Chiral 4-phenyl-2-trifluoromethyloxazolidine: A high-performance chiral auxiliary for the alkylation of amides

Article abstract of DOI:10.1002/anie.200600738

(Chemical Equation Presented) A bit on the side: Extremely high diastereoselectivities (> 99% de) were attained in the α-alkylation and -allylation of amides by using a trifluoromethylated (sphere) oxazolidine as a chiral auxiliary. Reductive cleavage of the amide bond led to the recovery of this fluorinated chiral auxiliary in high yield.

Full text of DOI:10.1002/anie.200600738

Angewandte
Chemie
Asymmetric Synthesis
DOI: 10.1002/anie.200600738
Chiral 4-Phenyl-2-trifluoromethyloxazolidine:
A High-Performance Chiral Auxiliary for the
Alkylation of Amides**
Arnaud Tessier, Julien Pytkowicz, and Thierry Brigaud*
Chiral-auxiliary-based alkylation at the a-position of amides
remains the strategy of choice for the preparation of various
building blocks useful for the synthesis of bioactive com-
pounds. Oxazolidinones[1] and related heterocyclic struc-
tures,[2] sultames,[3] and amino alcohols, such as pseudoephe-
drine,[4] count among the most efficient chiral auxiliaries
reported. The use of oxazolidines as chiral auxiliaries for the
diastereoselective alkylation of amide enolates has rarely
been reported.[5] This is probably due to the harsh reaction
conditions required for the removal of the aminoacetal
functional group and its low stability. Although the introduc-
tion of fluorine atoms into molecules dramatically perturbs
their physical and chemical properties,[6] little is known about
the use of fluorine-containing chiral auxiliaries in asymmetric
synthesis.[7] Chiral 2-trifluoromethyloxazolidines were first
reported by Mikami and co-workers[8] and have recently
found several applications as synthons in the stereoselective
synthesis of chiral trifluoromethylated amines and amino
acids.[9] We now report their use as chiral auxiliaries for highly
diastereoselective alkylation reactions of amide enolates. The
introduction of the trifluoromethyl group in the 2-position of
the oxazolidine ring is intended to increase its stability to
hydrolysis and to enable the chiral auxiliary to be recovered.
Unique effects of the fluorinated group on the diastereose-
lectivity are also expected.
The starting N-acyloxazolidines 2a–d and 3a–d were
conveniently prepared by an acylation reaction of a diaste-
reomeric mixture of the corresponding 2-trifluoromethylox-
azolidines 1[8a] (Scheme 1). The separation of (2S,4R)-1 and
(2R,4R)-1 was quite difficult. However, after the acylation
reaction, the separation of both the 2,4-trans and 2,4-cis
diastereomers was achieved very efficiently by chromatog-
raphy on silica gel (eluent: cyclohexane/ethyl acetate, 9:1).
With this eluent system, the Rf value of each acylated
diastereomer varied from 0.13 to 0.23. Each diastereomer
[*] A. Tessier, Dr. J. Pytkowicz, Prof. Dr. T. Brigaud
Laboratoire “Synth›se Organique SØlective et Chimie Organo-
mØtallique” (SOSCO)
UMR CNRS 8123, UniversitØ de Cergy-Pontoise
5 Mail Gay-Lussac, Neuville sur Oise
95031 Cergy-Pontoise cedex (France)
Fax: (+33)134-257-071
E-mail: thierry.brigaud@chim.u-cergy.fr
[**] We thank the French ministry of research for awarding a research
fellowship to A.T. and the Central Glass Company for the generous
gift of trifluoroacetaldehyde hemiacetal.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 2: Diastereoselective alkylation reactions of N-acyl oxazolidines
2a–d.
Entry
Substrate
R2X
Product
Yield [%][a]
de [%]
1
2
3
4
5
6
7
8
9
2a, R1 =Me
2a, R1 =Me
2a, R1 =Me
2a, R1 =Me
2a, R1 =Me
2a, R1 =Me
2b, R1 =Bn
2c, R1 =iPr
2d, R1 =tBu
EtI[b]
(S)-5a
(S)-6a
(S)-7a
(S)-7a
(S)-8a
(S)-9a
(R)-4a
(R)-4c
(R)-4d
78
88
>99[c]
>98[d]
54[e]
allylBr[b]
MOMBr[b]
MOMBr[b,f]
iBuI[h]
Scheme 1. Synthesis of N-acyl oxazolidines 2a–d and 3a–d. pyr=pyr-
idine.
60[e]
50[e]
74
90[g]
>99[c]
>99[c]
>99[c]
>99[c]
>99[c]
iPrI[i]
76[j]
78
MeI[b]
2a–d and 3a–d was then obtained in good yield as the pure
isolated product.
