Synthetic studies of 3-(3-fluorooxindol-3-yl)-l-alanine

Article abstract of DOI:10.1016/j.jfluchem.2008.06.026

Oxidative fluorination of several protected tryptophans 8b-g with Selectfluor proceeded smoothly in aqueous media to give a diastereomeric mixture of the corresponding 3-fluorooxindoles 9b-g. Attempted deprotection of the 3-fluorooxindoles 9b-g under various conditions did not afford 3-(3-fluorooxindol-3-yl)-l-alanine (6). Reaction of the suitably protected tryptophan derivative 16 with Selectfluor produced the fluorinated product 17. Simultaneous cleavage of all protective groups of 17 under acidic conditions successfully gave the target compound 6 in excellent yield.

Full text of DOI:10.1016/j.jfluchem.2008.06.026

Journal of Fluorine Chemistry 129 (2008) 829–835
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthetic studies of 3-(3-fluorooxindol-3-yl)-
L
-alanine
a
a
b
a
Tomoya Fujiwara a, , Bin Yin , Meixiang Jin , Kenneth L. Kirk , Yoshio Takeuchi
*
a Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan
b Laboratory of Bioorganic Chemistry, National Institute of Diabetes, and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD 20892, USA
Dedicated to the memory of Professor Toshio Satoh of Tokushima Bunri University who made many lasting contributions to the field of
medicinal chemistry.
A R T I C L E I N F O
A B S T R A C T
Oxidative fluorination of several protected tryptophans 8b–g with SelectfluorTM proceeded smoothly in
aqueous media to give a diastereomeric mixture of the corresponding 3-fluorooxindoles 9b–g. Attempted
deprotection of the 3-fluorooxindoles 9b–g under various conditions did not afford 3-(3-fluorooxindol-3-
Article history:
Received 24 March 2008
Received in revised form 25 June 2008
Accepted 25 June 2008
Available online 3 July 2008
yl)-L
-alanine (6). Reaction of the suitably protected tryptophan derivative 16 with SelectfluorTM produced
the fluorinated product 17. Simultaneous cleavage of all protective groups of 17 under acidic conditions
successfully gave the target compound 6 in excellent yield.
Keywords:
ß 2008 Elsevier B.V. All rights reserved.
Epimerization
Fluorooxindole
Hydroxyoxindole
Indole
Oxindole
Oxindolylalanine
SelectfluorTM
Tryptophan
1. Introduction
synthase and the (2S,4R)-isomer inhibits only tryptophanase [7].
Identification of this stereochemistry dependent-biological activ-
The oxindole structure 1 is often found in natural products and
is also formed during the metabolism of tryptophan (Fig. 1) [1,2].
Oxindoles have been recognized as probes for investigation of
biological processes and leads for drug discovery [3,4]. Among
many examples of oxindoles, 3-hydroxyoxindoles have signifi-
cance in that these frequently occur in natural products and are
important structures in medicinal chemistry. Many 3-hydroxyox-
indoles have useful biological and pharmacological activities [2,4].
ity is possible with the 3-hydoxylated structure 5 since epimer-
ization is blocked by the 3-substituent. Similar studies with other
oxindoles such as the simple oxindole structure 4 is difficult
because of epimerization at the C-4 stereogenic center [6,7].
To provide tools for investigating the relationship between
biological activity and absolute configuration of epimerizable
substrates, we have been studying the design, synthesis, and
biological evaluation of chiral fluorinated bioorganic molecules
that possess a fluorine atom at the stereogenic center [8]. Since
replacement of a hydrogen of a prototype molecule with a fluorine
results in minimal steric alterations, many fluorinated biomole-
cules and medicinal agents interact with recognition sites of
enzyme and receptors in a manner similar to the fluorine-free
molecules [9]. This adds to the value of these probes of
stereochemistry vs. reactivity. Of course, introduction of fluorine
atoms into bioactive molecules often brings about enhanced,
additional and/or altered biological activities. In one example, we
earlier replaced the labile proton at the stereogenic center of the
epimerizable biomolecule thalidomide [10] with a fluorine atom to
give a non-epimerizable analog [8a]. Substitution of a hydroxyl
group of prototype molecules with fluorine can also provide the
For example, the compounds TMC-95A–D (3a–d) having
a
multifunctional 3-hydroxyoxindole structure inhibit the proteo-
lytic activity of proteasome. This is a protease complex that is
targeted in the design of new drugs for many diseases including
cancer and autoimmune diseases [5]. 3-Oxindol-3-yl-L-alanine (4)
is a tryptophan metabolite and was found to be a potent
competitive inhibitor of both tryptophan synthase and trypto-
phanase [6]. It should be noted that the (2S,4S)-isomer of 3-(3-
hydroxyoxindol-3-yl)-L-alanine (5) inhibits only tryptophan
* Corresponding author. Fax: +81 76 434 7556.
E-mail address: tfuji@pha.u-toyama.ac.jp (T. Fujiwara).
0022-1139/$ – see front matter ß 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2008.06.026

830
T. Fujiwara et al. / Journal of Fluorine Chemistry 129 (2008) 829–835
clinical application of BMS-204532 (Maxipost, 7) as a potassium
channel opener [13] further encouraged us to pursue the synthesis
the fluorinated tryptophan analog 6 as a potential building block
for drug development.
2. Results and discussion
We have previously reported the synthesis of 3-fluorooxindole
a
9a from N -acetyl-
L-tryptophan methyl ester (8a) by electrophilic
fluorination with SelectfluorTM (Table 1, entry 1) [14]. However, we
were unable to find conditions to convert 9a to the free amino acid
6. We report here the results of fluorination of oxindole substrates
8 with varying protecting groups on the fluorination reaction as
well as defining substrates that allow facile deprotection to the
a
amino acid (Table 1). In initial attempts, treatment of N -(tert-
butoxycarbonyl)-L-tryptophan methyl ester (8b) with 3 equiv. of
SelectfluorTM [15] in acetonitrile/water (1/1) produced a diaster-
eomeric mixture of the corresponding 3-fluorooxindole 9b (entry
2). However, the yield of 9b was quite low. Fluorination of the other
tryptophan derivatives 8c and 8d having the same urethane
protective groups gave the corresponding 3-fluorooxindoles 9c
and 9d, again in rather low yields (entries 3 and 4). It should be
noted that substantial amounts of the 3a-fluoropyrrolo[2.3-
b]indole derivatives 10 were formed as side products during the
fluorination of 8b–d. The formation of the cyclized compounds 10
was presumably due to the rather nucleophilic character of the Nb-
acyloxy moiety of 8b–d compared to the Nb-acyl moiety of 8a.
