Oxazoline-oxazinone oxidative rearrangement. Divergent syntheses of (2S,3S)-4,4,4-trifluorovaline and (2S,4S)-5,5,5-trifluoroleucine

Article abstract of DOI:10.1021/jo900654y

(Chemical Equation Presented) Stereoselective syntheses of the valuable fluorinated amino acids (2S,3S)-4,4,4-trifluorovaline and (2S,4S)-5,5,5- trifluoroleucine have been achieved starting from 4,4,4-trifluoro-3- methylbutanoic acid by using a conceptual

Full text of DOI:10.1021/jo900654y

pubs.acs.org/joc
Oxazoline-Oxazinone Oxidative Rearrangement. Divergent Syntheses
of (2S,3S)-4,4,4-Trifluorovaline and (2S,4S)-5,5,5-Trifluoroleucine
Julie A. Pigza, Tim Quach, and Tadeusz F. Molinski*
The Department of Chemistry and Biochemistry and Skaggs School of Pharmacy and Pharmaceutical
Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093
tmolinski@ucsd.edu
Received March 31, 2009
Stereoselective syntheses of the valuable fluorinated amino acids (2S,3S)-4,4,4-trifluorovaline and
(2S,4S)-5,5,5-trifluoroleucine have been achieved starting from 4,4,4-trifluoro-3-methylbutanoic
acid by using a conceptually simple transformation: conversion to a chiral oxazoline, SeO2-promoted
oxidative rearrangement to the dihydro-2H-oxazinone, and face-selective hydrogenation of the CdN
bond, followed by hydrogenolysis-hydrolysis. The transformation is limited by the tendency of the
intermediate β-trifluoromethyldihydrooxazinone to undergo imine-enamine isomerization. Both
amino acids were obtained as configurationally pure hydrochloride salts identical in all respects with
those in literature reports.
Introduction
fluorous forces.4f Most protein biosynthesis studies use
commercially available, unresolved mixed isomers of tri-
fluorovaline and trifluoroleucine for incorporation studies.
Although it has been shown that only the (2S,3R)-isomer of
4,4,4-trifluorovaline is selected by Val t-RNA in protein
biosynthesis,4d it is not clear that this selection would be
preserved in nonribosomal peptide syntheses that generate
natural product peptides. In our biosynthetic studies of
marine natural product peptides, we required diastereomeri-
cally pure isomers of fluorinated valine and leucine. Synth-
eses of trifluorovaline and trifluoroleucine has been reported
by several research groups,5 including Kumar and co-work-
ers, who resolved all four diastereomers of both amino acids
using a combination of chromatography and lipase-
mediated hydrolysis of the corresponding N-acyl amino
acids.5a,5b
Fluorinated amino acids have attracted attention as en-
zyme inhibitors1 and antitumor and antibacterial agents.2
Trifluoro analogues of proteinogenic amino acids (e.g.,
diastereomers of L-4,4,4-trifluorovaline and L-5,5,5-trifluor-
oleucine) have attracted particular interest in protein struc-
tural biology3 owing to their isosteric compatibility with
their natural counterparts, incorporation into proteins under
control of cellular ribosomal protein assembly, and their
ability to induce altered secondary structure.3c,4 For exam-
ple, fluorinated leucine participates in leucine coiled coil
motifs that favor homologous association by attractive
(1) Kollonitsch, J.; Patchett, A. A.; Marburg, S.; Maycock, A. L.;
Perkins, L. M.; Doldouras, G. A.; Duggan, D. E.; Aster, S. D. Nature
1978, 274, 906.
In this paper, we present a flexible approach to the
synthesis of (2S,3S)-4,4,4-trifluorovaline (1) and (2S,4S)-
5,5,5-trifluoroleucine (2) through a conceptually simple
transformation (Figure 1): carboxylic acids i to amino acids
(2) Tsushima, T.; Kawada, K.; Ishihara, S.; Uchida, N.; Shiratori, O.;
Higaki, J.; Hirata, M. Tetrahedron 1988, 44, 5375.
