Synthesis of fluorinated glutamic acid derivatives via vinylalumination

Article abstract of DOI:10.1016/j.jfluchem.2006.10.003

A variety of structural types of fluorinated allylic acetates, prepared by vinylalumination of fluorinated aldehydes, were reacted with the benzophenone imine of glycine tert-butyl ester to provide 4-(fluorobenzylidenyl)- and 4-(fluoroalkylidenyl) glutami

Full text of DOI:10.1016/j.jfluchem.2006.10.003

Journal of Fluorine Chemistry 128 (2007) 78–83
www.elsevier.com/locate/fluor
Synthesis of fluorinated glutamic acid derivatives via vinylalumination
a
b
P. Veeraraghavan Ramachandran a, , Sateesh Madhi , Martin J. O’Donnell
*
a Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN 47907-2084, United States
b Department of Chemistry and Chemical Biology, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202-3274, United States
Received 29 August 2006; received in revised form 26 September 2006; accepted 3 October 2006
Available online 10 October 2006
Abstract
A variety of structural types of fluorinated allylic acetates, prepared by vinylalumination of fluorinated aldehydes, were reacted with the
benzophenone imine of glycine tert-butyl ester to provide 4-(fluorobenzylidenyl)- and 4-(fluoroalkylidenyl) glutamic acid derivatives in 61–96%
yield. The 4-(4-fluorobenzylidenyl) glutamic acid derivative was hydrolyzed to give the 4-(4-fluorobenzylidenyl)pyroglutamate and then
hydrogenated to the 4-(4-fluorobenzyl)pyroglutamate. The catalytic enantioselective conjugate addition-elimination of the benzophenone imine
of glycine tert-butyl ester with the fluorinated allylic acetates prepared from fluoral, pentafluorobenzaldehyde, and 2,6-difluorobenzaldehyde
provided the corresponding 4-(fluoroalkylidenyl)- and 4-(fluorobenzylidenyl) glutamic acid derivatives in 42, 45 and 80% ee, respectively.
# 2006 Elsevier B.V. All rights reserved.
Keywords: Fluorine-containing amino acids; Conjugate addition-elimination; Glutamates; Vinylalumination; Excitatory amino acids
1. Introduction
glutamate analogs, such as 4-substituted alkylidene glutamic
acids, have been the targets of several synthetic and pharma-
cological studies [9]. Many 4-substituted glutamates are
available in nature, and others with various substituents have
beensynthesizedtostudyvariousstructure–activityrelationships
in biological systems [10]. It was found that a critical size and
structure ofthe alkylidenegroupgave potentandselectiveGluR5
receptor agonists [9a]. Although several classes of fluorinated
amino acids have been synthesized, the preparation of 4-
substituted alkylidene glutamates containing fluorine substitu-
tion on the alkylidene group is not known. Hence, new methods
for the synthesis of such fluorinated glutamates are highly
desirable. Herein we report a simple, general and new procedure
for the synthesis of 4-(fluoroalkylidenyl)- and 4-(fluorobenzy-
lidenyl) glutamic acid derivatives, which is based on the tandem
conjugate addition-elimination of the Schiff base of glycine tert-
butyl ester with fluorinated allylic acetates prepared by
vinylalumination.
Due to the similarity in size, hydrogen has been replaced
with fluorine in many biologically active organic molecules,
including amino acids [1]. Naturally occurring amino acids
play an important role in living systems, and therefore synthetic
fluorine-containing amino acids have been of significant
interest in a variety of biological applications [2]. Fluorinated
amino acids can be used as tracers and mechanistic probes for
investigations into the structure and properties of enzymes [3].
They are also useful in the control of blood pressure, tumour
growth, and allergies [4] and find applications as key
intermediates in the synthesis of bioactive natural products
[5]. Moreover, fluorinated amino acids have recently emerged
as valuable building blocks for the design of hyperstable protein
folds as well as directing highly specific protein–protein
interactions [6], aiding the remarkable progress in protein
engineering involving fluorinated amino acids [7]. It has also
been demonstrated that the presence of monofluorinated amino
acid residues in peptides can influence enzyme inhibition [8].