Indeed, Hino et al. reported that such cyclization occurs readily
during electrophilic attack at the 3-position of Nb-alkoxycarbonyl
protected tryptamines [16].
Based on these results, we explored the use of the tryptophans
having Nb-acyl protective groups, such as acetyl or trifluoroacetyl,
which would be less nucleophilic than Nb-acyloxy groups. Indeed,
when Nb-acyl protected tryptophans 8e and 8f were submitted to
the same fluorination procedure, 3-fluorooxindoles 9e and 9f were
obtained in 70% and 53% yields, respectively (entries 5 and 6),
without detectable formation of 10. The tryptophan derivative
Fig. 1. Structures of oxindoles 1–7
isosteric analogs because of similar electronic character and ability
as hydrogen bond acceptor of fluorine to hydroxyl group [9]. In
addition, apart from a hydroxyl group, a fluorine moiety is not
subjected to further metabolization. For example, Prestwich et al.
reported the substitution of one hydroxyl group of lysopho-
sphatidic acids (LPA, 1- or 2-acyl-sn-glycerol-3 phosphate) with
fluorine in order to prevent the acyl migration and evaluate the
inherent biological activities of LPA under the acyl migration-free
conditions [11].
As a part of our synthetic studies of chiral fluorinated bioorganic
molecules, we earlier attempted the synthesis of 3-(3-fluoroox-
indol-3-yl)-L-alanine (6). The non-epimerizable compound 6
8g with the
a-amino group being fully protected was also
should be a suitable model to study the relationship between
the stereochemistry and the biological activities of 4. Introduction
of fluorinated amino acids such as 6 into peptides often changes
the original conformation and biological properties [12]. Moreover,
fluorinated to give the corresponding 3-fluorooxindole 9g in good
yield (entry 7).
Although we have succeeded in the fluorination of 8b–g,
stereoselectivity of the reaction was rather poor with the
Table 1
Synthesis of 3-fluorooxindoles 9a–g from protected tryptophans 8a–ga
Entry
Indole 8
R1
R2
R3
3-Fluorooxindole
Yield (%)
1
2
3
4
5
6
7
8ab
8b
8c
8d
8e
8f
Ac
H
Me
Me
Me
Me
Me
But
Me
9a
9b
9c
9d
9e
9f
70
15
40
42
70
53
71
Boc
Cbz
Fmoc
CF3CO
Ac
H
H
H
H
H
8g
Boc
Boc
9g
a
Experimental conditions: three equivalent of SelectfluorTM was added to a solution of 8 in CH3CN/H2O (=1/1) and the mixture was stirred at room temperature overnight.
b
Ref. [14].

T. Fujiwara et al. / Journal of Fluorine Chemistry 129 (2008) 829–835
831
Table 2
Deprotection of the carboxyl groups of fluorooxindoles 9b,c,f,g
Entry
3-Fluorooxindole
R1
R2
R3
Conditions
Product (yield)
1
2
3
4
9ba
9ca
9ga
9fb
Boc
Cbz
Boc
Ac
H
Me
Me
Me
But
0.2N NaOH/MeOH
0.2N NaOH/MeOH
0.2N NaOH/MeOH
HBr/AcOH
11b (72%)
H
11c (77%)
Boc
H
Decomposition
11f (48%)
a
Diastereomeric mixture was used.
Less polar isomer was used.
b
diastereomeric excess of 4–46%. Separation of the diastereomers of
3-fluorooxindoles 9d–g was carried out readily using silica gel
column chromatography. In order to determine the absolute
configurations, we attempted to get single crystals of 9d,e,g.
However, no crystals suitable for X-ray analysis were obtained.
We then examined stepwise deprotection of 3-fluorooxindoles.
Saponification of the diastereomeric mixture of 9b and 9c in
aqueous NaOH/MeOH gave the corresponding carboxylic acids 11b
and 11c in 72% and 77% yields, respectively (Table 2, entries 1 and
2). However, reaction of 9g under the same conditions led to
decomposition (entry 3). This may result from lactam ring cleavage
that occurs instead of the hydrolysis of the ester moiety, the
reactivity of which would be lowered due to the sterically hindered
compound 12 although as mixtures with some inseparable
products (Table 3, entries 1 and 2). N-Deprotection of 9d and 9e
under basic conditions (piperidine and potassium carbonate) gave
a complicated mixture of mostly decomposition products. Finally,
treatment of 9b,g with HBr/AcOH gave the corresponding free
amine, which was successfully isolated as HCl salt 12 in excellent
yield (entries 3 and 4). However, in spite of extensive efforts,
hydrolysis of the methyl ester 12 under acidic conditions either did
not proceed or gave decomposition products under drastic
conditions. Saponification of 12 did not yield the desired product
6, instead producing mixtures of non-fluorinated compounds.