(3) (a) Bilgic-er, B.; Xing, X.; Kumar, K. J. Am. Chem. Soc. 2001, 123,
11815. (b) Xing, X.; Fichera, A.; Kumar, K. Org. Lett. 2001, 3, 1285 and
references cited therein. (c) Yoder, N. C.; Kumar, K. Chem. Soc. Rev. 2002,
31, 335.
(4) (a) Hagan, D. O.; Rzepa, H. S. Chem. Commun. 1997, 645. (b)
Resnati, G. Tetrahedron 1993, 49, 9385. (c) Tang, Y.; Ghirlanda, G.; Vaidehi,
N.; Kua, J.; Mainz, D. T.; Goddard, W. A. III; DeGrado, W. F.; Tirrell, D.
A. Biochemistry 2001, 40, 2790. (d) Wang, P.; Fichera, A.; Kumar, K.; Tirrell,
D. A. Angew. Chem., Int. Ed. 2004, 43, 3664. (e) Montclare, J. K.; Son, J.;
Clark, G.; Kumar, K.; Tirrell, D. ChemBioChem 2009, 10, 84. (f) Yoder, N.;
(5) (a) Xing, X.; Fichera, A.; Kumar, K. J. Org. Chem. 2002, 67, 1722.
(b) Xing, X.; Fichera, A.; Kumar, K. J. Org. Chem. 2002, 67, 8290
(correction to ref 5a). (c) Chen, Q.; Qiu, X.-L.; Qing, F.-L. J. Org. Chem.
2006, 71, 3762. (d) Matsumura, Y.; Urushihara, M.; Tanaka, H.; Uchida, K.;
Yasuda, A. Chem. Lett. 1993, 1255. (e) Weinges, K.; Kromm, E. Liebigs Ann.
Chem. 1985, 90.
€
Yuksel, D.; Dafik, L.; Kumar, K. Curr. Opin. Chem. Biol. 2006, 10, 576.
5510 J. Org. Chem. 2009, 74, 5510–5515
Published on Web 06/18/2009
DOI: 10.1021/jo900654y
r
2009 American Chemical Society

Pigza et al.
JOCArticle
SCHEME 1. Retrosynthetic Analysis of 1 and 2
FIGURE 1. Generalized approach to amino acids via oxazoline-
oxazinone rearrangement.
ii, via our previously reported6 oxidative rearrangement of
oxazolines iii to dihydro-2H-oxazinones iv (hereafter, re-
ferred to as “oxazinones”), followed by hydrogenolysis-
hydrolysis.
The use of phenylglycinol-derived oxazinones, morpholi-
nones (dihydro-iv), and 5,6-diphenylmorpholinones as chiral
auxiliaries for amino acid syntheses have been widely re-
ported.7 Whereas the preparations of oxazinone auxiliaries
in several of these reports required 4-6 step syntheses for
each desired R-amino acid,7g,7h the transformation of iii to iv
via the oxazoline-oxazinone rearrangement gives facile
access to the requisite morpholinone after hydrogenation
of iv. The advantage offered by this approach is maximum
flexibility for the synthesis of virtually any nonpolar R-amino
acid starting with a simple alkanoic acid. Since both the
oxidative rearrangement and hydrogenation steps are parti-
cularly efficient in the preparation of β-branched amino
acids,6a,7k it was attractive to investigate their utility in the
preparation of fluorinated analogues of the nonpolar amino
acids valine and leucine.
amides 5 and 6 derived from (R)-phenylglycinol and opti-
cally enriched carboxylic acids (S)-78 and (S)-8, respectively.
