Synthesis of 4-monofluoromethylenyl- and cis-4-monofluoromethyl-L- pyroglutamic acids via a novel dehydrofluorination

Article abstract of DOI:10.1016/j.tet.2004.04.044

Novel dehydrofluorination reactions accidentally found were used to synthesize terminal monofluoro olefin lactam analogues in good yield. The following hydrogenation of the resulting defluorinated product was systematically investigated. Two important fluorinated amino acids: 4-monofluoromethylenyl-L-pyroglutamic acid 16 and cis-4-monofluoromethyl-L- pyroglutamic acid 17 were synthesized using the methodology.

Full text of DOI:10.1016/j.tet.2004.04.044

Tetrahedron 60 (2004) 5201–5206
Synthesis of 4-monofluoromethylenyl- and
cis-4-monofluoromethyl-L-pyroglutamic acids
via a novel dehydrofluorination
Xiao-Long Qiu,a Wei-Dong Mengb and Feng-Ling Qinga,b
,
*
aKey Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science,
354 Fenglin Lu, Shanghai 200032, China
bCollege of Chemistry and Chemical Engineering, Donghua University, 1882 West Yanan Lu, Shanghai 200051, China
Received 31 December 2003; revised 15 April 2004; accepted 16 April 2004
Abstract—Novel dehydrofluorination reactions accidentally found were used to synthesize terminal monofluoro olefin lactam analogues in
good yield. The following hydrogenation of the resulting defluorinated product was systematically investigated. Two important fluorinated
amino acids: 4-monofluoromethylenyl-L-pyroglutamic acid 16 and cis-4-monofluoromethyl-L-pyroglutamic acid 17 were synthesized using
the methodology.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
the difficulties in stereoselective introduction of mono-
fluoromethyl group into specific position of pyroglutamic
acids. Herein reported is the efficient synthesis of two novel
fluorinated amino acids: 4-monofluoromethylenyl-L-pyro-
glutamic acid and cis-4-monofluoromethyl-L-pyroglutamic
acid via a novel dehydrofluorination reaction.
In recent years, the application of the fluorinated amino
acids has been progressed a great deal. As well as being used
as the biological tracers and mechanistic probes for
investigations on the structures and properties of enzymes,
fluorinated amino acids have also played an important role
in medicinal chemistry, especially in the control of blood
pressure, allergies and tumor growth.1 In particular,
fluorinated amino acids have recently emerged as valuable
building blocks for designing hyperstable protein folds, as
well as directing highly specific protein–protein inter-
actions.2 For these reasons, the stereoselective synthesis of
novel fluorinated amino acids is of great interest and
intensive demand.1,3,4
2. Results and discussion
We accidentally found that the dehydrofluorination reaction
occurred when the amino group of 5-tert-butyldimethyl-
silyloxymethyl-3-difluoromethyl-pyrrolidin-2-one 2 was
protected with tert-butoxycarbonyl group (Boc) (Scheme 1).
That was: treatment of compound 2 with di-tert-butyl
Pyroglutamic acid and its derivatives are important amino
acids in many bioactive compounds.5 The 4-substituted
pyroglutamic acid derivatives are important for their
conformation and activities. For example, some natural
and synthetic 4-substituted glutamic acids have been used to
study their structure-–activity relationships of excitatory
effects on the nervous system.6 Although efficient asym-
metric synthesis of fluorinated pyroglutamic acids have
been reported,7 to the best of our knowledge, there is no
report on the synthesis of monofluoromethyl and mono-
fluoromethylenyl pyroglutamic acids, probably because of
Keywords: Fluorinated amino acids; Pyroglutamic acids; Dehydro-
fluorination.