After these extensive investigations and taking into considera-
tion all aspects of reaction conditions and isolation procedures, we
a
a
a
a
neighboring N ,N -di-tert-butoxycarbonylamino group. Treat-
ment of 9f with HBr/AcOH also produced the corresponding
carboxylic acid 11f in 48% yield (entry 4).
eventually focused on N ,N -di-(tert-butoxycarbonyl)-
L-trypto-
phan tert-butyl ester (16) as a likely suitable precursor to the target
a
structure. Condensation of N -(tert-butoxycarbonyl)-L-tryptophan
Having established conditions to achieve ester hydrolysis, we
then addressed the final stage of the synthesis, i.e., N -deprotec-
(13) with tert-butanol in the presence of DCC (N,N0-dicyclohex-
ylcarbodiimide) gave tert-butyl ester 14 in 43% yield with ee of 46%
(Scheme 1). Protection of the indole nitrogen of 14 with benzyl
chloroformate [17] followed by treatment with di-tert-butyl
carbonate gave the fully protected tryptophan derivative 15 in
moderate yield. Catalytic hydrogenation of 15 gave the fluorina-
tion precursor 16 in good yield. Compound 16 was then allowed to
react with SelectfluorTM in the usual manner to produce a
diastereomeric mixture of the corresponding fluorooxindole 17
in 51% yield. Finally, treatment of 17 with HBr/AcOH successfully
produced the target compound 6 as HBr salt in excellent yield,
although as a mixture of diastereomers.
a
tion of 11b,c and 11f thus prepared. Although various conditions
were applied for these compounds, we encountered difficulty in
isolation of the target molecule 6 from the organic and inorganic
salts mixture. Attempted simultaneous removal of all protecting
groups of 9d and 9e under saponificative conditions (piperidine
and/or potassium carbonate) were unsuccessful.
Faced with these difficulties, we also attempted the alternative
a
strategy that involves initial N -deprotection followed by ester
hydrolysis. Removal of the Cbz groups of 9c occurred under
hydrogenative or acidic conditions to produce the desired
Table 3
Deprotection of the
a-amino groups of fluorooxindoles 9b,c,g
Entry
3-Fluorooxindole
R1
R2
Conditions
Yield (%)
1
2
3
4
9ca
9ca
9ba
9ga
Cbz
Cbz
Boc
Boc
H
HBr/AcOH
Mixtureb
Mixtureb
99%
H
Pd–C, HCOOꢀNH4+, MeOH
HBr/AcOH
H
Boc
HBr/AcOH
94%
a
Diastereomeric mixture was used.
b
Inseparable mixture with unidentified products.

832
T. Fujiwara et al. / Journal of Fluorine Chemistry 129 (2008) 829–835
Scheme 1. Synthesis of 6.
3. Conclusion
at room temperature. After stirring overnight, the mixture was
concentrated and extracted with EtOAc. The organic layer was then
dried over Na2SO4 and the solvent was evaporated. The residue
was purified by silica gel column chromatography (eluent: hexane/
CHCl3/EtOAc = 5/1/1) to give the less polar isomer (80.5 mg,
0.231 mmol, 33%) and the more polar isomer (90.3 mg,
0.259 mmol, 37%) of (2S)-2-(trifluoroacetylamino)-3-(3-fluoro-2-
oxoindoline-3-yl)propionic acid methyl ester (9e). Diastereomeric
excess (de) was determined to be 12% from the 1H NMR of crude
We have synthesized 3-(3-fluorooxindol-3-yl)-L-alanine (6) by
fluorination of the suitably protected tryptophan derivative 16
with SelectfluorTM followed by simultaneous deprotection under
acidic conditions. Having available this new fluorinated amino acid
in unprotected form will allow several new applications. In order
to evaluate the potential of 6 as a biological tool and precursor for
drug development, diastereomeric and enantiomeric separations
of 6 are currently underway. Use of the strategy presented here to
prepare derivatives suitable for peptide incorporation will also be
studied.
mixture. Less polar isomer: colorless solid; mp 122–123 8C; ½a D28
ꢁ
ꢀ12.2 (c 1.0, CHCl3); IR (KBr)
n ;
3291, 1755, 1737, 1703, 1628 cmꢀ1
d 2.56 (1H, ddd, J = 24.2, 15.1, 4.1 Hz),
1H NMR (400 MHz, CDCl3)
3.05 (1H, dt, J = 15.1, 6.9 Hz), 3.81 (3H, s), 4.77 (1H, ddd, J = 8.2, 6.9,
4.1 Hz), 6.91 (1H, d, J = 7.8 Hz), 7.17 (1H, dd, J = 7.8, 7.3 Hz), 7.39
(1H, ddt, J = 7.8, 2.3, 1.4 Hz), 7.44 (1H, d, J = 7.3 Hz), 8.10 (1H, br s);
4. Experimental
4.1. General
19F NMR (376 MHz, CDCl3)
d
ꢀ76.48 (3F, s), ꢀ156.16 (1F, d,
J = 23.8 Hz); MS (EI) m/z: 348 (M+), 289 (M+ꢀCOOMe), 269
(M+ꢀCOOMe–HF); HRMS (EI) calcd. for C14H12F4N2O4 (M+):
348.0733; found 348.0714. More polar isomer: colorless solid;
Melting points were measured with a Yanaco micro-melting
point apparatus and are uncorrected. Spectroscopic measurements
were carried out with the following instruments: optical rotations,
JASCO DIP-1000 digital polarimeter; IR spectra, JEOL FT/IR-
460Plus; mass spectra (MS), JEOL JMS-GCmate; high resolution
mass spectra (HRMS), JEOL JMS-AX 505; 1H NMR spectra, JEOL
ECX-400P (400 MHz) in CDCl3 or CD3OD with TMS (=0.00 ppm) as
an internal standard; 19F NMR spectra, JEOL ECX-400P (376 MHz)
in CDCl3 or CD3OD with CFCl3 (=0.00 ppm) as an internal standard.
Column chromatography and thin layer chromatography were
performed on Kanto chemical silica gel 60N (0.040–0.050 mm) or
Merck 9385 silica gel 60 (0.040–0.063 mm) and on Merck 5715,
respectively.
mp 129–130 8C; ½a D28
ꢁ
+15.8 (c 1.1, CHCl3); IR (KBr) 3388, 3301,
1H NMR (400 MHz, CDCl3)
2.64
1754, 1726, 1710, 1625 cmꢀ1
;
d
(1H, ddd, J = 22.4, 15.1, 7.3 Hz), 2.90 (1H, dt, J = 15.1, 5.0 Hz), 3.72
(3H, s), 4.87 (1H, dt, J = 7.3, 5.0 Hz), 6.91 (1H, d, J = 7.8 Hz), 7.14 (1H,
dd, J = 7.8, 7.3 Hz), 7.38 (1H, ddt, J = 7.8, 1.8, 0.9 Hz), 7.44 (1H, d,
J = 7.3 Hz), 7.65 (1H, br d, J = 6.9 Hz), 7.92 (1H, br s); 19F NMR
(376 MHz, CDCl3)
d
ꢀ76.54 (3F, s), ꢀ153.89 (1F, dd, J = 22.4,
15.1 Hz); MS (EI) m/z: 348 (M+), 289 (M+ꢀCOOMe), 269
(M+ꢀCOOMe–HF); HRMS (EI) calcd. for C14H12F4N2O4 (M+):
348.0733; found 348.0705.
