Pigza et al.
JOCArticle
using the Harwood conditions7j to afford the desired mor-
pholinone with high diastereoselectivity ((2S,4S)-21, dr 19:1
by HPLC, 67% yield). Operationally, it was more convenient
to hydrogenate unenriched 4 (dr 4:1) since the epimers of 21
were now readily separated by flash chromatography, in
contrast to 4.
(SiO2, 3:37 EtOAc:hexanes) to give oxazinone 3 (75.6 mg, 65%,
dr7:1)asa yellowoil;FTIR (ATR, neat)ν 3065, 3033, 3000, 2952,
2894, 1742, 1645, 1497, 1456, 1384, 1342, 1308, 1260, 1224, 1172,
1115, 1078, 1049, 1037, 1030, 1001, 984, 920, 870, 819, 795, 758,
697, 670, 662 cm-1; [R]20D -110 (c 1.20, CHCl3); 1H NMR (400
MHz, CDCl3) δ 7.46-7.29 (m, 5H), 5.06 (dd, J=9.2, 4.4 Hz, 1H),
4.64 (dd, J=11.6, 4.4 Hz, 1H), 4.31 (dd, J=11.6, 9.2 Hz, 1H), 4.16
(m, 1H), 1.49 (d, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
159.0 (C), 154.6 (C), 136.2 (C), 129.4 (CH), 128.8 (CH), 127.2
(CH), 126.1 (q, J=281 Hz, CF3), 71.4 (CH2), 59.9 (CH), 41.1 (q,
J=28.2Hz, CH), 12.7(CH3);HREIMSm/z [M]+ 271.0812, calcd
for C13H12F3NO2 271.0815.
Cleavage of the auxiliary was performed in two steps.
Hydrogenolysis (H2, 6 atm) in the presence of CF3CO2H and
20
Pd(OH)2 followed by subjection of the crude material
to stronger hydrolysis conditions (6 M HCl, reflux, 14 h)
provided the HCl salt of 2. The salt was purified by ion-
exchange chromatography (strong cationic resin, H+ form,
elution with 2 M NH4OH) to provide enantiomerically pure
free amino acid, (2S,4S)-trifluoroleucine (2), after removal
(3S,5R)-5-Phenyl-3-((S)-1,1,1-trifluoropropan-2-yl)morpho-
lin-2-one (17). A mixture of oxazinone 3 (dr 7:1, 16.6 mg, 61.2
μmol) and PtO2 (9.7 mg, 39.6 μmol) in PhCF3 (1.5 mL) was
evacuated twice and then stirred under 1 atm of H2 for 1.5 h. The
reaction mixture was filtered through cotton wool and concen-
trated under reduced pressure to give the crude product. Purifica-
tion by flash chromatography (SiO2, 1:19 f 1:9 EtOAc:hexanes)
gave morpholinone 17 (9.1 mg, 54%) as a colorless oil; FTIR
(ATR, neat) ν 3338, 3065, 3033, 2989, 2952, 2917, 2848, 1737,
1497, 1458, 1407, 1389, 1371, 1323, 1288, 1260, 1208, 1178, 1154,
1118, 1092, 1069, 1040, 996, 977, 920, 875, 802, 782, 760, 701, 665
cm-1;[R]20D -57.6 (c 2.755, CH2Cl2);1H NMR(500 MHz, C6D6)
δ 7.04-7.02 (m, 3H), 6.96-6.94 (m, 2H), 3.86 (m, 1H), 3.68 (td,
J=10.6, 1.8 Hz, 1H), 3.61 (dq, J=10.6, 3.0 Hz, 1H), 3.34 (m, 1H),
3.27 (m, 1H), 1.44 (br s, 1H), 1.11 (d, J=6.9 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 167.3 (C), 137.1 (C), 129.0 (CH), 128.9
(CH), 127.7 (q, J=278 Hz, CF3), 127.1 (CH), 74.9 (CH2), 58.5 (d,
J=2.3 Hz, CH), 56.7 (CH), 40.5 (q, J = 25.8 Hz, CH), 8.37
(d, J = 2.3 Hz, CH3); HREIMS m/z [M]+ 273.0970, calcd for
C13H14F3NO2 273.0971. HPLC analysis (silica 5 μm, 250 Â
4.6 mm, 3:7 Et2O:hexanes, flow rate =1 mL/min, UV detection
atλ =210, 220nm) showed a retentiontime oftR=5.7 min for 17.
Repeating the reaction with 3 as a single diastereomer gave
a mixture of products that was analyzed under the HPLC
conditions described above. Integration of the peaks for 17
(tR= 5.7 min) and 3-epi-17 (tR = 13.7 min) indicated a dr of 3:1.