Glutamic acid is the main excitatory amino acid in the
mammalian central nervous system (CNS). 4-Substituted
2. Results and discussion
Baylis–Hillman reaction of acrylates and aldehydes is
normally used to prepare functionalized allylic acetates [11];
however, this reaction was not facile with fluorinated
aldehydes. For example, it is known that the simplest
fluorocarbonyl compound, fluoral, polymerize instantaneously
* Corresponding author. Tel.: +1 765 494 5303; fax: +1 765 494 0239.
E-mail address: chandran@purdue.edu (P.V. Ramachandran).
0022-1139/$ – see front matter # 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2006.10.003

P.V. Ramachandran et al. / Journal of Fluorine Chemistry 128 (2007) 78–83
79
Scheme 1. Synthesis of the fluorinated allylic acetates (Æ)-1.
Scheme 2. Synthesis of the 4-(fluoroalkylidenyl)- and 4-(fluorobenzylidenyl) glutamic acid derivatives (Æ)-3.
in the presence of amines [12]. Accordingly, a series of
fluorinated allylic alcohols was recently prepared by vinyla-
lumination (Scheme 1) [13]. These alcohols were then
converted to the corresponding acetates 1, which were used
as starting materials for the conjugate addition-elimination
reaction.
catalytic Pd/C gave the 4-(4-fluorobenzyl) pyroglutamate (5)
in 82% isolated yield (Scheme 3). This pyroglutamate can be
converted to the 4-(4-fluorobenzyl) glutamic acid (6) by known
procedures [10a].
Table 1
Initially we focused on standardizing the reaction conditions
and determining the scope of the methodology by preparing the
racemic 4-(fluoroalkylidenyl)- and 4-(fluorobenzylidenyl)
glutamic acid derivatives 3. Reaction of the lithium enolate
of the benzophenone imine of glycine tert-butyl ester (2)
[14,15] with fluorinated allylic acetate 1a, synthesized from
fluoral by the vinylalumination method gave the racemic 4-
(trifluoroethylidenyl) glutamic acid derivative 3a in 65% yield
(Scheme 2) (Table 1, entry 1). THF was found to be the solvent
of choice and best results were obtained at À78 8C [16].
This methodology was extended to a series of fluorosub-
stituted benzaldehydes, which gave products in high yields
(61–96%) (Table 1, 3b–3g, 3i). Even a fluorosubstituted
heteroaromatic allylic acetate (1h) underwent the conjugate
addition-elimination to provide 82% yield of 3h (Table 1, entry
8). It is noteworthy that, with allylic acetates that are not
activated with an ester group at the 2-position, palladium
catalysis is required in similar reactions [17].
Synthesis of the 4-(fluoroalkylidenyl)- and 4-(fluorobenzylidenyl) glutamic
acid derivativesa
Entry Allylic
acetate (1)
RF
Reaction Glutamate (3) Yield (%)b
time (h)
1
2
3
4
5
6
7
8
9
(Æ)-1a
CF3
6
(Æ)-3a
(Æ)-3b
(Æ)-3c
(Æ)-3d
(Æ)-3e
(Æ)-3f
(Æ)-3g
(Æ)-3h
(Æ)-3i
65
84
96
92
95
88
95
82
61c
(Æ)-1b
(Æ)-1c
(Æ)-1d
(Æ)-1e
(Æ)-1f
(Æ)-1g
(Æ)-1h
(Æ)-1i
C6F5
3.5
4
4-F–Ph
3-F–Ph
4
2-F–Ph
5
4-CF3O–Ph
4-CF3–Ph
3-F–Pyridinyl
2,6-F2–Ph
5
4.5
6
4.5
To further demonstrate the utility of this procedure, the 4-
(4-fluorobenzylidenyl) glutamic acid (3c) derivative was
converted to the corresponding 4-(4-fluorobenzylidenyl)
pyroglutamate (4) in 87% by treatment with 15% aqueous
citric acid in THF at ambient temperature. Hydrogenation with
a
The benzophenone imine of glycine tert-butyl ester 2 (1 mmol), fluorinated
allylic acetate 1 (1 mmol) and n-BuLi (1.2 equiv.) in THF were stirred at
À78 8C for the indicated time.
b
Isolated yield.
c
Ref. [16].

