Concise synthesis of enantiopure α-trifluoromethyl alanines, diamines, and amino alcohols via the Strecker-type reaction

Article abstract of DOI:10.1021/jo0607717

Diastereomerically pure α-trifluoromethyl α-amino nitriles obtained by Strecker-type reactions from chiral CF₃ imines and iminium proved to be very attractive versatile intermediates for the synthesis of various α-trifluoromethyl amino compound

Full text of DOI:10.1021/jo0607717

fluorine atoms producing significant changes in the physical,
chemical, and biological properties of molecules.2 Curiously,
although the Strecker-type reaction is extensively used in the
nonfluorinated series for the stereoselective synthesis of R-amino
acids,3 this strategy has been very rarely reported in the
fluorinated series.4,5 Different methods are known for the
stereoselective synthesis of trifluoromethyl 1,2-diamines,6 but
to our knowledge, their synthesis by reduction of R-trifluoro-
methyl R-amino nitriles has never been reported. In the course
of our studies, we have already reported that chiral trifluoro-
methyl iminiums are effective intermediates for the stereose-
lective synthesis of various R-trifluoromethylated amino
compounds.4a,7 We now report the straightforward synthesis of
enantiopure R-trifluoromethyl alanines, amino alcohols, and 1,2-
diamines from R-amino nitriles obtained by Strecker-type
reaction starting from chiral CF3 imines or oxazolidines.
The Strecker-type reaction from CF3 imines or iminium has
been mainly reported in the racemic series,8 and to our
knowledge, the synthesis of enantiopure R-amino nitriles through
resolution is not documented in the literature. In this work, we
first investigated the asymmetric Strecker-type reaction with
various chiral trifluoromethylated N-benzylimines (Table 1).
These diastereomerically pure (E)-imines were very conve-
niently prepared from trifluoroacetaldehyde hemiacetal or
trifluoromethyl ketones and (S)-R-methylbenzylamine or (R)-
phenylglycinol and derivatives. These chiral auxiliaries are
inexpensive and easily removable to get the target free amino
compounds. In all cases, the Strecker-type reaction with TMSCN
required a Lewis acid activation of the fluorinated aldimines or
ketimines to occur. The reaction was very efficiently promoted
in mild conditions with a catalytic amount of Yb(OTf)3, which
Concise Synthesis of Enantiopure
r-Trifluoromethyl Alanines, Diamines, and
Amino Alcohols via the Strecker-type Reaction
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
thierry.brigaud@u-cergy.fr
ReceiVed April 12, 2006
Diastereomerically pure R-trifluoromethyl R-amino nitriles
obtained by Strecker-type reactions from chiral CF3 imines
and iminium proved to be very attractive versatile intermedi-
ates for the synthesis of various R-trifluoromethyl amino
compounds. From these synthons, both enantiomers of
R-trifluoromethyl alanine, trifluoromethyl 1,2-diamines, and
amino alcohols were conveniently obtained in enantiopure
form in high yields in a few steps.
(2) (a) Hiyama, T. Organofluorine Compounds, Chemistry and Applica-
tions; Yamamoto, H., Ed.; Springer-Verlag: Berlin, Heidelberg, 2000. (b)
Organofluorine Chemistry, Principles and Commercial Applications; Banks,
R. E., Smart, B. E., Tatlow, J. C., Eds.; Plenum: New York, 1994. (c)
Smart, B. E. J. Fluorine Chem. 2001, 109, 3-11. (d) O’Hagan, D.; Rzepa,
H. S. Chem. Commun. 1997, 645-652. (e) Schlosser, M. Angew. Chem.,
Int. Ed. 1998, 37, 1496-1513. (f) ChemBioChem 2004, 5, 557-726 (special
issue).
(3) (a) Ohfune, Y.; Shinada, T. Eur. J. Org. Chem. 2005, 5127-5143.
(b) Enders, D.; Shilvock, J. P. Chem. Soc. ReV. 2000, 29, 359-373. (c)
Groeger, H. Chem. ReV. 2003, 103, 2795-2827. (d) Duthaler, R. O.
