Synthesis of 2-trifluoromethyl-1,3-oxazolidines as hydrolytically stable pseudoprolines

Article abstract of DOI:10.1021/jo100518t

Trifluoromethyl group containing oxazolidines (Fox) are conveniently synthesized by condensation of serine esters with trifluoroacetaldehyde hemiacetal or trifluoroacetone. These oxazolidines can undergo N-acylation and amidification reactions and are com

Full text of DOI:10.1021/jo100518t

pubs.acs.org/joc
Synthesis of 2-Trifluoromethyl-1,3-oxazolidines as Hydrolytically
Stable Pseudoprolines
†
Gregory Chaume, Olivier Barbeau, Philippe Lesot, and Thierry Brigaud*
†
‡
,†
ꢀ
†
ꢀ
Laboratoire SOSCO, Universite de Cergy-Pontoise, 5 Mail Gay-Lussac, Neuville sur Oise,
95000 Cergy-Pontoise cedex, France, and ‡RMN en Milieu Orienteꢀ, ICMMO, UMR CNRS 8182,
ꢀ
Bat. 410, Universite Paris Sud 11, Orsay 91405, France
thierry.brigaud@u-cergy.fr
Received March 18, 2010
Trifluoromethyl group containing oxazolidines (Fox) are conveniently synthesized by condensation of
serine esters with trifluoroacetaldehyde hemiacetal or trifluoroacetone. These oxazolidines can undergo
N-acylation and amidification reactions and are completely configurationally and hydrolytically stable.
Therefore, they can be considered as highly valuable proline surrogates (Tfm-pseudoprolines).
Introduction
The biological activity of peptides is highly dependent on
their conformation. Thus, the synthesis of constrained peptides
is a challenge for structure-activity relationship studies and the
design of new peptides of therapeutic interest. A promising
strategy consists of using cyclic amino acids (prolines,1 pyroglu-
tamic acid2...) or pseudopeptides in order to control the cis-
trans isomerization of the amide bond and then the geometry of
the peptides. In this context, a very attractive approach invol-
ving oxazolidines and thiazolidines synthesized by condensa-
tion reactions of serine, threonine, or cysteine with aldehydes,
ketones, or their acetals was reported by Mutter et al.3 These
proline surrogates named pseudoprolines (Ψpro) are very
attractive tools for peptide synthesis and biological properties.
Pseudoprolines are acting as molecular hinges to induce cis
FIGURE 1. Amide isomer equilibrium in pseudoprolines (Ψpro).
amide bonds in peptide backbones (Figure 1).3 For this reason,
the pseudoproline strategy has been successfully applied to the
synthesis of cyclic peptides.4 Pseudoprolines are also powerful
intermediates for enhancing synthetic efficiency in Fmoc SPPS
by temporary disruption of the formation of the secondary
structures during the peptide synthesis.5 Moreover, these pseudo-
prolines are very interesting tools for investigating the peptides
bioactive conformations.6
(1) (a) Moroder, L.; Renner, C.; Lopez, J. J.; Mutter, M.; Tuchscherer, G. In
Cis-trans Isomerization in Biochemistry; Dugave, C., Ed; Wiley-VCH:
Weinheim, 2006; pp 225-259. (b) Karoyan, P.; Sagan, S.; Lequin, O.; Quancard,
J.; Lavielle, S.; Chassaing, G. Targets Heterocycl. Syst. 2004, 8, 216–273.
(c) van Esseveldt, B. C. J.; Vervoort, P. W. H.; van Delft, F. L.; Rutjes, F. P. J. T.
J. Org. Chem. 2005, 70, 1791–1795. and references therein. (d) Jenkins, C. L.;
Lin, G.; Duo, J.; Rapolu, D.; Guzei, I. A.; Raines, R. T.; Krow, G. R. J. Org. Chem.
2004, 69, 8565–8573. and references therein. (e) Del Valle, J. R.; Goodman, M.
J. Org. Chem. 2003, 68, 3923–3931. and references therein.
A characteristic of the oxazolidine pseudoprolines is
their hydrolytic weakness in acidic medium. This can be
(4) (a) Sager, C.; Mutter, M.; Dumy, P. Tetrahedron Lett. 1999, 40, 7987–
7991. (b) Ruckle, T.; de Lavallaz, P.; Keller, M.; Dumy, P.; Mutter, M.
Tetrahedron 1999, 55, 11281–11288. (c) Skropeta, D.; Jolliffe, K. A.; Turner,
P. J. Org. Chem. 2004, 69, 8804–8809. (d) Sayyadi, N.; Skropeta, D.; Jolliffe,
K. A. Org. Lett. 2005, 7, 5497–5499.
(2) Bernardi, F.; Garavelli, M.; Scatizzi, M.; Tomasini., C.; Trigari, V.;
Crisma, M.; Formaggio, F.; Peggion, C.; Toniolo, C. Chem.;Eur. J. 2002, 8,
2516–2525. Tomasini, C.; Villa, M. Tetrahedron Lett. 2001, 42, 5211–5214.
€
(3) (a) Dumy, P.; Keller, M.; Ryan, D. E.; Rohwedder, B.; Wohr, T.;
€
Mutter, M. J. Am. Chem. Soc. 1997, 119, 918–925. (b) Keller, M.; Sager, C.;
Dumy, P.; Schutkowski, M.; Fischer, G. S.; Mutter, M. J. Am. Chem. Soc.
1998, 120, 2714–2720.
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Mutter, M. J. Am. Chem. Soc. 1996, 118, 9218–9227. (b) Haack, T.; Mutter,
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DOI: 10.1021/jo100518t
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Published on Web 05/19/2010
J. Org. Chem. 2010, 75, 4135–4145 4135
2010 American Chemical Society

Chaume et al.
JOCArticle
Moreover, by analogy with trifluoromethyl group con-
taining amino acids (Tfm-AAs) and pseudopeptides,12 spe-
cific effects are expected from the incorporation of Tfm-
pseudoprolines into peptides such as increase of the lipo-
philicity and a better affinity for lipid membranes, better
stability toward proteases,13 particular conformations sta-
bilizations, and better autoassembly.14 Moreover, the fluori-
nated pseudoprolines can be used as efficient probes for 19F
NMR studies.15
Results and Discussion
Synthesis of Tfm-pseudoprolines. In the nonfluorinated
series, the main strategy employed for the incorporation of
oxazolidine pseudoproline units into a peptide chain is the
post-insertion method involving the condensation of alde-
hydes or ketones or their acetals with preformed serine-based
dipeptides or analogues under an acidic catalysis.3-5,16 The
alternative strategy consisting of the N-acylation of a free
NH oxazolidine was not extensively used because it fre-
quently results in moderate yield and it involves low stability
oxazolidines.17 For the synthesis of the more stable thiazo-
lidine-type pseudoprolines, both methods were reported so
far.18 The synthesis of trifluoromethyl group containing N-
acylated oxazolidines was at first examined from N-acetyl
and N-Cbz serine esters with trifluoroacetaldehyde ethyl
hemiacetal under acidic catalysis according to the post-
insertion strategy (Scheme 1). Unfortunately, no reaction
occurred under these conditions. The tentative condensation
of fluoral hydrate with a preformed Fmoc-Gly-Ser-OMe
FIGURE 2. CF3-pseudoprolines (Tfm-Ψpro) containing tripeptide
models for amide isomer ratio and stability studies.
considered as an advantage for their use as temporary
molecular hinge in peptide synthesis because the pseudo-
proline cyclic system is hydrolyzed when the peptide is
cleaved from the resin to give the target peptide. On the
other hand, the acid lability of the oxazolidine ring can be
considered as a disadvantage when the expected applica-
tion is the synthesis of conformationally constrained pep-
tides. This drawback could be partially surmounted by
using thiazolidine-type pseudoprolines obtained from
cysteine.7
It is now well documented that the introduction of fluorine
atoms into biomolecules significantly modifies their chemical
and biological properties,8 and a growing number of methods
are reported for the synthesis of fluorine-containing com-
pounds.9 As a new application in peptide and amino acids che-
mistry, we report here that the introduction of a trifluoromethyl
group at the C-2 carbon of the oxazolidine ring of pseudo-
prolines strongly increased its stability in acidic medium and
favor the cis amide conformation of tripeptide models (Figure 2).
This is mainly due to the strong electron-withdrawing effect
of the trifluoromethyl group and its steric hindrance.10 The
tripeptide models represented in Figure 2 were chosen in order
to compare the properties of the Tfm-pseudoprolines with
unfluorinated pseudoprolines3a or prolines reported by other
authors.11
dipeptide under PTSA or BF3 OEt2 activation also failed
3
to give the expected Tfm-pseudoproline containing dipep-
tide. Therefore, we decided to investigate the two-step strat-
egy involving the synthesis of the oxazolidine ring followed
by the N-acylation reaction. The targets Tfm-Ψpro esters 1
and 2 were conveniently obtained in satisfactory isolated
(12) (a) Uneyama, K. In Fluorine in Medicinal Chemistry and Chemical
Biology; Ojima, I., Ed.; John Wiley & Sons Ltd.: Chichester, UK, 2009; 213-256.
(b) Kukhar, V. P.; Soloshonok, V. A. In Fluorine Containing Amino Acids:
Synthesis and Properties; Wiley: New York, 1995. (c) Zanda, M. New J. Chem.
2004, 28, 1401–1411. and references cited therein. (d) Molteni, M.; Pesenti, C.;
Sani, M.; Volonterio, A.; Zanda, M. J. Fluorine Chem. 2004, 125, 1335–1743.
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ChemBioChem 2004, 5, 79–86. (f) Smits, R.; Cadicamo, C. D.; Burger, K.;
Koksch, B. Chem. Soc. Rev. 2008, 37, 1727–1739. and references therein.
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H.-D. J. Pept. Sci. 1997, 3, 157–167.
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O. V.; Ulrich, A. S.; Komarov, I. V. Angew. Chem., Int. Ed. 2008, 47, 5765–
5767. (b) Mikhailiuk, P. K.; Afonin, S.; Chernega, A. N.; Rusanov, E. B.;
Platonov, M. O.; Dubinina, G. G.; Berditsch, M.; Ulrich, A. S.; Komarov,
I. V. Angew. Chem., Int. Ed. 2006, 45, 5659–5661. (c) Maisch, D.; Wadhwani,
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422. (b) Woehr, T.; Mutter, M. Tetrahedron Lett. 1995, 36, 3847–3848.
(17) (a) Haack, T.; Mutter, M. Tetrahedron Lett. 1992, 33, 1589–1592.
(b) Seebach, D.; Sommerfeld, T. L.; Jiang, Q.; Venanzi, L. M. Helv. Chim.
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Patiny, L.; Acha-Orbea, H.; Mutter, M. Angew. Chem., Int. Ed. 2000, 39,
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C.; Mutter, M.; Schiller, P. W. J. Med. Chem. 2001, 44, 3896–3903.
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2848. (e) Wittelsberger, A.; Patiny, L.; Slaninova, J.; Barberis, C.; Mutter, M.
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SCHEME 1. Synthesis of Tfm-Ψpro Esters
FIGURE 3. Selected NOE identifying the relative configuration of
(S,S)-1 and (R,S)-1.
SCHEME 2. Synthesis of Tfm-Ψpro Methyl Esters 3 and 4
yields through the condensation reaction of trifluoroacetal-
dehyde ethyl hemiacetal with serine esters or their N-Boc
derivatives (Scheme 1). We previously reported that the N-
Boc protection of the amino alcohol is acting as a temporary
protecting group of the nitrogen atom which facilitates the
condensation reaction.19 The ratio of each diastereomer was
dependent on the reaction conditions. Starting from the
serine methyl ester hydrochloride, the trans (S,S)-1 and the
cis (R,S)-1 pseudoproline esters were obtained in similar
isolated yields (32%).20 When the reaction was performed
from the N-Boc-serine methyl ester under acidic catalysis
(0.1 equiv PPTS), the most stable trans (S,S)-1 oxazolidine
was obtained as the major compound (65% isolated yield).