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P.V. Ramachandran et al. / Journal of Fluorine Chemistry 128 (2007) 78–83
Scheme 3. Synthesis of 4-(4-fluorobenzyl) pyroglutamate.
Scheme 4. Enantioselective synthesis of 4-(fluoroalkylidenyl)- and 4-(fluorobenzylidenyl) glutamic acid derivatives by catalytic enantioselective PTC.
With these encouraging results, the catalytic asymmetric
out to obtain chiral 4-(fluoroalkylidenyl)- and 4-(fluorobenzy-
lidenyl) glutamic acid derivatives in modest enantioselectivities.
Furtherinvestigationsfocusedonimprovingtheyieldsinthecase
of aliphatic fluorinated allylic acetates and the enantioselec-
tivities of the chiral PTC process are currently underway.
version of the conjugate addition-elimination reaction of
fluorinated allylic acetates under PTC conditions was then
investigated. O-Allyl-N-(9-anthracenylmethyl)cinchonidinium
bromide (7) was chosen as the PTC for alkylation reactions,
since it provided the best enantioselectivity in our earlier
studies [16]. Thus, the conjugate addition-elimination of 2 with
1b using 0.1 equiv. of 7 and 10 equiv. of CsOHÁH2O in CH2Cl2
at À78 8C gave the product (S)-3b in 88% yield and 45% ee.
The 2,6-difluorobenzaldehyde derivative (S)-3i was obtained in
80% ee [16] (Scheme 4). The products are assumed to have the
(S) absolute configuration based on extensive literature
precedence [14,16]. The aliphatic fluorinated allylic acetate
1a also gave only a modest enantioselectivity (42% ee) under
the same reaction conditions with a 66% yield (S)-3a.
4. Experimental
Unless otherwise noted, all manipulations were carried out
under an inert atmosphere using flame-dried glassware.
Tetrahydrofuran (THF) was freshly distilled before use from
sodium benzophenone ketyl and anhydrous diethyl ether was
purchased from Mallinckrodt chemicals. Sure SealTM bottles of
n-butyl lithium (2.5 M in hexanes), cinchonidine, CsOHÁH2O,
DIBAL-H, NMO, Pd/C and fluorinated aldehydes were
purchased from the Aldrich Chemical Co. The benzophenone
imine of glycine tert-butyl ester (2) and phase-transfer catalysts
were prepared by literature procedures. Other chemicals were
used without further purification, unless otherwise noted.
3. Conclusion
In conclusion, we have presented a general and simple
procedure for the synthesis of 4-(fluoroalkylidenyl)- and 4-
(fluorobenzylidenyl)glutamic acidderivatives, whichisbasedon
the tandem conjugate addition-elimination of the Schiff base of
glycine tert-butyl ester with fluorinated allylic acetates. The
generality of the methodology has been demonstrated for the
synthesis of a wide range of 4-(fluoroalkylidenyl)- and 4-
(fluorobenzylidenyl) glutamic acid derivatives. In addition,
enantioselective conjugate addition-elimination was also carried
1
The H, 13C and 19F nuclear magnetic resonance (NMR)
spectra were plotted on a Varian Gemini-300 spectrometer
(300, 75 and 282 MHz, respectively) with a Nalorac-quad
1
probe. H NMR spectra were obtained using CDCl3 as the
solvent with either tetramethylsilane (TMS: d 0 ppm) or
chloroform (CHCl3: d 7.2 ppm) as the internal standard. 19F
NMR spectra were recorded in CDCl3 using CFCl3 or
1
trifluoroacetic acid (TFA) as the internal standard. H NMR

P.V. Ramachandran et al. / Journal of Fluorine Chemistry 128 (2007) 78–83
81
data are reported as chemical shifts (d ppm), multiplicity (s,
singlet; d, doublet; t, triplet; q, quartet; m, multiplet), coupling
constant (Hz), and integration. Enantiomeric excesses (% ee)
were measured using a Dynamax HPLC fitted with an HPXL
Solvent Delivery System and a Dynamax UV (l 254 nm)
detector, and a (S,S)-Whelk-O1 (Regis Technologies1) chiral
HPLC column. Mass spectra were recorded using a Hewlett
Packard 5989B mass spectrometer/5890 series II gas chroma-
tograph or a Finnigan mass spectrometer model 4000. The
chemical ionization gas used was isobutene. Flash chromato-
graphy was performed on 40–60 mm silica gel (230–400 mesh).
benzophenone imine of glycine tert-butyl ester (2) (1 mmol,
1 equiv.) in THF (5 mL) at À78 8C. Then a previously prepared
solution of the fluorinated allylic acetate 1 (1 mmol, 1 equiv.) in
THF (2 mL) was transferred to the reaction flask via syringe.
