Solution and fluorous phase synthesis of β,β-difluorinated 1-amino-1-cyclopentane carboxylic acid derivatives

Article abstract of DOI:10.1016/j.jfluchem.2008.04.006

An efficient protocol for the preparation of β,β-difluorinated 1-amino-1-cyclopentane carboxylic acid derivatives was developed. 2,2-Difluro-4-phenyl-3-butenoic acid 6 was used as substrate for the preparation of the starting vinyl difluoro imino esters 8

Full text of DOI:10.1016/j.jfluchem.2008.04.006

Journal of Fluorine Chemistry 129 (2008) 943–950
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Solution and fluorous phase synthesis of
b,b-difluorinated
1-amino-1-cyclopentane carboxylic acid derivatives
b
a
a
Santos Fustero a,b, , Vanessa Rodrigo , Marıa Sanchez-Rosello , Fatemeh Mojarrad ,
*
´
´
´
a
a
a
´
Ana Vicedo , Teresa Moscardo , Carlos del Pozo
a
´
´
Departamento de Quımica Organica, Universidad de Valencia, E-46100 Burjassot, Spain
b
´
´
Centro de Investigacion Prıncipe Felipe, E-46013 Valencia, Spain
A R T I C L E I N F O
A B S T R A C T
Article history:
An efficient protocol for the preparation of
b,b-difluorinated 1-amino-1-cyclopentane carboxylic acid
Received 15 March 2008
Received in revised form 22 April 2008
Accepted 22 April 2008
Available online 30 April 2008
derivatives was developed. 2,2-Difluro-4-phenyl-3-butenoic acid 6 was used as substrate for the
preparation of the starting vinyl difluoro imino esters 8. The key steps of this methodology rely on the
chemo- and diastereoselective addition of allylzinc bromides over the iminic functionality of 8 and
subsequent RCM reaction. This synthetic sequence was successfully applied to fluorous synthesis.
ß 2008 Elsevier B.V. All rights reserved.
Dedicated to Prof. Dennis Curran on the
occasion of his winning of the ACS Award.
Keywords:
Fluorinated
Fluorinated
a
a
-imino esters
-amino acids
Diastereoselective
Fluorous synthesis
1. Introduction
but, in the context of asymmetric catalysis, they are also less able to
discriminate between enantiotopic faces because they lack a
a
-Amino acids are ubiquitous scaffolds in biologically active
hydrogen substituent. We have very recently overcome these
limitations by making use of phenylglycinol-derived -imino
compounds. However, when these amino acids are
a
,a
-disub-
a
stituted, they are not readily available from the chiral pool. Their
medicinal and biological relevance has thus motivated the search
for new methodologies to access them [1]. In addition, the
incorporation of fluorine atoms into these structures only serves to
heighten interest in their preparation since fluorinated amino
acids are substructures found in enzyme inhibitors, receptor
antagonists, and lipophilicity enhancing agents [2].
esters [4]. This allowed us to carry out the addition of allylzinc
bromide to allyl difluoroimino esters 1 in a completely chemo- and
diastereoselective fashion to afford the corresponding amino ester
derivatives as single diastereoisomers. Subsequently, an RCM
reaction followed by the removal of the protecting group led to the
formation of
b,b-difluorinated 1-amino-1-cyclohexanecarboxylic
acid 2 in enantiomerically pure form (Scheme 1).
Addition of nucleophiles to fluorinated
the simplest methods of preparing fluorinated
a
-imino esters is one of
1-Amino-1-cyclopentanecarboxylic acid derivatives are also
important substructures in the preparation of conformationally
restricted peptidic chains. Indeed, this type of unit has recently
been incorporated into the peptidic chain of bradikynin, resulting
in new analogues that show reduced antagonistic properties [5]. In
the same vein, a similar derivative was included in the structure of
peptidomimetics to afford effective inhibitors of cathepsin K [6].
Very recently, 1-amino-1-cyclopentanecarboxylic acid was used as
a building block in the preparation of spiroimidazolin-4-ones,
which are extremely important in the preparation of antihyper-
tensive drugs [7]. As an extension of the aforementioned
methodology, we thus decided to prepare fluorinated analogues
of 1-amino-1-cyclopentanecarboxylic acid. In this paper, we report
a
-amino acids
bearing a quaternary carbon center. In contrast to the common
strategy involving 1,2-addition of organometallic reagents to
aldimines [3], the same reaction with ketimines and imino esters
has proven to be much more challenging. Not only are these
compounds less electrophilic than their aldimine counterparts,
´
´
* Corresponding author at: Departamento de Quımica Organica, Facultad de
Farmacia, Universidad de Valencia, Avda. Vicente Andre´s Estelle´s, s/n, 46100
Burjassot, Valencia, Spain. Tel.: +34 963544279; fax: +34 963544939.
E-mail address: santos.fustero@uv.es (S. Fustero).
0022-1139/$ – see front matter ß 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2008.04.006