The isolated diastereomerically pure pseudoproline esters 1
and 2 are extremely stable and can be stored with no trouble.
As expected from the strong electron-withdrawing effect of
the trifluoromethyl group, there is no epimerization of the
C-2 center of the oxazolidine ring through ring-opening and
ring-closing equilibrium. In order to have in hand both (S,S)-
1 and (R,S)-1 diastereomers for future studies, we investi-
gated the epimerization of (S,S)-1 into (R,S)-1. This was
results obtained with NOESY 2D experiments, the structure
of the (S,S)-1 and (R,S)-1 has been modeled. The theoretical
calculations were performed using a semiempirical force field
(AM1) and the Hyperchem 5.0 package.21 The analysis of
geometrical data for hydrogen atoms (see Figure 3) mea-
sured in the lowest energy equilibrium molecular structure
shows that the H2-H4 distance in (S,S)-1 is larger than
H2-H4 distance in (R,S)-1. The absence of NOE correlation
peaks on the NOESY map for (S,S)-1 for this pair of
hydrogen is in agreement with this difference in H2-H4
distances in both isomers. The same occurrence was ob-
served for the hydrogen pairwise H2-H5a. For the concerned
hydrogen pairs, these NOE results are perfectly consistent
with a cis and trans relationship for (R,S)-1 and (S,S)-1,
respectively.
As an exploratory study, the synthesis of disubstituted
oxazolidines was also investigated by mean of the condensa-
tion of the serine methyl ester hydrochloride with trifluoro-
acetone. The expected pseudoprolines 3 were obtained in
good yields (Scheme 2). The major diastereomer of 3 was
isolated in 74% yield.22 A preliminary experiment showed
that trifluoromethyl group containing thiazolidines can also
be obtained by the condensation of the cysteine methyl ester
with trifluoroacetaldehyde ethyl hemiacetal. Unfortunately,
the expected pseudoprolines 4 were obtained in low yields
(33%) with the undesired bicyclic compound 5 (Scheme 2).
The unprotected Tfm-pseudoprolines (S,S)-6 and (R,S)-6
were very conveniently obtained through saponification of
the corresponding methyl esters (S,S)-1 and (R,S)-1 in,
respectively, 52% and 68% yield (Scheme 3). Due to the
achieved by treating (S,S)-1 with BF3 OEt2 in dichloro-
3
methane. After workup, the (R,S)-1 pseudoproline was
isolated in 61% yield and proved to remain configurationally
stable (Scheme 1).
The absolute configuration of (S,S)-1 and (R,S)-1 was
determined by the presence or the absence of nuclear Over-
hauser effect between the proton of the C2 and both the
protons of the C4 and C5 carbons. To confirm the NMR
(19) (a) Chaume, G.; VanSeveren, M.-C.; Ricard, L.; Brigaud, T.
ꢁ
J. Fluorine Chem. 2008, 129, 1104–1109. (b) Caupene, C.; Chaume, G.;
Ricard, L.; Brigaud, T. Org. Lett. 2009, 11, 209–212.
(20) Both diastereomers are very conveniently separated by silica gel
chromatography because of high Rf values differences.
(21) HyperChem is a registered trademark of Hypercube, Inc.
(22) The absolute configurations of 3 and 4 could not be assigned.
J. Org. Chem. Vol. 75, No. 12, 2010 4137

Chaume et al.
JOCArticle
SCHEME 3. Synthesis of Tfm-Ψpro 6
TABLE 1. Acylation Reactions of Tfm-Ψpro Esters (S,S)-1 and (R,S)-1
starting
material
acylation
conditions
entry
product
yielda (%)
1
2
3
4
5
6
7
8
9
(S,S)-1
(S,S)-1
(S,S)-1
(R,S)-1
(R,S)-1
(S,S)-1
(S,S)-1
(R,S)-1
(R,S)-1
(R,S)-1
(S,S)-1
(S,S)-1
AcCl, Pyr.
Ac2O
Ac2O, cat I2
Ac2O
Ac2O, cat I2
(EtCO)2O
EtCOCl, Pyr.
(EtCO)2O
PhCOCl
PhCOCl, Pyr.
PhCOClb
PhCOCl, Et3N
R = Me, (S,S)-8
R = Me, (S,S)-8
R = Me, (S,S)-8
R = Me, (R,S)-8
R = Me, (R,S)-8
R = Et, (S,S)-9
R = Et, (S,S)-9
R = Et, (R,S)-9
R = Ph, (R,S)-10
R = Ph, (R,S)-10
R = Ph, (R,S)-10
R = Ph, 10c
74
84
85
79
86
65
97
89
96
99
90
60c
SCHEME 4. Synthesis of Tfm-Ψpro N-Methylamides 7
10
11
12
aIsolated yield. bWhen the reaction was performed in the presence of
pyridine, (S,S)-1 was converted into (S,S)-10 with a 20% conversion.
c54:46 mixture of (R,S)-10 and (S,S)-10.
trifluoromethyl group,23 strong electrophiles such as acyl ha-
lides or acid anhydrides have to be used.24 The N-acetylation of
the (S,S)-1 or the (R,S)-1 oxazolidines was conveniently
achieved in good yields using acetyl chloride in the presence of
pyridine or using acetic anhydride (Table 1, entries 1-5). In the
acetyl anhydride conditions, the yield was increased by using an
iodine catalysis (Table 1, entry 5).25 Under all conditions, the
acetylation reaction occurred without any epimerization. The
trans-(S,S)-1 and the cis-(R,S)-1 oxazolidines gave the trans-(S,
S)-8 and the cis-(R,S)-8 N-acetylated oxazolidines, respectively.
The N-propanoylation of (S,S)-1 and (R,S)-1 occurred in a
similar manner to give (S,S)-9 and (R,S)-9 (Table 1, entries
6-8). The N-benzoylation of the cis-(R,S)-1 oxazolidine into
cis-(R,S)-10 was performed in very high yields (96-99%) using
benzoyl chloride neat or in the presence of pyridine (Table 1,
entries 9 and 10). The trans-(S,S)-1 oxazolidine presented a
different behavior when it reacted with benzoyl chloride. When
the reaction was carried out with neat benzoyl chloride, epimer-
ization occurred and the cis-(R,S)-10 was obtained in 90% yield
(Table 1, entry 11). When the reaction was performed in the
presence of pyridine, preventing the epimerization of the ox-
azolidine ring, the conversion of trans-(S,S)-1 into trans-(S,S)-
10 was very low (20%). The benzoylation reaction of trans-(S,
S)-1 with benzoyl chloride in the presence of triethylamine gave
a 54:46 mixture of (R,S)-10 and (S,S)-10 in 60% yield (Table 1,
entry 12). These results suggest that the C-2 epimerization of the
trans-(S,S)-1 oxazolidine into the less hindered and more reac-
tive cis-(R,S)-1 oxazolidine is concomitant to the benzoylation
reaction when the reaction is carried out in acidic conditions.26
In a similar manner, the major diastereomer of the
Ψ(CF3,CH3Pro) methyl ester 3maj was submitted to the N-acyla-
tion reaction with acetic anhydride in the presence of iodine
to give the corresponding N-acetylated pseudoproline methyl
ester 11 in 55% yield. The yield is lower than in the case of
the monosubstituted Tfm-pseudoprolines because of the
electron-withdrawing effect of the trifluoromethyl group,
these oxazolidines are very stable toward ring-opening and
can be considered as valid δ-trifluoromethylated proline
surrogates.
Synthesis of Tfm-pseudoproline-Based Peptide Models. In
order to anticipate the coupling reaction of an amino acid at
the C-terminal position of the Tfm-Ψpro 6, the synthesis of
the corresponding N-methyl amides 7 was investigated. The
amide synthesis was achieved from the Tfm-Ψpro methyl
esters 1 in a two-step procedure involving the saponification
of the ester function followed by the amidification reaction
with methylamine using standard peptide bond formation
conditions (Scheme 4). Starting from the esters (S,S)-1 and
(R,S)-1, the N-methylamides (S,S)-7 and (R,S)-7 were ob-
tained in, respectively, 81% and 71% yields. It should be
noticed that the amidification reaction can be performed
without prerequisite protection of the oxazolidine amino
group. Because of the deactivation of this nitrogen atom by
the trifluoromethyl group, the diketopiperazine formation
side reaction is avoided. The coupling reaction occurred
without any epimerization at the C-2 or the C-4 centers.
Therefore, the Tfm-pseudoprolines could be useful config-
urationally stable surrogates of substituted prolines at the N-
terminal position of peptides.
In order to probe the peptide coupling reactions on the
deactivated nitrogen atom in the R position of the trifluoro-
methyl group and to study cis/trans amide equilibrium, the
N-acylation of the Tfm-pseudoproline methyl esters 1 was
achieved (Table 1). Because of the dramatic decrease of the
nucleophilicity of the amino group in the R-position of the
(23) Schlosser, M. Angew. Chem., Int. Ed. 1998, 110, 1496–1513.
(24) For examples of peptides coupling at the N-terminal position of R-
Tfm-amino acids, see: (a) Koksch, B.; Quaedflieg, P. J. L. M.; Michel, T.;
Burger, K.; Broxterman, Q. B.; Schoemaker, H. E. Tetrahedron: Asymmetry
2004, 15, 1401–1407. (b) Dal Pozzo, A.; Ni, M.; Muzi, L.; Caporale, A.; de
Castiglione, R.; Kaptein, B.; Broxterman, Q. B.; Formaggio, F. J. Org.
Chem. 2002, 67, 6372–6375. (c) Chaume, G.; Lensen, N.; Caupene, C.;
Brigaud, T. Eur. J. Org. Chem. 2009, 5717–5724.
(25) (a) Philippe, C.; Milcent, T.; Nguyen Thi Ngoc, T.; Crousse, B.;
Bonnet-Delpon, D. Eur. J. Org. Chem. 2009, 71, 5215–5223. (b) Varala, R.;
Nuvula, S.; Adapa, S. R. J. Org. Chem. 2006, 71, 8283–8286.
(26) Ando, W.; Igarashi, Y.; Huang, L. Chem. Lett. 1987, 1361–1364.
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1
SCHEME 5. Synthesis of Tfm-Ψpro N-Methylamides 12
amide conformer ratio was determined by H and 13C-{1H}
NMR measurements in CDCl3 according to the work pre-
viously reported by Lubell et al.11 The ratio of cis/trans amide
conformers was determined by 1H and 19F NMR integration.