The reaction mixture was stirred for 3.5–6 h at À78 8C. After
completion of the reaction (monitored periodically by TLC),
the reaction mixture was warmed to ambient temperature,
quenched with water (2 mL), diluted with diethyl ether (3 mL),
and the phases were separated. The aqueous layer was extracted
with ether (2 Â 3 mL), and the combined organic layers were
dried over anhydrous Na2SO4, filtered, and concentrated in
vacuo. Purification of the residue by flash chromatography
(silica, hexanes:ethyl acetate; 9:1, v/v) afforded the desired 4-
(fluoroalkylidenyl)- and 4-(fluorobenzylidenyl) glutamic acid
derivatives.
5. Experimental procedure and analytical data for
products
5.1. Synthesis of fluorinated allylic acetates [(Æ)-1]
5.3.1. 1-(1,1-Dimethylethyl)-5-methyl-N-
(diphenylmethylene)-(4E)-(1,1,1-trifluoro ethylidene)-(Æ)-
glutamate [(Æ)-3a]
ToastirredsuspensionofNMO(2.1 g,18 mmol)inanhydrous
THF (50 mL) was added DIBAL-H (2.7 mL, 15 mmol) at 0 8C
andthemixturewasstirredfor0.5 htodissolvethe NMO. Methyl
propiolate (0.89 mL, 10 mmol) was added dropwise and the
mixture was stirred at 0 8C for 1 h, followed by the dropwise
addition of the fluorinated aldehyde (12 mmol). The mixturewas
warmed to rt, stirred for 4 h, quenched with 10 mL of 1.0 M HCl,
and the product was extracted with ether (3 Â 50 mL). The
combined ether layers were washed with brine, dried over
MgSO4, filtered, and evaporated in vacuo. Purification by flash
chromatography over silica gel (95:5, hexanes:ethyl acetate)
provided the desired fluorinated allylic alcohol. These alcohols
were converted to the corresponding acetates using acetyl
chloride (1.2 equiv.) in the presence of pyridine (1.5 equiv.) at
0 8C for 4–6 h in dichloromethane.
1
65% yield: H NMR (300 MHz, CDCl3) d (ppm) 1.46 (s,
9H), 3.03–3.08 (m, 1H), 3.38-3.47 (m, 1H), 3.55 (s, 3H), 4.36–
4.41 (m, 1H), 7.11–7.76 (m, 10H), 7.80 (s, 1H, vinyl proton).
5.3.2. 1-(1,1-Dimethylethyl)-5-methyl-N-
(diphenylmethylene)-(4E)-(2,3,4,5,6-pentafluorophenyl
methylene)-(Æ)-glutamate [(Æ)-3b]
1
84% yield: H NMR (300 MHz, CDCl3) d (ppm) 1.41 (s,
9H), 2.80–2.88 (m, 1H), 3.06-3.12 (m, 1H), 3.61 (s, 3H), 4.11–
4.16 (m, 1H), 7.09–7.43 (m, 11H); 19F NMR (282 MHz,
CDCl3) d À137.5 (2H), À154.0 (1H), À161 4 (2H); 13C NMR
(75 MHz, CDCl3) d (ppm): 28.0, 29.7, 32.3, 52.2, 60.4, 64.5,
81.5, 125.6, 127.9, 128.1, 128.2, 128.5, 128.6, 128.8, 130.4,
136.0, 137.2, 138.9, 166.3, 170.0, 170.7; MS (EI/CI) m/z calcd
for [C30H26F5NO4 + H]+ 559, found: 559.
