (m-Ar), 133.2 (1C-
Ar), 168.6 (CO).
(R)-3-Phenyl-2-[1,1-bis(trifluoromethyl)-2,2,2-trifluoroethoxy]propionic acid [(R)-
7]
Yield: 0.71 g (71%), mp: 60–64 °C, [
a
]
578 = +3 (c = 2.0, MeOH), 1H NMR (250 MHz,
3
3
CDCl3) d (ppm): 3.23 (2H, d, JHH = 5.7 Hz, CH2), 4.87 (1H, t, JHH = 5.7 Hz, CH),
7.2–7.3 (5H, m, Ar), 9.12 (1H, br s, COOH); 13C NMR (62.9 MHz, CDCl3) d (ppm):
(signals missing for (CF3)3C), 40.1 (CH2), 78.2 (CH), 128.0 (p-Ar), 128.9 (m-Ar),
130.1 (o-Ar), 134.0 (1C-Ar), 174.6 (COOH); 19F NMR (235.4 MHz, CDCl3) d (ppm):
À70.6 (CF3).
Methyl (S)-2-(methanesulfonyloxy)-3-phenylpropionate [(S)-18]
Yield: 4.60 g (88%), mp: 52–54 °C,
[
a
]
=+32 (c = 1.0, MeOH), 1H NMR
578
(250 MHz, CDCl3) d: 2.76 (3H, s, COOCH3), 3.21 (2H, ddd, J1 = 6.5 Hz,
J2 = 14.35 Hz, J3 = 23.1 Hz, CH2), 3.79 (3H, s, SO2CH3), 5.17 (1H, dd,
J1 = 4.25 Hz, J2 = 8.7 Hz, CH); 7.23–7.36 (5H, m, Ar); 13C NMR (62.9 MHz,
CDCl3) d (ppm): 38.61 (CH2), 38.87 (SO2CH3), 53.24 (COOCH3), 79.02 (CH),
127.94 (p-Ar), 129.13 (m-Ar), 129.89 (o-Ar), 135.29 (1C-Ar), 169.25 (CO).
General procedure for the synthesis of esters (R)-9, (RS)-11 by Williamson
synthesis
20. (a) Warmerdam, E. G. J. C.; Brussee, J.; Kruse, C. G.; van der Gen, A. Tetrahedron
1993, 49, 1063–1070; (b) Brown, R. F. C.; Jackson, W. R.; McCarthy, T. D.
Tetrahedron 1994, 50, 5469–5488.
21. General procedure for the synthesis of mesylates (S)-16, (S)-17, (S)-18
To a solution of the
a-hydroxy ester (20 mmol) and Et3N (2.00 g, 20 mmol) in
A solution of the corresponding mesylate (S)-16 or (S)-17 (16 mmol) and
CH2Cl2 (20 ml) was added a solution of MsCl (2.26 g, 20 mmol) in CH2Cl2
(10 ml) at 0 °C. The mixture was stirred for 2 h at 0 °C, washed with H2O
(2 Â 15 ml) and dried over Na2SO4. The solvent was removed in vacuo and the
crude product was used in the next step without further purification.
Ethyl (S)-2-(methanesulfonyloxy)propionate [(S)-16]
sodium
1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-olate
(4.64 g,
18 mmol) in DMSO (35 ml) was stirred at 100 °C for 6 h. The mixture was
diluted with H2O (100 ml) and the separated aqueous layer was extracted with
Et2O (3 Â 30 ml). The combined organic phases were dried and the solvent
removed. The crude product was purified by distillation in vacuo. Yields: 62%
and 42% for (R)-9 and (RS)-11, respectively. Physical data were identical to
those obtained in the case of the Mitsunobu procedure.
Yield: 3.05 g (78%), [
a
]
578
= À59 (c = 2.0, MeOH), 1H NMR (250 MHz, CDCl3) d
3
3
(ppm): 1.27 (3H, t, JHH = 7.1 Hz, CH2CH3), 1.59 (3H, d, JHH = 7.0 Hz, CH3CH),