Convenient asymmetric synthesis of β-trifluoromethyl-β-amino acid, β-amino ketones, and γ-amino alcohols via Reformatsky and Mannich-type reactions from 2-trifluoromethyl-1,3-oxazolidines

Article abstract of DOI:10.1021/jo052323p

The stereoselective syntheses of β-trifluoromethyl-β-amino ester, β lactams, and β-amino ketones starting from an oxazolidine derived from trifluoroacetaldehyde hemiacetal and (R)-phenylglycinol are reported. The Mannich-type reaction involving a chiral f

Full text of DOI:10.1021/jo052323p

γ-amino alcohols resulting from their reduction are also very
useful molecules for their biological properties and their
application as ligands in asymmetric syntheses.3 Moreover, the
introduction of fluorine atoms into a molecule often produces
significant changes in its physical, chemical, and biological
properties.4 In particular, fluorinated amino acids and amino
alcohols have proven to be of great interest.5 In this context,
the design of new synthetic methodologies for the asymmetric
synthesis of fluorinated â-amino acids, â-amino ketones, and
γ-amino alcohols is of considerable current interest. Several
synthetic approaches of chiral â-trifluoromethyl â-amino acids
have been reported in the literature,6 but the preparation of chiral
â-trifluoromethyl-â-amino ketones and γ-amino alcohols is less
documented.7 Among the various methods involving nucleo-
philic additions on trifluoromethyl imines or related acetals and
Convenient Asymmetric Synthesis of
â-Trifluoromethyl-â-amino Acid, â-Amino
Ketones, and γ-Amino Alcohols via Reformatsky
and Mannich-Type Reactions from
2-Trifluoromethyl-1,3-oxazolidines
Florent Huguenot† and Thierry Brigaud*,‡
Laboratoire “Re´actions Se´lectiVes et Applications”, UMR CNRS
6519, UniVersite´ de Reims-Champagne-Ardenne, Faculte´ des
Sciences, BP 1039, 51687 Reims Cedex 2, France, and
Laboratoire “Synthe`se Organique Se´lectiVe et Chimie
Organome´tallique” (SOSCO), UMR CNRS 8123, UniVersite´ de
Cergy-Pontoise, 5, Mail Gay-Lussac - NeuVille sur Oise - 95031
Cergy-Pontoise Cedex, France
(3) (a) Kochi, T.; Tang, T. P.; Ellman, J. A. J. Am. Chem. Soc. 2003,
125, 11276-11282 and references therein. (b) Enders, D.; Moser, M.;
Geibel, G.; Laufer, M. C. Synthesis 2004, 2040-2046 and references therein.
(4) (a) Hiyama, T. In Organofluorine Compounds, Chemistry and
applications; Yamamoto, H., Ed.; Springer-Verlag: Berlin and Heidelberg,
Germany, 2000. (b) Organofluorine Chemistry, Principles and Commercial
Applications; Banks, R. E., Smart, B. E., Tatlow, J. C., Eds.; Plenum: New
York, 1994. (c) Biomedical Frontiers of Fluorine Chemistry; Ojima, I.,
McCarthy, J. R., Welch, J. T., Eds.; American Chemical Society: Wash-
ington, DC, 1996. (d) Smart, B. E. J. Fluorine Chem. 2001, 109, 3-11. (e)
O’Hagan, D.; Rzepa, H. S. Chem. Commun. 1997, 645-652. (f) Schlosser,
M. Angew. Chem., Int. Ed. 1998, 110, 1496-1513. (g) ChemBioChem 2004,
5, 557-726 (special issue).
thierry.brigaud@chim.u-cergy.fr
ReceiVed NoVember 9, 2005
(5) (a) Qiu, X.-L.; Meng, W.-D.; Qing, F.-L. Tetrahedron 2004, 60,
6711-6745 and references therein. (b) Sutherland, A.; Wilis, C. L. Nat.