5.2. Preparation of the benzophenone imine of glycine tert-
butyl ester (2) [15a]
5.3.3. 1-(1,1-Dimethylethyl)-5-methyl-N-
(diphenylmethylene)-(4E)-(4-fluorophenyl methylene)-(Æ)-
A mixture of tert-butyl chloroacetate (45.2 g, 0.30 mol),
benzophenone imine (36.3 g, 0.20 mol), and anhydrous
potassium carbonate (41.5 g, 0.30 mol) was stirred under
argon overnight at 130 8C in a 250 mL flask equipped with a
reflux condenser. After cooling to room temperature, the
mixture was filtered with filter paper in a Buchner funnel using
suction. The inorganic solids were washed with ethyl acetate
(3 Â 50 mL). The filtrates were dissolved with warming and
stirring in ethyl acetate (375 mL). The organic phase was
washed with water (200 mL), dried over sodium sulphate,
filtered and evaporated in vacuo. The solid residue was
dissolved in hexanes (450 mL), which required warming with
stirring. After refrigeration overnight, the crystalline product
was filtered to yield product as white crystals (61% yield).
glutamate [(Æ)-3c]
96% yield: 1H NMR (300 MHz, CDCl3) d (ppm) 1.52 (s, 9H),
3.06–3.11 (m, 1H), 3.40–3.48 (m, 1H), 3.63 (s, 3H), 4.41–4.45
(m, 1H), 7.04–7.75 (m, 15H); 19F NMR (282 MHz, CDCl3) d
À113.43; 13C NMR (75 MHz, CDCl3) d (ppm): 28.1, 31.2, 51.8,
64.9, 81.3, 115.3, 115.6, 128.0, 128.1, 128.3, 128.5, 128.8, 128.9,
130.4, 131.3, 132.0, 132.1, 136.2, 139.2, 141.0, 168.1, 170.6,
170.8; MS (EI/CI) m/z calcd for [C30H30FNO4 + H]+ 488,
found: 488.
5.3.4. 1-(1,1-Dimethylethyl)-5-methyl-N-
(diphenylmethylene)-(4E)-(3-fluorophenyl methylene)-(Æ)-
glutamate [(Æ)-3d]
92% yield: 1H NMR (300 MHz, CDCl3) d (ppm) 1.52 (s, 9H),
3.07–3.13 (m, 1H), 3.42–3.50 (m, 1H), 3.64 (s, 3H), 4.40–4.45
(m, 1H), 7.10–7.64 (m, 14H), 7.75 (s, 1H, vinyl proton); 19F
NMR (282 MHz, CDCl3) d À112.88; 13C NMR (75 MHz,
CDCl3) d (ppm): 28.1, 31.2, 51.9, 64.9, 81.3, 115.4, 115.7, 116.4,
116.9, 125.8, 128.0, 128.1, 128.4, 128.5, 129.0, 129.9, 130.2,
130.4, 136.2, 137.3, 137.5, 139.1, 140.8, 164.3, 167.9, 170.7.
5.3. General experimental procedure for the preparation of
4-(fluoroalkylidenyl)- and 4-(fluorobenzylidenyl) glutamic
acid derivatives [(Æ)-3]
n-Butyl lithium (2.5 M solution in hexanes, 1.2 mmol,
1.2 equiv.) was added dropwise over 5 min by syringe to the

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P.V. Ramachandran et al. / Journal of Fluorine Chemistry 128 (2007) 78–83
5.3.5. 1-(1,1-Dimethylethyl)-5-methyl-N-
(diphenylmethylene)-(4E)-(2-fluorophenyl methylene)-(Æ)-
glutamate [(Æ)-3e]
5.4. Synthesis of 4-(4-fluorobenzyl) glutamic acid (Æ)-6
[10a]
1
95% yield: H NMR (300 MHz, CDCl3) d (ppm) 1.52 (s,
5.4.1. Synthesis of 4-(4-fluorobenzylidenyl) pyroglutamate
(Æ)-4
9H), 3.13–3.19 (m, 1H), 3.40–3.48 (m, 1H), 3.65 (s, 3H), 4.45–
4.49 (m, 1H), 7.05–7.64 (m, 13H), 7.91 (s, 1H, vinyl proton),
Excess 15% aqueous citric acid (5 mL) was added to
compound 3c (0.33 g, 0.68 mmol) dissolved in THF (3 mL).