The assignments of the isomers’ geometry were performed by
the comparison of the 13C chemical shifts of the R, β, and γ
carbons of the cis and the trans isomers. On the 13C NMR
spectra, the R- and β-carbon signals of the trans isomers should
appear upfield compared to the R- and β-carbon signals of the
cis isomers. On the other hand, the δ-carbon signals of the trans
isomers should appear downfield compared to the δ-carbon
signals of the cis isomers. (Table 2). The average 40:60 cis/trans
amide ratio observed is consistent with literature data obtained
with similar structures in the proline11 and the unfluorinated
pseudoproline series.3
SCHEME 6. Peptide Coupling Reaction with the Nitrogen
Atom of a Tfm-pseudoproline
Stability Study of Tfm-pseudoprolines. In order to demon-
strate the great increased of stability of the Tfm-pseudo-
prolines toward acid-mediated ring-opening, the pseudo-
peptides 8, 11, and 12 were treated with different acidic media
(Table 3). Both diastereomers of the N-acetylpseudoproline
methyl esters 8 proved to be completely stable under treat-
ment with 5% trifluoroacetic acid in CDCl3 at room tem-
perature after several days (Table 3, entries 1 and 2). The
incorporation of the trifluoromethyl group exerts a remark-
able stabilization effect since unfluorinated similar pseudo-
prolines undergo quantitative ring-opening within minutes
under these conditions.5a Moreover, the N-acetylated pseudo-
proline methyl esters 8 and 11 as well as their methylamide
analogues 12 are totally stable under treatment with 90% or
95% TFA/H2O at room temperature for several hours
(Table 3, entries 3-7). These results suggest that, compared
to unfluorinated pseudoprolines, Tfm-pseudoprolines would
be completely hydrolytically stable under Fmoc/t-Bu solid-
phase peptide synthesis strategy. It should also be noticed
that in opposition to the unfluorinated series5a and the un-
acylated Tfm-pseudoprolines 1 (Scheme 1), Tfm-pseudopro-
lines are stable toward Lewis acids. The diastereomerically
pure N-acylated Tfm-pseudoprolines (S,S)- or (R,S)-8 and
-12 do not undergo epimerization or ring-opening when
increased steric hindrance at the C-2 position of the oxazo-
lidine ring. The synthesis of the N-acetylated CF3-pseudo-
prolines containing tripeptide models (S,S)-12 and (R,S)-12
was achieved through the saponification reactions of the
methyl esters (S,S)-8 and (R,S)-8 followed by their amidifi-
cation reaction with methylamine (Scheme 5). This strategy
proved to be more satisfactory than the acetylation of the
pseudoproline amides (S,S)-7 and (R,S)-7, which gave side
products resulting from the acetylation reaction on both
oxazolidine and amide nitrogen atoms.
treated with an excess of BF3 OEt2 in CDCl3 for several
3
hours. The combined electron-withdrawing effects of the
trifluoromethyl group and the acyl group on the nitrogen
atom prevent the ring-opening of the oxazolidine ring.
In order to anticipate the use of Tfm-pseudoprolines in pep-
tide chemistry, a preliminary experiment of peptide coupling of
o-Nbs-Ala-OH with the nitrogen atom of the pseudoproline (R,
S)-1 was investigated (Scheme 6). Because of the strong deac-
tivation of the amino group of the Tfm-pseudoproline, a highly
electrophilic amino acid halide27 (7 equiv) was required to
achieve the peptide coupling in a good yield (90%). The
expected (R,S)-13 dipeptide was obtained in 68% isolated yield
with the (S,S)-13 diastereomer (22% isolated yield).
Cis/Trans Amide Isomer Ratio Determination. As expec-
ted, all the new synthesized N-acylated Tfm-pseudoprolines
were obtained as cis/trans amide isomers.28 For each diastereo-
isomer of pseudoprolines 7, 8, 9, 11, and 12, the cis/trans
Conclusion
In conclusion, we report that fluorinated oxazolines (Fox)
are conveniently synthesized by condensation reaction of
serine esters and trifluoroacetaldehyde hemiacetal or tri-
fluoroacetone. These oxazolidines are stabilized toward
ring-opening by the trifluoromethyl group and can be con-
sidered as pseudoprolines. Despite the great deactivation of
their nitrogen atom, these oxazolidines can be efficiently N-
acylated to give stable pseudoproline-type structures as cis/
trans conformers. The conformational study of the Tfm-
pseudoprolines and their cis/trans isomerization are under
investigation and will be reported soon. For future applica-
tions in peptide chemistry, it is anticipated that Fox-
pseudoprolines would be hydrolytically stable authentic
proline surrogates compatible with Fmoc/t-Bu SPPS strat-
egy. After removal of the peptide from the resin, the con-
formational features induced by the trifluoromethyl group
(27) (a) Dal Pozzo, A.; Bergonzi, R.; Ni, M. Tetrahedron Lett. 2001, 42,
3925–3927. (b) Dal Pozzo, A.; Ni, M.; Muzi, L.; Caporale, A.; de Castiglione,
R.; Kaptein, B.; Broxterman, Q. B.; Formaggio, F. J. Org. Chem. 2002, 67,
6372–6375.
(28) Cis/trans amide isomers were discriminated from possible diastereo-
mers or side products by coalescence of NMR signals at higher temperature.
J. Org. Chem. Vol. 75, No. 12, 2010 4139

Chaume et al.
JOCArticle
TABLE 2. Cis/Trans Amide Isomer Ratio of Pseudoprolines 8, 9, 11, and 12 in CDCl3 at 298 K
CR
Cβ
Cδ
compd
R1
R2
R3
cis
trans
cis
trans
cis
trans
cis/trans ratio
(S,S)-8 (CDCl3)
(R,S)-8 (CDCl3)
(S,S)-9 (CDCl3)
(R,S)-9 (CDCl3)
11 (CDCl3)
H
H
H
H
CH3
H
H
CH3
CH3
Et
OMe
OMe
OMe
OMe
OMe
NHMe
NHMe
59.0
58.1
58.4
57.4
60.6
60.0
60.0
58.1
56.6
58.2
56.8
60.4
59.0
57.5
72.1
70.5
72.2
70.4
67.5
73.0
71.4
70.5
69.4
70.3
69.0
69.1
71.0
68.7
84.6
84.3
84.4
84.3
91.6
84.1
85.0
84.8
85.5
84.7
84.3
93.9
84.7
85.0
40:60
48:52
40:60
52:48
31:69
40:60
33:66
Et
CH3
CH3
CH3
(S,S)-12 (CDCl3)
(R,S)-12 (CDCl3)
TABLE 3. Hydrolytic Stability of Tfm-pseudoprolines
for 1 h. Then, 20 mL of toluene was added, and the reaction
mixture was warmed to reflux using a Dean-Stark apparatus
for 20 h. The reaction mixture was then cooled to 0 °C with an ice
bath and filtered, and toluene was evaporated. The crude
residue was purified by silica gel chromatography (90:10 petro-
leum ether/ethyl acetate) to give (S,S)-1 (291 mg, 65%) as a
colorless oil and (R,S)-1 (33 mg, 7%) as a white solid.
(S,S)-1: colorless oil; Rf=0.31 (80:20 cyclohexane/ethyl ace-
tate); [R]23 -50.4 (c 4.95, CHCl3); IR (neat) 3338, 2962, 1740,
entry
compd
R1
R2
acidic conditions
D
1
1439, 1287, 1223, 1158, 1131, 665 cm-1; H NMR (600 MHz,
1
2
3
4
5
6
7
(S,S)-8
(R,S)-8
(S,S)-8
(R,S)-8
11
H
H
H
H
CH3
H
H
OMe
OMe
OMe
OMe
OMe
NHMe
NHMe
5% TFA in CDCl3, rt, 72 h
5% TFA in CDCl3, rt, 72 h
90% TFA/H2O, rt, 4 h
90% TFA/H2O, rt, 4 h
90% TFA/H2O, rt, 5 h
95% TFA/H2O, rt, 5 h
95% TFA/H2O, rt, 5 h
CDCl3) δ 3.28 (m, 1 H, NH), 3.79 (s, 3 H, OMe), 3.83 (ddd, J=7.8,
6.2, 1.0 Hz, 1 H), 4.02 (dd, J=7.8, 6.2 Hz, 1 H), 4.23 (t, J=7.8 Hz,
1H),5.04(q, J=5.7 Hz, 1 H); 13C NMR (100.5 MHz, CDCl3) δ52.9,
58.5, 69.7, 87.8 (q, J = 34.5 Hz), 123.2 (q, J = 283.6 Hz), 171.9; 19
F
(S,S)-12
(R,S)-12
NMR (376.2 MHz, CDCl3) δ -85.0 (dd, J = 5.7, 1.0 Hz); MS (EI)
m/z = 199 [Mþ], 140 [Mþ - CO2Me] (100), 130, 112, 92, 70;
HRMS (EI) calcd for C6H8F3NO3 199.0456, found 199.0457.
(R,S)-1: white solid; mp 65 °C; Rf = 0.10 (80:20 cyclohexane/
ethyl acetate); [R]23D -17.61 (c 4.9, CHCl3); IR (neat) 3309, 1737,
containing pseudoproline would be preserved. The incor-
poration of Tfm-pseudoprolines into peptide chains is in
progress and will be reported in due course.
1
1462, 1285, 1231, 1156, 1127, 669 cm-1; H NMR (600 MHz,
CDCl3) δ 3.18 (m, 1 H, NH), 3.71 (s, 3 H, OMe), 4.08 (ddq, J=6.5,
6.0, 0.7 Hz, 1 H), 4.11 (t, J=6.0 Hz, 1 H), 4.15 (ddq, J= 6.5, 6.0, 1.1
Hz, 1 H), 4.89 (q, J = 5.2 Hz, 1 H); 13C NMR (100.5 MHz, CDCl3)
δ 52.6, 58.6, 68.8, 87.6 (q, J = 34.5 Hz), 122.9 (q, J = 283.6 Hz),
171.1; 19F NMR (376.2 MHz, CDCl3) δ -84.1 (ddd, J = 5.2, 1.1,
0.7 Hz); MS (EI) m/z = 199 [Mþ], 140 [Mþ - CO2Me] (100), 130,
112, 92, 70; HRMS (EI) calcd for C6H8F3NO3 199.0456; found
199.0458.
Experimental Section
Synthesis of Oxazolidine 1-3 and Thiazolidine 4. (4S)-2-
Trifluoromethyloxazolidine-4-carboxylic Acid Methyl Esters
(S,S)-1 and (R,S)-1. Representative Procedure from (S)-Serine
Methyl Ester Hydrochloride. To a solution of (S)-serine methyl
ester hydrochloride (2.33 g, 15.0 mmol) in toluene (5 mL) at 0 °C
were added sodium acetate (1.23 g, 15.0 mmol, 1 equiv) and
trifluoroacetaldehyde ethyl hemiacetal (3.48 mL, 30.0 mmol,
2 equiv). The resulting mixture was stirred at room temperature
for 30 min and warmed to 90 °C for 2 h. Toluene (30 mL) was
then added to the reaction mixture, which was warmed to reflux
using a Dean-Stark apparatus for 6 h. The reaction mixture was
then cooled to 0 °C with an ice bath and filtered, and toluene was
evaporated. Purification by silica gel chromatography (90:10
petroleum ether/ethyl acetate) gave of (S,S)-1 (945 mg, 32%) as
a colorless oil and (R,S)-1 (945 mg, 32%) as a white solid.
Representative Procedure from (S)-BocNH-serine Ester. To a
solution of (S)-BocNH-serine methyl ester (490 mg, 2.23 mmol,
1.0 equiv) in toluene (1 mL) at room temperature were added
trifluoroacetaldehyde ethyl hemiacetal (311 μL, 2.68 mmol,
1.2 equiv) and pyridinium p-toluenesulfonate (PPTS) (112 mg,
0.45 mmol, 0.2 equiv). The resulting mixture was stirred at 90 °C
(4S)-2-Trifluoromethyloxazolidine-4-carboxylic Acid Benzyl
Esters (S,S)-2 and (R,S)-2. (S,S)-2 and (R,S)-2 were prepared
according to the same procedure from (S)-serine benzyl ester (716
mg, 3.67 mmol, 1.0 equiv) in toluene (12 mL), trifluoroacetalde-
hyde ethyl hemiacetal (447 μL, 3.85 mmol, 1.05 equiv), and PPTS
(92 mg, 0.37 mmol, 0.1 equiv). The resulting mixture was stirred at
90 °C for 1 h and then warmed to reflux using a Dean-Stark
apparatus for 3 h. Purification by silica gel chromatography (85:15
cyclohexane/ethyl acetate) gave (S,S)-2 (431 mg, 43%) as a
colorless oil and (R,S)-2 (119 mg, 12%) as a white solid.
(S,S)-2: Rf = 0.66 (70:30 cyclohexane/ethyl acetate); [R]26
D
-39.8 (c 1.08, CHCl3); IR (neat) 3333, 3036, 2958, 1738, 1285,
1131 cm-1; 1H NMR (400 MHz, CDCl3) δ 3.39 (dd, J=8.2, 7.3 Hz,
1 H, NH), 3.82 (dd, J = 7.8, 6.4 Hz, 1 H), 4.09 (ddd, J=7.8, 7.3, 6.4
Hz, 1 H), 4.26 (t, J=7.8 Hz, 1 H), 5.07 (dq, J=8.2, 5.5 Hz, 1 H),
5.17 (d, J = 11.9 Hz, 1 H), 5.21 (d, J = 11.9 Hz, 1 H), 7.31-7.41
(m, 5 H); 13C NMR (100.5 MHz, CDCl3) δ 58.6, 67.8, 69.6, 87.7 (q,
4140 J. Org. Chem. Vol. 75, No. 12, 2010

Chaume et al.