The preparation of the common precursor to the optically
active carboxylic acids (S)-7 and (S)-8 is depicted in
Scheme 2. N-Acylation of Oppolzer’s (-)-sultam (10)9 using
the acid chloride derived from commercially available (E)-
4,4,4-trifluoro-3-methylbut-2-enoic acid (9) provided 119d in
49% yield.10 The CF3 stereocenter was then introduced by
hydrogenation of 11 under heterogeneous catalysis (Pd-C,
H2, 6 atm, EtOH, 1.5 h). However, the major isomer (3S)-12
was obtained with only moderate diastereoselectivity (dr 4:1)
in contrast to hydrogenation of the nonfluorinated N-croto-
nyl sultam (dr 20:1).11 The configuration of the newly
established stereocenter was proved by reductive cleavage
of the sultam auxiliary (LiAlH4)12 to provide known alcohol
Results and Discussion
The antithetical work flow for the preparation of (2S,3S)-
1 and (2S,4S)-2 is outlined in Scheme 1. The R-stereocenter
of 1 and 2 is installed by face-selective hydrogenation7j,7k of
oxazinones 3 and 4, respectively, directed by a phenylglyci-
nol-derived auxiliary. Oxazinones 3 and 4 can be obtained by
SeO2-mediated oxidative rearrangement6 of the correspond-
ing oxazolines. The oxazolines, in turn, originate from
(-)-(S)-13 ([R]22D -8.9, c 2.0, CHCl3, 60% ee; lit.5e [R]20
7.3, c 1.3, CHCl3, 42% ee).
-
D
(6) (a) Shafer, C. M.; Molinski, T. F. J. Org. Chem. 1996, 61, 2044. (b)
Shafer, C. M.; Morse, D. I.; Molinski, T. F. Tetrahedron 1996, 52, 14475.
(7) Alkylation of morpholinones: (a) Williams, R. M.; Sinclair, P. J.;
Zhai, D.; Chen, D. J. Am. Chem. Soc. 1988, 110, 1547. (b) Williams, R. M.
Aldrichim. Acta 1992, 25, 11. (c) Dellaria, J. F.; Santarsiero, B. D. J. Org.
Chem. 1989, 54, 3916. (d) Currie, G. S.; Drew, M. G. B.; Harwood, L. M.;
Hughes, D. J.; Luke, R. W. A.; Vickers, R. J. J. Chem. Soc., Perkin Trans 1,
2000, 2982. Alkylation of 6H-oxazinones: (e) Chinchilla, R.; Falvello, L. R.;
Galindo, N.; Najera, C. Angew. Chem., Int. Ed. Engl. 1997, 36, 995.
(f) Chinchilla, R.; Galindo, N.; Najera, C. Synthesis 1999, 704. Nucleophilic
addition to oxazinones: (g) Tohma, S.; Rikimaru, K.; Endo, A.; Shimamoto,
K.; Kan, T.; Fukuyama, T. Synthesis 2004, 909. (h) Chen, Y.-J.; Lei, F.; Liu,
L.; Wang, D. Tetrahedron 2003, 59, 7609. (i) Harwood, L. M.; Vines, K. J.;
Drew, M. G. B. Synlett 1996, 1051. Hydrogenation of substituted oxazi-
nones: (j) Cox, G. G.; Harwood, L. M. Tetrahedron: Asymmetry 1994, 5,
1669. (k) Liu, C.; Masuno, M. N.; MacMillan, J. B.; Molinski, T. F. Angew.
Chem., Int. Ed. 2004, 43, 5951. (l) Vigneron, J. P.; Kagan, H.; Horeau, A.
Tetrahedron Lett. 1968, 9, 5681. Cycloadditions onto morpholinone-derived
ylides or oxazinones: (m) Harwood, L. M.; Macro, J.; Watkin, D.; Williams,
C. E.; Wong, L. F. Tetrahedron: Asymmetry 1992, 3, 1127. (n) Chinchilla, R.;
Falvello, L. R.; Galindo, N.; Najera, C. Eur. J. Org. Chem. 2001, 3133. (o)
Ager, D.; Cooper, N.; Cox, G. G.; Garro-Helion, F.; Harwood, L. M.