The benzylation of the Z enolate using the 2,4-trans-
oxazolidine (2S,4R)-1 as the chiral auxiliary, performed under
standard conditions, occurred in good yield and with complete
diastereoselectivity (Table 1). The S configuration of the new
BnBr[b]
BnBr[k]
71
56[l]
[a] Yield of isolated product. [b] Condiditions: 1.9 equivalents, À788C, 2–
6 h. [c] One single diastereomer was detected by GC analysis of the crude
reaction mixture. [d] One single diastereomer was detected by 19F and
1H NMR spectroscopic analysis of the crude reaction mixture. [e] Con-
version of 2a=66%. [f] Reaction performed in the presence of DMPU as
a cosolvent. [g] GC analysis of the crude reaction mixture. [h] Conditions:
4 equivalents, À558C, 24 h. [i] Conditions: 8 equivalents, À558C, 35 h.
[j] Conversion=95%. [k] Conditions: 4 equivalents, À558C, 35 h. [l] Con-
version=62%.
Table 1: Highly diastereoselective benzylation of N-propanoyl oxazoli-
dine 2a.
proceeded through the methylation reaction of 3-phenyl-
propanoylamide (2b; entry 7). This result highlights the great
potential of this (R)-phenylglycinol-based fluorinated oxazo-
lidine as a chiral auxiliary for asymmetric alkylation reactions.
The benzylation of the isopropyl-substituted amide 2c was
performed under standard conditions to give (R)-4c in good
yield with a total diastereoselectivity (entry 8). The benzyla-
tion of the more hindered tert-butyl-substituted amide 2d
occurred also with complete diastereoselectivity, but required
a higher temperature (À558C), a longer reaction time, and
4 equivalents of alkyl halide (entry 9).
The complete diastereoselectivity of the alkylation reac-
tions was confirmed by epimerization reactions of 4–6a, 8,
and 9a (Scheme 2).[10] These side-chain epimers were not
detected by GC or NMR spectroscopic analysis of the crude
mixture of the alkylation reaction.
Entry
Base[a]
Yield [%][b]
de [%][c]
1
2
3
LiHMDS
NaHMDS
KHMDS
82
85
63
>99 (S)
>99 (S)
>99 (S)
[a] 1.9 equivalents. [b] Yield of the isolated product. [c] One single
diastereomer was detected by GC analysis of the crude reaction mixture.
stereogenic center was assigned after removal of the chiral
auxiliary (see below). LiHMDS, NaHMDS, and KHMDS
(HMDS = hexamethyldisilazane) proved to be the most
suitable bases for this reaction. Difluoromethylene com-
pounds that resulted from a base-mediated dehydrofluorina-
tion were detected as side products when lithium diisopropy-
lamide (LDA) was used.
The NaHMDS-promoted alkylation of 2a was then
performed with various halogenated derivatives (Table 2).
The alkylation was completely diastereoselective with ethyl
iodide and allyl bromide (entries 1 and 2). The conversion and
the stereoselectivity decreased when methoxymethyl (MOM)
bromide was used (entry 3). However, the stereoselectivity
could be raised up to 90% de by adding 1,3-dimethyltetrahy-
dro-2-pyrimidinone (DMPU) as a cosolvent (entry 4). The
reaction of 2a with more hindered branched alkyl halides,
such as isobutyl iodide (entry 5) and isopropyl iodide
(entry 6), occurred in good yield and was also completely
stereoselective. However, with these less reactive electro-
philes, the reaction had to be performed at higher temper-
ature (À558C) with longer reaction times and with 4–
8 equivalents of alkyl halide. The influence of various
substituents on the amide moiety was then investigated. The
(R)-4a epimer was also obtained in good yield with complete
diastereoselectivity by the complementary strategy which
Scheme 2. Epimerization reactions of 4–6a, 8, and 9a.
The results of the alkylation reactions using the 2,4-cis-
oxazolidine (2R,4R)-1 as the chiral auxiliary were somewhat
disappointing (Scheme 3). The stereoselectivity of the benzy-
lation of 3a was very low and no stereoselectivity was induced
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Scheme 3. Alkylation reactions of N-propanoyl oxazolidines 3a,b.
during the methylation of 3b. It is worthwhile noting that the
same major S diastereomer was obtained from the benzyla-
tion of (2S,4R)-2a and (2R,4R)-3a. This underlines the
preponderant influence of the configuration at C4 in the
chiral auxiliary on the stereoselective induction. The pseudo-
C2 symmetry of the 2,4-trans-oxazolidine could be an
explanation of its high performance as a chiral auxiliary.
With this auxiliary, the same diastereotopic face of the enolate
Scheme 5. Removal of the chiral auxiliary from (S)-4a, thus selectively
giving aldehyde 13 in enantiomerically pure form.
À
is shielded around the C1 N3 bond in both major conforma-
tions.
the reduction of the oxazolidine ring occurred. The key
intermediate of this reaction should be an aluminum hemi-
acetal, which is stable under the reaction conditions. The
corresponding hemiacetal is then hydrolyzed[15] to give the
expected aldehyde and the fluorinated oxazolidine in high
yield. The hydrolysis should be performed under neutral
rather than acidic conditions to avoid epimerization. As the
aldehyde 13 could be quantitatively reduced into alcohol 11
and the chiral auxiliary was very efficiently recovered, this
two-step procedure proved to be more efficient than the
direct reduction of (S)-4a with LiH2NBH3.