JOCArticle
J = 34.5 Hz), 123.2 (q, J = 283.7 Hz), 128.4, 128.7, 128.8, 134.7,
171.2; 19F NMR (376.2 MHz, CDCl3) δ -85.0 (d, J = 5.5 Hz);
HRMS (EI) calcd for C12H12F3NO3 275.0769, found 275.0777.
(R,S)-2: white solid; mp 96-98 °C; Rf = 0.34 (70:30 cyclo-
Hz, 1 H), 3.80 (s, 3 H, OMe), 4.07 (dd, J = 9.2, 6.0 Hz, 1 H), 4.89
(q, J = 6.0 Hz, 1 H); 13C NMR (100.5 MHz, CDCl3) δ 35.7,
52.7, 65.2, 66.5 (q, J = 33.5 Hz), 124.4 (q, J = 277.9 Hz), 170.5;
19F NMR (376.2 MHz, CDCl3) δ -78.0 (d, J = 6.0 Hz); HRMS
(EI) calcd for C6H8F3NSO2 215.0228, found 215.0225.
hexane/ethyl acetate); [R]22 -31.4 (c 0.8, CHCl3); IR (neat)
D
3315, 2962, 2902, 1741, 1290, 1135 cm-1; 1H NMR (400 MHz,
CDCl3) δ 3.15 (m, 1 H, NH), 4.10-4.20 (m, 3 H), 4.91 (dq, J =
7.8, 5.0 Hz, 1 H), 5.18 (s, 2 H), 7.34-7.37 (m, 5 H); 13C NMR
(100.5 MHz, CDCl3) δ 58.8, 67.5, 68.9, 87.8 (q, J = 34.5 Hz),
122.8 (q, J = 283.7 Hz), 128.4, 128.6, 128.7, 135.0, 170.4; 19F
NMR (376.2 MHz, CDCl3) δ -84.1 (d, J = 5.0 Hz); HRMS (EI)
calcd for C12H12F3NO3 275.0769, found 275.0760.
4min: colorless oil; Rf = 0.14 (90:10 cyclohexane/ethyl acetate);
[R]22 -81.6 (c 1.15, CHCl3); IR (neat) 3333, 2958, 2853, 1788,
D
1737, 1438, 1145, 1111 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.97
(dd, J = 10.5, 6.9 Hz, 1 H), 3.20 (m, 1 H, NH), 3.41 (dd, J = 10.5,
6.4 Hz, 1 H), 3.81 (s, 3 H, OMe), 4.12 (dd, J = 6.9, 6.4 Hz, 1 H),
4.89 (q, J = 6.0 Hz, 1 H); 13C NMR (100.5 MHz, CDCl3) δ 36.8,
52.9, 64.2, 66.5 (q, J= 34.5 Hz), 124.8 (q, J= 278.8 Hz), 171.6; 19
F
Lewis Acid Epimerization Procedure. To a stirred solution of
pure (S,S)-1 (912 mg, 4.58 mmol, 1.0 equiv) in dichloromethane
NMR (376.2 MHz, CDCl3) δ -79.5 (d, J = 6.9 Hz); HRMS (EI)
calcd for C6H8F3NSO2 215.0228, found 215.0228.
Bicyclic side product (5): white solid; mp 70-74 °C; Rf = 0.47
(9:1 cyclohexane/ethyl acetate); [R]22D -39.0 (c 2.45, CHCl3); IR
(neat) 2954, 1802, 1267, 1157, 1112, 998, 881 cm-1;1H NMR (400
MHz, CDCl3) δ 3.51 (dquint, J = 12.4, 1.9 Hz, 1 H), 4.38 (dd, J =
12.4, 7.8, 1.0 Hz, 1 H), 4.38 (dd, J = 7.8, 1.9 Hz, 1 H), 4.79 (qd, J =
7.2, 1.0 Hz, 1 H), 5.32 (q, J = 4.5 Hz, 1 H); 13C NMR (100.5 MHz,
CDCl3) δ 34.8, 64.6, 74.6 (q, J = 34.5 Hz), 91.7 (q, J = 37.4 Hz),
120.8 (q, J = 282.7 Hz), 123.8 (q, J = 279.8 Hz), 171.4; 19F NMR
(376.2 MHz, CDCl3) δ -79.7 (dd, J = 7.2, 1.9 Hz), -85.7 (d, J =
(10 mL) at 0 °C was added BF3 OEt2 complex (610 μL, 4.80
3
mmol, 1.05 equiv). The mixture was stirred for 8 h at room
temperature. Subsequently, 5 mL of brine was added to the
reaction mixture, and the product was extracted with dichloro-
methane (3 ꢀ 5 mL) and then dried over MgSO4. Purification by
flash chromatography (80:20 cyclohexane/ethyl acetate) gave
193 mg (21%) of (S,S)-1 as colorless oil and 553 mg (61%) of (R,
S)-1 as a white solid.
(4S)-2-Trifluoromethyl-2-methyloxazolidine-4-carboxylic Acid
Methyl Ester (3). The compound 3 was prepared from (S)-serine
methyl ester hydrochloride (450 mg, 2.89 mmol) in toluene (1 mL),
sodium acetate (237 mg, 2.89 mmol, 1 equiv), and trifluoro-
acetone (517 μL, 5.78 mmol, 2 equiv). The resulting mixture was
stirred at room temperature for 6 h, and 6 mL of toluene was
added to the reaction mixture which was warmed to reflux using
a Dean-Stark apparatus for 18 h. Purification by silica gel
chromatography (70:30 pentane/ether) gave 3maj (453 mg, 74%)
as a colorless oil and 3min (44 mg, 7%) as a colorless oil.
Major diastereomer (3maj): colorless oil; Rf = 0.9 (7:3 pen-
tane/Et2O); [R]28D -33.3 (c 5.1, CHCl3); IR (neat) 3325, 2959,
1741, 1438, 1220, 1153, 1101, 1034 cm-1; 1H NMR (400 MHz,
CDCl3) δ 1.59 (d, J = 1.0 Hz, 3 H), 3.00 (d, J = 6.4 Hz, 1 H,
NH), 3.80 (s, 3 H, OMe), 3.90 (ddq, J = 8.2, 6.9, 1.0 Hz, 1 H),
4.5 Hz); MS (EI) m/z = 281 [Mþ], 237 [Mþ - CO2], 212 [Mþ
-
CF3] (100), 184, 149, 123, 109, 69; HRMS (EI) calcd for C7H5F6-
NSO2 280.9945, found 280.9958.
(2S,4S)-2-Trifluoromethyloxazolidine-4-carboxylic Acid (S,
S)-6. To a solution of of (S,S)-1 (490 mg, 2.46 mmol) in THF
(15 mL) at 0 °C was added a 1 M aqueous solution of 2.95 mL of
LiOH (2.95 mmol, 1.1 equiv). The reaction mixture was stirred
vigorously for 4 h. Subsequently, Et2O (25 mL) was added, and
the reaction mixture was extracted with water (2 ꢀ 25 mL). The
aqueous layers were combined, and water was removed under
reduced pressure to afford of the corresponding lithium carbo-
xylate (470 mg) as a yellow oil which was used in the next step
without further purification: 1H NMR (400 MHz, D2O) δ 3.49
(t, J = 7.8 Hz, 1 H), 3.66 (t, J = 7.8 Hz, 1 H), 4.09 (t, J = 7.8 Hz,
1 H), 5.09 (q, J = 5.9 Hz, 1 H); 13C NMR (100.5 MHz, D2O) δ
60.5, 70.3, 87.3 (q, J = 34.5 Hz), 123.2 (q, J = 282.8 Hz), 176.5;
19F NMR (376.2 MHz, D2O) δ -84.6 (d, J = 5.9 Hz). The
lithium carboxylate was taken up with 2.7 mL of a 1 M aqueous
solution of acetic acid (2.7 mmol, 1.1 equiv). The product was
extracted with AcOEt (3 ꢀ 5 mL) then dried over MgSO4 to
give (S,S)-6 (237 mg, 52%) as colorless crystals: mp 69 °C;
[R]26D -26.3 (c 1.4, MeOH); IR (neat) 3297, 2921, 2853, 1725,
1425, 1163, 1124, 946, 923 cm-1; 1H NMR (400 MHz, CDCl3)
δ 4.00 (dd, J = 7.8, 5.5 Hz, 1 H), 4.17 (dd, J = 7.8, 5.5 Hz, 1 H),
4.35 (t, J = 7.8 Hz, 1 H), 5.11 (q, J = 5.5 Hz, 1 H); 13C NMR
(100.5 MHz, CDCl3) δ 58.3, 69.7, 87.6 (q, J = 34.5 Hz), 123.1
(q, J = 283.6 Hz), 175.8; 19F NMR (376.2 MHz,CDCl3) δ
-85.0 (d, J = 5.5 Hz); MS (EI) m/z = 155, 140 (Mþ - CO2H)
(80), 116 (Mþ - CF3) (100), 112, 92, 70. Anal. Calcd for
C5H6F3NO3 (185.03): C, 32.44; H, 3.27; N, 7.57. Found: C,
32.55; H, 3.19; N, 7.53.
(2R,4S)-2-Trifluoromethyloxazolidine-4-carboxylic Acid (R,
S)-6. To a solution of of (R,S)-1 (161 mg, 0.81 mmol) in THF
(4.4 mL) at 0 °C was added a 1 M aqueous solution of LiOH (890
μL, 0.89 mmol, 1.1 equiv). The reaction mixture was stirred
vigorously for 4 h. Then Et2O (10 mL) was added, and the
reaction mixture was extracted with water (2 ꢀ 10 mL). The
aqueous layers were combined, and the water was removed
under reduced pressure to afford the corresponding lithium
carboxylate (106 mg) as a yellow oil which was used in next step
without further purification: 1H NMR (400 MHz, D2O) δ
3.78-3.88 (m, 2 H), 3.97 (m, 1 H), 4.88 (q, J = 5.2 Hz, 1 H);
13C NMR (100.5 MHz, D2O) δ 60.7, 69.4, 87.2 (q, J = 32.6 Hz),
123.0 (q, J = 282.8 Hz), 178.0; 19F NMR (376.2 MHz, D2O) δ
-83.6 (d, J = 5.2 Hz). The lithium carboxylate was treated with
4.10 (ddd, J = 8.2, 6.9, 6.4 Hz, 1 H), 4.31 (t, J = 8.2 Hz, 1 H); 13
C
NMR (100.5 MHz, CDCl3) δ 19.7, 52.8, 59.5, 70.1, 94.6 (q, J =
30.7 Hz), 124.6 (q, J = 286.6 Hz), 172.4; 19F NMR (376.2 MHz,
CDCl3) δ -85.9 (s); MS (EI) m/z = 198 [Mþ - CH3], 154 [Mþ -
CO2Me] (100), 144, 126, 84; HRMS (EI) calcd for C7H10F3NO3
213.0613, found 213.0623.
Minor diastereomer (3min): colorless oil; Rf=0.16 (7:3 pentane/
Et2O); [R]27 -19.3 (c 3.4, CHCl3); IR (neat): 3360, 3000,
D
2958, 1741, 1438, 1224, 1153, 1104, 1039 cm-1 1H NMR
;
(400 MHz, CDCl3) δ 1.53 (d, J = 0.9 Hz, 3 H), 2.89 (d, J =
6.9 Hz, 1 H, NH), 3.78 (s, 3 H, OMe), 4.16-4.32 (m, 3 H);
13C NMR (100.5 MHz, CDCl3) δ 20.6, 52.6, 59.1, 69.3, 94.0
(q, J = 30.7 Hz), 124.4 (q, J = 287.5 Hz), 171.2; 19F NMR
(376.2 MHz, CDCl3) δ -85.5 (s); MS (EI) m/z = 198 [Mþ
-
CH3], 154 [Mþ - CO2Me] (100), 144, 126, 84; HRMS (EI) calcd
for C7H10F3NO3 213.0613, found 213.0616.