(2S,3S)-4,4,4-Trifluorovaline (1). A mixture of morpholinone
17 (51.5 mg, 0.188 mmol), Pd(OH)2 (20% Pd content, 25.1 mg,
0.0471 mmol), and 2.4 M HCl (314 μL, 0.753 mmol) in MeOH
(6 mL) and H2O (0.4 mL) contained in a thick-walled flask was
shaken under 90 psi (6 atm) of H2 for 2 h with use of a Parr
hydrogenation apparatus. The reaction mixture was filtered
through a pad of diatomaceous earth and concentrated under
reduced pressure, then redissolved in 6 M HCl (6 mL) and
heated at 110 °C for 20 h. The reaction mixture was again
1
of the volatiles. The H and 19F NMR data and optical
rotations of both the free amino acid and the hydrochloride
salt of 2 matched the corresponding literature values.5a,5e
Comparison of the syntheses of amino acids 1 and 2
reveals both advantages of the oxazoline-oxazinone rear-
rangement approach and liabilities when the CF3 group is
close to the R-carbon. The dipole associated with the CF3
group diminishes diastereoselectivity in the heterogeneous
catalytic reduction of both trifluoromethyl-substituted al-
kene 11 and imine 3.
In addition, the electron-withdrawing effect of a β-CF3
group appears to promote acid-catalyzed imine-enamine
equilibration of 3, which further erodes the configurational
composition at the β-stereocenter. These effects are absent
in the synthesis of 2 where the CF3 group is removed to the
γ-position and insulated from the R-center by a CH2 group.
Nevertheless, with judicious choice of conditions it may be
possible to exploit the enamine-imine equilibration in 3 for
additional reactions, including dynamic kinetic resolution,
incorporation of isotopic label (e.g., 2H, 3H) at the β-center,
or additional C-C bond forming reactions for preparation
of homologated trifluorovaline analogues. Finally, it should
be mentioned that both 1 and 2 appear to have good
configurational stability upon exposure to standard hydro-
lytic conditions for amino acids (6 M HCl, 110 °C).
In summary, the stereoselective syntheses of amino acids
(2S,3S)-1 and (2S,4S)-2 have been achieved from a common
precursor (3S)-12, derived from commercially available (E)-
4,4,4-trifluoro-3-methylbut-2-enoic acid (9). This method is
applicable to the synthesis of any of the four diastereomers of
1 and 2 by appropriate choice of configurations of the chiral
auxiliaries: the Oppolzer sultam to control the CF3-substi-
tuted stereocenter (Scheme 2) and the phenylglycinol to
control the C2 stereocenter (Schemes 3 and 4).
concentrated under reduced pressure to give 1 HCl (40.0 mg) as
3
an orange solid; [R]24D +7.0 (c 1.0, 1.0 N HCl) (lit.5a,5b [R]24
+
D
7.2 (c 0.75, 1.0 N HCl)); 1H NMR (500 MHz, D2O) δ 4.33 (d,
J = 2.6 Hz, 1H), 3.25 (m, 1H), 1.21 (d, J = 7.4 Hz, 3H); 19F
NMR (471 MHz, D2O/1% CF3CO2H) δ -71.62 (s) (lit.5a 19
F
NMR (283 MHz, D2O/CF3CO2H) δ -71.69 (d, J = 9.3 Hz)).
Ion-exchange chromatography (strong cation-exchange resin,
200-400 dry-mesh, H+ form, eluting with 2.0 M NH4OH) gave
Experimental Section
amino acid (2S,3S)-1 (28.7 mg, 89%) as a white solid; [R]22
+
D
For general procedures and experimental data for all new
compounds, refer to the Supporting Information.
1
0.22 (c 1.0, H2O); H NMR (500 MHz, D2O) δ 4.08 (d, J =
2.3 Hz, 1H), 3.16 (m, 1H), 1.18 (d, J = 7.5 Hz, 3H); HRESIMS
m/z [M + H]+ 172.0579, calcd for C5H9F3NO2 172.0580.
(R)-5-Phenyl-3-((R)-3,3,3-trifluoro-2-methylpropyl)-5,6-dihy-
dro-2H-1,4-oxazin-2-one (4). SeO2 (40.9 mg, 369 μmol) was
added to oxazoline 20 (50.0 mg, 184 μmol) in 1,4-dioxane
(1.8 mL) in a 10 mL microwave reaction vessel with cap and
heated at 90 °C under microwave irradiation for 5 min. The
reaction was cooled to 60 °C and then filtered through magne-
sium silicate (200 mesh) with Et2O. The filtrate was concentra-
ted and directly purified by flash chromatography (SiO2, 8:92f
12:88 f 15:85 EtOAc:hexanes) to provide oxazinone 4 (32.8 mg,
(R)-5-Phenyl-3-((S)-1,1,1-trifluoropropan-2-yl)-5,6-dihydro-
2H-1,4-oxazin-2-one (3). A solution of oxazoline 15 (110 mg,
0.428mmol) in1,4-dioxane(1.4mL) was addedtoa suspensionof
SeO2 (94.9 mg, 0.855 mmol) in 1,4-dioxane (1.4 mL) and the
mixture was heated at reflux for 50 min. The reaction mixture
was cooled tort andthen filteredthrough magnesium silicate (200
mesh). Evaporation of the solvent under reduced pressure gave
the crude product, which was purified by flash chromatography
(20) Harwood, L. M.; Tyler, S. N. G.; Anslow, A. S.; MacGilp, I. D.;
Drew, M. G. B. Tetrahedron: Asymmetry 1997, 8, 4007.
5514 J. Org. Chem. Vol. 74, No. 15, 2009