Tetrahedron: Asymmetry 1996, 7, 2563. Radical addition to oxazinones: (p)
Bertrand, M. P.; Feray, L.; Nouguier, R.; Stella, L. Synlett 1998, 780. (q)
Ueda, M.; Miyabe, H.; Teramachi, M.; Miyata, O.; Naito, T. Chem.
Commun. 2003, 426.
Attempts were made to improve the diastereoselectivity of
the reduction of N-acyl sultam 11 (see Table 1) under other
conditions. Changing the solvent gave no significant
improvement (entries 1 and 2), while 1,4-conjugate reduc-
11
tion with either L-Selectride or LiAlH4/CoCl2 also gave
(8) (()-7: (a) Loncrini, D. F.; Walborsky, H. M. J. Med. Chem. 1964, 7,
369. (b) Walborsky, H. M.; Baum, M.; Loncrini, D. F. J. Am. Chem. Soc.
1955, 77, 3637. Optically enriched 7: (c) Uemura, T.; Zhang, X.; Matsumura,
K.; Sayo, N.; Kumobayashi, H.; Ohta, T.; Nozaki, K.; Takaya, H. J. Org.
Chem. 1996, 61, 5510. (d) Zhang, X.; Uemura, T.; Matsumura, K.; Sayo, N.;
Kumobayashi, H.; Takaya, H. Synlett 1994, 61, 501.
(9) (a) Bartlett, P. D.; Knox, L. H. Organic Syntheses; Wiley: New York,
1973; Collect. Vol. V, p 196; Vol. 45, 1965, p.14. (b) Davis, F. A.; Towson, J. C.;
Weismiller, M. C.; Lal, S.; Carroll, P. J. J. Am. Chem. Soc. 1988, 110, 8477. (c)
Oppolzer, W. Pure Appl. Chem. 1990, 62, 1241. (d) Vallgarda, J.; Appelberg, U.;
Csoregh, I.; Hacksell, U. J. Chem. Soc., Perkin Trans. 1 1994, 461.
(10) The trans configuration of the double bond was assigned based on
the absence of NOE enhancements in either the methyl or vinyl proton upon
irradiation of the other signal.
(11) Oppolzer, W.; Mills, R. J.; Reglier, M. Tetrahedron Lett. 1986, 27,
183.
(12) Vandewalle, M.; Van der Eycken, J. Tetrahedron 1986, 42, 4035.
J. Org. Chem. Vol. 74, No. 15, 2009 5511

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SCHEME 2. Synthesis of N-Acyl Sultam 12
TABLE 1. Reductions of N-Acyl Sultam 11
entry
conditions
temp
time (h)
conversiona
dr 3S:3Rb
1
2
3
4
5
6
7
8
9
H2, Pd/C, CF3CH2OHc
rt
rt
rt
rt
rt
1.5
1.5
1.5
2.0
1.5
1.5
1.2
12.0
0.5
0.5
0.5
0.2
100
100
100
100
100
100
59
4.2:1
1.7:1
5.0:1
9.6:1
8.8:1
7.2:1
1:1.4f
2.8:1f
---
H2, Pd/C, hexanesc
H2, Pd/BaSO4, EtOHc
CeCl3 7H2O (5 equiv), H2, Pd/C, EtOHc
3
CoCl2 6H2O (5 equiv), H2, Pd/C, EtOHc
3
MgCl2 (5 equiv), H2, Pd/C, EtOHc
L-Selectride (1.2 equiv), THFd
rt
-78 to -40 °C
-78 °C to rt
-20 °C
-20 °C
-50 °C
-5 °C
CoCl2 (2.4 equiv), LiAlH4 (1.2 equiv), THFe
NaBH4 (10 equiv), THF
NiCl2 6H2O (2 equiv), NaBH4 (10 equiv), MeOH
52
100g
100
100
100
10
11
12
9.8:1
4.4:1
8.5:1
3
NiCl2 6H2O (2 equiv), NaBH4 (10 equiv), MeOH
NiCl2 6H2O (2 equiv), NaBH4 (10 equiv), MeOH
3
3
a Conversions were calculated from NMR integration of the crude product. b Diastereoselectivity was determined from chiral HPLC; see the
Supporting Information for full details. c 6 atm of H2. d L-Selectride (1.2 equiv) and BF3 OEt2 (1.2 equiv) did not improve the dr or conversion.