*
Corresponding author. Tel.: þ86-21-641-63300; fax: þ86-21-64166128;
e-mail address: flq@mail.sioc.ac.cn
Scheme 1.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.04.044

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X.-L. Qiu et al. / Tetrahedron 60 (2004) 5201–5206
Table 1. Influence of base and solvent on dehydrofluorination reaction of 6
Entry
Base
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
THF
Time (h)
Product 7a (%)
Product 8a (%)
Conversion (%)
1
2
3
4
5
6
7
8
Pyridine
i-Pr2NEt
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
24
24
24
24
24
18
3
2.7b
77
90
74
81
90
70
85
0
5
0
15
0
0
10
92
100
96
100
100
100
100
DMF
CH3CN
CH3CN/H2O
THF/H2O
0
0
3
a
Isolated yield.
Determined by 1H NMR and 19F NMR.
b
dicarbonate (Boc2O) and Et3N under the catalysis of
4-(dimethylamino)pyridine (DMAP) provided the mono-
fluoro olefin 5 in 25% yield along with desired compound 3
in very low yield (9%). The dehydrofluorination reaction
was not observed during the protection of the hydroxy group
of 5-hydroxymethyl-3-difluoromethyl-pyrrolidin-2-one 1
with tert-butyldimethylsilyl group using imidazole as a
base (Scheme 1). In our opinion, dehydrofluorination
reaction occurred after the desired product 3 was formed.
It was induced by the enhancement of acidity of 4-H as a
result of the protection of amino group of 2 by electron-
withdrawing groups (Boc). Recently, the synthesis of
terminal monofluoro olefins of the general structure
R1R2CvCHF has been summarized by Gen et al.8 Because
loss of HCl, HBr or HI seems sufficiently favorable over
dehydrofluorination, only a few syntheses have applied the
dehydrofluorination reaction of difluoromethyl groups.9–11
Among these synthetic methods of terminal monofluoro
olefins, all of the dehydrofluorination reactions were carried
out in the presence of strong bases (NaOEt, KOH or NaOH)
which could cause the racemization of some chiral
substrates. The discovery of the dehydrofluorination
reaction caused by weak organic amine base (Et3N)
promoted us to improve the yield of this novel dehydro-
fluorination for the synthesis of 4-monofluoromethylenyl-L-
pyroglutamic acid.
yield after 24 h without isomeric compound 8 formed (entry
3). These experiments showed that the amine bases had a
profound influence. Then the investigation of the solvent
effect on the reaction was followed (Et3N as the base, entries
3–8). When the reaction was conducted in THF at room
temperature for 24 h, 7 and 8 were isolated in 74 and 15%
yields with a little starting material (entry 4). When DMF
was used as the solvent, 7 was obtained in 81% yield
without the formation of the isomeric compound 8 (entry 5).
The reaction was completed in 18 h in CH3CN to give 7 as
the single product in 90% yield (entry 6). Surprisingly, H2O
had not altered the dehydrofluorination reaction, but had
enhanced the reaction rate dramatically (entries 7 and 8).
When reactions were conducted in a mixed solvent
(CH3CN/H2O, v/v¼2:1; THF/H2O, v/v¼2:1), the dehydro-
fluorination reaction was finished in 3 h to give 7 in 70 and
85% isolated yields, respectively, without a trace of
compound 8 observed. It was easily concluded that Et3N
was the best amine base and THF/H2O (v/v¼2:1) was the
most suitable solvent system for the novel dehydrofluorina-
tion reaction. The absolute configuration of 7 was confirmed
by NOE correlation.