4.2.1. (2S)-2-(tert-Butoxycarbonylamino)-3-(3-fluoro-2-
oxoindoline-3-yl)propionic acid methyl ester (9b)
Yield: 15% (as a diastereomeric mixture). De was determined to
be 4% from the 1H NMR of crude mixture: pale yellow oil; IR (neat)
n ;
3246, 1736, 1718, 1697, 1686, 1624 cmꢀ1 1H NMR (400 MHz,
4.2. General procedure for the synthesis of the protected 3-(3-
fluorooxindol-3-yl)alanine
SelectfluorTM (755 mg, 2.13 mmol) was added to a solution of
a
N -trifluoroacetyl-L-tryptophan methyl ester (8e) (223 mg,
CDCl3)
d 1.37 (9H, s), 1.41 (9H, s), 2.57–2.79 (4H, m), 3.66 (3H, s),
0.710 mmol) in a mixture of acetonitrile and water (1:1, 14 mL)
3.71 (3H, s), 4.27 (1H, m), 4.53 (1H, dd, J = 12.8, 7.8 Hz), 5.14 (1H, br

T. Fujiwara et al. / Journal of Fluorine Chemistry 129 (2008) 829–835
833
d, J = 7.8 Hz), 5.25 (1H, br d, J = 7.8 Hz), 6.88 (1H, d, J = 7.8 Hz), 6.90
(1H, d, J = 7.8 Hz), 7.11 (1H, t, J = 7.3 Hz), 7.13 (1H, t, J = 7.3 Hz), 7.34
(1H, t, J = 7.8 Hz), 7.36 (1H, t, J = 7.8 Hz), 7.45–7.48 (2H, m), 8.06
J = 7.8, 7.3 Hz), 7.35 (1H, t, J = 7.8 Hz), 7.45 (1H, d, J = 7.3 Hz), 8.23
(1H, br s); 19F NMR (376 MHz, CDCl3)
d
ꢀ151.97 (1F, t, J = 13.0 Hz);
MS (EI) m/z: 336 (M+), 280 (M+ꢀC4H8), 235 (M+ꢀCOOBut); HRMS
(1H, br s), 8.18 (1H, br s); 19F NMR (376 MHz, CDCl3)
d
ꢀ152.05 (1/
(EI) calcd. for C17H21FN2O4 (M+): 336.1485; found 336.1493.
6F, br s), ꢀ152.30 (5/6F, br s), ꢀ152.55 (5/6F, br t, J = 14.7 Hz),
ꢀ152.69 (1/6F, br s); MS (EI) m/z: 352 (M+), 296 (M+ꢀC4H8).
4.2.5. (2S)-2-[Bis(tert-butoxycarbonyl)amino]-3-(3-fluoro-2-
oxoindoline-3-yl)propionic acid methyl ester (9g)
4.2.2. (2S)-2-(Benzyloxycarbonylamino)-3-(3-fluoro-2-oxoindoline-
3-yl)propionic acid methyl ester (9c)
Yield = 71% (as a diastereomeric mixture). De was determined
to be 12% from the 1H NMR of crude mixture. Each diastereomer
gave the following data after partial separation.
Yield = 40% (as a diastereomeric mixture). De was determined
to be 16% from the 1H NMR of crude mixture: pale yellow oil; IR
Less polar isomer: colorless solid; mp 151–152 8C; ½a D29
ꢀ62.1
ꢁ
(neat)
n
3310, 1739, 1624 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
(c 1.0, CHCl3); IR (KBr) n ;
3230, 2983, 1742, 1733, 1702, 1630 cmꢀ1
2.58–2.85 (4H, m), 3.66 (3H, s), 3.72 (3H, s), 4.26 (1H, dt, J = 9.6,
4.1 Hz), 4.59 (1H, dt, J = 7.8, 5.0 Hz), 4.94 (1H, d, J = 12.4 Hz), 5.03
(1H, d, J = 12.4 Hz), 5.05 (1H, d, J = 12.4 Hz), 5.09 (1H, d,
J = 12.4 Hz), 5.39 (1H, br d, J = 9.2 Hz), 5.52 (1H, br d,
J = 8.2 Hz), 6.65 (1H, d, J = 7.8 Hz), 6.85 (1H, d, J = 7.8 Hz), 7.09
(1H, t, J = 7.8 Hz), 7.11 (1H, m), 7.26–7.45 (14H, m), 7.81 (1H, br
1H NMR (400 MHz, CDCl3)
d 1.46 (18H, s), 2.90 (1H, ddd, J = 15.1,
11.0, 9.6 Hz), 3.02 (1H, ddd, J = 21.3, 15.1, 3.2 Hz), 3.70 (3H, s), 5.23
(1H, dd, J = 9.6, 3.2 Hz), 6.85 (1H, d, J = 7.8 Hz), 7.08 (1H, t,
J = 7.8 Hz), 7.31 (1H, t, J = 7.8 Hz), 7.52 (1H, br s), 7.53 (1H, d,
J = 7.8 Hz); 19F NMR (376 MHz, CDCl3)
d
ꢀ153.15 (1F, br m); MS (EI)
m/z: 452 (M+), 396 (M+ꢀC4H8); HRMS (EI) calcd. for C22H29FN2O7
s), 7.98 (1H, br s); 19F NMR (376 MHz, CDCl3)
d
ꢀ152.11 (1F, t,
(M+): 452.1959; found 452.1985.
