Nucleophilic addition of 3,3,3-trifluoropropynyllithium to d-glyceraldimine: Concise synthesis of both enantiomers of 5,5,5-trifluoronorvaline

Article abstract of DOI:10.1016/j.jfluchem.2007.02.010

3,3,3-Trifluoropropynyllithium, in situ generated by treatment of 2-bromo-3,3,3-trifluoro-1-propene 1 with 2.0 equiv. of LDA at -78 °C, was trapped with d-glyceraldimine 2 to give trifluoromethylated propargylic amine 4 in 55% yield. Starting from the key

Full text of DOI:10.1016/j.jfluchem.2007.02.010

Journal of Fluorine Chemistry 128 (2007) 1182–1186
www.elsevier.com/locate/fluor
Nucleophilic addition of 3,3,3-trifluoropropynyllithium to
D-glyceraldimine: Concise synthesis of both
enantiomers of 5,5,5-trifluoronorvaline
Qi Chen a, Xiao-Long Qiu b, Feng-Ling Qing a,b,
*
a Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science,
354 Fenglin Lu, Shanghai 200032, China
b Institute of Biological Sciences and Biotechnology, Donghua University, 2999 North Renmin Lu, Shanghai 201620, China
Received 8 January 2007; received in revised form 12 February 2007; accepted 12 February 2007
Available online 16 February 2007
Abstract
3,3,3-Trifluoropropynyllithium, in situ generated by treatment of 2-bromo-3,3,3-trifluoro-1-propene 1 with 2.0 equiv. of LDA at À78 8C, was
trapped with D-glyceraldimine 2 to give trifluoromethylated propargylic amine 4 in 55% yield. Starting from the key intermediate 4, Boc-protected
(R)-5,5,5-trifluoronorvaline and (S)-5,5,5-trifluoronorvaline were concisely synthesized over three steps in 62% and 63% yield, respectively.
# 2007 Published by Elsevier B.V.
Keywords: Fluorinated amino acids; 3,3,3-Trifluoropropynyllithium; 5,5,5-Trifluoronorvaline
1. Introduction
report about the stereoselective synthesis of 5,5,5-trifluoro-
norvaline, in which the fluorinated reagent SF4 was used [19].
Therefore, the development of efficient and stereoselective
route to 5,5,5-trifluoronorvaline was anticipated. Herein we
report a concise synthesis of both enantiomers of trifluor-
onorvaline using nucleophilic addition of 3,3,3-trifluoropro-
pynyllithium to D-glyceraldimine 2 as the key step.
In recent years, incorporation of trifluoromethyl-containing
amino acids (TFAAs) into peptides and proteins has become an
important tool in the design of peptides and proteins [1–7]. The
importance of TFAAs made the development of new and
efficient enantioselective methodologies or strategies to their
synthesis a significant and active area of research [8–11].
Among these trifluoromethylated amino acids, 5,5,5-trifluor-
onorvaline had attracted attention earlier. In 1955, Loncrini and
co-workers described that 5,5,5-trifluoronorvaline could inhibit
the growth of Escherichia coli and may be used as a growth
regulatory factor in microbiology [12]. Ojima et al. reported in
1992 that the new methonine–enkephalin analogs bearing (D)-
trifluoronorvaline in place of one glycine exhibited ca. 100,000
times enhancement in in vivo analgesic activity in comparison
with methionine–enkephalin [13]. Therefore, several synthetic
routes to 5,5,5-trifluoronorvaline were developed. In most cases
racemic mixtures of 5,5,5-trifluoronorvaline were obtained
[14–20]. To the best of our knowledge, there was only one
2. Results and discussion
In general, the additions of Grigard reagents or organo-
lithium reagents to imine were found to be rather complicated.
However, the additions of Grigard reagents or organolithium
reagents to D-glyceraldimine proceeded very well [21], which
were attributed to prior formation of a five-membered chelate
with the 2-alkoxy group [21–25]. Using this kind of addition
reactions, Cativiela et al. [26–28] successfully prepared a
number of important unnatural amino acids. Thus, we proposed
that the additions of fluoroalkyl substituted organometallic
reagents to glyceraldimine should present an efficient synthetic
strategy for fluorinated amino acids (Scheme 1) [29].
Tarrant and co-workers described that the addition of 3,3,3-
trifluoroisopropenyllithium, in situ generated from the reaction
of 2-bromo-3,3,3-trifluoro-1-propene and n-butyl lithium at
* Corresponding author. Fax: +86 21 64166128.