With compound 7 in hand, we turned our attention to
synthesize 4-monofluoromethyl pyroglutamic acid via the
catalytic hydrogenations of 7 (Table 2). There are only a few
reports on the catalytic hydrogenation of a- or b-fluoro-a,
b-unsaturated esters and ketones.12 This may be due to the
hydrogenolyic lability of vinylic fluorine compared to the
saturated counterpart.13 The catalytic hydrogenation of 7
was first carried out under usual condition (Table 2, entries
1–3). However, the desired compound 10 was not observed,
and only defluorinated compound 9 was isolated in
moderate yields and good diastereoselectivities (entry 1,
10% Pd/C, 81% yield, cis/trans¼19.3:1; entry 2, 10% Pt/C,
83% yield, cis/trans¼5.9:1). Even with Ranney Ni as the
catalyst in MeOH, compound 10 was still not observed
except 9 (entry 3). In our opinion, these three catalysts
caused the hydrogenolytic cleavage of carbon–fluorine
bonds due to their strong catalytic activities. Thus, some
weak catalysts were tried (entries 4–6). Surprisingly, cis-10
was obtained in 12% yield along with 9 (77% yield) when
We first studied the novel dehydrofluorination reactions
with (2S, 4S)-tert-butyl-N-tert-butoxycarbonyl-4-difluoro-
methylpyroglutamate 6 as the substrate (Table 1) which was
easily prepared from trans-4-hydroxy-L-proline.7a First, the
effect of bases on dehydrofluorination reaction was
investigated by conducting the model reaction in CH2Cl2
at room temperature (Table 1, entries 1–3). When pyridine
was used as the base, the dehydrofluorination reaction
proceeded slowly and the defluorinated compound 7 was
afforded only in 2.7% yield even after 24 h (entry 1).
However, when i-Pr2NEt was used, the reaction rate
increased dramatically and the desired compound 7 was
isolated in 77% yield along with the isomeric compound 8
in 5% yield (entry 2). The reaction was performed smoothly
with Et3N as the base and compound 7 was obtained in 90%

X.-L. Qiu et al. / Tetrahedron 60 (2004) 5201–5206
Table 2. Influence of catalysts and solvents on hydrogenation of 7
5203
Entry
Catalyst
Solvent
Time (h)
9 Yield (%) (cis:trans)
10 Yield (%) (cis:trans)
11 Yield (%)
Conversion (%)
1
2
3
4
5
6
7
8
10% Pd/C
5% Pd/C
EtOH
EtOH
MeOH
EtOH
EtOH
EtOH
EtOHd
THF
CH2Cl2
EtOAc
Dioxane
5
0.5
1
0.5
0.5
1
24
24
24
2
81 (19.3:1.0)a
—
—
—
—
—
—
—
—
—
9.7g
12.0g
—
100
100
100
100
100
100
84f
83 (5.9:1.0)a
Ranney Ni
Pd(OH)2/C
Pd–CaSO4
Pd–BaSO4
Pd–BaSO4
Pd–BaSO4
Pd–BaSO4
Pd–BaSO4
Pd–BaSO4
96b
—
12c
77 (25.0:1.0) a
74 (36.0:1.0) a
19c
75 (74.0:1.0) a
20c
47b
45b
8b
1.5e
37c
95f
9
10
11
29c
88f
100
100
20b
13b
77 (.38.5:1.0)h
78 (.78.0:1.0)h
2
—
a
Cisand trans were isolated by flash chromatography.
No or trace trans-9 was observed or determined.
No trans-10 was isolated or detected.
Several drops of quinoline was added.
Determined by 1H NMR.
Starting material was recovered.
Isolated yield.
Trace trans-10 was detected or isolated.
b
c
d
e
f
g
h
Pd(OH)2/C was used in EtOH (entry 4). cis-10 was also
isolated in 19 and 20% yields, respectively, with Pd–CaSO4
and Pd–BaSO4 as catalysts in EtOH (entries 5 and 6).
However, when Pd–BaSO4 was poisoned with several
drops of quinoline, 10 was observed only in 1.5% yield
together with 9 (47%) and starting material even after 24 h
(entry 7). Then, different solvents were investigated with
Pd–BaSO4 as the catalyst (entries 8–11). The usage of THF
Figure 1. Mechanism of hydrogenation of compound 7.