J = 16.9 Hz), ꢀ152.39 (1F, br t, J = 10.9 Hz); MS (EI) m/z: 386 (M+),
More polar isomer: colorless solid; mp 140–141 8C; ½a D29
ꢁ
ꢀ39.7
327 (M+ꢀCOOMe).
(c 1.0, CHCl3); IR (KBr)
n ;
3275, 2985, 1777, 1739, 1626 cmꢀ1 1H
NMR (400 MHz, CDCl3) d1.47 (18H, s), 2.90 (1H, dt, J = 15.1, 8.7 Hz),
4.2.3. (2S)-2-(9-Fluorenylmethoxycarbonylamino)-3-(3-fluoro-2-
oxoindoline-3-yl)propionic acid methyl ester (9d)
3.08 (1H, ddd, J = 21.6, 15.1, 3.7 Hz), 3.69 (3H, s), 5.24 (1H, dd,
J = 8.7, 3.7 Hz), 6.86 (1H, d, J = 7.8 Hz), 7.10 (1H, dd, J = 7.8, 7.3 Hz),
7.34 (1H, t, J = 7.8 Hz), 7.41 (1H, d, J = 7.3 Hz), 7.60 (1/2H, br s), 7.64
De was determined to be 8% from the 1H NMR of crude mixture.
Less polar isomer: yield = 16%; pale pink solid; mp 81–82 8C;
(1/2H, br s); 19F NMR (376 MHz, CDCl3)
d
ꢀ154.39 (1F, br dd,
½
a 2D9
ꢁ
ꢀ26.2 (c 1.0, CHCl3); IR (KBr)
n
3298, 2954, 1739, 1624 cmꢀ1
;
J = 21.6, 8.7 Hz); MS (EI) m/z: 452 (M+), 396 (M+ꢀC4H8); HRMS (EI)
1H NMR (400 MHz, CDCl3)
d
2.71–2.75 (2H, m), 3.73 (3H, s), 4.18
calcd. for C22H29FN2O7 (M+): 452.1959; found 452.1967.
(1H, br t, J = 6.4 Hz), 4.28 (1H, br q, J = 7.8 Hz), 4.32 (1H, br s), 4.33
(1H, br s), 5.39 (1H, br d, J = 9.2 Hz), 6.77 (1H, d, J = 7.8 Hz), 7.11
(1H, br t, J = 7.3 Hz), 7.12 (1H, br s), 7.30–7.44 (6H, m), 7.59 (1H, d,
J = 7.8 Hz), 7.62 (1H, d, J = 7.8 Hz), 7.76–7.81 (2H, m); 19F NMR
4.3. General procedure for saponification of the protected 3-(3-
fluorooxindol-3-yl)alanine methyl ester 9b and 9c
(376 MHz, CDCl3)
d
ꢀ152.21 (1F, br t, J = 11.7 Hz); MS (EI) m/z: 474
To a solution of 3-fluorooxindole 9b (23 mg, 0.0653 mmol) in
methanol (0.45 mL) was added 0.2N aqueous NaOH (0.49 mL,
0.1 mmol) at 0 8C. The mixture was stirred for 20 min at 0 8C and
for 40 min at room temperature. The mixture was then concen-
trated and extracted with ether. The aqueous layer was acidified
(pH ꢂ 2) with 5% aqueous KHSO4 at 0 8C. The solution was
saturated with NaCl and extracted with EtOAc. The organic layer
was washed with brine and dried over Na2SO4. The solution was
concentrated to give a diastereomeric mixture of (2S)-2-(tert-
butoxycarbonylamino)-3-(3-fluoro-2-oxoindoline-3-yl)propionic
acid (11b) as a colorless solid (16 mg, 0.0473 mmol, 72%).
(M+), 456 (M+ꢀH2O); HRMS (EI) calcd. for C27H23FN2O5 (M+):
474.1591; found 474.1629.
More polar isomer: yield = 26%; pale yellow solid; mp 80–81 8C;
½
a 2D9
ꢁ
ꢀ41.4 (c 1.1, CHCl3); IR (KBr) 3307, 2954, 1742, 1625 cmꢀ1; 1H
NMR (400 MHz, CDCl3)
d 2.64 (1H, ddd, J = 16.9, 15.1, 7.8 Hz), 2.82
(1H, ddd, J = 17.4, 15.1, 4.6 Hz), 3.69 (3H, s), 4.19 (1H, br t,
J = 6.9 Hz), 4.32 (1H, br s), 4.33 (1H, br s), 4.61 (1H, ddd, J = 7.8, 7.3,
4.6 Hz), 5.55 (1H, br d, J = 8.3 Hz), 6.85 (1H, d, J = 7.3 Hz), 7.07 (1H,
t, J = 7.3 Hz), 7.28–7.46 (7H, m), 7.58 (2H, d, J = 6.9 Hz), 7.77 (2H, d,
J = 7.3 Hz); 19F NMR (376 MHz, CDCl3)
J = 17.1 Hz); MS (EI) m/z: 456 (M+–H2O); HRMS (EI) calcd. for
27H23FN2O5 (M+): 474.1591; found 474.1618.
d
ꢀ152.30 (1F, t,
IR (KBr)
n
3700–2900 (br), 2980, 2932, 1728, 1624 cmꢀ1
;
1H
C
NMR (400 MHz, CD3OD)
d
1.28 (5H, br s), 1.34 (4H, br s), 1.39 (9H,
s), 2.27–2.82 (4H, m), 3.60 (1/3H, m), 3.65 (2/3H, m), 3.95 (1/3H,
m), 4.01 (2/3H, dd, J = 11.0, 1.8 Hz), 6.87 (1H, d, J = 7.3 Hz), 6.88
(1H, d, J = 7.8 Hz), 7.05 (1H, dt, J = 7.8, 0.9 Hz), 7.10 (1H, t,
J = 7.3 Hz), 7.24 (1H, dt, J = 7.8, 0.9 Hz), 7.34–7.38 (2H, m), 7.46 (1H,
4.2.4. (2S)-2-(Acetylamino)-3-(3-fluoro-2-oxoindoline-3-
yl)propionic acid tert-butyl ester (9f)
De was determined to be 46% from the 1H NMR of crude
mixture.