Prod. Rep. 2000, 17, 621-631 and references therein. (c) Kukhar, V. P.;
Soloshonok, V. A. Fluorine Containing Amino Acids: Synthesis and
Properties; Wiley: New York, 1995. (d) Enantiocontrolled Synthesis of
Fluoro-Organic Compounds; Soloshonok, V. A., Ed.; Wiley: Chichester,
U.K., 1999. (e) Zanda, M. New J. Chem. 2004, 28, 1401-1411. (f) Molteni,
M.; Pesenti, C.; Sani, M.; Volonterio, A.; Zanda, M. J. Fluorine Chem.
2004, 125, 1335-1743. (g) Kuznetsova, L.; Ungureanu, I. M.; Pepe, A.;
Zanardi, I.; Wu, X.; Ojima, I. J. Fluorine Chem. 2004, 125, 487-500. (h)
Be´gue´, J.-P.; Bonnet-Delpon, D. Trifluoromethylated Amino Alcohols: New
Synthetic Approaches and Medicinal Targets. In Biomedical Frontiers of
Fluorine Chemistry; Ojima, I., McCarthy, J. R., Welch, J. T., Eds.; American
Chemical Society: Washington, DC, 1996; pp 59-72. (i) Bravo, P.;
Crucianelli, M.; Ono, T.; Zanda, M. J. Fluorine Chem. 1999, 112, 27-49.
(6) (a) Funabiki, K.; Nagamori, M.; Matsui, M. J. Fluorine Chem. 2004,
125, 1347-1350. (b) Jiang, Z.-X.; Qing, F.-L. J. Org. Chem. 2004, 69,
5486-5489. (c) Lazzaro, F.; Crucianelli, M.; De Angelis, F.; Frigerio, M.;
Malpezzi, L.; Volonterio, A.; Zanda, M. Tetrahedron: Asymmetry 2004,
15, 889-893. (d) Fustero, S.; Pina, B.; Salavert, E.; Navarro, A.; Ram´ırez
de Arellano, M. C.; Fuentes, A. S. J. Org. Chem. 2002, 67, 4667-4679.
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Bellosta, S.; Bravo, P.; Canavesi, M.; Corradi, E.; Meille, S. V.; Monetti,
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F. Tetrahedron: Asymmetry 1999, 10, 2361-2371. (i) Abouabdellah, A.;
Be´gue´, J.-P.; Bonnet-Delpon, D.; Nga, T. T. T. J. Org. Chem. 1997, 62,
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The stereoselective syntheses of â-trifluoromethyl-â-amino
ester, â lactams, and â-amino ketones starting from an
oxazolidine derived from trifluoroacetaldehyde hemiacetal
and (R)-phenylglycinol are reported. The Mannich-type
reaction involving a chiral fluorinated iminium ion occurred
in a good yield and with a higher stereoselectivity (dr up to
96:4) than that of the Reformatsky-type reaction. This
straightforward strategy was applied to the short syntheses
of (R)-3-amino-4,4,4-trifluorobutanoic acid, a series of novel
enantiopure unprotected fluorinated â-amino ketones, and
their corresponding γ-amino alcohols.
Introduction
In the field of amino acid chemistry, â-amino acids have
proven to be of great interest because of their unique biological
properties.1 Likewise, â-amino carbonyl compounds, generally
obtained by Mannich-type reactions, are very important com-
pounds as biologically active molecules.2 The corresponding
* To whom correspondence should be addressed. Phone: + 33/(0)134257066.
Fax: + 33/(0)134257071.
† Universite´ de Reims-Champagne-Ardenne.
‡ Universite´ de Cergy-Pontoise.
(1) (a) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991-8035. (b) Cheng,
R. P.; Gellman, S. H.; DeGrado, W. F. Chem. ReV. 2001, 101, 3219-3232.
(c) Seebach, D.; Beck, A. K.; Bierbaum, D. J. Chem. BiodiVersity 2004, 1,
1111-1239. (d) Seebach, D.; Kimmerlin, T.; Sebesta, R.; Campo, M. A.;
Beck, A. K. Tetrahedron 2004, 60, 7455-7506.
(2) Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998,
37, 1044-1070.