Tetrahedron 1994, 50, 1539-650.
R-Trifluoromethyl R-amino acids (R-Tfm AAs), trifluoro-
methylated 1,2-amino alcohols, and 1,2-diamines are very
attractive target molecules for the design of biologically active
molecules.1 This is mainly due to the specific properties of
(4) For examples in the trifluoromethyl series, see: (a) Lebouvier, N.;
Laroche, C.; Huguenot, F.; Brigaud, T. Tetrahedron Lett. 2002, 43, 2827-
2830. (b) Wang, H.; Zhao, X.; Li, Y.; Lu, L. Org. Lett. 2006, 8, 1379-
1381.
(5) For examples in the difluoromethyl and monofluoromethyl series,
see: (a) Bravo, P.; Capelli, S.; Meille, S. V.; Seresini, P.; Volonterio, A.;
Zanda, M. Tetrahedron: Asymmetry 1996, 7, 2321-2332. (b) Schlosser,
M.; Brugger, N.; Schmidt, W.; Amrhein, N. Tetrahedron 2004, 60, 7731-
7742. (c) Davis, F. A.; Srirajan, V.; Titus, D. D. J. Org. Chem. 1999, 64,
6931-6934.
(6) (a) Yamauchi, Y.; Kawate, T.; Katagiri, T.; Uneyama, K. Tetrahedron
2003, 59, 9839-9847. (b) Katagiri, T.; Takahashi, M.; Fujiwara, Y.; Ihara,
H.; Uneyama, K. J. Org. Chem. 1999, 64, 7323-7329. (c) Molteni, M.;
Volonterio, A.; Zanda, M. Org. Lett. 2003, 5, 3887-3890. (d) Prakash, G.
K. S.; Mandal, M. J. Am. Chem. Soc. 2002, 124, 6538-6539.
(7) Huguenot, F.; Brigaud, T. J. Org. Chem. 2006, 71, 2159-2162.
(8) (a) Fuchigami, T.; Nakagawa, Y.; Nonaka, T. J. Org. Chem. 1987,
52, 5489-5491. (b) Fuchigami, T.; Ichikawa, S.; Konno, A. Chem. Lett.
1989, 1987-1988. (c) Yamasaki, Y.; Maekawa, T.; Ishihara, T.; Ando, T.
Chem. Lett. 1985, 1387-1390. (d) Xu, Y.; Dolbier, W. R., Jr. J. Org. Chem.
2000, 65, 2134-2137. (e) Koos, M.; Mosher, H. S. Tetrahedron 1993, 49,
1541-1546. (f) Dessipri, E.; Tirrell, D. A. Macromolecules 1994, 27, 5463-
5470. (g) Burger, K.; Huber, E.; Kahl, T.; Partscht, H.; Ganzer, M. Synthesis
1988, 44-49. (h) For recent examples in the asymmetric series, see ref 4.
* To whom correspondence should be addressed. Phone: + 33/(0)134257066.
Fax: + 33/(0)134257071.
† Universite´ de Reims-Champagne-Ardenne.
‡ Universite´ de Cergy-Pontoise.
(1) For review, see: (a) Qiu, X.-L.; Meng, W.-D.; Qing, F.-L. Tetrahe-
dron 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,
UK, 1999. (e) Asymmetric Fluoroorganic Chemistry: Synthesis, Applica-
tions, and Future Directions; Ramachandran, P. V., Ed.; ACS Symposium
Series 746; American Chemical Society: Washington, DC, 2000. (f)
Biomedical Frontiers of Fluorine Chemistry; Ojima, I., McCarthy, J. R.,
Welch, J. T., Eds.; American Chemical Society: Washington, DC, 1996.
(g) Jaeckel, C.; Koksch, B. Eur. J. Org. Chem. 2005, 4483-4503. (h) Yoder,
N. C.; Kumar, K. Chem. Soc. ReV. 2002, 31, 335-341. (i) Zanda, M. New
J. Chem. 2004, 28, 1401-1411. (j) Molteni, M.; Pesenti, C.; Sani, M.;
Volonterio, A.; Zanda, M. J. Fluorine Chem. 2004, 125, 1335-1743. (k)
Bravo, P.; Crucianelli, M.; Ono, T.; Zanda, M. J. Fluorine Chem. 1999,
112, 27-49. (l) Fustero, S.; Sanz-Cervera, J. F.; Piera, J.; Sanchez-Rosello,
M.; Chiva, G.; Simon-Fuentes, A. J. Fluorine Chem. 2004, 125, 621-627.