5204
X.-L. Qiu et al. / Tetrahedron 60 (2004) 5201–5206
and CH2Cl2 gave 10 in 37 and 29% yields, respectively,
together with 9 (entries 8 and 9), to our surprise, the
unexpected defluorinated compound 11 was also observed
in 9.7 and 12.0% yields, respectively. The best results were
obtained when EtOAc and dioxane were used as the
solvents. 10 was isolated in 77 and 78% yields, respectively,
with a small amount of 9 formed (entries 10 and 11). It was
concluded from these results that the catalysts and solvents
had great effects on the hydrogenation of 7. The absolute
configuration of cis-10 was confirmed by X-ray diffraction.
compounds could be applied to synthesize other a-mono-
fluoromethylenyl amide analogues and corresponding
a-monofluoromethyl amide analogues. Studies on detailing
the application of this novel reaction to other substrates and
incorporation of these two novel important fluorine-
containing amino acids into peptides, domimetics and
potential bioactive molecules are in intensive progress.
3. Experimental
How to explain the hydrogenation mechanism was a
challenge for us. According to the different products, the
reaction probably proceeded through the following mecha-
nism (Fig. 1). Attachment of 7 to Pd carrier gave the
intermediate 12 which could be directly hydrogenated to
give the desired compound 10. 12 could also transform to 13
due to the enolization of lactam. Elimination of HF from 13
by rearranging the enol followed by reattachment of Pd
afforded the intermediate 14 that could be reductive
eliminated to furnish 9. 14 could be converted to 15 via
reduction elimination followed by re-attachment to Pd
carrier. Finally, compound 11 was provided via elimination
of 3-H of 15.
3.1. General procedure for dehydrofluorination of
comound 6
To a solution of 6 (around 100 mg) in the different solvent
(10 mL), organic base (5.0 equiv.) was added dropwise.
Then, the mixture was stirred at room temperature. The
reaction was quenched with H2O (5 mL) and the resulted
mixture was extracted with CH2Cl2. The combined organic
phases were washed with brine and dried over anhydrous
Na2SO4. Filtration and removal of the solvent gave a
residue, which was purified by silica gel chromatography to
afford the corresponding products.
3.1.1. (2S)-tert-Butyl-N-tert-butoxycarbonyl-4-mono-
fluoromethylenylpyroglutamate 7. White solid; Mp
104–105 8C; [a]D20 217.1 (c 0.5, CHCl3); 1H NMR
(300 MHz, CDCl3) d 7.51 (dt, J¼78.4, 3.0 Hz, 1H), 4.52
(dd, J¼3.3, 2.7 Hz, 1H), 3.02 (m, 1H), 2.72 (dq, J¼17.6,
3.0 Hz, 1H), 1.53 (s, 9H), 1.48 (s, 9H); 19F NMR (282 MHz,
CDCl3) d 2120.6–120.8 (dq, J¼78.3, 3.0 Hz, 1F); IR (thin
With 7 and cis-10 in hand, one-step removal of protective
groups with trifluoroacetic acid in CH2Cl2 successfully
afforded two important fluorine-containing amino acids:
4-monofluoromethylenyl-L-pyroglutamic acid 16 and cis-4-
monofluoromethyl-L-pyroglutamic acid 17 in 72 and 66%
yields, respectively, (Scheme 2).
film) nmax 1784, 1772, 1747, 1711, 1690, 1294, 1149 cm21
;
MS (ESI) m/z 338 (MþþNa); Anal. Calcd for C15H22FNO5:
In conclusion, we have described a novel dehydrofluorina-
tion reaction caused by weak organic amino base and have
systematically investigated the effects of the different bases
and solvents on the reaction. The process of this reaction
was simple operated with readily available and cheap
reagents and occurred under very mild condition. We have
also described the hydrogenation of the resulting desired
compound 7 in view of different catalysts and solvents, and
have proposed a corresponding hydrogenation mechanism.