10.1021/jo052323p CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/02/2006
J. Org. Chem. 2006, 71, 2159-2162
2159

iminium8 are the Reformatsky9 and the Mannich-type10 reac-
tions, which have emerged as powerful approaches for the
synthesis of â-trifluoromethylated â-amino carbonyl compounds,
mainly in the racemic series. In the course of our studies, we
have reported the Lewis-acid promoted ring opening of chiral
2-trifluoromethyl-1,3-oxazolidines into a chiral iminium salt,
and its use for the stereoselective C-C bond formation.11 These
2-trifluoromethyl-1,3-oxazolidines have already been reported
as very powerful synthons for the stereoselective synthesis of
chiral trifluoromethyl amino compounds.12-14 We now report
our results about the application of the Reformatsky and the
Mannich-type reactions to the straightforward stereoselective
synthesis of trifluoromethylated â-amino acid, â-amino ketones,
and γ-amino alcohols in enantiopure form.
SCHEME 1
SCHEME 2
Results and Discussion
The Reformatsky reaction with a diastereomeric mixture of
nonfluorinated chiral amino alcohol-based oxazolidines gener-
ally occurs with a high diastereoselectivity. This can be
explained by the formation of a single chiral imine intermediate
resulting from the ring opening of the oxazolidine by the
organometallic reagent.15 The rigidity of this intermediate is due
to a chelation of the zinc atom of the alcoholate with the nitrogen
atom of the imine.15,16 We first investigated the Reformatsky-
type reaction between chiral 2-trifluoromethyl-1,3-oxazolidines,
1a,b, and ethyl bromoacetate. Oxazolidines, 1a,b, were very
conveniently prepared in high yield by the condensation of
trifluoroacetaldehyde methyl hemiacetal and (R)-phenylglyci-
nol.12 The reaction of ethyl bromoacetate with 1a,b (62:38
mixture of diastereomers) in the presence of zinc dust at the
reflux temperature of THF furnished 4-trifluoromethylazetidin-
2-one, 2a,b, in 42% yield as a 74:26 mixture of diastereomers.
A pure fraction of 2a was isolated (Scheme 1). The decrease of
the stereoselectivity of this reaction, compared to results reported
with nonfluorinated oxazolidines,15 can be explained by the
inhibition of the oxazolidine ring opening into imine as a result
of the electron-withdrawing effect of the trifluoromethyl group.
In our case, the Reformatsky reagent should directly attack the
C-2 carbon of the oxazolidine in a nucleophilic substitution
process. Such an unusual behavior of 2-trifluoromethyl-1,3-
oxazolidines has already been reported by Mikami et al.12,13
The fact that we were unable to detect the open-chain â-amino
esters suggests the efficient cyclization of the intermediate
metalloamines into azetidinones 2a,b. This reaction proved to
be more selective than previously reported methods in the
fluorinated series, affording either the â-amino ester9b or a
mixture of azetidin-2-one and â-amino ester.9a The pure major
diastereomer, 2a, was easily converted into â-amino ester 3a
by ethanolysis under acidic catalysis (Scheme 1). The config-
uration of 3a proved to be R,R (vide infra).
To increase the stereoselectivity of the trifluoromethyl
â-amino ester formation, we then considered using the Mannich-
type reaction, which would involve a unique iminium intermedi-
ate starting from a diastereomeric mixture of oxazolidines 1a,b.
We have already reported that the same iminium is formed in
situ starting from either 1a or 1b under a Lewis-acid activation.11
Contrary to unfluorinated oxazolidines,17 the trifluoromethylated
oxazolidines, 1a,b, exhibited very poor reactivity toward ethyl
(tert-butyldimethylsilyl)ketene acetal under Lewis-acid (BF3‚
OEt2, TMSOTf, GaCl3) activation in dichloromethane or pro-
pionitrile even at reflux temperature. Only trace amounts of the
expected â-amino esters were obtained in these conditions.