The suspension was stirred overnight at room temperature. After
completion of the reaction (monitored periodically by thin layer
chromatography),thereactionmixturewasextractedwithEtOAc
(3Â 5 mL) and then the aqueous layer was made basic by adding
10% aqueous K2CO3 (5 mL), followed by additional EtOAc
(5 mL). The combined organic layers were dried over Na2SO4
and concentrated in vacuo. Purification of the residue by column
chromatography(silica, hexanes:ethylacetate;8:2, v/vtoremove
benzophenone and hexanes:ethyl acetate; 1:1, v/v to elute
product) afforded the desired 4-(4-fluorobenzylidenyl) pyroglu-
tamate (Æ)-4 (87% yield): 1H NMR (300 MHz, CDCl3) d (ppm)
1.50 (s, 9H), 3.19–3.27 (m, 1H), 3.38–3.49 (m, 1H), 4.28–4.33
(m, 1H), 6.61 (bs, 1H), 7.30–7.58 (m, 5H); 13C NMR (75 MHz,
CDCl3) d (ppm): 28.2, 30.2, 53.7, 82.9, 128.1, 128.8, 129.1,
129.6, 131.8, 135.2, 170.6, 171.3.
8.04–8.09 (t, 1H); 19F NMR (282 MHz, CDCl3) d À113.41; 13
C
NMR (75 MHz, CDCl3) d (ppm): 28.1, 31.4, 51.9, 64.7, 81.3,
115.3, 115.6, 123.2, 123.4, 124.1, 127.9, 128.2, 128.3, 128.5,
128.9, 130.3, 130.5, 135.6, 131.0, 131.1, 134.6, 136.2, 139.3,
167.7, 170.7, 170.8.
5.3.6. 1-(1,1-Dimethylethyl)-5-methyl-N-
(diphenylmethylene)-(4E)-(4-trifluoromethoxyphenyl
methylene)-(Æ)-glutamate [(Æ)-3f]
1
88% yield: H NMR (300 MHz, CDCl3) d (ppm) 1.53 (s,
9H), 3.07–3.13 (m, 1H), 3.418–3.49 (m, 1H), 3.65 (s, 3H),
4.42–4.46 (m, 1H), 7.16–7.80 (m, 14H), 7.83 (s, 1H, vinyl
proton); 19F NMR (282 MHz, CDCl3) d À57.67; 13C NMR
(75 MHz, CDCl3) d (ppm): 28.1, 31.1, 51.9, 64.8, 81.4, 120.7,
127.8, 128.1, 128.3, 128.5, 128.9, 129.8, 130.4, 131.6, 133.9,
136.2, 139.2, 140.5, 149.3, 168.0, 170.7, 170.8.
5.4.2. Hydrogenation of 4-(4-fluorobenzylidenyl)
pyroglutamate: preparation of 4-(4-fluorobenzyl)
5.3.7. 1-(1,1-Dimethylethyl)-5-methyl-N-
(diphenylmethylene)-(4E)-(4-trifluoromethylphenyl
methylene)-(Æ)-glutamate [(Æ)-3g]
pyroglutamate (Æ)-5
To a solution of [(Æ)-4] (0.15 g, 0.51 mmol) in ethyl acetate
(5 mL) was added 10% Pd/C (90 mg). Hydrogenation was
carried out under a hydrogen atmosphere at room temperature
and atmospheric pressure for 12 h. After completion of the
reaction (monitored periodically by thin layer chromatogra-
phy), the reaction mixture was filtered and the filtrate was
concentrated in vacuo. Purification of the residue by column
chromatography (silica, hexanes:ethyl acetate; 9:1, v/v)
1
95% yield: H NMR (300 MHz, CDCl3) d (ppm) 1.53 (s,
9H), 3.08–3.148 (m, 1H), 3.40–3.48 (m, 1H), 3.66 (s, 3H),
4.41–4.46 (m, 1H), 7.19–7.85 (m, 15H); 19F NMR (282 MHz,
CDCl3) d À62.62; 13C NMR (75 MHz, CDCl3) d (ppm): 28.1,
31.1, 52.0, 64.7, 81.5, 125.4, 128.0, 128.1, 128.3, 128.6, 128.9,
130.1, 130.4, 131.1, 136.1, 138.9, 139.1, 140.4, 167.8, 170.5,
170.7; MS (EI/CI) m/z calcd for [C31H30F3NO4 + H]+ 538,
found: 538.