3
e Significant amide bond cleavage was observed. No improvement in dr was found by replacing THF with Et2O. f The dr and conversion were determined by
19F NMR; see the Supporting Information for details. g Cleavage of the amide bond was the main product; only 10% of 12 was observed (dr 1:1).
unsatisfactory results (entries 7 and 8). The use of metal ion
additives in heterogeneous catalytic hydrogenation was in-
vestigated (entries 3-6). Hydrogenation of 11 over Pd/BaSO4
led to complete conversion but only a modest improvement in
diastereoselectivity (dr 5:1). Further improvement was ob-
served upon catalytic hydrogenation over Pd-C in the pre-
sence of salts of CeIII, CoII, and MgII with the greatest
Schemes 3 and 4, respectively. Hydrolysis of 12 afforded
enantiomerically enriched carboxylic acid (S)-7, which was
immediately coupled with optically pure (R)-phenylglycinol
1414 to give amide 5 in 75% yield as a 4:1 mixture of
diastereomers at the CF3 stereocenter. Partial separation of
the mixture (silica flash chromatography) provided the
major isomer 5 (56%) that was carried through the remain-
der of the sequence.
diastereoselectivity obtained in the case of CeCl3 7H2O
(dr 9.6:1, entry 4). Enhanced selectivity of reduction of 11
was also achieved with “nickel boride” generated in situ
3
Treatment of 5 with DAST15 gave oxazoline 15 in good
yield and without loss of stereochemical integrity. Oxidative
6a
rearrangement of 15 in the presence of SeO2 in refluxing
(NiCl2 6H2O, NaBH4,13 entries 10-12) with optimum dia-
3
stereoselectivity observed at a temperature of -20 °C (dr 9.8:1,
entry 10). While the highest diastereoselectivity was observed
with the latter reagent, separation of the diastereomers was not
possible under practical preparative conditions. For conveni-
ence of through-put, compound 12 with the 4:1 diastereomeric
composition obtained under catalytic hydrogenation was car-
ried forward in the syntheses of the target amino acids.
Sultam 3S-12 (dr 4:1) served as the common starting
material for preparation of both 1 and 2 as illustrated in
1,4-dioxane gave oxazinone 3 as a 7:1 mixture of diastereo-
mers. The cause of the partial epimerization at the R-stereo-
center is likely the presence of adventitious acid for-
med during the oxidative transformation (e.g., H2SeO3)
that may catalyze the imine-enamine (16) isomerization.
(14) (a) For the procedure, see: Hsiao, Y.; Hegedus, L. S. J. Org. Chem.
1997, 62, 3586. (b) For the optical rotation of (R)-phenylglycinol, see:
Garcia Ruano, J. L.; Alcudia, A.; Del Prado, M.; Barros, D.; Maestro, M. C.;
Fernandez, I. J. Org. Chem. 2000, 65, 2856.
(15) Phillips, A. J.; Uto, Y.; Wipf, P.; Reno, M. J.; Williams, D. R. Org.
Lett. 2000, 2, 1165.
(13) Ganem, B.; Osby, J. O. Chem. Rev. 1986, 86, 763.