However, the reaction of oxazolidines 1a,b with ethyl trimeth-
ylsilyl ketene acetal18 occurred in propionitrile at reflux tem-
perature in the presence of a Lewis acid (Scheme 2). With TiCl4
activation, the expected â-amino ester was not detected. The
major reaction product was the R,â-unsaturated amide, 4, which
was isolated in 48% yield. Such acrylic trifluoromethyl com-
pounds have already been reported in the literature as a result
(7) (a) Funabiki, K.; Nagamori, M.; Goushi, S.; Matsui, M. Chem.
Commun. 2004, 1928-1929. (b) Fustero, S.; Jimenez, D.; Sanz-Cervera, J.
F.; Sanchez-Rosello, M.; Esteban, E.; Simon-Fuentes, A. Org. Lett. 2005,
7, 3433-3436.
(8) Be´gue´, J.-P.; Bonnet-Delpon, D.; Crousse, B.; Legros, J. Chem. Soc.
ReV. 2005, 34, 562-572.
(9) (a) Gong, Y.; Kato, K. J. Fluorine Chem. 2001, 111, 77-80. (b)
Costerousse, G.; Teutsch, G. Tetrahedron 1986, 42, 2685-2694.
(10) (a) Takaya, J.; Kagoshima, H.; Akiyama, T. Org. Lett. 2000, 2,
1577-1579. (b) Blond, G.; Billard, T.; Langlois, B. R. J. Org. Chem. 2001,
66, 4826-4830. (c) Xu, Y.; Dolbier, W. R. J. Org. Chem. 2000, 65, 2134-
2137. (d) Xu, Y.; Dolbier, W. R. Tetrahedron Lett. 1998, 39, 9151-9154.
(e) Sergeeva, N. N.; Golubev, A. S.; Hennig, L.; Burger, K. Synthesis 2002,
17, 2579-2584.
(11) Lebouvier, N.; Laroche, C.; Huguenot, F.; Brigaud, T. Tetrahedron
Lett. 2002, 43, 2827-2830.
(12) Higashiyama, K.; Ishii, A.; Mikami, K. Synlett 1997, 1381-1382.
(13) Ishii, A.; Miyamoto, F.; Higashiyama, K.; Mikami, K. Tetrahedron
Lett. 1998, 39, 1199-1202.
(17) Higashiyama, K.; Kyo, H.; Takahashi, H. Synlett 1998, 39, 489-
490.
(18) Ethyl (trimethylsilyl)ketene acetal was obtained as a 70:30 insepa-
rable mixture with ethyl 2-trimethylsilyl acetate: Colvin, E. Silicon Reagents
in Organic Synthesis; Academic Press: London, U.K., 1988. As ethyl
2-trimethylsilyl acetate proved to be completely inert in the Mannich-type
reaction conditions, the 70:30 mixture was used for the next reaction.
(14) Gosselin, F.; Roy, A.; O’Shea, P. D.; Chen, C.-y.; Volante, R. P.
Org. Lett. 2004, 6, 641-644.
(15) Marcotte, S.; Pannecoucke, X.; Feasson, C.; Quirion, J.-C. J. Org.
Chem. 1999, 64, 8461-8464.
(16) Mokhallalati, M. K.; Wu, M. J.; Pridgen, L. N. Tetrahedron Lett.
1993, 34, 47-50.
2160 J. Org. Chem., Vol. 71, No. 5, 2006

TABLE 1. Mannich-Type Reactions of Oxazolidines 1a,b with
Various Enoxysilanesa
SCHEME 3
entry
R1, R2
products
yieldb (%)
drc
1
2
3
H, Ph
H, t-Bu
(CH2)4
6a (R,R), 6b (R,S)
7a (R,R), 7b (R,S)
8a (R,R), 8′a (R,R)
66
88
60
6a:6b, 96:4
7a:7b, 94:6
8a:8′a, 54:46
a Enoxysilane, 2 equiv; Lewis acid, 3 equiv. b Isolated yield. c Measured
by the 19F NMR of the crude reaction mixture.