(4R)-2-Trifluoromethylthiazolidine-4-carboxylic Acid Methyl
Ester (4). Compound 4 was prepared from (R)-cysteine methyl
ester hydrochloride (1.54 g, 9.0 mmol) in toluene (5 mL), sodium
acetate (738 mg, 9.0 mmol, 1 equiv), and trifluoroacetaldehyde
ethyl hemiacetal (2.10 mL, 18.0 mmol, 2 equiv). The resulting
mixture was stirred at room temperature for 30 min and then
warmed to reflux using a Dean-Stark apparatus for 16 h. Puri-
fication by silica gel chromatography (90:10 cyclohexane/ethyl
acetate) gave 4min (140 mg, 7%) as an orange oil, 4maj (491 mg,
26%) as an orange oil, and the bicyclic side product 5 as a white
solid (977 mg, 39%).
4
maj: orange oil; Rf = 0.06 (90:10 cyclohexane/ethyl acetate);
[R]22 -31.9 (c 1.05, CHCl3); IR (neat) 3352, 2956, 1788, 1737,
D
1438, 1148, 1111 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.8 (m,
1 H, NH), 3.11 (dd, J = 10.5, 9.2 Hz, 1 H), 3.27 (dd, J = 10.5, 6.0
J. Org. Chem. Vol. 75, No. 12, 2010 4141

Chaume et al.
JOCArticle
of a 1 M aqueous solution of acetic acid (890 μL, 0.89 mmol, 1.1
equiv). The product was extracted with AcOEt (3 ꢀ 5 mL) and
then dried over MgSO4 to give (R,S)-6 (101 mg, 68%) as an
Acid Anhydride Procedure. A stirred solution of oxazolidine 1
(1 equiv) in acid anhydride (10 equiv) was warmed to 140 °C for
20 h. Upon cooling, excess acid anhydride was removed under
vacuum. Purification by flash chromatography gave the corres-
ponding acylated oxazolidines 8 and 9 in 65-89% yield.
Acid Anhydride Procedure with Iodine Catalysis. A solution of
oxazolidines 1 (1 equiv) and iodine (0.1 equiv) in acid anhydride
(10 equiv) was stirred at room temperature until the reaction was
completed as monitored by 19F NMR analysis. Subsequently,
dichloromethane was added, and the organic layer was washed
with a 1 M aqueous solution of NaHSO3 (3ꢀ). The aqueous
layer was extracted with dichloromethane (3ꢀ), and the com-
bined organic extracts were dried over MgSO4, filtered, and
concentrated under reduced pressure. Purification by flash
chromatography gave the corresponding acylated oxazolidines
8 in 85-86% yield.
(2S,4S)-N-Acetyl-2-trifluoromethyloxazolidine-4-carboxylic
Acid Methyl Ester (S,S)-8. The product was prepared by the acyl
choride procedure using 89 mg of (S,S)-1 (0.44 mmol, 1.0 equiv) in
dichloromethane (500 μL), 110 μL of pyridine (1.34 mmol, 3
equiv), and 95 μL of acetyl chloride (1.34 mmol, 3 equiv).
Purification by flash chromatography (70:30 cyclohexane/ethyl
acetate) gave 78 mg (74%) of acylated oxazolidine (S,S)-8 as a
41:59 inseparable mixture of cis/trans rotational isomers (in CDCl3
at 298 K).
orange oil: [R]27 -7.4 (c 1.15, MeOH); IR (neat) 3050, 2950,
D
1558, 1501, 1404, 1340, 1149, 1085, 1033 cm-1; 1H NMR (400
MHz, CDCl3) δ 4.25-4.29 (m, 3 H), 5.03 (q, J = 5.2 Hz, 1 H);
13C NMR (100.5 MHz, CDCl3) δ 58.5, 69.5, 87.5 (q, J = 34.5
Hz), 122.8 (q, J = 282.8 Hz), 173.4; 19F NMR (376.2 MHz,
CDCl3) δ -84.2 (d, J = 5.2 Hz); MS (EI) m/z = 155, 140 [Mþ -
CO2H] (80), 116 [Mþ - CF3] (100), 112, 92, 70; HRMS (EI)
calcd for C5H6F3NO3 185.0300; found 185.0300.
(2S,4S)-2-Trifluoromethyloxazolidine-4-N-methylamide (S,
S)-7. To a solution of lithium carboxylate (1.43 g, 7 mmol)
prepared from (S,S)-1 acording to the previous procedure in
DMF (16 mL) were successively added at room temperature
methylamine hydrochloride (708 mg, 10.5 mmol, 1.5 equiv),
HOBt (945 mg, 7 mmol, 1 equiv), NaHCO3 (1.76 g, 21 mmol,
3 equiv), and EDCI (1.47 g, 0.7.7 mmol, 1.1 equiv). The reaction
mixture was stirred overnight at room temperature and then
diluted with AcOEt and water. The layers were separated, and
the aqueous phase was extracted with AcOEt (3 ꢀ 20 mL). The
combined organic layers were dried over MgSO4, filtered, and
concentrated under reduced pressure. Purification by silica gel
chromatography (60:40 AcOEt/cyclohexane) gave (S,S)-7 (1.00 g,
81%) as white solid: mp 77-78 °C; Rf = 0.42 (3:7 cyclohexane/
ethyl acetate); [R]26D -50.8 (c 0.5, CHCl3); IR (neat) 3325, 3128,
2953, 2886, 1656, 1577, 1138 cm-1; 1H NMR (400 MHz, CDCl3) δ
2.86 (d, J = 5.0 Hz, 3 H), 3.28 (t, J = 8.3 Hz, 1 H), 3.89 (t, J = 7.3
Hz, 1 H), 3.97 (dt, J = 8.3, 7.3 Hz, 1 H), 4.19 (t, J = 7.3 Hz, 1 H),
5.00 (dq, J = 8.3, 5.2 Hz, 1 H), 6.75 (m, 1 H); 13C NMR (100.5
MHz, CDCl3) δ 26.3, 59.4, 70.2, 87.7 (q, J = 33.5 Hz), 123.0 (q,
J = 282.7 Hz), 170.4; 19F NMR (376.2 MHz, CDCl3) δ -84.5 (d,
J = 5.2 Hz); MS (EI) m/z = 140 [Mþ - CONHMe] (100), 112, 92,
58. Anal. Calcd for C6H9F3N2O2 (198.06): C, 36.67; H, 4.58; N,
14.14. Found: C, 36.52; H, 4.55; N, 14.03.
The product was prepared by the acid anhydride procedure
using 102 mg of (S,S)-1 (0.51 mmol, 1.0 equiv) in 480 μL of acetic
anhydride (5.1 mmol, 10 equiv). Purification by flash chromato-
graphy (70:30 cyclohexane/ethyl acetate) gave 103 mg (84%) of
acetylated oxazolidine (S,S)-8 as a 40:60 inseparable mixture of
cis/trans rotational isomers (in CDCl3 at 298 K).
The product was prepared by the acid anhydride procedure with
iodine catalysis using 875 mg of (S,S)-1 (4.39 mmol, 1.0 equiv),
111 mg iodine (0.44 mmol, 0.1 equiv), and 4.1 mL of acetic anhy-
dride (44.0 mmol, 10 equiv). The reaction was completed in 18 h at
room temperature. Purification by flash chromatography (70:30
cyclohexane/ethyl acetate) gave 898 mg (85%) of acetylated ox-
azolidine (S,S)-8 as a 39:61 inseparable mixture of cis/trans rota-
tional isomers (in CDCl3 at 298 K): colorless oil; Rf = 0.17 (70:30
cyclohexane/ethyl acetate); [R]22D -53.8 (c 1.7, CHCl3); IR (neat)
2960, 1749, 1678, 1384, 1342, 1281, 1206, 1175, 1147, 1118, 943, 844
(2R,4S)-2-Trifluoromethyloxazolidine-4-N-methylamide (R,S)-7.
To a solution of lithium carboxylate (1.06 g, 5.5 mmol) prepared
acording to the previous procedure from (R,S)-1 in DMF (16 mL)
were successively added at room temperature methylamine hydro-
chloride (631 mg, 1,7 equiv, 9.3 mmol), HOBt (842 mg, 1.13 equiv,
6.23 mmol), NaHCO3 (1.57 g, 3.4 equiv, 18.7 mmol), and EDCI
(1.31 g, 1.2 equiv, 6.8 mmol). The reaction mixture was stirred
overnight at room temperature and then diluted with AcOEt and
water. The layers were separated, and the aqueous phase was
extracted with AcOEt (3 ꢀ 20 mL). The combined organic layers
were dried over MgSO4, filtered, and concentrated under reduced
pressure. Purification by silica gel chromatography (60:40 AcOEt/
cyclohexane) gave (R,S)-7 (776 mg, 71%) as a white solid: mp
cm-1 1H NMR (400 MHz, CDCl3, 298 K) (trans rotational
;
isomer) δ 2.21 (s, 3 H), 3.78 (s, 3 H), 4.24 (d, J = 9.6 Hz, 1 H),
4.50 (dd, J = 9.6, 8.2 Hz, 1 H), 4.55-4.65 (m, 1 H), 5.60 (q, J = 4.6
Hz, 1 H); (cis rotational isomer) δ2.06 (s, 3 H), 3.85 (s, 3 H), 4.38 (d,
J = 7.8 Hz, 1 H), 4.55-4.65 (m, 2 H), 5.87 (q, J = 4.6 Hz, 1 H); 13C
NMR (100.5 MHz, CDCl3, 298 K) (trans rotational isomer) δ 22.3,
52.7, 58.1, 70.5, 84.8 (q, J = 35.4 Hz), 122.9 (q, J = 287.5 Hz),
168.9, 169.9; (cis rotational isomer) δ 22.7, 53.3, 59.0, 72.1, 84.6 (q,
J = 34.5 Hz), 122.9 (q, J = 287.5 Hz), 170.0, 170.2; 19F NMR
(376.2 MHz, CDCl3, 298 K) (trans rotational isomer) δ -81.7 (d,
J = 4.6 Hz); (cis rotational isomer) -81.4 (d, J = 4.6 Hz); MS (EI)
m/z = 241 [Mþ], 182 [Mþ - CO2Me] (50), 172, 140 (100), 130, 112;
HRMS (EI) calcd for C8H10F3NO4 241.0562, found 241.0561.
(2R,4S)-N-Acetyl-2-trifluoromethyloxazolidine-4-carboxylic
Acid Methyl Ester (R,S)-8. The product was prepared by the
acid anhydride procedure using 100 mg of (R,S)-1 (0.50 mmol,
1.0 equiv) in 470 μL of acetic anhydride (5.0 mmol, 10 equiv).
Purification by flash chromatography (70:30 cyclohexane/ethyl
acetate) gave 96 mg (79%) of acetylated oxazolidine (R,S)-8 as a
48:52 inseparable mixture of cis/trans rotational isomers (in CDCl3
at 298 K).
73-75 °C; Rf = 0.13 (3:7 cyclohexane/ethyl acetate); [R]21.4
D
-38.8 (c 0.66, CHCl3); IR (neat) 3450, 3304, 2936, 1654, 1544,
1414, 1287, 1151, 1126 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.84
(d, J = 5.0 Hz, 3 H), 3.32 (t, J = 8.7 Hz, 1 H), 4.07 (dt, J = 8.7, 8.2
Hz, 1 H), 4.21 (t, J = 8.2 Hz, 1 H), 4.29 (t, J = 8.2 Hz, 1 H), 5.00
(dq, J = 8.7, 5.5 Hz, 1 H), 7.19 (m, 1 H); 13C NMR (100.5 MHz,
CDCl3) δ25.9, 59.6, 70.5, 87.6 (q, J= 33.6 Hz), 123.3 (q, J= 283.6
Hz), 171.6; 19F NMR (376.2 MHz, CDCl3) δ -84.2 (d, J = 5.5
Hz); MS (EI) m/z = 140 [Mþ - C(O)NHMe] (100), 112, 92, 58.