(m) Uneyama, K. J. Fluorine Chem. 1999, 97, 11-25. (n) Uneyama, K.;
Amii, H. J. Fluorine Chem. 2002, 114, 127-131.
10.1021/jo0607717 CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/11/2006
J. Org. Chem. 2006, 71, 7075-7078
7075

TABLE 1. Strecker-type Reactions of Imines 1a-g
TABLE 2. Strecker-type Reactions of Oxazolidines 5a-c Derived
from (-)-Ephedrine and (-)-Norephedrine
imine
(R1, R2)
Lewis
acid
yield
entry
product (%)a
drb
oxazolidine
(R1, R2)
dr
yield
(%)a
entry
oxazolidines
product
drb
c
1
2
3
4
5
6
7
8
9
1a (H, CH3)
1b (CH3, CH3)
1c (Ph, CH3)
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
2a
2b
2c
2c
2d
2d
2e
2f
80
80
90
93
58
62
92
75
93
93
50:50
77:23
75:25
67:33
50:50
80:20
55:45
75:25
68:32
60:40
d
1
2
3
5a (H, CH3)
5b (H, H)
5c (CH3, H)
79:21
85:15
60:40
6a
6b
6c
80
90
90
63:37
66:34
67:33
c,e
f
1c (Ph, CH3)
MgBr2
c
1d (H, CH2OMe)
1d (H, CH2OMe)
1e (CH3, CH2OH)
1f (CH3, CH2OTBDMS) Yb(OTf)3
1f (CH3, CH2OTBDMS) MgBr2
Yb(OTf)3
a Isolated yield. b Measured by 19F and H NMR of the crude reaction
1
f
MgBr2
mixture.
c
c
Yb(OTf)3
f
2f
2g
and the Strecker-type reaction can be carried out on the mixture
of oxazolidines. The Strecker-type reactions from (-)-ephedrine-
and (-)-norephedrine-derived oxazolidines were first investi-
gated (Table 2). The corresponding R-amino nitriles were
obtained in high yields (80-90%).
c
10
1g (CH3, CH2ODPMS)
Yb(OTf)3
a Isolated yield. b Measured by 19F NMR of the crude reaction mixture.
c 0.1 equiv. d 0.2 equiv. e The reaction performed with Et2AlCN (1.5 equiv)
as the cyanide donor and Yb(OTf)3 (0.1 equiv) gave 2c in 90% yield and
76:24 dr. f 1.5 equiv.
To anticipate a convenient removal of the chiral auxiliary
for the synthesis of free amino compounds, the reactivity of
(R)-phenylglycinol-based oxazolidines was then studied. The
phenylglycinol side chain can be easily removed by Pb(OAc)4
treatment or hydrogenolysis, and this strategy has been widely
used in the nonfluorinated series for the stereoselective synthesis
of R-amino acids from oxazolidines10 or imines.11 The Strecker-
type reaction of various (R)-phenylglycinol-based trifluoro-
methylated oxazolidines occurred in high yields (84-97%)
provided that the oxazolidines were activated with a stoichio-
metric amount of BF3‚OEt2 or a catalytic amount of TMSOTf
(Table 3). Unlike the corresponding more reactive imines, no
reaction occurred in the presence of a catalytic amount of Yb-
(OTf)3 (Table 3, entry 1). The same diastereomeric ratio of
R-amino nitriles 8a was obtained, whatever the diastereomeric
ratio of the starting oxazolidines 7a (Table 3, entries 2-5). This
result confirms that the same iminium intermediate should be
formed from both oxazolidines, and consequently, a tedious
separation of the oxazolidines is useless. The diastereoselectivity
of this Strecker-type reaction was increased compared to that
of the corresponding trifluoroacetaldehyde imines 1a,d (Table
1). With the same substrate 7a, the diastereoselectivity of the
Strecker reaction proved to be higher than the allylation and
propargylation reactions we already reported.4a The (R,R)