SCHEME 4
of elimination reactions of â-amino ketones.10b,c In our case,
the compound 4 should arise from the in situ â elimination of
an intermediate azetidin-2-one promoted by TiCl4. When BF3‚
OEt2 was used as the Lewis acid, the expected â-amino esters
3a and 3b were obtained in 73% yield as an 84:16 diastereo-
meric mixture. The major 3a diastereomer was obtained in pure
form after silica-gel chromatography. The synthesis of the target
â-amino acid required the removal of the chiral auxiliary and
the hydrolysis of the ester function. This was achieved in 90%
yield in a three-step procedure involving the reaction with Pb-
(OAc)4, HCl (6 N) hydrolysis, and propylene oxide treatment
(Scheme 2). The R configuration of the â-trifluoromethyl-â-
amino acid 5 obtained was assigned by comparison with the
optical rotation reported in the literature6p ([R]25D +26.6 (c 0.5,
6 N HCl), [R]25D(lit.) -27.6 (c 1.4, 6 N HCl) for S enantiomer).
As very few examples of stereoselective methods for the
synthesis of â-trifluoromethyl-â-amino ketones are reported in
the literature, we next designed to investigate the Mannich-type
reaction with enoxysilanes. The trimethylsilyl enol ethers derived
from acetophenone, tert-butyl methyl ketone, and cyclohex-
anone19 were submitted to the Mannich-type reaction with the
oxazolidines 1a,b in CH2Cl2 in the presence of BF3‚Et2O. The
reaction proceeded very smoothly at room temperature, and the
corresponding â-amino ketones 6, 7, and 8 were obtained in
good yield. The new amino stereogenic center was formed with
a high stereoselectivity control (Table 1). It is worthwhile noting
that the reaction of the trimethylsilyl enol ether derived from
cyclohexanone produced only two of the four possible â-amino
ketone diastereomers (Table 1, entry 3). Further stereochemical
arguments demonstrated that they were syn/anti diastereomers
(vide infra).
SCHEME 5
conveniently assigned by correlation with the known configu-
ration of the â-amino esters 3a. Indeed, the reaction of (R,R)-
3a with PhLi and t-BuLi afforded (R,R)-6a and (R,R)-7a
(Scheme 4).
As the reaction of the cyclohexanone-derived trimethylsilyl
enol ether gave only two of the four diastereomers to be
expected, the question was to know whether it was syn-anti,
both syn, or both anti diastereomers. To make a decision, the
8a,8′a mixture was submitted to Pb(OAc)4 removal of the
phenylglycinol chiral auxiliary. As a result, a mixture of two
diastereomers 13a and 13′a in the same ratio as that found in
the starting mixture was obtained proving that 8a and 8′a were
syn/anti diastereomers (Scheme 5). By correlation with the R
configuration of the acyclic analogues 3a, 6a, and 7a, the
configuration of the trifluoromethylated amino chiral centers
of 8a, 8′a and 13a, 13′a were anticipated to be R. According to
the model we previously proposed for the Strecker-type reac-
tion,11 all these results are consistent with the attack of the
intermediate iminium on the less-hindered re face (Figure 1).
The LAH reduction of the (R,R)-â-amino ester 3a in diethyl
ether gave the corresponding (R,R)-amino diol 14 in 87% yield.
The removal of the chiral (R)-phenylglycinol side chain of 14
was achieved in 79% yield to give the enantiopure (R)-γ-amino
alcohol hydrochloride 15 (Scheme 6).
The removal of the (R)-phenylglycinol side chain was then
very conveniently achieved by the standard Pb(OAc)4 method
to give the corresponding novel chiral free â-amino ketones
(Scheme 3). Enantiopure â-amino ketones 11a and 12a were
obtained in a few steps from the corresponding major 6a and
7a diastereomers.
We first designed to determine the absolute configuration of
the unknown â-amino ketones 6a and 7a by means of their
conversion into the (R,R)-â-amino ester 3a through a Bayer-
Villiger oxidation.20 Unfortunately, the only products obtained
after mCPBA oxidation were a result of the nitrogen-atom
oxidation. However, the R configuration of 11a and 12a was
(19) Cazeau, P.; Duboudin, F.; Moulines, F.; Babot, O.; Dunogues, J.
Tetrahedron 1987, 43, 2075-2088.