Finally, we have synthesized two important fluorine-
containing amino acids: 4-monofluoromethylenyl-L-pyro-
glutamic acid 16 and cis-4-monofluoromethyl-L-pyrogluta-
mic acid 17. We believe that the novel dehydrofluorination
reaction and hydrogenation of corresponding defluorinated
C, 57.13; H, 7.03; N, 4.44. Found: C, 57.18; H, 7.12; N 4.33.
3.1.2. (2S,4R)-tert-Butyl-N-tert-butoxycarbonyl-4-di-
fluoromethylpyroglutamate 8. White solid; Mp 66–
1
68 8C; [a]2D0 221.1 (c 0.6, CHCl3); H NMR (300 MHz,
CDCl3) d 6.23 (td, J¼55.4, 2.1 Hz, 1H), 4.51 (dd, J¼1.8,
2.1 Hz, 1H), 3.30–3.12 (m, 1H), 2.58–2.47 (m, 1H), 2.12
(ddd, J¼13.8, 1.8, 1.8 Hz, 1H), 1.52 (s, 9H), 1.49 (s, 9H);
19F NMR (282 MHz, CDCl3) d 2124.0 to 2125.2 (dd,
J¼277.5, 54.1 Hz, 1F), 2127.3–128.6 (ddd, J¼286.2, 25.0,
27.6 Hz, 1F); IR (thin film) nmax 1758, 1739, 1717, 1327,
1158 cm21; MS (ESI) m/z 353 (MþþNH4); Anal. Calcd for
C15H23 F2NO5: C, 53.72; H, 6.91; N, 4.18. Found: C, 53.92;
H, 6.99; N, 4.02.
3.2. General procedure for hydrogenation of compound
7
To a solution of compound 7 in the solvent, Pd-catalyst
(5–10% mmol) was added. The mixture was hydrogenated
at room temperature. Filtration and removal of the solvent
gave a residue that was purified by silica gel chroma-
tography to afford the corresponding products.
3.2.1. (2S,4S)-tert-Butyl-N-tert-butoxycarbonyl-4-
methylpyroglutamate 9 (cis). White solid; Mp 58–60 8C;
1H NMR (300 MHz, CDCl3) d 4.41–4.36 (m, 1H), 2.67–
2.50 (m, 2H), 1.62–2.56 (m, 1H), 1.51 (s, 9H), 1.49 (s, 9H),
1.23 (d, J¼6.9 Hz, 3H); 13C NMR spectra was identical to
that of literature (J. Chem. Soc., Perkin Trans. 1 1996, 507).
Scheme 2.

X.-L. Qiu et al. / Tetrahedron 60 (2004) 5201–5206
5205
3.2.2. (2S,4R)-tert-Butyl-N-tert-butoxycarbonyl-4-
methylpyroglutamate 9 (trans). White solid; Mp 63–
64 8C; 1H NMR (300 MHz, CDCl3) d 4.43 (dd, J¼1.5,
1.8 Hz, 1H), 2.73–2.59 (m, 1H), 2.28–2.20 (m, 1H), 1.95–
1.84 (m, 1H), 1.51 (s, 9H), 1.48 (s, 9H), 1.23 (d, J¼7.2 Hz,
1H) (literature reported: 4.42 (d, J¼9.5 Hz, 1H), 2.65 (m,
1H), 2.24 (ddd, J¼13.5, 8.7, 1.0 Hz, 1H), 1.89 (m, 1H), 1.51
(s, 9H), 1.48 (s, 9H), 1.21 (t, J¼7.0 Hz, 1H). J. Chem. Soc.,
Perkin Trans. 1 2001, 2367.)