5512 J. Org. Chem. Vol. 74, No. 15, 2009

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JOCArticle
SCHEME 3. Synthesis of (2S,3S)-1
SCHEME 4. Synthesis of (2S,4S)-2
The enamine (16) was isolated in small amounts from the
1
reaction mixture and assigned based on evidence from H
NMR data and mass spectrometry. Attempted conversion
of 15 to 3 in either 1,4-dioxane or THF with MgO as an
additive resulted in lower yields (30-40%), albeit with less
epimerization (dr 10:1). Substitution of the solvent (EtOAc,
CHCl3) also gave lower yields of 3 (40-50%), with no
change in the dr.
(R)-phenylglycinol (14) in the presence of ZnCl216 in reflux-
ing dichlorobenzene gave 20 in only 15% yield, while reac-
tion in the presence of Zn(OTf)217 did not provide 20 at all.
Consequently, nitrile 19 was hydrolyzed (conc HCl) to the
carboxylic acid (S)-8 and coupled with 14 to afford amide 6
in 84% yield. Cyclization of 6 (DAST, Et3N, CH2Cl2) gave
oxazoline 20 (86%).
Exposure of 3 (dr 7:1) to H2 (1 atm) and PtO27j in R,R,R-
trifluorotoluene gave a 54% yield of 17, which could be
separated from the more polar minor diastereomers by flash
chromatography. To estimate the diastereoselectivity of this
reaction, a small sample of pure 3, obtained as a single
diastereomer by HPLC purification, was exposed to the
hydrogenation conditions described above. HPLC analysis
of the crude reaction showed a dr of 3:1 favoring 17. The low
diastereoselectivity for this hydrogenation compared to lit-
erature precedents (e.g., dr >15:1 when the trifluoroisopro-
pyl group is replaced by tert-butyl)7k is likely the result of
dipole effects exerted by the proximal CF3 group. It appears
the strong trifluoromethyl group dipole erodes stereoselec-
tivity in both the catalytic reduction of 3 and 11. Hydro-
genolysis of 17 at elevated pressure, followed by treatment of
the crude product with 6 M HCl gave the hydrochloride salt
of 1, which matched literature data in every respect.5a,5b Ion-
exchange chromatography (strong cationic resin, H+ form,
elution with 2 M NH4OH) provided amino acid (2S,3S)-1 in
89% yield from 3.
SeO2-mediated oxidative rearrangement of 20 under
the standard conditions (1,4-dioxane, 100 °C)6a gave only
traces of oxazinone 4. The 1H NMR spectrum of the crude
product showed a complex mixture of compounds, including
small peaks corresponding to desired product 4. A dramatic
improvement in the oxidative rearrangement of 20 was
realized under microwave irradiation conditions. Following
a procedure for microwave-promoted SeO2-mediated allylic
oxidations,18 20 was heated to 110 °C with SeO2 in 1,4-
dioxane for 10 min, filtered, and purified by column chro-
matography. While 4 was obtained in only 14% yield as a
mixture of inseparable diastereomers, the crude product was
cleaner and suggested that the low yield was a result of over-
oxidation at the R-CH2 group of oxazinone 4.19 Optimal con-
ditions were found by lowering the temperature to 90 °C and
keeping the reaction time to only 5 min, which provided oxa-
zinone 4 in 62% yield. The dr of 4 (4:1) was unchanged from
12 suggesting no racemization of the CF3-substituted stereo-
center in 4, in contrast to the more activated stereocenter in 3.
The diastereomeric purity of imine 4 was enriched by
HPLC purification (dr >20:1) prior to hydrogenation by
The synthesis of 2 follows a similar sequence as 1 but
requires the homologous carboxylic acid 8 (Scheme 4). The
camphor sultam 3S-12 (dr 4:1) was reductively cleaved
(LiAlH4)12 to provide alcohol (S)-13,5e which was subse-
quently activated as the tosylate ester 18 (55%, 2 steps). SN2
displacement of 18 with NaCN gave nitrile 19 in good yield
(85%). Direct conversion of nitrile 19 to oxazoline 20 with
(17) Cornejo, A.; Fraile, J. M.; Garcia, J. I.; Gil, M. J.; Martinez-Merino,
V.; Mayoral, J. A.; Pires, E.; Villalba, I. Synlett 2005, 2321.