(20) Kobayashi, S.; Tanaka, H.; Amii, H.; Uneyama, K. Tetrahedron
2003, 59, 1547-1552.
FIGURE 1. Attack (re face) of the postulated iminium ion intermedi-
ate.
J. Org. Chem, Vol. 71, No. 5, 2006 2161

SCHEME 6
The temperature was cooled to -78 °C, and BF3OEt2 (0.9 mL, 6.9
mmol) was added. The reaction mixture was warmed to room
temperature overnight. The mixture was then poured into a saturated
aqueous solution of NaHCO3 (20 mL). The aqueous layer was
extracted with dichloromethane (3 × 20 mL), and the combined
organic extracts were dried over Na2SO4, filtered, and concentrated
under reduced pressure. Purification by flash chromatography (4:1
petroleum ether/ethyl acetate) gave pure 6a (1.03 g, 66%) as a
colorless oil. [R]20 -27.0 (c 1.1, CHCl3); IR (neat) 3349, 3030,
D
2928, 2932, 1686, 1266 cm-1; 1H NMR δ 1.78 (m, 2H), 3.24 (dd,
JAB ) 12.5, J ) 2.0 Hz, 1H), 3.33 (d, JAB ) 12.5 Hz, 1H), 3.58
(dd, JAB ) 11.3, J ) 7.9 Hz, 1H), 3.79 (dd, JAB ) 11.3, J ) 3.8
Hz, 1H), 4.04 (qd, J ) 7.2, 2.0 Hz, 1H), 4.07 (dd, J ) 7.9, 3.8 Hz,
1H), 7.2-7.4 (m, 5H), 7.49 (dd, J ) 7.3, 5.2 Hz, 2H), 7.62 (tt, J
) 5.2, 1.2 Hz, 1H), 7.95 (td, J ) 7.3, 1.2 Hz, 2H); 13C NMR δ
38.6, 54.0 (q, J ) 28.6 Hz), 62.4, 67.0, 126.5 (q, J ) 274.7 Hz),
127.3, 127.7, 128.2, 128.6, 128.8, 133.9, 136.2, 140.4, 196.9; 19F
NMR δ -74.9 (d, J ) 7.2 Hz); MS (EI 70 eV) m/z 338 (M+ + 1),
320, 306, 225, 218, 200, 186. Anal. Calcd for C18H18F3NO2: C,
64.09; H, 5.38; N, 4.15. Found: C, 64.13; H, 5.59; N, 3.90.
Removal of the (R)-Phenylglycinol Side Chain of â-Amino
Ketones with Pb(OAc)4. (R)-3-Amino-4,4,4-trifluoro-1-phenyl-
butanone Hydrochloride (9a). To a solution of 6a (338 mg, 1
mmol) in 10 mL of a mixture of MeOH/CH2Cl2 (2:1) was added
Pb(OAc)4 (620 mg, 1.4 mmol) at 0 °C. After 20 min of stirring at
0 °C, the reaction mixture was poured into a buffer aqueous solution
(pH ) 7, 10 mL) at room temperature and then filtered on Celite.
The aqueous layer was extracted with dichloromethane (4 × 10
mL), and the combined organic extracts were dried over Na2SO4,
filtered, and concentrated under reduced pressure. To the crude
product was then added 5 mL of 5 N HCl, and the mixture was
stirred for 24 h at room temperature. The organic layer was extracted
with diethyl ether (3 × 5 mL), and the combined aqueous extracts
were concentrated under reduced pressure to afford hydrochloride
9a (202 mg, 80%) as a pale yellow powder. [R]25D +23.4 (c 0.80,
HCl 1 N); IR (KBr) 3382, 2950, 2920, 1694, 1685, 1596, 1205
SCHEME 7
In a similar manner, enantiopure â-amino ketones 6a and 7a
were converted into the corresponding γ-amino alcohols 16 and
17 in high yield (90 to 92%) but with a low diastereoselectivity
(22 to 24% de; Scheme 7). Fortunately, each diastereomer 16a
(major) and 16b (minor) could easily be separated by chroma-
tography on silica gel, and the two diastereomers 17a (major)
and 17b (minor) were efficiently separated by recrystallization.