Anal. Calcd for C6H9F3N2O2 (198.06): C, 36.67; H, 4.58; N, 14.14.
Found: C, 36.70; H, 4.56; N, 14.36.
Acylation of Oxazolidines 1. Acyl Chloride Procedure. To a
stirred solution of oxazolidine 1 (1 equiv) in dichloromethane at
0 °C were successively added pyridine (3 equiv) and acyl chloride
(3 equiv). The mixture was stirred for 20 h at room temperature.
Dichloromethane was added, and the reaction mixture was
washed with brine. The product was extracted with dichloro-
methane (3ꢀ) and then dried over MgSO4. Purification by flash
chromatography gave the corresponding acylated oxazolidines
8-10 in 74-97% yield.
The product was prepared by the acid anhydride procedure
with iodine catalysis using 910 mg of (R,S)-1 (4.57 mmol, 1.0
equiv), 114 mg of iodine (0.46 mmol, 0.1 equiv), and 4.3 mL of
acetic anhydride (45.7 mmol, 10 equiv). The reaction was
completed in 18 h at room temperature. Purification by flash
chromatography (70:30 cyclohexane/ethyl acetate) gave 953 mg
4142 J. Org. Chem. Vol. 75, No. 12, 2010

Chaume et al.
JOCArticle
(86%) of acetylated oxazolidine (R,S)-8 as a 45:55 inseparable
mixture of cis/trans rotational isomers (in CDCl3 at 298 K):
(R,S)-9 as a 52:48 inseparable mixture of cis/trans rotational
isomers (in CDCl3 at 298 K): colorless oil; Rf = 0.14 (80:20
colorless oil; Rf = 0.16 (70:30 cyclohexane/ethyl acetate); [R]29
cyclohexane/ethyl acetate); [R]28 -63.3 (c 5.0, CHCl3); IR
(neat): 2922, 2853, 1751, 1681, 1175, 1211, 1148, 1116, 684
D
D
-62.9 (c 4.8, CHCl3); IR (neat) 2959, 1751, 1681, 1438, 1390,
1349, 1285, 1212, 1148, 1121, 956, 845, 695 cm-1; 1H NMR (400
MHz, CDCl3, 298 K) (trans rotational isomer) δ 2.22 (s, 3 H),
3.78 (s, 3 H), 4.37 (m, 1 H), 4.50 (m, 1 H), 5.00 (m, 1 H), 5.53 (m, 1
H); (cis rotational isomer) δ 2.22 (s, 3 H), 3.83 (s, 3 H), 4.43-4.58
(m, 2 H), 4.72 (m, 1 H), 5.92 (m, 1 H); 13C NMR (100.5 MHz,
CDCl3, 298 K) (trans rotational isomer) δ 22.2, 52.8, 56.6, 69.4,
85.5 (q, J = 34.5 Hz), 122.8 (q, J = 286.6 Hz), 169.0, 170.1; (cis
rotational isomer) δ 22.2, 53.1, 58.1, 70.5, 84.3 (q, J = 37.4 Hz),
122.8 (q, J = 286.6 Hz), 169.0, 170.1; 19F NMR (376.2 MHz,
CDCl3, 298 K) (trans rotational isomer) δ -82.0 (s); (cis
1
cm-1; H NMR (400 MHz, CDCl3, 298 K) (trans rotational
isomer) δ 1.19 (t, J = 7.0 Hz, 3 H), 2.29-2.54 (m, 2 H), 3.80 (s,
3 H), 4.30-4.54 (m, 2 H), 4.97 (m, 1 H), 5.58 (m, 1 H); (cis
rotational isomer) δ 1.19 (t, J = 7.0 Hz, 3 H), 2.29-2.54 (m,
2 H), 3.80 (s, 3 H), 4.30-4.54 (m, 2 H), 4.70 (m, 1 H), 5.97 (m, 1 H);
13C NMR (CDCl3, 298 K) (trans rotational isomer) δ 8.4, 27.4,
52.9, 56.8, 69.0, 84.3, 122.6 (q, J = 286.6 Hz), 169.0, 172.3; (cis
rotational isomer) δ 8.4, 27.4, 52.9, 57.4, 70.4, 84.3, 122.6 (q, J =
286.6 Hz), 169.0, 173.0; 19F NMR (CDCl3, 298 K) (trans
rotational isomer): δ -81.9 (s); (cis rotational isomer): δ
-82.2 (s); 1H NMR (CDCl3, 323 K) (single rotational isomer)
δ 1.19 (t, J = 7.3 Hz, 3 H), 2.41 (q, J = 7.3 Hz, 2 H), 3.79 (s, 3 H),
4.41 (t, J = 8.7 Hz, 1 H), 4.46 (t, J = 8.7 Hz, 1 H), 4.85 (m, 1 H),
5.75 (m, 1 H); 13C NMR (100.5 MHz, CDCl3, 323 K) (single
rotational isomer) δ 8.4, 27.4, 52.7, 57.3, 69.8, 84.8 (q, J = 36.4
Hz), 122.8 (q, J = 286.6 Hz), 169.0, 172.7; 19F NMR (376,2
MHz, CDCl3, 323 K) (single rotational isomer) δ -81.7 (s); MS
(EI) m/z = 256 [MHþ], 196 [Mþ - CO2Me] (70), 186, 140, 130,
57 (100). Anal. Calcd for C9H12F3NO4 (255.07): C, 42.36; H,
4.74; N, 5.49. Found: C, 42.48; H, 4.55; N, 5.49.
N-Benzoyl-2-trifluoromethyloxazolidine-4-carboxylic Acid
Methyl Ester 10. (2R,4S)-N-Benzoyl-2-trifluoromethyloxazoli-
dine-4-carboxylic Acid Methyl Ester (R,S)-10. The product was
prepared by the acyl chloride procedure using 213 mg of (R,S)-1
(1.07 mmol, 1.0 equiv) in dichloromethane (1.3 mL), 260 μL of
pyridine (3.21 mmol, 3 equiv), and 373 μL of benzoyl chloride
(3.21 mmol, 3 equiv). Purification by flash chromatography
(80:20 cyclohexane/ethyl acetate) gave 321 mg (99%) of ben-
zoylated oxazolidine (R,S)-10 as a colorless oil.
1
rotational isomer) δ -82.2 (s); H NMR (400 MHz, CDCl3,
323 K) (single rotational isomer) δ 2.19 (s, 3 H), 3.79 (s, 3 H),
4.36-4.52 (m, 2 H), 4.85 (m, 1 H), 5.73 (m, 1 H); 13C NMR
(100.5 MHz, CDCl3, 323 K) (single rotational isomer) δ 22.0,
52.8, 57.5, 69.9, 84.8, 122.7 (q, J = 286.6 Hz), 168.9; 19F NMR
(376.2 MHz, CDCl3, 323 K) (single rotational isomer) δ -81.8
(s); MS (EI) m/z = 242 [Mþ þ H], 182 [Mþ - CO2Me] (50), 172,
140 (100), 130, 112. Anal. Calcd for C8H10F3NO4 (241.06): C,
39.84; H, 4.18; N, 5.81. Found: C, 40.08; H, 4.21; N, 5.82.
(2S,4S)-N-Propionyl-2-trifluoromethyloxazolidine-4-carboxy-
lic Acid Methyl Ester (S,S)-9. The product was prepared by the acyl
choride procedure using 150 mg of (S,S)-1 (0.75 mmol, 1.0 equiv)
in dichloromethane (500 μL), 182 μL of pyridine (2.26 mmol, 3
equiv), and 196 μL of propionyl chloride (2.26 mmol, 3 equiv).
Purification by flash chromatography (70:30 cyclohexane/ethyl
acetate) gave 187 mg (97%) of acylated oxazolidine (S,S)-9
as a 40:60 inseparable mixture of cis/trans rotational isomers
(in CDCl3 at 298 K).
The product was prepared by the acid anhydride procedure
using 493 mg of (S,S)-1 (2.47 mmol, 1.0 equiv) in 3.2 mL of
propionic anhydride (24.7 mmol, 10 equiv). Purification by flash
chromatography (80:20 cyclohexane/ethyl acetate) gave 432 mg
(65%) of acylated oxazolidine (S,S)-9 as a 40:60 inseparable
mixture of cis/trans rotational isomers (in CDCl3 at 298 K): white
solid; mp 36-37 °C; Rf = 0.21 (80:20 cyclohexane/ethyl acetate);
[R]28D -50.4 (c 2.85, CHCl3); IR (neat) 2987, 2951, 1741, 1685,
1359, 1275, 1177, 1142, 1114, 991, 939, 846 cm-1; 1H NMR (400
MHz, CDCl3, 298 K) (trans rotational isomer) δ 1.12-1.23 (m,
3 H), 2.37 (m, 1 H), 2.47 (m, 1 H), 3.78 (s, 3 H), 4.22 (d, J = 8.7 Hz,
1 H), 4.49 (t, J = 8.7 Hz, 1 H), 4.59 (m, 1 H), 5.64 (q, J = 4.6 Hz,
1 H); (cis rotational isomer) δ 1.12-1.23 (m, 3 H), 2.15 (m, 1 H),
2.26 (m, 1 H), 3.83 (s, 3 H), 4.37 (m, 1 H), 4.52-4.66 (m, 2 H), 5.89
(q, J = 4.1 Hz, 1 H); 13CNMR(100.5MHz, CDCl3, 298K) (trans
rotational isomer) δ 8.7, 27.8, 52.8, 58.2, 70.3, 84.7 (q, J = 35.5
Hz), 122.9 (q, J = 288.5 Hz), 170.1, 172.5; (cis rotational isomer)
δ 8.7, 28.5, 53.3, 58.4, 72.2, 84.4 (q, J = 36.4 Hz), 122.9 (q, J =
288.5 Hz), 170.4, 173.6; 19F NMR (376.2 MHz, CDCl3, 298 K)
(trans rotational isomer) δ -81.6 (d, J = 4.6 Hz); (cis rotational
isomer): δ -81.4 (d, J = 4.1 Hz); 1H NMR (400 MHz, CDCl3,
323 K) (single rotational isomer) δ 1.18 (td, J = 7.0, 2.5 Hz, 3 H),
2.20-2.50 (m, 2 H), 3.79 (s, 3 H), 4.26(m, 1 H), 4.50 (m, 1 H), 4.58
(m, 1 H), 5.66 (m, 1 H); 13C NMR (100.5 MHz, CDCl3, 323 K)
(single rotational isomer) δ 8.7, 28.1, 52.9, 58.5, 70.8 and 72.1,
84.9 (q, J = 30.7 Hz), 123.1 (q, J = 288.5 Hz), 170.2, 172.8 and
173.1; 19F NMR (376.2 MHz, CDCl3, 323 K) (single rotational
A stirred solution of 98 mg of (R,S)-1 (0.49 mmol, 1.0 equiv)
in 60 μL of benzoyl chloride (0.51 mmol, 1.05 equiv) at room
temperature was warmed to 100 °C for 1 h. The reaction mixture
was then cooled to room temperature, and the resulting crude
was directly purified by flash chromatography (80:20 cyclohex-
ane/ethyl acetate) to give 143 mg (96%) of benzoylated oxazo-
lidine (R,S)-10 as a colorless oil.
A stirred solution of 300 mg of (S,S)-1 (1.5 mmol, 1.0 equiv) in
184 μL of benzoyl chloride (1.58 mmol, 1.05 equiv) at room
temperature was warmed to 100 °C for 1 h. The reaction mixture
was then cooled to room temperature, and the resulting crude
was directly purified by flash chromatography (90:10 cyclohexane/
ethyl acetate) to give 412 mg (90%) of benzoylated oxazolidine
(R,S)-10 as a colorless oil.