d, J = 7.3 Hz); 19F NMR (376 MHz, CD3OD)
d
ꢀ150.31 (1/11F, m),
Less polar isomer: yield = 35%; pale red oil; ½a D28
ꢁ
ꢀ13.4 (c 1.0,
ꢀ151.05 (5/11F, m), ꢀ151.47 (16/11F, m); MS (EI) m/z: 318 (M+–
CHCl3); IR (neat)
(400 MHz, CDCl3)
n
3284, 2981, 1739, 1658, 1625 cmꢀ1
;
1H NMR
HF).
d
1.44 (9H, s), 1.83 (3H, s), 2.53 (1H, ddd, J = 16.0,
14.6, 9.2 Hz), 2.68 (1H, ddd, J = 20.1, 14.6, 4.1 Hz), 4.72 (1H, ddd,
J = 9.2, 7.8, 4.1 Hz), 6.11 (1H, br d, J = 7.8 Hz), 6.88 (1H, d, J = 7.8 Hz),
7.11 (1H, t, J = 7.8 Hz), 7.33 (1H, ddt, J = 7.8, 1.8, 1.4 Hz), 7.46 (1H, d,
J = 7.8 Hz), 7.84 (2/3H, br s), 7.95 (1/3H, br s); 19F NMR (376 MHz,
4.3.1. (2S)-2-(Benzyloxycarbonylamino)-3-(3-fluoro-2-oxoindoline-
3-yl)propionic acid (11c)
Diastereomeric mixture: colorless solid; IR (KBr)
n
3700–3000
2.36
(br), 2924, 1725, 1624 cmꢀ1 1H NMR (400 MHz, CD3OD)
;
d
CDCl3)
d
ꢀ152.43 (1F, t, J = 18.0 Hz); MS (EI) m/z: 336 (M+), 280
(1H, dt, J = 14.2, 10.5 Hz), 2.50–2.84 (3H, m), 4.02 (1/2H, dd,
J = 10.5, 2.7 Hz), 4.09 (1/2H, dd, J = 10.5, 2.7 Hz), 4.19 (3/4H, dd,
J = 10.5, 2.7 Hz), 4.26 (1/4H, dd, J = 10.5, 2.7 Hz), 4.89 (2H, s), 5.02
(2H, s), 6.83 (1H, d, J = 7.8 Hz), 6.84 (1/2H, d, J = 7.8 Hz), 6.86 (1/2H,
d, J = 8.2 Hz), 6.99 (1/2H, t, J = 7.3 Hz), 7.02 (1H, t, J = 7.8 Hz), 7.07
(1/2H, t, J = 7.3 Hz), 7.17–7.46 (14H, m); 19F NMR (376 MHz,
(M+ꢀC4H8), 235 (M+ꢀCOOBut); HRMS (EI) calcd. for C17H21FN2O4
(M+): 336.1485; found 336.1460.
More polar isomer: yield = 18%; pale red oil; ½a D29
ꢁ
ꢀ4.4 (c 1.0,
CHCl3); IR (neat)
n ;
3285, 2979, 1736, 1660, 1624 cmꢀ1 1H NMR
(400 MHz, CDCl3)
d 1.48 (9H, s), 1.95 (3H, s), 2.67 (1H, d,
J = 12.8 Hz), 2.68 (1H, d, J = 12.8 Hz), 4.43 (1H, dt, J = 7.6, 6.9 Hz),
6.30 (1H, br d, J = 9.2 Hz), 6.87 (1H, d, J = 7.8 Hz), 7.13 (1H, dd,
CD3OD)
d
ꢀ150.29 (2/5F, m), ꢀ152.07 (1/4F, m), ꢀ152.63 (27/20F,
m); MS (EI) m/z: 352 (M+ꢀHF).

834
T. Fujiwara et al. / Journal of Fluorine Chemistry 129 (2008) 829–835
4.4. (2S)-2-(Acetylamino)-3-(3-fluoro-2-oxoindoline-3-yl)propionic
6.0 Hz), 4.54 (1H, ddd, J = 7.8, 6.0, 5.5 Hz), 5.06 (1H, br d, J = 7.8 Hz),
7.03 (1H, br d, J = 2.3 Hz), 7.11 (1H, dt, J = 7.8, 0.9 Hz), 7.19 (1H, dt,
J = 8.2, 0.9 Hz), 7.35 (1H, d, J = 8.2 Hz), 7.62 (1H, d, J = 7.8 Hz), 8.07
(1H, br s); MS (EI) m/z: 360 (M+); HRMS (EI) calcd. for C20H28N2O4
(M+): 360.2049; found 360.2060.
acid (11f)
To a solution of the less polar isomer of 3-fluorooxindole 9f
(20 mg, 0.0595 mmol) in acetic acid (0.75 mL) was added 33% HBr/
AcOH (0.75 mL) at 0 8C. The mixture was stirred for 20 min at room
temperature. The mixture was poured into saturated aqueous
NaHCO3 and extracted with EtOAc. The aqueous layer was acidified
(pH ꢂ 1) with 10% aqueous HCl at 0 8C. The solution was saturated
with NaCl and extracted with EtOAc. The organic layer was washed
with brine, dried over Na2SO4, and concentrated in vacuo. The
residue was purified by recrystallization from n-hexane/CHCl3/
EtOH to give 11f as a pale brown solid (8 mg, 0.0285 mmol, 48%).