configurational assignment of the major 8a diastereomer is in
accordance with the less hindered re face attack of the
intermediate iminium.4a,7 The configurations of the amino nitriles
were determined by correlation with the corresponding amino
acid configuration (vide infra). The diastereoselectivity de-
creased for the N-benzyl oxazolidine 7b (Table 3, entry 6), and
no reaction occurred from the N-benzoyl oxazolidine 7c (Table
3, entry 7). With this substrate, the oxazolidine ring opening
SCHEME 1
is a very easy to handle Lewis acid. The expected amino nitriles
were obtained in high yields with a low to moderate diastereo-
selectivity. However, in most cases (Table 1, entries 1-4, 7,
and 10), each diastereomer was efficiently obtained in diaste-
reomerically pure form after silica gel separation. The diaste-
reoselectivity could be slightly improved by using (R)-R-
methoxymethylbenzylimine and MgBr2 (1.5 equiv) as the Lewis
acid (Table 1, entry 6). The chelation of both nitrogen and
oxygen by the magnesium should explain the diastereoselectivity
increase because this effect was not observed with Yb(OTf)3
(Table 1, entry 5). No enhancement of the stereoselectivity was
achieved by the introduction of a more hindered silylated
substituent on the benzylic side chain (Table 1, entries 8-10).
The Strecker-type reaction was also performed starting from
the silylated hemiacetal of fluoral 3a and the silylated hemiacetal
of trifluoroacetophenone 3b under BF3‚OEt2 activation (Scheme
1). The corresponding R-amino nitriles 4a and 4b were obtained
in 91 and 87% yields, respectively.
To investigate the scope of this reaction in the asymmetric
series, we turned our attention to chiral 2-trifluoromethylox-
azolidines, which are stable fluorinated chiral iminium precur-
sors under Lewis acid activation.4a,7 These oxazolidines were
very conveniently prepared from fluoral or trifluoromethyl
ketones and commercially available amino alcohols.9 The
oxazolidines were obtained in high yield as stable diastereomeric
mixtures. In a preliminary account,4a we have reported that the
same iminium is formed in situ starting from both oxazolidines
under a Lewis acid activation. So their separation is useless,
(10) Andres, C.; Maestro, A.; Pedrosa, R.; Perez-Encabo, A.; Vicente,
M. Synlett 1992, 45-47.
(11) (a) Chakraborty, T. K.; Hussain, K. A.; Reddy, G. V. Tetrahedron
1995, 51, 9179-9190. (b) Inaba, T.; Kozono, I.; Fujita, M.; Ogura, K. Bull.
Chem. Soc. Jpn. 1992, 65, 2359-2365. (c) Zhu, J.; Bouillon, J.-P.; Singh,
G. P.; Chastanet, J.; Bengelmans, R. Tetrahedron Lett. 1995, 36, 7081-
7084. (d) Hosangadi, B. D.; Dave, R. H. Tetrahedron 1999, 55, 11295-
11308. (e) Ma, D.; Tian, H.; Zou, G. J. Org. Chem. 1999, 64, 120-125.
(f) Vedejs, E.; Kongkittingam, C. J. Org. Chem. 2001, 66, 7355-7364. (g)
Truong, M.; Lecornue, F.; Fadel, A. Tetrahedron: Asymmetry 2003, 14,
1063-1072.
(9) (a) Higashiyama, K.; Ishii, A.; Mikami, K. Synlett 1997, 1381-1382.
(b) Ishii, A.; Miyamoto, F.; Higashiyama, K.; Mikami, K. Tetrahedron Lett.
1998, 39, 1199-1202. (c) Gosselin, F.; Roy, A.; O’Shea, P. D.; Chen, C.-
y.; Volante, R. P Org. Lett. 2004, 6, 641-644.