(18) Zou, Y.; Chen, C.-H.; Taylor, C. D.; Foxman, B. M.; Snider, B. B.
Org. Lett. 2007, 9, 1825.
(19) The 1H NMR of a mixture of side products from the reaction lacked
the CH2 signals adjacent to the CdN bond, suggesting that a second
oxidation took place at this position at higher temperature and longer
reaction times. Reaction times of less than 5 min returned only starting
material, suggesting a short induction period.
(16) (a) Takeuchi, K.; Takeda, T.; Fujimoto, T.; Yamamoto, I. Tetra-
hedron 2007, 63, 5319. (b) Caputo, C. A.; Carneiro, F. D. S.; Jennings, M. C.;
Jones, N. D. Can. J. Chem. 2007, 85, 85.
J. Org. Chem. Vol. 74, No. 15, 2009 5513

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

Pigza et al.
JOCArticle
62%, dr 4:1) as a pale yellow oil. The major diastereomer could be
separated by HPLC (SiO2, 250 Â 10 mm, 12:88 Et2O:hexanes,
flow rate = 3 mL/min, tR(major) = 20.7 min, tR(minor) = 21.3
min, with some partial peak overlap) but resulted in only 40%
recovery of the desired product. The following data are for the 4:1
diastereomeric mixture: [R]21D -178.7 (c 1.0, CHCl3); Rf 0.33 (1:4
(2S,4S)-5,5,5-Trifluoroleucine (2). A mixture of morpholi-
none 21 (5.0 mg, 17 μmol), Pd(OH)2 (20% Pd content, 3.0 mg,
4.3 μmol), and TFA (5.2 μL, 68 μmol) in MeOH/H2O (10:1,
870 μL) contained in a thick-walled flask was shaken under 90 psi
(6 atm) of H2 for 12h with use ofa Parrhydrogenationapparatus.
The reaction was filtered through diatomaceous earth and con-
centrated to give the crude product, which was redissolved in 6 M
HCl (870 μL) and heated at 100 °C for 14 h. After concentration,
the crude material was purified by ion-exchange chromatography
(strong cation-exchange resin, 200-400 dry-mesh, H+ form,
elution with 2.0 M NH4OH) to provide amino acid (2S,4S)-2 as
EtOAc:hexanes); FTIR (ATR, neat) ν 1737, 1644 cm-1 1H
;
NMR (500 MHz, CDCl3) δ 7.45-7.41 (m, 2H), 7.40-7.32 (m,
3H), 4.93-4.88 (m, 1H), 4.58 (dd, J = 11.4, 4.6 Hz, 1H), 4.21 (dd,
J = 11.8, 11.2 Hz, 1H), 3.10 (ddd, J=16.6, 5.2, 2.8 Hz, 1H),
3.03-2.93 (m, 1H), 2.83 (ddd, J = 16.5, 8.3, 2.6 Hz, 1H), 1.20 (d,
J = 6.8 Hz, 3H); signals of the minor diastereomer are par-
tially resolved: δ 4.22 (dd, J = 11.4, 11.4 Hz, 1H), 1.24 (d,
J = 6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 160.0 (C),
155.2 (C), 136.6 (C), 129.1 (CH), 128.6 (CH), 128.1 (q, J = 278.1
Hz, CF3), 127.1 (CH), 71.4 (CH2), 59.9 (CH), 35.0 (q, J = 26.4
Hz, CH), 34.3 (CH2), 13.3 (q, J = 2.4 Hz, CH3); HRESIMS
m/z [M + H]+ 286.1052, calcd for C14H15F3NO2 286.1049.