4.7. (2S)-2-[Bis(tert-butoxycarbonyl)amino]-3-(1-
benzyloxycarbonylindol-3-yl)propionic acid tert-butyl ester (15)
To a solution of 14 (344 mg, 0.954 mmol) in dry CH2Cl2 (10 mL)
was added benzyl chloroformate (0.125 mL, 1.43 mmol), pulver-
ized NaOH (57.2 mg, 1.43 mmol), and benzyl tri-n-butylammo-
nium chloride (29.8 mg, 0.0954 mmol) at 0 8C. The mixture was
stirred for 15 h at room temperature. After filtration with celite, the
filtrate was concentrated. The residue was dissolved in EtOAc and
washed with water and brine. The organic layer was then dried
over Na2SO4 and concentrated in vacuo. The residue was purified
by silica gel column chromatography (eluent: hexane/EtOAc = 5/1)
to give (2S)-2-(tert-butoxycarbonylamino)-3-(1-benzyloxycarbo-
nylindol-3-yl)propionic acid tert-butyl ester (420 mg) as a color-
less solid, which was then dissolved in dry acetonitrile (8 mL). 4-
Dimethylaminopyridine (51.9 mg, 0.425 mmol) and di-tert-butyl
dicarbonate (0.305 mL, 1.27 mmol) were added to the solution at
0 8C. After stirring overnight, the mixture was concentrated and
dissolved in EtOAc. The solution was washed with water and dried
over Na2SO4. The solvent was evaporated and the residue was
purified by silica gel column chromatography (eluent: hexane/
EtOAc = 8/1) to give 15 as a colorless oil (281 mg, 0.473 mmol,
50%).
½
a 2D9
ꢁ
ꢀ27.0 (c 0.5, MeOH); IR (KBr)
n
3650–2900 (br), 2923,
1.62 (3H, s),
2853, 1733, 1625 cmꢀ1; 1H NMR (400 MHz, CD3OD)
d
2.58 (1H, dt, J = 14.2, 10.5 Hz), 2.73 (1H, ddd, J = 16.4, 14.2, 3.2 Hz),
4.52 (1H, dd, J = 10.5, 3.2 Hz), 6.89 (1H, d, J = 7.8 Hz), 7.09 (1H, t,
J = 7.8 Hz), 7.34 (1H, ddt, J = 7.8, 1.8, 1.4 Hz), 7.44 (1H, d, J = 7.8 Hz);
19F NMR (376 MHz, CD3OD)
d
ꢀ150.09 (1F, dd, J = 16.2, 10.8 Hz);
MS (EI) m/z: 280 (M+); HRMS (EI) calcd. for C13H13FN2O4 (M+):
280.0859; found 280.0860.
4.5. (2S)-2-Amino-3-(3-fluoro-2-oxoindoline-3-yl)propionic acid
methyl ester hydrochloride (12)
To a solution of 3-fluorooxindole 9g (45 mg, 0.0995 mmol) in
acetic acid (0.5 mL) was added 25% HBr/AcOH (0.5 mL) at ꢀ20 8C.
After stirring for 20 min at room temperature, water was added to
the solution. The mixture was extracted with ether. The aqueous
layer was basified (pH ꢂ 11) with K2CO3 at 0 8C. The solution was
saturated with NaCl and extracted with EtOAc. The organic layer
was washed with brine, dried over Na2SO4, and concentrated in
vacuo. The residue was dissolved in ca. 2.5 M HCl/MeOH. The
solution was concentrated to give a diastereomeric mixture of 12
as a pale yellow solid (27 mg, 0.0935 mmol, 94%).
½
a 2D9
ꢁ
ꢀ11.5 (c 0.39, CHCl3); IR (neat)
n 2979, 2934, 1737,
1.32 (18H, s), 1.48 (9H, s),
1698 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
3.35 (1H, dd, J = 15.1, 10.1 Hz), 3.45 (1H, ddd, J = 15.1, 5.0, 0.9 Hz),
5.11 (1H, dd, J = 10.1, 5.0 Hz), 5.41 (1H, d, J = 11.9 Hz), 5.43 (1H, d,
J = 11.9 Hz), 7.23 (1H, dt, J = 7.6, 1.4 Hz), 7.30 (1H, dt, J = 7.8,
0.9 Hz), 7.36–7.48 (6H, m), 7.54 (1H, d, J = 7.8 Hz), 8.16 (1H, br s);
MS (EI) m/z: 594 (M+); HRMS (EI) calcd. for C33H42N2O8 (M+):
594.2941; found 594.2933.
IR (KBr)
n
3700–2150 (br), 3423, 1736, 1624 cmꢀ1
;
1H NMR
(400 MHz, CD3OD)
d
2.54 (1H, ddd, J = 27.9, 15.6, 7.3 Hz), 2.62 (1H,
ddd, J = 34.3, 16.0, 4.6 Hz), 2.92 (1H, ddd, J = 16.0, 12.4, 9.2 Hz), 3.01
(1H, ddd, J = 16.0, 12.4, 5.0 Hz), 3.79 (3H, s), 3.83 (3H, s), 4.47 (1H,
dd, J = 7.3, 5.0 Hz), 4.77 (1H, dd, J = 9.2, 4.6 Hz), 6.98 (1H, d,
J = 7.8 Hz), 6.99 (1H, d, J = 7.8 Hz), 7.14 (1H, t, J = 7.8 Hz), 7.16 (1H, t,
J = 7.8 Hz), 7.39–7.45 (2H, m), 7.48 (1H, ddd, J = 7.8, 1.8, 1.4 Hz),
4.8. (2S)-2-[Bis(tert-butoxycarbonyl)amino]-3-(indol-3-yl)propionic
acid tert-butyl ester (16)
To a solution of 15 (658 mg, 1.11 mmol) in methanol (20 mL)
was added 5% palladium on carbon (132 mg) at room temperature.
The mixture was stirred for 33 h under hydrogen at room
temperature. The palladium on carbon was filtered and the filtrate
was concentrated. The residue was purified by silica gel column
chromatography (eluent: hexane/EtOAc = 6/1) to give 16 as a
colorless solid (405 mg, 0.879 mmol, 80%).