E-mail address: flq@mail.sioc.ac.cn (F.-L. Qing).
0022-1139/$ – see front matter # 2007 Published by Elsevier B.V.
doi:10.1016/j.jfluchem.2007.02.010

Q. Chen et al. / Journal of Fluorine Chemistry 128 (2007) 1182–1186
1183
proceeded smoothly and the isolated yield of trifluoromethy-
lated propargylic amine 4 was increased to 55%. The ratio of
two diastereomers of compound 4 was 1:1.5. The two
diastereomers could not be separated by flash column
chromatography. We noticed that Yamazaki et al. described
the failure of the reaction of the trifluoropropynyllithium
with imines due to the less active imine carbon, but the
structures of imines were not given [32]. The successful
reaction between trifluoropropynyllithium and glyceraldimine
was attributed to prior formation of a five-membered chelate
with the 2-alkoxy group [21–25], which lowers the transition
state energy and thus increase the reaction rate [21–25].
Probably, this intermolecular chelation also stabilized the
lithium reagent.
Scheme 1.
low temperature, to carbonyl compounds gave trifluoromethy-
lated alcohols in moderate yields [30]. Recently, Ichikawa re-
examined the reaction of 2-bromo-3,3,3-trifluoro-1-propene
with butyl lithium and succeeded in efficiently trapping highly
unstable 3,3,3-trifluoroisopropenyllithium by strained cyclic
ethers [31]. We were interested in extending Tarrant’s reaction
to glyceraldimine. Initially treatment of D-glyceraldimine 2
with in situ generated 3,3,3-trifluoroisopropenyllithium in Et2O
at À95 8C was complicated and the desired allylic amine 3 was
not obtained (Scheme 2). When THF was used as solvent
instead of Et2O, the trifluoromethylated propargylic amine 4
(syn/anti = 1: 2.5) was isolated in 13% yield. In our opinion, the
formation of trifluoromethylated propargylic amine 4 resulted
from the addition of in situ generated trifluoropropynyllithium
to D-glyceraldimine 2 [32]. The generation of trifluoropropy-
nyllithium indicated 2-bromo-3,3,3-trifluoro-1-propene upon
treatment with nBuLi in THF underwent partly a dehydro-
bromination reaction to form 3,3,3-trifluoropropynyl anion,
although the lithium–bromine exchange followed by lithium
fluoride elimination was major pathway of the reaction of 2-
bromo-3,3,3-trifluoro-1-propene with nBuLi [30,31]. This
result promoted us to further study the reaction between
3,3,3-trifluoropropynyllithium and D-glyceraldimine for
improving the yield of compound 4, because propargylic
amine 4 is a potential precursor for the synthesis of
trifluoromethylated amino acids. Yamazaki et al. reported that
the convenient generation of 3,3,3-trifluoropropynyl anion was
realized from 2-bromo-3,3,3-trifluoro-1-propene in the pre-
sence of less nucleophilic LDA [32]. Accordingly, the addition
of 3,3,3-trifluoropropynyllithium, in situ generated from the
reaction of 2-bromo-3,3,3-trifluoro-1-propene with 2.0 equiv.
of LDA in THF at À78 8C, to D-glyceraldimine 2 was carried
out (Scheme 2). We were pleased to find that the reaction
With the propargylic amine 4 in hand, both enantiomers of
trifluoronorvaline were synthesized in a straightforward fashion
(Scheme 3). Reduction of the triple bond and removal of the
benzyl group of compound 4 by hydrogenation in the presence of
5% Pd/C and protection of the resultant amino group with Boc2O
were accomplished in a one-pot process to give the compounds
5a and 5b in 94% yield (5a/5b = 1:1.5). Compounds 5a and 5b
were easily separated by flash column chromatography.
Treatment of 5a with TsOH/MeOH afforded the diol 6a in
87% yield. Finally, oxidation of the dihydroxyl moiety with
RuCl3/NaIO4 successfully provided the desired Boc-protected
(R)-5,5,5-trifluoronorvaline 7a in 76% yield. In addition, Boc-
protected (S)-5,5,5-trifluorovaline 7b was also obtained in 67%
yield over two steps from 5b using the same procedure.