1
afforded the desired reduced product (Æ)-5 (82% yield): H
NMR (300 MHz, CDCl3) d (ppm) 1.44 (s, 9H), 2.05–2.22 (m,
2H), 2.65–2.74 (m, 2H), 3.09–3.14 (m, 1H), 3.84–3.90 (m, 1H),
6.33 (bs, 1H), 6.93–7.15 (m, 4H); 19F NMR (282 MHz, CDCl3)
d À116.58; 13C NMR (75 MHz, CDCl3) d (ppm): 27.9, 30.9,
36.8, 43.4, 55.0, 82.3, 126.1, 128.6, 128.9, 139.4, 171.1, 178.7.
5.3.8. 1-(1,1-Dimethylethyl)-5-methyl-N-
(diphenylmethylene)-(4E)-(3-fluoropyridinyl methylene)-
(Æ)-glutamate [(Æ)-3h]
1
82% yield: H NMR (300 MHz, CDCl3) d (ppm) 1.46 (s,
9H), 3.03–3.08 (m, 1H), 3.38–3.47 (m, 1H), 3.55 (s, 3H), 4.36–
4.41 (m, 1H), 7.11–7.76 (m, 13H), 7.80 (s, 1H, vinyl proton);
19F NMR (282 MHz, CDCl3) d À136.32; 13C NMR (75 MHz,
CDCl3) d (ppm): 28.1, 31.3, 51.8, 64.9, 81.2, 127.8, 128.0,
128.2, 128.3, 128.5, 128.7, 129.0, 130.0, 130.2, 135.3, 136.3,
139.4, 142.0, 168.3, 170.5, 170.9.
5.5. Catalytic enantioselective PTC alkylations
5.5.1. 1-(1,1-Dimethylethyl)-5-methyl-N-
(diphenylmethylene)-(4E)-(1,1,1-trifluoro ethylidene)-L-
glutamate [(S)-3a]
Fluorinated allylic acetate 1a (1 mmol, 1 equiv. in 1 mL
CH2Cl2) was added dropwise at À78 8C to a mixture of the
benzophenone imine of glycine tert-butyl ester (2) (1 mmol,
1 equiv.), O-allyl-N-(9-anthracenylmethyl) cinchonidium bro-
mide (0.1 mmol, 0.1 equiv.) and CsOHÁH2O (10 mmol,
10 equiv.) in CH2Cl2 (3 mL). The reaction mixture was stirred
vigorously in a cryobath for 48 h. The suspension was diluted
with ether, washed with water, brine, dried over Na2SO4,
filtered and concentrated in vacuo. Purification of the residue by
flash chromatography (silica, hexanes:ethyl acetate; 9:1, v/v)
afforded the desired 4-(trifluoroethylidenyl) glutamic acid
5.3.9. 1-(1,1-Dimethylethyl)-5-methyl-N-
(diphenylmethylene)-(4E)-(2,6-difluorophenyl methylene)-
(Æ)-glutamate [(Æ)-3i]
1
61% yield: H NMR (300 MHz, CDCl3) d (ppm) 1.47 (s,
9H), 2.96–3.04 (m, 1H), 3.11–3.17 (m, 1H), 3.63 (s, 3H), 4.26–
4.30 (m, 1H), 6.86–6.92 (m, 2H), 7.19–7.50 (m, 12H); 13C
NMR (75 MHz, CDCl3) d (ppm): 28.1, 32.5, 51.8, 64.6, 81.2,
111.5, 111.8, 127.7, 128.2, 128.3, 128.4, 128.7, 128.9, 129.9,
130.1, 134.9, 136.3, 139.4, 167.0, 170.4, 170.6; MS (ESI) m/z
calcd for [C30H29F2NO4 + H]+ 505, found: 505.