Key features of the use of this fluorinated oxazolidine as a
chiral auxiliary that warrant future synthetic study are its
removal and recovery. As all the standard methods known for
the hydrolysis of amide bonds in acidic or basic media failed
to give the corresponding carboxylic acid or caused epime-
rization, we examined reductive conditions. First lithium
amidotrihydroborate (LiH2NBH3),[11] which transforms ter-
tiary amides into the corresponding primary alcohols, was
used (Scheme 4). With this reagent, the expected S alcohol 11
The corresponding enantiopure carboxylic acid (S)-14[16]
was also obtained in high yield and enantiomeric excess from
(S)-4a in a two-step procedure, which involved the reduction
of (S)-4a with LiAlH4 followed by the oxidation of the
aldehyde (Scheme 6). The chiral auxiliary was recovered in
97% yield.
Scheme 4. Removal of the chiral auxiliary from (S)-4a with LiH2NBH3.
was obtained in enantiomerically pure form,[12] provided that
the reaction was performed at 08C.[13] Unfortunately, the
chiral auxiliary 1 was only recovered in 49% yield and the
amino alcohol 12 that resulted from the reduction of the
oxazolidine 1 was obtained in 20% yield.
Scheme 6. Removal of the chiral auxiliary from (S)-4a, thus selectively
giving carboxylic acid 14 in enantiomerically pure form.
This over-reduction of the chiral auxiliary could be easily
avoided by using LiAlH4 (Scheme 5). Under these conditions,
aldehyde 13 was selectively obtained in good yield without
any epimerization when the hydrolysis step was performed in
a neutral medium. The S configuration of 13 was assigned by
comparison with literature data[14] of the Mosher ester of the
alcohol 11 obtained by quantitative reduction of 13 with
LiAlH4. The chiral auxiliary (2S,4R)-1 was very efficiently
recovered in 90% yield. It is important to note that neither
the complete reduction of the amide group into an amine nor
In summary, we have reported the use of a 2-trifluoro-
methyloxazolidine as a chiral auxiliary for the first time.
Alkylation reactions of the corresponding amides occurred
with extremely high diastereoselectivity. As representative
target molecules, (S)-a-methylbenzenepropanal, (S)-b-meth-
ylbenzenepropanol, and (S)-a-methylbenzenepropanoic acid
were obtained in high yield in enantiopure form. Moreover,
the highly stable fluorinated oxazolidine was conveniently
recovered in high yield. Further investigations into under-
standing the extremely high diastereoselectivity and other
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Experimental Section
General procedure for the alkylation reactions: The oxazolidine 2a–c
(1.19 mmol) was dissolved in THF (10 mL) under argon and cooled
down to À788C. NaHMDS was added dropwise (1.1 mL, 2m in THF,
2.24 mmol), the reaction mixture was stirred for 45 min–1.5 h at this
temperature, and the electrophile (2.24 mmol) was added slowly. The
reaction mixture was stirred for a further 2h at À788C, quenched with
a saturated solution of NH4Cl (15 mL), and extracted with diethyl
ether (2” 30 mL) and dichloromethane (30 mL). The combined
organic layers were dried over MgSO4, evaporated under reduced
pressure, and the resulting crude mixture was purified by filtration
through a short pad of silica gel (20 g).
Reductive cleavage of (S)-4a: (S)-4a (400 mg, 1.1 mmol) was
dissolved in anhydrous diethyl ether (10 mL) under argon and the
solution was cooled down to À108C. LiAlH4 (167 mg, 4.4 mmol) was
added slowly and the reaction mixture was stirred for 1.5 h at À108C.
A saturated solution of NH4Cl (10 mL) was added dropwise at
À108C, and the solution was vigorously stirred for 2.5 h at room
temperature. At this stage, the intermediate hemiacetal could be
detected. The aqueous layer was extracted with diethyl ether (2”
20 mL) and dichloromethane (20 mL). The combined organic layers
were dried over MgSO4 and concentrated under reduced pressure.
The resulting crude mixture was purified by column chromatography
(cyclohexane/diethyl ether 98:2–95:5) to afford 13 as a colorless oil
(116 mg, 71%) and (2S,3R)-1 (213 mg, 90%).
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Published online: April 26, 2006
Keywords: alkylation · asymmetric synthesis · chiral auxiliaries ·
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diastereoselectivity · fluorine
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[12] One single diastereomer of the corresponding Mosher ester was
1
detected by 19F and H NMR spectroscopy; the corresponding
aldehyde 13 was also obtained as a side product (15% yield of
the isolated product).
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[10] The removal of the chiral auxiliary proved that no epimerization
had occurred at C2of the oxazolidine.
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