Treatment of 7b with trifluoroacetic acid at room temperature
gave free amino acid (S)-5,5,5-trifluoronorvaline 8 in quantita-
tive yield. The optical rotation of 8 ([a]D20 = +8.0 (c 0.35, H2O))
is in accordance with its reported value ([a]D20 = +7.2 (c 1.5,
H2O)) [20]. Therefore, the absolute configuration of Boc-
protected (S)-5,5,5-trifluorovaline 7b was confirmed.
In conclusion, we found that the nucleophilic addition of
3,3,3-trifluoropropynyllithium to D-glyceraldimine gave the
corresponding trifluoromethylated propargylic amine 4 in
moderate yield (55%). Starting from the compound 4, a concise
synthetic approach to both enantiomers of 5,5,5-trifluoronorva-
line was developed.
Scheme 2.

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Q. Chen et al. / Journal of Fluorine Chemistry 128 (2007) 1182–1186
Scheme 3.
3. Experimental
3.3. tert-Butyl (R)-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-
4,4,4-trifluorobutylcarbamate (5a) and tert-butyl (S)-1-((S)-
2,2-dimethyl-1,3-dioxolan-4-yl)-4,4,4-
trifluorobutylcarbamate (5b)
3.1. General
All reagents were used as received from commercial
sources, unless specified otherwise, or prepared as described
in the literature. Reactions requiring anhydrous conditions
were performed in vacuum flame-dried glasswares under
nitrogen atmosphere. NMR spectra were recorded on either
300 MHz (1H NMR), 75 MHz (13C NMR) or 282 MHz (19F
NMR, FCCl3 as outside standard and low field is positive).
Chemical shifts (d) are reported in ppm, and coupling
constants (J) are in Hz.
A mixture of 10% palladium on charcoal (500 mg), di-tert-
butyl dicarbonate (1.37 g, 6.28 mmol) and 4 (982 mg,
3.13 mmol) in ethyl acetate (20 mL) was stirred under 1 atm
hydrogen for 8 h at room temperature. Filtration and removal of
the solvent gave the crude product, which was purified by
column chromatography on silica gel (petroleum ether/ethyl
acetate = 10/1) to give 5a (394 mg, 37%) and 5b (570 mg,
57%) as white solids, respectively. 5a: mp 65–66 8C;
1
[a]D20 = +46.1 (c 1.0, CHCl3); H NMR (300 MHz, CDCl3)
3.2. N-Benzyl-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-
4,4,4-trifluorobut-2-yn-1-amine (4)
d 4.69 (d, J = 9.9 Hz, 1H), 4.16–4.12 (m, 1H), 4.02 (dd,
J = 8.4 Hz, 6.6 Hz, 1H), 3.75–3.63 (m, 2H), 2.27–2.11 (m, 2H),
1.84–1.75 (m, 2H), 1.45 (s, 9H), 1.44 (s, 3H), 1.34 (s, 3H); 19
F
To a solution of LDA (8.6 mmol) in THF (4 mL) was added
dropwise a solution of 2-bromo-3,3,3-trifluoropropene 1
(710 mg, 4.0 mmol) in THF (4 mL) at À78 8C. After the
mixture was stirred for 15 min, a solution of D-glyceraldimine
2 (876 mg, 4.0 mmol) in THF (2 mL) was added dropwise and
the reaction mixture was stirred for 1.5 h. The reaction
mixture was quenched with 1N HCl (10 mL) and extracted
with EtOAc three times. The organic layer was dried over
Na2SO4 and concentrated. The residue was purified on silica
gel column (petroleum ether/ethyl acetate = 5/1) to afford the
compound 4 (500 mg, 55%) as a yellow oil. 1H NMR
(300 MHz, CDCl3) d 7.36–7.25 (m, 5H) 4.30–4.22 (m, 1H),
4.11–4.04 (m, 2H), 3.97–3.80 (m, 2H), 3.56–3.47 (m, 1H),
2.26 (br, 1H), 1.45–1.35 (m, 6H); 19F NMR (282 MHz,
CDCl3) d À50.17 (s, 1.2F), À50.38 (s, 1.8F); 13C NMR
(75.5 MHz, CDCl3) d 138.7, 138.6, 128.5, 128.3, 128.2,
127.4, 114.0 (q, J = 154.5 Hz), 113.9 (q, J = 154.7 Hz), 110.3,
110.2, 86.4 (q, J = 3.7 Hz), 86.1 (q, J = 3.7 Hz), 76.9, 76.6,
72.5 (q, J = 31.3 Hz), 72.2 (q, J = 31.7 Hz), 66.7, 66.3, 51.9,
51.3, 51.2, 26.4, 26.2, 25.1, 25.0; IR (thin film) nmax 3327,
2991, 2270, 1456, 1374, 1278, 1142, 847 cmÀ1; MS (ESI) m/z
314 (M + H)+; HRMS calcd for C16H19F3NO2: 314.1362.