Mp 153–154.5 8C; [a]2D0þ37.6 (c 1.1, H2O); 1H NMR
(300 MHz, MeOH-d4) d 7.44 (dt, J¼78.3, 3.0 Hz, 1H), 4.50
(dd, J¼4.2, 4.2 Hz, 1H), 3.37–3.26 (m, 1H), 3.04–2.97 (m,
1H); 19F NMR (282 MHz, MeOH-d4) d 2123.5 to 2123.8
(dt, J¼78.5, 3.9 Hz, 1F); 13C NMR (75.5 MHz, MeOH-d4) d
176.6, 173.6 (d, J¼19.5 Hz), 154.2 (d, J¼270.3 Hz), 116.1
(d, J¼13.4 Hz), 54.7, 26.6; IR (thin film) nmax 3370, 3319,
3101, 2471, 1918, 1726, 1703, 1642, 1257, 1087 cm21; MS
(EI) m/z 159 (Mþ, 2), 114 (Mþ –COOH, 100); Anal. Calcd
for C6H6FNO3: C, 45.29; H, 3.80; N, 8.80. Found: C, 45.17;
H, 3.78; N, 8.54.
3.2.3. (2S,4S)-tert-Butyl-N-tert-butoxycarbonyl-4-mono-
fluoromethylpyroglutamate 10 (cis). White solid; Mp 68–
1
70 8C; [a]2D0 235.7 (c 1.0, CHCl3); H NMR (300 MHz,
3.3.3. (2S,4S)-4-Monofluoromethylpyroglutamic acid
(17). Compound 17 (66 mg, 66%) was prepared as an off-
white solid from compound 10 (cis) (198 mg, 0.625 mmol)
following the procedure described for compound 16. Mp
110–112 8C; [a]2D0 228.4 (c 0.60, H2O); 1H NMR
(300 MHz, DMSO-d6) d 12.87 (s, 1H), 8.15 (s, 1H), 4.61
(ddd, J¼34.9, 4.5, 4.5 Hz, 1H), 4.51 (ddd, J¼34.9, 3.0,
3.0 Hz, 1H) 4.11 (t, J¼7.2 Hz, 1H), 2.80–2.55 (m, 2H),
1.95–1.85 (m, 1H); 19F NMR (282 MHz, DMSO-d6) d
2227.8 (m, 1F); 13C NMR (75.5 MHz, MeOH-d4) d 189.6,
186.4, 93.2 (d, J¼165.6 Hz), 65.2, 53.4 (d, J¼20.5 Hz),
37.4 (d, J¼4.0 Hz); IR (thin film) nmax 3366, 1716, 1664,
1642, 1265, 948 cm21; MS (EI) m/z 161 (Mþ, 2), 116 (Mþ
–COOH, 100); Anal. Calcd for C6H8FNO3: C, 44.72; H,
5.00; N, 8.69. Found: C, 44.46; H, 4.95; N, 8.56.
CDCl3) d 4.73 (ddd, J¼21.4, 5.1, 5.0 Hz, 1H), 4.58 (ddd,
J¼20.9, 5.1, 5.0 Hz, 1H) 4.48 (dd, J¼5.4, 5.7 Hz, 1H),
3.01–2.84 (m, 1H), 2.62–2.51 (m, 1H), 2.08–2.00 (m, 1H),
1.52 (s, 9H), 1.48 (s, 9H); 19F NMR (282 MHz, CDCl3) d
2227.9 (m, 1F); 13C NMR (75.5 MHz, CDCl3) d 171.5 (d,
J¼9.6 Hz), 170.1, 149.2, 83.8, 83.2, 81.7 (d, J¼112.6 Hz),
58.0, 44.0 (d, J¼21.7 Hz), 29.7, 27.9, 27.8, 23.9 (d, J¼
3.2 Hz); IR (thin film) nmax 1757, 1740, 1713, 1321,
1156 cm21; MS (ESI) m/z 657 (2Mþ þNa), 652 (2Mþþ
NH4), 335 (MþþNH4); Anal. Calcd for C15H24FNO5: C,
56.77; H, 7.62; N, 4.41. Found: C, 56.93; H, 7.69; N 4.12.
3.3. X-ray crystal structures of 10 (cis)
A white crystal having approximate dimension of
0.36£0.26£0.20 mm3 was used for X-ray study. The data
were collected on Bruker Smart APEX CCD diffractometer.