7076 J. Org. Chem., Vol. 71, No. 18, 2006

SCHEME 2a
TABLE 3. Strecker-type Reactions of Oxazolidines 7a-e Derived
from (R)-Phenylglycinol
oxazolidine
(R1, R2)
Lewis
acid
yield
entry
dr
product (%)a
drb
1c
2
3
4
5
7a (H, H)
7a (H, H)
7a (H, H)
7a (H, H)
7a (H, H)
7b (H, Bn)
7c (H, Bz)
7d (Ph, H)
62:38 Yb(OTf)3
62:38 BF3‚OEt2
d,e
f
8a
8a
8a
8a
8b
90
87
87
84
87
83:17
82:18
81:19
83:17
50:50
62:38 TMSOTfg
87:13 TMSOTfg,h,i
20:80 TMSOTfg,i
f
6
67:33 BF3‚OEt2
f
7c
8
100:0
71:29 BF3‚OEt2
BF3‚OEt2
f
f
8d
2e
97
91
72:28
54:46
9
7e (CH3, H) 100:0
BF3‚OEt2
1
a Isolated yield. b Measured by 19F and H NMR of the crude reaction
mixture. c No reaction. d 0.2 equiv. e No reaction occurred also with La(OTf)3
(0.2 equiv) and Ti(OiPr)4 (1.5 equiv). f 1.5 equiv, 0 °C to rt. g 0.1 equiv,
-78 °C to rt. h Same yield and diastereoselectivity was achieved with 1.5
equiv. i Similar diastereoselectivity was achieved with BF3‚Et2O.
should be prevented by the combined electron-withdrawing
effect of the trifluoromethyl group and the amide function. The
Strecker-type reaction was then successfully extended to the
trifluoromethyl ketone-derived oxazolidines 7d,e, giving the
corresponding quaternary amino nitriles 8d and 2e in high yields
(Table 3, entries 8 and 9). A very interesting feature of all these
(R)-phenylglycinol-based amino nitriles was that both diaster-
eomers were very easily separated by chromatography on silica
gel (eluent: petroleum ether/ethyl acetate 85:15). For example,
with this eluent system, the Rf value difference between (R,R)-
2e and (S,R)-2e was 0.27. Even if the stereoselectivity of the
Strecker reaction was low, it constitutes a powerful strategy for
the synthesis of both amino nitrile diastereomers in enantiopure
form from the unique (R)-phenylglycinol chiral auxiliary.
We already reported that the R-amino nitrile (R,R)-8a was a
precursor of enantiomerically enriched (R)-trifluoroalanine.4a We
wish to report here the straightforward synthesis of enantiopure
(R)- and (S)-R-trifluoromethyl alanine from the corresponding
R-amino nitriles (Scheme 2). Several biological applications of
enantiomerically pure R-trifluoromethyl alanine were recently
reported,1g,12 and its efficient preparation in enantiopure form
is of considerable interest.13
a Reagents and conditions: (a) MeOH, HClg, 6 h reflux; (b) H2, Pd(OH)2,
MeOH then 1 N HCl; (c) 6 N HCl, AcOH; (d) propene oxide; (e)
concentrated HCl, 14 h reflux.
SCHEME 3
at same time. The optical rotation and the spectroscopic data
of (R)-11e and (S)-11e were identical to those reported in the
literature.13a
The (R)-R-trifluoromethyl alanine 12e was obtained in 66%
yield from the amino nitrile (R,R)-2e through a three-step
procedure involving the methanolysis of the nitrile, hydro-
genolysis of the phenylglycinol side chain, and hydrolysis of
the ester function. The (S)-R-trifluoromethyl alanine hydrochlor-
ide (S)-12e was obtained in 60% yield in only one step by
concentrated HCl treatment of the amino nitrile (S,R)-2e. The
removal of the side chain and hydrolysis of the nitrile occurred
Our second objective to exhibit the high versatility of chiral
R-trifluoromethyl R-amino nitriles was to demonstrate their easy
transformation into enantiopure diamines and amino alcohols.