Found: 314.1372.
NMR (282 MHz, CDCl3) d À66.44 (t, J = 11.5 Hz, 3F); 13C
NMR (75.5 MHz, CDCl3) d 156.1, 127.0 (q, J = 276.6 Hz),
109.3, 79.7, 76.6, 66.2, 49.6, 30.8 (q, J = 29.0 Hz), 28.2, 26.3,
26.2 (q, J = 2.9 Hz), 24.8; IR (thin film) nmax 3408, 2992, 1691,
1516, 1370, 1260, 1175, 1047, 848 cmÀ1; MS (ESI) m/z 350
(M + Na)+; HRMS calcd for C14H24F3NO4Na: 350.1550.
Found: 350.1554. 5b: mp 121–122 8C; [a]D20 = À25.5 (c
1
1.2, CHCl3); H NMR (300 MHz, CDCl3) d 4.50 (d, J = 9.3,
1H), 4.08–4.00 (m, 2H), 3.82–3.76 (m, 1H), 3.70–3.61 (m, 1H),
2.27–2.10 (m, 2H), 2.01–1.92 (m, 1H), 1.58–1.50 (m, 1H), 1.44
(s, 9H), 1.42 (s, 3H), 1.34 (s, 3H); 19F NMR (282 MHz, CDCl3)
d À66.42 (t, J = 11.0 Hz, 3F); 13C NMR (75.5 MHz, CDCl3) d
155.6, 127.1 (q, J = 276.4 Hz), 109.8, 79.7, 76.6, 66.7, 52.3,
30.6 (q, J = 29.0 Hz), 28.2, 26.3, 24.9, 23.7; IR (thin film) nmax
3372, 3012, 2989, 1685, 1522, 1369, 1248, 1173, 1043,
847 cmÀ1; MS (ESI) m/z 350 (M + Na)+; HRMS calcd for
C14H24F3NO4Na: 350.1549. Found: 350.1554.
3.4. tert-Butyl (2S,3R)-6,6,6-trifluoro-1,2-dihydroxyhexan-
3-ylcarbamate (6a)
A mixture of 5a (285 mg, 0.87 mmol) and p-toluenesulfonic
acid monohydrate (233 mg, 0.87 mmol) in methanol (9 mL)

Q. Chen et al. / Journal of Fluorine Chemistry 128 (2007) 1182–1186
1185
was stirred overnight. The reaction mixture was quenched with
3.7. (S)-2-(tert-Butoxycarbonyl)-5,5,5-trifluoropentanoic
acid (7b)
water and extracted with ethyl acetate (3Â 10 mL). The
combined organic layers were washed with water and brine,
then dried over anhydrous Na2SO4 and concentrated in vacuo.
The residue was purified by silica gel column chromatography
(petroleum ether/ethyl acetate = 2/1) to give 6a (210 mg, 87%)
as a white solid. mp 88–89 8C; [a]D20 = +29.1 (c 1.1, CHCl3);
1H NMR (300 MHz, CDCl3) d 5.93 (d, J = 9.6 Hz, 1H), 4.28 (d,
J = 4.8 Hz, 1H), 4.03 (t, J = 6.0 Hz, 1H), 3.83–3.69 (m, 2H),
3.53–3.49 (m, 2H), 2.40–2.24 (m, 2H), 1.98–1.79 (m, 2H), 1.46
(s, 9H); 19F NMR (282 MHz, CDCl3) d À66.73 (t, J = 11.5 Hz,
3F); 13C NMR (75.5 MHz, CD3COCD3) d 157.0, 128.0 (q,
J = 275.6 Hz), 78.7, 73.2, 63.4, 50.8, 30.8 (q, J = 27.9 Hz),
27.9, 24.6 (q, J = 2.7 Hz); IR (thin film) nmax 3556, 2918, 1683,
1529, 1255, 1175, 1044 cmÀ1; MS (ESI) m/z 310 (M + Na)+;
HRMS calcd for C11H20F3NO4Na: 310.1237. Found: 310.1247.