The relative configuration of the 1,3-amino alcohol sequence
of each diastereomer could not be assigned. Nevertheless, each
isolated amino diol, 16a, 16b, 17a, and 17b, was treated with
Pb(OAc)4 to furnish the four corresponding trifluoromethylated
γ-amino alcohol hydrochlorides, 18a, 18b, 19a, and 19b, in
enantiopure form and in good yield (70-86%).
1
cm-1; H NMR (D2O) δ 3.53 (dd, JAB ) 19.1, J ) 9.5 Hz, 1H),
3.72 (dd, JAB ) 19.1, J ) 2.3 Hz, 1H), 4.6 (dqd, J ) 9.5, 7.7, 2.3
Hz, 1H), 7.3 (m, 2H), 7.5 (m, 1H), 7.8 (m, 2H); 13C NMR (D2O)
δ 37.6, 51.3 (q, J ) 32.5 Hz), 126.1 (q, J ) 279.6 Hz), 130.8,
131.5, 137.1, 137.4, 199.5; 19F NMR (D2O) δ -71.8 (d, J ) 7.7
Hz).
(3R)-3-Amino-1-phenyl-4,4,4-trifluorobutanone (11a). Hydro-
chloride 9a (202 mg, 0.8 mmol) was dissolved in propylene oxide
(10 mL) and stirred for 1 h at room temperature. The crude mixture
was concentrated under reduced pressure. Purification by flash
chromatography (17:3 petroleum ether/ethyl acetate) followed by
recrystallization in hexane gave 11a (88 mg, 51%) as a yellow solid.
Mp 30 °C; [R]25 +23.5 (c 0.4, HCl 1 N); IR (KBr) 3382, 2950,
D
Conclusion
2920, 1694, 1685, 1596, 1205 cm-1; H NMR δ 1.56 (m, 2H),
1
3.09 (dd JAB ) 17.5, J ) 9.5 Hz, 1H), 3.24 (dd, JAB ) 17.5, J )
3.0 Hz, 1H), 3.93 (dqd, J ) 9.5, 7.8, 3.0 Hz, 1H), 7.40 (dd, J )
8.8, 6.3 Hz, 2H), 7.52 (dd, J ) 6.3, 1.3, 1H), 7.87 (dd, J ) 8.8,
1.3, 2H); 13C NMR δ 38.2, 51.3 (q, J ) 24.7 Hz), 125.4 (q, J )
280.3 Hz), 127.1, 127.8, 132.7, 135.3, 195.2; 19F NMR δ -78.6
(d, J ) 7.8 Hz). Anal. Calcd for C10H10F3NO: C, 55.84; H, 4.64;
N, 6.45. Found: C, 55.47; H, 4.55; N, 6.34.
In conclusion, we have developed an efficient straightforward
synthetic route for the synthesis of â-trifluoromethylated
â-amino acid, â-amino ketones, and γ-amino alcohols from a
trifluoacetaldehyde and an (R)-phenylglycinol-based oxazolidine.
The diastereoselectivity of the reported Reformatsky and
Mannich-type reactions was varied (dr up to 96:4). However,
the separation of the diastereomers was very efficient due to
the phenylglycinol side chain, and the novel target compounds
were very conveniently obtained in enantiopure form.
Acknowledgment. The authors thank the MRT for the grant
(F.H.) and Central Glass Company for the generous gift of
trifluoroacetaldehyde hemiacetal.
Experimental Section
Supporting Information Available: General experimental
methods, complete experimental procedures, and characterization
data for all compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
General Procedure for the Mannich-Type Reaction. (3R)-
4,4,4-Trifluoro-3-((1R)-2-hydroxy-1-phenylethylamino)-1-
phenylbutanone (6a). To a solution of oxazolidines 1a,b (62:38
mixture, 1.0 g, 4.6 mmol) in dichloromethane (20 mL) under argon
was added acetophenone trimethylsilyl enol ether (1.3 g, 6.9 mmol).
JO052323P
2162 J. Org. Chem., Vol. 71, No. 5, 2006