These target compounds are interesting fluorinated synthons and
potential ligands for organometallic chemistry. The lithium
aluminum hydride reduction of diastereomerically pure isolated
R-amino nitriles 8a,d and 2e gave the corresponding diastereo-
merically pure diamino alcohols 13a,d,e in 72-98% isolated
yield (Scheme 3). As both (R,R) and (S,R) starting materials
are readily available, both diastereomers of diamino alcohol
13d,e were obtained. Furthermore, these two diamino alcohols
proved to be very easily converted into the corresponding
diastereomerically pure (R,R) and (S,R) amino diols 14e through
a diazotization reaction (Scheme 4).
(12) Margiotta, N.; Papadia, P.; Lazzaro, F.; Crucianelli, M.; De Angelis,
F.; Pisano, C.; Vesci, L.; Natile, G. J. Med. Chem. 2005, 48, 7821-7828.
(13) (a) Bravo, P.; Capelli, S.; Meille, S. V.; Viani, F.; Zanda, M.;
Kukhar, V. P.; Soloshonok, V. A. Tetrahedron: Asymmetry 1994, 5, 2009-
2018. (b) Asensio, A.; Bravo, P.; Crucianelli, M.; Farina, A.; Fustero, S.;
Soler, J. G.; Meille, S. V.; Panzeri, W.; Viani, F.; Volonterio, A.; Zanda,
M. Eur. J. Org. Chem. 2001, 1449-1458. (c) Bravo, P.; Crucianelli, M.;
Vergani, B.; Zanda, M. Tetrahedron Lett. 1998, 39, 7771-7774. (d) Koksch,
B.; Quaedflieg, P. J. L. M.; Michel, T.; Burger, K.; Broxterman, Q. B.;
Schoemaker, H. E. Tetrahedron: Asymmetry 2004, 15, 1401-1407.
To obtain the corresponding novel enantiopure unprotected
fluorinated diamines, the removal of the phenylglycinol side
J. Org. Chem, Vol. 71, No. 18, 2006 7077

SCHEME 4
was stirred at room temperature until disappearance of the starting
material (14 h, GC monitoring). The reaction mixture was then
poured into a saturated aqueous solution of NaHCO3 (25 mL). The
aqueous layer was extracted with dichloromethane (3 × 25 mL),
and the combined organic extracts were dried over Na2SO4, filtered,
and concentrated under reduced pressure. Purification by flash
chromatography (85:15 petroleum ether/ethyl acetate) gave pure
isolated fractions of (R,R)-2e (634 mg, 49%) and (S,R)-2e (540
mg, 42%). (R,R)-2e: Rf ) 0.46. Pale yellow oil; [R]20 -144.6°
D
(c 1.0, CHCl3); IR (neat) 3329, 3032, 2937, 1603, 1455, 1174 cm-1
;
1H NMR δ 1.33 (s, 3H), 1.86 (dd, J ) 7.3, 4.4 Hz, 1H), 2.84 (s,
1H), 3.51 (ddd, J ) 11.2, 9.2, 7.3 Hz, 1H), 3.81 (dt, J ) 11.2, 4.4
Hz, 1H), 4.12 (dd, J ) 9.2, 4.4 Hz, 1H), 7.20-7.50 (m, 5H); 13C
NMR δ 20.2, 59.9 (q, J ) 30.3 Hz), 61.2, 66.8, 116.5, 123.1 (q, J
) 283.6 Hz), 127.0, 128.0, 128.7, 140.3; 19F NMR δ -79.8 (s);
MS (EI 70 eV) m/z 258 (M+), 227, 200 (100), 162, 120, 77. Anal.
Calcd for C12H13F3N2O: C, 55.81; H, 5.07; N, 10.85. Found: C,
SCHEME 5
55.45; H, 5.15; N, 10.51. (S,R)-2e: Rf ) 0.19. Yellow solid; mp
1
81-83 °C; [R]20 -93° (c 0.6, CHCl3); H NMR δ 1.75 (s, 3H),
D
1.88 (dd, J ) 6.6, 5.6 Hz, 1H), 2.45 (d, J ) 6.0 Hz, 1H), 3.59
(ddd, J ) 11.3, 7.8, 5.6 Hz, 1H), 3.83 (ddd, J ) 11.3, 6.6, 4.5 Hz,
1H), 4.15 (ddd, J ) 7.8, 6.0, 4.5 Hz, 1H), 7.30-7.50 (m, 5H); 13
C
NMR δ 20.3, 58.3 (q, J ) 30.3 Hz), 60.9, 66.8, 116.2, 123.0 (q, J
) 285.0 Hz), 126.9, 127.9, 128.5, 139.2; 19F NMR δ -78.6 (s).