The crystal structure has been deposited at the Cambridge
crystallographic Data center and allocated the deposition
number CCDC 236000.
Acknowledgements
We thank the National Natural Science Foundation of China
and the Ministry of Education of China for financial support.
Crystal data: C15H24FNO5, M¼317.35, Orthorhombic,
Space group P2(1)2(1)2(1), a¼8.7047(13), b¼
3
˚
˚
11.2204(16), c¼17.628 (3) A, V¼1721.7(4) A , Z¼4,
Dcalc¼1.224 mg cm23, m¼0.098 mm21, F(000)¼680,
T¼293 K, 2umax¼56.568, 4036 independent reflections
scanned, 1716 reflections observed (I^2s(I)), 296 para-
meters, R1¼0.0420, wR2¼0.0654.
References and notes
1. (a) Welch, J. T.; Eswarakrishnan, S. Fluorine in Bioorganic
Chemistry; Wiley: New York, 1991. (b) Kukhar, V. P.;
Soloshonok, V. A. Fluorine Containing Amino Acids:
Synthesis and Properties; Wiley: New York, 1995. (c) Filler,
R.; Kobayashi, Y.; Yagupolski, L. M. Biomedical Aspects of
Fluorine Chemistry; Elsevier: Amsterdam, 1993.
3.3.1. (2S)-tert-Butyl-N-tert-butoxycarbonyl-4-methyl-3,
4-dehydropyroglutamate 11. White solid; Mp 59–61 8C;
[a]2D0 2218.1 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) d
6.71–6.69 (m, 1H), 4.91–4.89 (m, 1H), 1.92 (t, J¼4.8 Hz,
3H), 1.55 (s, 9H), 1.48 (s, 9H); 13C NMR (75.5 MHz,
CDCl3) d 169.1, 165.9, 148.8, 136.8, 135.9, 83.2, 83.1, 63.2,
28.0, 27.9, 11.0; IR (thin film) nmax 3082, 2982, 1787, 1747,
1721, 1657, 1160 cm21; MS (ESI) m/z 617 (2MþþNa), 612
(2MþþNH4); Anal. Calcd for C15H23NO5: C, 60.59; H,
7.80; N, 4.71. Found: C, 60.88; H, 7.78; N, 4.59.
2. For a recent review, see: Yoder, N. C.; Kumar, K. Chem. Soc.
Rev. 2002, 31, 335–341.
3. For reviews, see: (a) Haufe, G.; Kroger, S. Amino Acids 1996,
11, 409–424. (b) Tolman, V. Amino Acids 1996, 11, 15–36.
(c) Sutherland, A.; Willis, C. L. Nat. Prod. Rep. 2000, 17,
621–631.
4. For recent examples, see: (a) Vera-Ayoso, Y.; Borrachero, P.;
´ ´
Cabrera-Escribano, F.; Dianez, M. J.; Estrada, M. D.; Gomez-
´
´
´
Guillen, M.; Lopez-Castro, A.; Perez-Garrido, S. Tetrahedron:
Asymmetry 2001, 12, 2031–2041. (b) Xing, X.; Fichera, A.;
Kumar, K. Org. Lett. 2001, 3, 1285–1286. (c) Fustero, S.;
3.3.2. (2S)-4-Monofluoromethylenylpyroglutamic acid
(16). TFA (0.85 mL) was added to a solution of 7
(205 mg, 0.65 mmol) in CH2Cl2 (15 mL) at 0 8C. The
mixture was allowed to warm to room temperature and
stirred for 24 h. The reaction mixture was concentrated in
vacuo and the residue was triturated with Et2O–petroleum
ether to precipitate white solid, which was washed several
times with Et2O–petroleum ether. Remaining of the
resulted solid was dried under high vacuum at 60 8C for
several hours to give 16 (75 mg, 72%) as an off-white solid.
´
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