(R,S)-10: colorless oil; Rf = 0.21 (80:20 cyclohexane/ethyl
acetate); [R]28D -44.4 (c 6.8, CHCl3); IR (neat) 2959, 1746, 1670,
1447, 1361, 1284, 1178, 1146 cm-1; 1H NMR (400 MHz, CDCl3)
δ 3.81 (s, 3 H), 4.30 (t, J = 8.7 Hz, 1 H), 4.50 (dd, J = 8.7, 4.1 Hz,
1 H), 4.86 (m, 1 H), 5.94 (m, 1 H), 7.44 (t, J = 7.8 Hz, 2 H), 7.51
(t, J = 7.8 Hz, 1 H), 7.61 (d, J = 7.8 Hz, 2 H); 13C NMR (100.5
MHz, CDCl3) δ 52.9, 58.9, 69.9, 85.1 (q, J = 35.5 Hz), 122.4 (q,
J = 285.6 Hz), 127.2, 128.7, 131.3, 134.1, 169.2, 171.3; 19F NMR
(376.2 MHz, CDCl3) δ -81.2 (s); MS (EI) m/z = 303 [Mþ], 234,
105 (100), 77. Anal. Calcd for C13H12F3NO4 (303.07): C, 51.49;
H, 3.99; N, 4.62. Found: C, 51.42; H, 3.99; N, 4.62.
(2S,4S)-N-Benzoyl-2-trifluoromethyloxazolidine-4-carboxylic
Acid Methyl Ester (S,S)-10. To a stirred solution of 106 mg of (S,
S)-1 (0.53 mmol, 1.0 equiv) in THF (3.5 mL) were successively
added 148 μL of Et3N (1.06 mmol, 2.0 equiv) and 123 μL of
benzoyl chloride (1.06 mmol, 2.0 equiv) at room temperature.
The reaction mixture was warmed to reflux for 18 h, cooled to
room temperature, and evaporated. The resulting crude was
purified by flash chromatography (90:10 petroleum ether/
ethyl acetate) to give 45 mg (28%) of (S,S)-10 and 52 mg
(32%) of (R,S)-10.
isomer) δ -81.8 (s); MS (EI) m/z = 255 [Mþ], 196 [Mþ
-
CO2Me] (70), 186, 140, 130, 57 (100); HRMS (EI) calcd for
C9H12F3NO4 255.0718, found 255.0726.
(2R,4S)-N-Propionyl-2-trifluoromethyloxazolidine-4-carboxy-
lic Acid Methyl Ester (R,S)-9. The product was prepared by the
acid anhydride procedure using 115 mg of (R,S)-1 (0.57 mmol,
1.0 equiv) in 740 μL of propionic anhydride (5.7 mmol, 10 equiv).
Purification by flash chromatography (90:10 cyclohexane/
ethyl acetate) gave 130 mg (89%) of acylated oxazolidine
J. Org. Chem. Vol. 75, No. 12, 2010 4143

Chaume et al.
JOCArticle
(S,S)-10: white solid; mp 93-94 °C; Rf = 0.42 (75:25 cyclo-
hexane/ethyl acetate); [R]25D -173.3 (c 0.95, CHCl3); IR (neat)
3009, 2961, 2924, 2857, 1742, 1677, 1181, 1147, 1104, 1059, 844,
724 cm-1; 1H NMR (400 MHz, CDCl3) δ 3.55 (s, 3 H), 4.34 (d
J = 9.2 Hz, 1 H), 4.63 (dd, J = 9.2, 7.3 Hz, 1 H), 4.75 (d, J = 7.3
Hz, 1 H), 6.14 (m, 1 H), 7.42 (t, J = 6.9 Hz, 2 H), 7.49 (t, J = 6.9
Hz, 1 H), 7.58 (d, J = 6.9 Hz, 2 H); 13C NMR (100.5 MHz,
CDCl3) δ 53.0, 60.2, 72.2, 84.8 (q, J = 36.4 Hz), 123.0 (q, J =
288.5 Hz), 127.6, 128.6, 131.5, 134.7, 169.8, 170.8; 19F NMR
(376.2 MHz, CDCl3) δ -82.5 (s); MS (EI) m/z = 303 [Mþ], 244,
234, 105 (100), 77; HRMS (EI) calcd for C13H12F3NO4
303.0718, found 303.0729.
The combined organic layers were dried over MgSO4, filtered,
and concentrated under reduced pressure. Purification by flash
chromatography (96:4 dichloromethane/methanol) gave 80 mg
(21%) of oxazolidine (S,S)-12 as a 40:60 inseparable mixture of
cis/trans rotational isomers (in CDCl3 at 298 K): white solid; mp
198-203 °C; Rf = 0.38 (96:4 ethyl acetate/methanol); [R]25
D
-10.3 (c 0.85, MeOH); IR (neat) 3245, 3099, 2925, 1669, 1648,
1
1582, 861 cm-1; H NMR (400 MHz, CDCl3, 298 K) (trans
rotational isomer) δ 2.21 (s, 3 H), 2.86 (d, J = 4.8 Hz, 3 H);
4.30-4.45 (m, 3 H), 5.62 (q, J = 4.8 Hz, 1 H), 5.84 (m, 1 H); (cis
rotational isomer) δ 2.10 (s, 3 H), 2.90 (d, J = 4.8 Hz, 3 H),
4.30-4.45 (m, 2 H), 4.59 (t, J = 7.8 Hz, 1 H), 5.84 (m, 1 H), 5.98
(q, J = 5.2 Hz, 1 H); 13C NMR (100.5 MHz, CDCl3, 233 K)
(trans rotational isomer) δ 22.9, 26.7, 59.0, 71.0, 84.7 (q, J =
34.5 Hz), 122.7 (q, J = 288.5 Hz), 169.3, 169.6; (cis rotational
isomer) δ 23.2, 26.8, 60.0, 73.0, 84.1 (q, J = 34.5 Hz), 122.5 (q,
J = 288.5 Hz), 168.9, 169.7; 19F NMR (376.2 MHz, CDCl3, 298
K) (trans rotational isomer) δ -81.3 (d, J = 4.8 Hz); (cis rota-
tional isomer) δ -80.5 (d, J=5.2 Hz); MS (EI) m/z=240 [Mþ],
183 (100), 140, 58; HRMS (EI) calcd for C8H11F3N2O3
240.0722, found 240.0718.
Acylation of Oxazolidines 3maj. (4S)-N-Acetyl-2-trifluoro-
methyl-2-methyloxazolidine-4-carboxylic Acid Methyl Ester
(11). The product was prepared by the acid anhydride procedure
using 244 mg of the diastereomer 3maj (1.14 mmol, 1.0 equiv), 29
mg of iodine (0.11 mmol, 0.1 equiv), and 1.1 mL of acetic
anhydride (11.44 mmol, 10 equiv). The reaction was completed
in 40 h at room temperature. Purification by flash chromatog-
raphy (70:30 cyclohexane/ethyl acetate) gave 161 mg (55%) of
the N-acetylated oxazolidine 11 as a 31:69 inseparable mixture
of cis/trans rotational isomers (in CDCl3 at 298 K): colorless oil;
(2R,4S)-N-acetyl-2-trifluoromethyloxazolidine-4-N-methyl-
amide (R,S)-12. To a solution of 953 mg of (R,S)-8 (3.95 mmol)
in THF (20 mL) at 0 °C was added a 1 M aqueous solution of
4.35 mL of LiOH (4.35 mmol, 1.1 equiv). The reaction mixture
was stirred vigorously for 2 h. Subsequently, Et2O (15 mL) was
added, and the reaction mixture was extracted with water (2 ꢀ
15 mL). Aqueous layers were combined, and water was removed
under reduced pressure to afford 819 mg of the corresponding
lithium carboxylate as a 75:25 inseparable mixture of rotational
isomers (in D2O at 298 K) directly used in the next step without
Rf = 0.33 (75:25 cyclohexane/ethyl acetate); [R]26 -31.2
D
(c 0.95, CHCl3); IR (neat) 2959, 2922, 1749, 1685, 1380, 1341,
1176 cm-1 1H NMR (400 MHz, CDCl3) (trans rotational
;
isomer) δ 1.90 (s, 3 H), 2.07 (s, 3 H), 3.85 (s, 3 H), 4.26 (dquint,
J=9.2, 1.4 Hz, 1 H), 4.41 (ddq, J=9.2, 6.9, 1.4 Hz, 1 H), 4.58
(dd, J = 6.9, 1.4 Hz, 1 H); (cis rotational isomer) δ 1.93 (s, 3 H),
2.27 (s, 3 H), 3.78 (s, 3 H), 4.10 (dquint, J = 9.4, 1.4 Hz, 1 H), 4.34
(ddq, J = 9.4, 7.3, 1.4 Hz, 1 H), 4.77 (dd, J=7.3, 1.4 Hz, 1 H); 13
C
NMR (100.5 MHz, CDCl3) (trans rotational isomer) δ 18.4, 24.1,
53.2, 60.4, 69.1, 93.9 (q, J = 31.6 Hz), 123.9 (q, J = 291.4 Hz),
168.3, 170.6; (cis rotational isomer) δ 20.3, 22.3, 52.7, 60.6, 67.5,
1
further purification: H NMR (400 MHz, D2O) (major rota-
tional isomer) δ 1.95 (s, 3 H), 4.12 (ddq, J = 8.2, 6.9, 1.4 Hz, 1
H), 4.39 (ddq, J = 8.7, 8.2, 1.4 Hz, 1 H), 4.52 (dd, J = 8.7, 6.9
Hz, 1 H), 5.69 (q, J = 5.5 Hz, 1 H); (minor rotational isomer) δ
2.00 (s, 3 H), 4.03 (ddq, J = 8.2, 4.1, 1.4 Hz, 1 H), 4.33 (ddq, J =
8.7, 8.2, 1.4 Hz, 1 H), 5.04 (dd, J = 8.7, 4.1 Hz, 1 H), 5.73 (q, J =
5.2 Hz, 1 H); 19F NMR (376.2 MHz, D2O) (Major rotational
isomer) δ -81.5 (dt, J = 5.5, 1.4 Hz); (minor rotational isomer)
δ -81.4 (dt, J = 5.2, 1.4 Hz).
91.6 (q, J = 31.6 Hz), 124.1 (q, J = 290.4 Hz), 168.8, 170.6; 19
F
NMR (376.2 MHz, CDCl) (trans rotational isomer) δ -80.9 (d,
J = 1.4 Hz); (cis rotational isomer) δ -82.0 (d, J = 1.4 Hz); MS
(EI) m/z = 255 [Mþ], 154 (100), 126, 69; HRMS (EI) calcd for
C9H12F3NO4 255.0718, found 255.0720.
Synthesis of N-Acetyl-2-trifluoromethyloxazolidine-4-N-methyl-
amides (12). (2S,4S)-N-Acetyl-2-trifluoromethyloxazolidine-4-
N-methylamide (S,S)-12. To a solution of 638 mg of (S,S)-8
(2.65 mmol) in THF (15 mL) at 0 °C was added a 1 M aqueous
solution of 2.91 mL of LiOH (2.91 mmol, 1.1 equiv). The
reaction mixture was stirred vigorously for 4 h. Subsequently,
Et2O (10 mL) was added, and the reaction mixture was extracted
with water (2ꢀ10 mL). Aqueous layers were combined, and
water was removed under reduced pressure to afford 616 mg of
the corresponding lithium carboxylate as a 78:22 inseparable
mixture of rotational isomers (in D2O at 298 K) directly used in
next step without further purification: 1H NMR (400 MHz,
D2O) (minor rotational isomer) δ 2.03 (s, 3 H), 4.22 (dd, J = 8.2,
2.3 Hz, 1 H), 4.34-4.44 (m, 2 H), 5.82 (q, J = 4.1 Hz, 1 H);
(major rotational isomer) δ 1.88 (s, 3 H), 4.15 (dd, J = 7.8, 1.4
Hz, 1 H), 4.34-4.44 (m, 2 H), 5.72 (q, J = 5.2 Hz, 1 H); 13C
NMR (100.5 MHz, D2O) (minor rotational isomer) δ 21.9, 60.2,
72.1, 84.5 (q, J = 35.5 Hz), 123.0 (q, J = 274 Hz), 172.1, 176.5;
(major rotational isomer) δ 22.3, 61.1, 73.4, 84.2 (q, J = 37.4
Hz), 122.9 (q, J = 277 Hz), 174.3, 176.7; 19F NMR (376.2 MHz,
D2O) (minor rotational isomer) δ -81.6 (d, J = 4.1 Hz); (major
rotational isomer) δ -81.2 (d, J = 5.2 Hz).