Representative Procedure for the Reduction of Amino Ni-
triles: 3,3,3-Trifluoro-2-((1R)-2-hydroxy-1-phenylethylamino)-
propylamine ((R,R)-13a). To a solution of amino nitrile (R,R)-8a
(240 mg, 1 mmol) in dry diethyl ether (27 mL) was added LiAlH4
(160 mg, 4 mmol) at 0 °C. The mixture was stirred for 24 h at
room temperature, and the reaction mixture was hydrolyzed by
successive addition of water (0.2 mL), 15% KOH (0.2 mL), and
water (0.4 mL). The resulting precipitate was filtered on Celite.
The organic layer was dried over Na2SO4 and concentrated under
reduced pressure. The crude product was purified by recrystalli-
zation in pentane to give (R,R)-13a (198 mg, 80%) as a white
solid: mp 95-96 °C; [R]20D -38.7° (c 1.1, CHCl3); IR (KBr) 3625,
chain was carried out. This was done in good yields by Pb-
(OAc)4 treatment of the diamino alcohols 13a,e followed by 3
N HCl hydrolysis. The target R-trifluoromethyl diamines (R)-
15a, (R)-15e, and (S)-15e were conveniently obtained in
enantiopure form as their hydrochlorides (Scheme 5).
In conclusion, we have developed a straightforward synthetic
route for the synthesis of both enantiomers of R-trifluoromethyl
alanine and various enantiopure diamines and amino alcohols
from trifluoromethyl R-amino nitriles as key intermediates.
Despite the moderate diastereoselectivity of the Strecker-type
reaction, the high efficiency of the chromatographic separation
of each R-amino nitrile diastereomer assisted by the (R)-
phenylglycinol side chain allowed the very convenient synthesis
of enantiopure compounds.
1
3344, 3010, 2930, 1454, 1219 cm-1; H NMR δ 2.84 (dd, J )
13.2, 7.6 Hz, 1H), 3.09 (dd, J ) 13.2, 4.2 Hz, 1H), 3.25 (qdd, J )
8.1, 7.6, 4.2 Hz, 1H), 3.68 (dd, J ) 11.3, 7.8 Hz, 1H), 3.80 (dd, J
) 11.3, 3.8 Hz, 1H), 4.00 (dd, J ) 7.8, 3.8 Hz, 1H), 7.20-7.50
(m, 5H); 13C NMR δ 38.9, 58.6 (q, J ) 26.5 Hz), 62.6, 67.1, 126.1
(q, J ) 282.7 Hz), 127.3, 127.6, 128.4, 140.2; 19F NMR δ -75.4
(d, J ) 8.1 Hz); MS (EI 70 eV) m/z 248 (M+), 217, 189, 168 (100),
121, 77. Anal. Calcd for C11H15F3N2O: C, 53.22; H, 6.09; N, 11.28.
Found: C, 53.48; H, 6.27; N, 11.18.
Acknowledgment. The authors thank the MRT for the grant
to F.H., and Central Glass Company for the generous gift of
trifluoroacetaldehyde hemiacetal.
Experimental Section
Representative Procedure for the Preparation of Amino
Nitriles from Oxazolidines: 3,3,3-Trifluoro-2-((1R)-2-hydroxy-
1-phenylethylamino)-2-methylpropionitrile (2e). To a solution
of oxazolidines 7e (1.15 g, 5 mmol) in dichloromethane (50 mL)
under argon were added cyanotrimethylsilane (0.94 mL, 7.5 mmol)
and BF3‚OEt2 (0.9 mL, 7.5 mmol) at 0 °C. The reaction mixture
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.
JO0607717
7078 J. Org. Chem., Vol. 71, No. 18, 2006