Using the same procedure described for preparation of
compound 7a, to a stirred mixture of 6b (154 mg, 0.54 mmol)
in CCl4 (3 mL), CH3CN (3 mL) and H2O (4.5 mL) at room
temperature were added NaIO4 (480 mg, 2.24 mmol) and
RuCl3ÁxH2O (2 mg) to give 7b (120 mg, 82%) as a white solid.
mp 67–68 8C; [a]D20 = +4.3 (c 1.40, CHCl3); 1H NMR
(300 MHz, CD3COCD3) d 6.62 (d, J = 5.7 Hz, 1H), 4.54–
4.50 (m, 1H), 2.70–2.57 (m, 2H), 2.44–2.35 (m, 1H) 2.26–2.20
(m, 1H) 1.67 (s, 9H); 19F NMR (282 MHz, CDCl3) d À67.03 (t,
J = 10.7 Hz, 3F); 13C NMR (75.5 MHz, CD3COCD3) d 172.7,
155.9, 127.7 (q, J = 275.3 Hz), 78.9, 52.4, 30.2 (q, J = 28.2 Hz),
27.9, 24.5 (q, J = 3.0 Hz); IR (thin film) nmax 3420, 3117 (br),
2988, 1728, 1674, 1521,1257, 1141, 1023 cmÀ1; MS (ESI) m/z
294 (M + Na)+; HRMS calcd for C10H16F3NO4Na: 294.0924.
Found: 294.0921.
3.5. tert-Butyl (2S,3S)-6,6,6-trifluoro-1,2-dihydroxyhexan-
3-ylcarbamate (6b)
3.8. (S)-2-Amino-5,5,5-trifluoropentanoic acid (8)
Using the same procedure described for preparation of
compound 6a. A mixture of 5b (334 mg, 1.03 mmol) and p-
toluenesulfonic acid monohydrate (195 mg, 1.04 mmol) in
methanol (10 mL) was stirred overnight to give 6b (242 mg,
82%) as a white solid. mp 107–108 8C; [a]D20 = À20.2 (c 0.35,
To a stirred mixture of 7b (98 mg, 0.36 mmol) in CH2Cl2
(6 mL) at room temperature were added CF3CO2H (0.5 mL)
dropwise. The mixture was stirred overnight and then
concentrated in vacuo. The crude product was washed with
petroleum ether three times to give 8 (60 mg, 99%) as a white
solid. [a]D20 = +8.0 (c 0.35, H2O); 1H NMR (300 MHz, D2O)
d 3.74 (t, J = 6.6 Hz, 1H), 2.38–2.22 (m, 2H), 2.18–2.01 (m,
2H); 19F NMR (282 MHz, D2O) d À66.52 (t, J = 10.1 Hz,
3F).
1
CHCl3); H NMR (300 MHz, CDCl3) d 6.11 (d, J = 8.7 Hz,
1H), 4.12 (d, J = 4.8 Hz, 1H), 3.91 (t, J = 6.0 Hz, 1H), 3.67–
3.52 (m, 4H), 2.35–2.15 (m, 2H), 2.10–2.00 (m, 1H), 1.75–1.61
(m, 1H), 1.40 (s, 9H); 19F NMR (282 MHz, CDCl3) d À66.92 (t,
J = 11.0 Hz, 3F); 13C NMR (75.5 MHz, CD3COCD3) d 156.3,
127.8 (q, J = 275.6 Hz), 78.4, 74.0, 63.5, 51.4, 30.3 (q,
J = 30.0 Hz), 22.9; IR (thin film) nmax 3360, 2984, 1685, 1529,
1254, 1176, 1043 cmÀ1; MS (ESI) m/z 310 (M + Na)+; HRMS
calcd for C11H20F3NO4Na: 310.1237. Found: 310.1233.
Acknowledgements
National Natural Science Foundation of China, Ministry of
Education of China and Shanghai Municipal Scientific
Committee are greatly acknowledged for funding this work.
3.6. (R)-2-(tert-Butoxycarbonyl)-5,5,5-trifluoropentanoic
acid (7a)
References
To a stirred mixture of 6a (96 mg, 0.33 mmol) in CCl4
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vacuo. The residue was purified by silica gel column
chromatography (petroleum ether/ethyl acetate = 2/1) to give
7a (65 mg, 72%) as a white solid. mp 67–68 8C; [a]D20 = À4.1
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