P.V. Ramachandran et al. / Journal of Fluorine Chemistry 128 (2007) 78–83
83
ACS Symposium Series 746, American Chemical Society, Washington,
DC, 1999.
derivative (S)-3a, which was identical with analytical data
listed previously for (Æ)-3a.(66% yield and 42% ee.): Chiral
HPLC conditions: column, (S,S)-Whelk-O1; solvent, hex-
anes:2-propanol, 95:5, v/v; flow rate, 1.0 mL/min; l = 254,
retention times, tR = 13.97 (minor) 19.97 (major) min.
(c) P. Leverman, O.C. Boerman, F.H. Corsten, W.J. Oyen, Eur. J. Nucl.
Med. Mol. Imaging 29 (2002) 681–690.
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5.5.2. 1-(1,1-Dimethylethyl)-5-methyl-N-
(diphenylmethylene)-(4E)-(2,3,4,5,6-pentafluorophenyl
methylene)-L-glutamate [(S)-3b]
(b) J.T. Welch, A. Gyenes, J.M. Jung, in: V.P. Kukhar, V.A. Soloshonok
(Eds.), Fluorine Containing Amino Acids, John Wiley and Sons, New
York, 1994, p. 311.
Fluorinated allylic acetate 1b (1 mmol, 1 equiv. in 1 mL
CH2Cl2) was added dropwise at À78 8C to a mixture of the
benzophenone imine of glycine tert-butyl ester (2) (1 mmol,
1 equiv.), O-allyl-N-(9-anthracenylmethyl) cinchonidium bro-
mide (0.1 mmol, 0.1 equiv.) and CsOHÁH2O (10 mmol,
10 equiv.) in CH2Cl2 (3 mL). The reaction mixture was stirred
vigorously in a cryobath for 36 h. The suspension was diluted
with ether, washed with water, brine, dried over Na2SO4, filtered
and concentrated in vacuo. Purification of the residue by flash
chromatography (silica, hexane:ethyl acetate; 9:1, v/v) afforded
the desired 4-(2,3,4,5,6-pentafluorobenzylidenyl) glutamic acid
derivative (S)-3b, which was identical with analytical data listed
previously for (Æ)-3b.(88% yield and 45% ee.): Chiral HPLC
conditions: column, (S,S)-Whelk-O1; solvent, hexanes:2-propa-
nol, 95:5, v/v; flow rate, 1.0 mL/min; l = 254, retention times,
tR = 10.09 (minor) 13.33 (major) min.
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Fluorinated allylic acetate 1i (1 mmol, 1 equiv. in 1 mL
CH2Cl2) was added dropwise at À78 8C to a mixture of the
benzophenone imine of glycine tert-butyl ester (2) (1 mmol,
1 equiv.), O-allyl-N-(9-nthracenylmethyl) cinchonidium bro-
mide (0.1 mmol, 0.1 equiv.) and CsOHÁH2O (10 mmol,
10 equiv.) in CH2Cl2 (3 mL). The reaction mixture was stirred
vigorously in a cryobath for 48 h. The suspension was diluted
with ether, washed with water, brine, dried over Na2SO4,
filtered and concentrated in vacuo. Purification of the residue by
flash chromatography (silica, hexane:ethyl acetate; 9:1, v/v)
afforded the desired 4-(2,6-difluorobenzylidenyl) glutamic acid
derivative (S)-3i, which was identical with analytical data listed
previously for (Æ)-3i.(68% yield and 80% ee.): Chiral HPLC
conditions: column, (S,S)-Whelk-O1; solvent, hexanes:2-
propanol, 95:5 (v/v); flow rate, 1.0 mL/min; l = 254, retention
times, tR = 11.24 (major) 13.18 (minor) min.
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Acknowledgement
(b) S. Eils, K. Rossen, W. Jahn, I. Klement, Imination Process for the
Preparation of Substituted N-Methyleneglycinate Esters from Imines and
Leaving Group-Substituted Acetate Esters. Eur. Pat. Appl. 1207151, 2002;
Chem. Abstr. 136 (2002) 386395.
We gratefully acknowledge the National Institutes of Health
(R01 GM28193) for support of this research.
[16] P.V. Ramachandran, S. Madhi, L. Bland-Berry, M.V.R. Reddy, M.J.
O’Donnell, J. Am. Chem. Soc. 127 (2005) 13450–13451.
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