(3S,5R)-5-Phenyl-3-((S)-3,3,3-trifluoro-2-methylpropyl)mor-
pholin-2-one (21). A mixture of PtO2 (3.3 mg, 15 μmol) and
diastereomerically pure oxazinone 4 (9.3 mg, 33 μmol) in CH2Cl2
(650 μL) was purged with H2 before stirring under 1 atm of H2 for
2 h. The mixture was filtered and concentrated to a colorless oil.
HPLC separation of the crude material (SiO2, 250 Â 10 mm, 2:3
Et2O/hexanes, flow rate = 3 mL/min, tR(major) = 18.63 min,
tR(minor) = 23.15 min) provided the major isomer, morpholi-
none 21 (6.3 mg, 67%). Integration of the peaks for the major and
minor products showed the dr to be 19:1. Major diastereomer, 21:
[R]23.3D -82.8 (c 1.0, CHCl3); Rf 0.22 (1:4 EtOAc:hexanes); FTIR
(ATR, neat) ν 3315 (br), 1730 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.42-7.34 (m, 5H), 4.40 (dd, J = 16.8, 10.4 Hz, 1H), 4.31-4.25
(m, 2H), 3.87 (br dd, J = 11.2, 5.6 Hz, 1H), 2.60-2.49 (m, 1H),
2.11 (t, J = 6.8 Hz, 2H), 1.78 (br s, 1H), 1.20 (d, J = 6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 169.6 (C), 137.5 (C), 129.2 (CH),
129.0 (CH), 128.3 (q, J = 279.0Hz, CF3), 127.2 (CH), 74.7 (CH2),
57.3 (CH), 56.1 (CH), 34.9 (q, J = 27.0 Hz, CH), 33.4 (CH2), 12.8
(CH3); HRESIMS m/z [M + H]+ 288.1208, calcd for
C14H17F3NO2 288.1211.
1
a pale yellow solid (3.0 mg, 93%). H NMR (500 MHz, D2O)
δ 3.74 (dd, J = 9.4, 5.2 Hz, 1H), 2.55-2.44 (m, 1H), 2.11 (ddd, J
= 14.9, 9.4, 4.6 Hz, 1H), 1.94 (ddd, J = 14.9, 9.8, 5.2 Hz, 1H),
1.18 (d, J = 6.8 Hz, 3H); HR ESI-TOFMS m/z [M + H]+
186.0738, calcd for C6H11F3NO2 186.0736. A sample of 2,
obtained after treatment with 6 M HCl (500 μL) and evaporation
of the volatiles gave enantiomerically pure 2 HCl as a pale yellow
3
solid: [R]21.7 -3.2 (c 1.0, 1 N HCl) (lit.5e [R]20 -4.5 (c 1.0,
D
D
1 N HCl)); 1H NMR (500 MHz, D2O) δ 4.01 (dd, J =9.2, 5.8 Hz,
1H), 2.59-2.49 (m, 1H), 2.14 (ddd, J=14.8, 8.8, 4.8 Hz, 1H),
2.02 (ddd, J = 14.9, 9.2, 5.8 Hz, 1H), 1.13 (d, J = 6.8 Hz,
3H); 19F NMR (471 MHz, D2O/1% CF3CO2H) δ -74.13 (s)
(lit.5a 19F NMR (283 MHz, D2O/CF3CO2H) δ -74.11 (s)).
Acknowledgment. We thank C. Shafer for preliminary
investigations of the oxazoline-oxazinone rearrangement,
and an anonymous reviewer for the useful suggestion of
metal salt additives in catalytic hydrogenation of 11. HRMS
data were provided by UC Riverside and Scripps Research
Institute mass spectrometry facilities. This work was sup-
ported by the NIH (CA122256 and AI039987).
Supporting Information Available: General experimental
procedures, experimental details, characterization data, and
copies of spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 15, 2009 5515