To a solution of lithium carboxylate (819 mg, 3.51 mmol) in
DMF (7 mL) were successively added at room temperature
methylamine hydrochloride (356 mg, 1,5 equiv, 5.27 mmol),
HOBt (474 mg, 1 equiv, 3.51 mmol), NaHCO3 (885 mg, 3 equiv,
10.54 mmol), and EDCI (741 mg, 1.1 equiv, 3.86 mmol). The
reaction mixture was stirred overnight at room temperature and
then diluted with AcOEt and water. The layers were separated,
and the aqueous phase was extracted with AcOEt (3 ꢀ 10 mL).
The combined organic layers were dried over MgSO4, filtered,
and concentrated under reduced pressure. Purification by flash
chromatography (96:4 dichloromethane/methanol) gave 739
mg (88%) of oxazolidine (R,S)-12 as a 33:66 inseparable mixture
of cis/trans rotational isomers (in CDCl3 at 298 K): colorless oil;
Rf = 0.50 (96:4 ethyl acetate/methanol); [R]25 -60.3 (c 0.9,
D
CHCl31); IR (neat) 3291, 3080, 2917, 1666, 1542, 1052, 1026
cm-1; H NMR (400 MHz, CDCl3, 298 K) (trans rotational
isomer) δ 2.25 (bs, 3 H), 2.82 (bs, 3 H), 4.20-4.95 (m, 3 H), 5.68
(bs, 1 H), 6.92 (bs, 1 H); (cis rotational isomer) δ 2.25 (bs, 3 H),
2.82 (bs, 3 H); 4.20-4.95 (m, 3 H), 5.84 (bs, 1 H), 7.21 (bs, 1 H);
13C NMR (100.5 MHz, CDCl3, 298 K) (trans rotational isomer)
δ 22.0, 25.9, 57.5, 68.7, 85.0 (bs), 122.4 (q, J = 286.6 Hz), 168.4,
171.1; (cis rotational isomer) δ 22.0, 25.9, 60.0, 71.4, 85.0 (bs),
122.4 (q, J = 286.6 Hz), 168.4, 171.1; 19F NMR (376.2 MHz,
CDCl3, 298 K) (trans rotational isomer) δ -82.0 (s); (cis
To a solution of lithium carboxylate (373 mg, 1.60 mmol) in
DMF (8 mL) were successively added at room temperature
methylamine hydrochloride (162 mg, 1,5 equiv, 2.40 mmol),
HOBt (216 mg, 1 equiv, 1.60 mmol), NaHCO3 (403 mg, 3 equiv,
4.80 mmol), and EDCI (338 mg, 1.1 equiv, 1.76 mmol). The
reaction mixture was stirred overnight at room temperature and
then diluted with AcOEt and water. The layers were separated,
and the aqueous phase was extracted with AcOEt (3 ꢀ 10 mL).
1
rotational isomer) δ -81.1 (s); H NMR (400 MHz, CDCl3,
323 K) (single rotational isomer) δ 2.23 (bs, 3 H), 2.82 (bs, 3 H),
4.42 (bs, 1 H), 4.56 (bs, 1 H), 4.77 (bs, 1 H), 5.72 (bs, 1 H), 6.86
(bs, 1 H); 1H NMR (400 MHz, DMSO-d6, 298 K) (trans
4144 J. Org. Chem. Vol. 75, No. 12, 2010

Chaume et al.
JOCArticle
rotational isomer) δ 2.05 (bs, 3 H), 2.64 (bs, 3 H), 4.17 (bs,
1 H), 4.42 (bs, 1 H), 4.77 (bs, 1 H), 5.83 (bs, 1 H), 8.0 (bs, 1 H);
(cis rotational isomer) δ 2.15 (bs, 3 H), 2.61 (bs, 3 H); 4.17 (bs,
1 H), 4.42 (bs, 1 H), 4.70 (bs, 1 H), 6.10 (bs, 1 H), 7.73 (bs, 1 H);
13C NMR (100.5 MHz, DMSO-d6, 298 K) (trans rotational
isomer) δ 22.4, 25.8, 59.5, 71.2, 84.2 (q, J = 32.6 Hz), 123.0 (q,
J = 285.6 Hz), 168.4, 171.2; (cis rotational isomer) δ 22.4, 25.8,
58.1, 69.6, 85.0 (q, J = 34.5 Hz), 123.1 (q, J = 286.6 Hz), 168.4,
170.5; 1H NMR (400 MHz, DMSO-d6, 363 K) (single rotational
isomer) δ2.38(bs, 3H), 2.92(bs, 3H), 4.48(t, J= 7.3 Hz, 1 H), 4.69
(t, J = 7.3 Hz, 1 H), 5.01 (t, J = 7.3 Hz, 1 H), 6.19 (q, J = 5.0 Hz,
1 H), 7.93 (bs, 1 H); MS (EI) m/z = 240 [Mþ], 183 (100), 140;
HRMS (EI) calcd for C8H11F3N2O3 240.0722, found 240.0719.
Synthesis of o-Nbs-Ala-Ser(ΨCF3,Hpro)-OMe (13). To a sus-
pension of o-Nbs-L-alanine (1.3 g, 4.74 mmol, 7.0 equiv) in
DCM (4.8 mL) under argon at 0 °C was added 1-bromo-N,N-2-
trimethyl-1-propenylamine (628 μL, 4.74 mmol, 7.0 equiv). The
resulting solution was stirred at 0 °C until the disappearance of
the precipitate (usually 20 min). The total conversion of the
acids to chlorides was checked by TLC after quenching. When
the conversion was complete, the solution of amino acid chlor-
ide was added via cannula to a neat mixture of (R,S)-1 pseudo-
proline (135 mg, 0.68 mmol, 1.0 equiv) and collidine (0.68 mmol,
1.0 equiv) at 0 °C. The temperature was allowed to warm to
room temperature, and the solution was concentrated twice
using a stream of argon. After 24 h, the resulting mixture was
diluted with DCM and quenched with a saturated aqueous
solution of NaHCO3. The layers were separated, and the aqu-
eous layer was extracted with DCM (3 ꢀ ). The combined
organic layers were washed with water, dried over MgSO4,
filtered, and evaporated under reduced pressure. The crude
73:27 mixture of diastereomers was purified by flash chromato-
graphy (70:30 cyclohexane/ethyl acetate) to give 70 mg (22%) of
the minor (S,S)-13 diastereomer and 210 mg (68%) of the major
(R,S)-13 diastereomer as a 47:53 inseparable mixture of cis/trans
rotational isomers in CDCl3.
isomer): δ 1.27 (d, J = 5.5 Hz, 3 H), 3.67 (bs, 3 H), 4.13-4.68 (m,
3 H), 5.15-5.27 (m, 1 H), 5.80-5.92 (m, 1 H), 7.75-7.95 (m,
2 H), 7.98-8.10 (m, 2 H), 8.98-9.12 (m, 1 H); 13C NMR (100.5
MHz, DMSO-d6, 298 K) (trans rotational isomer) δ 18.3, 50.9,
52.6, 56.9, 69.8, 83.7 (q, J=36.4 Hz), 122.3 (q, J=279.9 Hz),
124.3, 129.5, 132.6, 133.1, 134.2, 147.3, 168.8, 170.8; (cis rota-
tional isomer) δ 19.3, 51.9, 52.6, 57.8, 70.7, 84.7 (q, J = 36.4 Hz),
122.3 (q, J = 279.9 Hz), 124.3, 129.5, 132.6, 133.5, 133.8, 147.3,
168.7, 170.8; 19F NMR (376.2 MHz, DMSO-d6, 298 K) (trans
rotational isomer) δ -80.9 (s); (cis rotational isomer) δ -81.7
1
(s); H NMR (400 MHz, DMSO-d6, 363 K) (single rotational
isomer) δ 1.31 (d, J = 6.9 Hz, 3 H), 3.71 (s, 3 H), 4.32-4.51
(m, 3 H), 5.01-5.10 (m, 1 H), 5.89-5.99 (m, 1 H), 7.84-7.92
(m, 2 H), 7.94-8.00 (m, 1 H), 8.06-8.11 (m, 1 H), 8.38-8.52
(m, 1 H); 13C NMR (100.5 MHz, DMSO-d6, 363 K) (single
rotational isomer) δ 17.6, 50.2, 52.0, 56.5, 68.9, 83.6 (q, J = 35.5
Hz), 122.1 (q, J = 287.5 Hz), 123.9, 129.2, 132.1, 133.2, 133.6,
147.0, 168.1, 170.3; 19F NMR (376.2 MHz, DMSO-d6, 363 K)
(single rotational isomer) δ -80.7 (s). Anal. Calcd for C15H16-
F3N3O8S (455.06): C, 39.56; H, 3.54; N, 9.23. Found: C, 39.45;
H, 3.47; N, 8.99.
(S,S)-13 minor diastereomer: colorless oil; Rf = 0.41 (50:50
cyclohexane/ethyl acetate); 1H NMR (400 MHz, CDCl3, 323 K)
(single rotational isomer) δ 1.43 (d, J = 6.9 Hz, 3 H), 3.82 (s, 3
H), 4.43 (dq, J = 8.7, 6.9 Hz, 1 H), 4.57 (d, J = 6.4 Hz, 2 H), 5.16
(t, J = Hz, 6.4 Hz, 1 H), 5.56 (q, J = 5.0 Hz, 1 H), 6.15 (d, J =
8.7 Hz, 1 H), 7.70-7.75 (m, 2 H), 7.88-7.92 (m, 2 H); 13C NMR
(100.5 MHz, CDCl3, 323 K) (single rotational isomer) δ 18.7,
51.3, 53.4, 57.2, 70.4, 84.0 (q, J = 36.4 Hz), 122.4 (q, J = 286.6
Hz), 125.8, 129.6, 133.0, 134.1, 134.3, 147.4, 168.7, 171.2; 19F
NMR (376.2 MHz, CDCl3, 323 K) (single rotational isomer) δ
-82.3 (d, J = 5.0 Hz).
Acknowledgment. We thank the CNRS for the grant to
O.B. and Central Glass Co. for financial support and the
gift of trifluoroacetaldehyde hemiacetal. We also thank the
French Fluorine Network.
(R,S)-13 major diastereomer: white solid; mp 182-183 °C;
Rf = 0.30 (60:40 cyclohexane/ethyl acetate); [R]24.0D -122.5 (c
1.8, CHCl3); IR (neat) 3300, 3107, 1730, 1677, 1535, 1440, 1154
cm-1; 1H NMR (400 MHz, DMSO-d6, 298 K) (trans rotational
isomer) δ 1.27 (d, J = 5.5 Hz, 3 H), 3.67 (bs, 3 H), 4.13-4.68 (m,
3 H), 4.86-5.00 (m, 1 H), 6.08-6.21 (m, 1 H), 7.75-7.95 (m,
2 H), 7.98-8.10 (m, 2 H), 8.62-8.78 (m, 1 H); (cis rotational
Supporting Information Available: General experimental
information and proton, fluorine, and carbon NMR spectra for
all new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 12, 2010 4145