7.55 (1H, ddd, J = 7.8, 1.8, 1.4 Hz); 19F NMR (376 MHz, CD3OD)
d
ꢀ154.38 (1F, dd, J = 27.9, 12.1 Hz), ꢀ155.98 (1F, dd, J = 34.2,
12.1 Hz).
4.6. (2S)-2-(tert-Butoxycarbonylamino)-3-(indol-3-yl)propionic acid
tert-butyl ester (14)
Mp 110–112 8C; ½a D27
ꢁ
ꢀ25.0 (c 0.33, CHCl3); IR (KBr) 3347,
n
To
(indol-3-yl)propionic acid (13) (202 mg, 0.664 mmol) in dry
CH2Cl2 (10 mL) was added tert-butanol (77 L, 0.796 mmol),
a
solution of (2S)-2-(tert-butoxycarbonylamino)-3-
3327, 2981, 1782, 1735 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d 1.32
(18H, s), 1.49 (9H, s), 3.40 (1H, dd, J = 15.1, 10.1 Hz), 3.54 (1H, ddd,
J = 15.1, 5.0, 0.9 Hz), 5.09 (1H, dd, J = 10.1, 5.0 Hz), 7.01 (1H, br d,
J = 2.3 Hz), 7.09 (1H, ddd, J = 8.2, 7.3, 0.9 Hz), 7.16 (1H, ddd, J = 8.2,
6.9, 0.9 Hz), 7.32 (1H, d, J = 8.2 Hz), 7.60 (1H, d, J = 7.3 Hz), 8.02 (1H,
br s); MS (EI) m/z: 460 (M+); HRMS (EI) calcd. for C25H36N2O6 (M+):
460.2573; found 460.2596.
m
N,N0-dicyclohexylcarbodiimide (164 mg, 0.796 mmol), and
4-dimethylaminopyridine (8 mg, 0.0664 mmol) at 0 8C. The mixture
was stirred for 20.5 h at room temperature. After filtration with
celite, the filtrate was concentrated. The residue was dissolved in
EtOAc and washed with 5% aqueous KHSO4, saturated aqueous
NaHCO3, water, and brine. The organic layer was then dried
over Na2SO4, and concentrated in vacuo. The residue was purified by
silica gel column chromatography (eluent: hexane/EtOAc = 4/1) to
give 14 as a colorless solid (102 mg, 0.283 mmol, 43%).
4.9. (2S)-2-[Bis(tert-butoxycarbonyl)amino]-3-(3-fluoro-2-
oxoindoline-3-yl)propionic acid tert-butyl ester (17)
Fluorination of 16 (2.08 g, 4.52 mmol) in the same manner as
that of 8b–g produced a diastereomeric mixture of 17 (1.13 g,
2.29 mmol, 51%) as a colorless oil after purification by silica gel
column chromatography (eluent: hexane/EtOAc = 6/1–4/1). De
was determined to be 14% from the 1H NMR of crude mixture.
Mp 180–184 8C; 46% ee (Chiralpak IA, eluent: n-hexane/2-
propanol = 9/1); ½a D29
ꢁ
+11.2 (c 0.24, CHCl3); IR (KBr) 3436, 3344,
n
2977, 1730, 1685 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d 1.37 (9H, s),
1.42 (9H, s), 3.23 (1H, dd, J = 15.1, 5.5 Hz), 3.27 (1H, dd, J = 15.1,

T. Fujiwara et al. / Journal of Fluorine Chemistry 129 (2008) 829–835
835
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1881;
IR (neat)
1625 cmꢀ1
n
3295, 3008, 2981, 2935, 1788, 1739, 1697,
;
1H NMR (400 MHz, CDCl3)
d
1.40 (18H, s), 1.45
(18H, s), 1.46 (18H, s), 2.84–3.07 (4H, m), 4.89 (1H, ddd, J = 9.6, 3.7,
0.9 Hz), 5.03 (1H, dd, J = 9.6, 3.2 Hz), 6.86 (1H, d, J = 7.8 Hz), 6.87
(1H, d, J = 7.3 Hz), 7.06 (1H, t, J = 7.3 Hz), 7.10 (1H, t, J = 7.8 Hz), 7.30
(1H, ddt, J = 7.8, 1.8, 1.4 Hz), 7.34 (1H, tt, J = 7.3, 1.4 Hz), 7.42 (1H, d,
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Jiang, Acta Pharmacol. Sin. 28 (2007) 140–152.
J = 7.8 Hz), 7.45 (1H, d, J = 7.3 Hz), 7.98 (1H, br s), 8.17 (1H, br s); 19
F
NMR (376 MHz, CDCl3)
d
ꢀ153.08 (1F, dd, J = 20.2, 10.8 Hz),
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ꢀ153.30 (1F, dd, J = 19.3, 8.1 Hz); MS (EI) m/z: 494 (M+), 438
(M+ꢀC4H8).
4.10. (2S)-2-Amino-3-(3-fluoro-2-oxoindoline-3-yl)propionic acid
hydrobromide (6)
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for 20 min at room temperature and then concentrated in vacuo.
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diastereomeric mixture of 6 as a pale brown solid (15 mg,
0.470 mmol, 93%).
IR (KBr)
n
3700–2400 (br), 3430, 1732, 1718, 1625 cmꢀ1
;
1H
NMR (400 MHz, CD3OD)
d
2.46 (1H, ddd, J = 27.9, 16.0, 8.7 Hz), 2.61
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(1H, ddd, J = 37.1, 16.5, 3.7 Hz), 2.91 (1H, ddd, J = 16.3, 11.4, 9.6 Hz),
3.03 (1H, ddd, J = 16.0, 12.8, 3.7 Hz), 4.50 (1H, dd, J = 8.7, 3.7 Hz),
4.76 (1H, dd, J = 9.6, 3.7 Hz), 6.97 (1H, d, J = 7.8 Hz), 6.98 (1H, d,
J = 7.8 Hz), 7.14 (1H, t, J = 7.8 Hz), 7.16 (1H, t, J = 7.8 Hz), 7.41 (1H,
tt, J = 7.8, 1.4 Hz), 7.43 (1H, tt, J = 7.8, 1.4 Hz), 7.47 (1H, d,
J = 7.8 Hz), 7.54 (1H, d, J = 7.8 Hz); 19F NMR (376 MHz, CD3OD)
d
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;
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.
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