944
S. Fustero et al. / Journal of Fluorine Chemistry 129 (2008) 943–950
be a suitable vinyl difluoro building block for the preparation of
imino esters 8 (Scheme 3). Indeed, acid 6 can be considered a
synthetic precursor of fluorinated diallyl amino esters 4 since the
RCM would remove the phenyl group as styrene.
Fluorinated acid
6 [8] was thus transformed into the
corresponding imidoyl chlorides 7 [9], which were then converted
into their imidoyl iodides. These are necessary for performing the
alkoxycarbonylation reaction mediated by a palladium complex
[10] that affords imino esters 8 (Scheme 4).
Scheme 1. Previous strategy for the preparation of fluorinated amino acid 2
developed by our group.
With imino esters 8 in hand, the next step of our synthetic
strategy was the chemoselective allylation of the iminic function.
The addition of allyl or methallylzinc bromide took place in an
efficient and chemoselective manner, affording dienic amino esters
9 in excellent yields (Table 1). It is worth noting that when chiral
imino ester 8c was used, the addition was completely diaster-
eoselective, furnishing dienic systems 9e,f as single diastereoi-
somers (Table 1, entries 5, 6). In these cases, an identical
stereochemical outcome of the allylzinc bromide addition to
phenylglycinol-derived imino esters 1 can be assumed, involving a
highly ordered transition state arising from chelation of the imine
nitrogen and the oxygen in the chiral auxiliary to the zinc atom [4].
Cyclization was carried out in refluxing dichloromethane in the
presence of second generation Grubbs catalyst [Cl2(IMes)(PCy3)
Scheme 2. Synthetic strategy for the preparation of 5.
Ru = CHPh] 11 to afford the desired
b,b-difluoro-1-amino-1-
cyclopentane carboxylic acid derivatives 10 in moderate to good
yields (Table 1).
Scheme 3. Acid 6 as synthetic precursor of imino esters 8.
Deprotection of the amino acid functionality was accomplished
in a two-step sequence. The TMSE ester moiety of (À)-10e was
removed through treatment with TBAF to afford N-protected
amino acid (À)-12 in 87% yield. Finally, the cleavage of the methyl
ether of phenyl glycinol was achieved by means of hydrogenolysis
with palladium hydroxide, which also produced the hydrogenation
of the double bond, giving rise to free amino acid (À)-5 in moderate
yield (Scheme 5).
on the preparation of the new fluorinated amino acid 5 in
enantiomerically pure form, both in solution and in fluorous phase.
Our synthetic strategy, which has previously been employed for
the preparation of fluorinated amino acid 2, relies on an RCM
reaction of the adequate dienic precursor 3 or 4 (Scheme 2).
Once we had successfully extended our previously described
methodology to the preparation of difluorinated 1-amino-1-
cyclopentanecarboxylic acid (À)-5, we decided to apply this
protocol to fluorous synthesis. One of the greatest benefits of this
technique is that it successfully combines solution phase reaction
conditions with easy purifications [11]. Recently introduced to
organic synthesis by Curran and coworkers, this method is based
on the use of perfluoroalkyl chains as phase tags that facilitates the
separation process. Our interest in fluorous chemistry prompted
us to develop a new fluorous tag, the fluorinated analogue of
2-(trimethylsilyl)ethanol 13 (FTMSE-OH), for the protection of
carboxylic acids (Fig. 1). This tag was successfully employed in the
synthesis of peptides and modified peptides, and the cleavage was
easily achieved under mild conditions through treatment with
TBAF [12].
2. Results and discussion
A chemoselective addition of vinylmagnesium bromide to
the iminic functionality of
a-imino esters 1 should render the
desired dienic compound 3 (Via A); however, all attempts to
perform the addition of vinylmagnesium bromide to compounds 1
were unsuccessful, resulting merely in the recovery of the
unaltered starting materials. We thus turned our attention to
the second route (Via B), which involves the preparation of diallyl
derivatives 4.
In this context, very recently Reglier et al. have described the
preparation of Z and E ethyl 4-phenyl-2,2-difluoro-3-butenoates
through reaction of ethyl chlorodifluoroacetate with phenyl
´
acetylene or
b-bromostyrene, respectively [8]. The procedure
consists of the stereocontrolled addition of
radical (ꢀCF2CO2Et) to phenyl acetylene or
seemed likely that acid 6, which results from the hydrolysis of one
a
,
a
-difluoroacetate
We started by performing the tagging process necessary in
fluorous chemistry. The anchoring was carried out through
alkoxycarbonylation of the corresponding imidoyl iodide (which
b
-bromostyrene. It
of those esters and is easily available on a multigram scale, would
Scheme 4. Preparation of fluorinated
a-imino esters 8.

S. Fustero et al. / Journal of Fluorine Chemistry 129 (2008) 943–950
945
Table 1
Preparation of fluorinated
a-amino acid derivatives 10
Entry
8
R1
R2
R3
9 (%)
10 (%)
1
2
3
4
5
6
8a
8a
8b
8b
8c
8c
PMP
Et
H
9a (92)
10a (80)
10b (65)
10c (86)
PMP
Et
Me
H
9b (89)
PMP
Bn
9c (85)
PMP
Bn
Me
H
9d (80)
10d (67)c
Pheglya
Pheglya
TMSEb
TMSEb
(S)-9e (92)
(S)-9f (86)
(S)-10e (88)
(S)-10f (55)d
Me
a
Phegly = (R)-PhCH(CH2OMe).
TMSE = trimethylsilylethyl.
b
c
Cyclization was performed in toluene.
d
Cyclization was performed in toluene with second generation Hoveyda-Grubbs catalyst Cl2(IMes)Ru = CHC6H4(O-iPr).
Scheme 5. Release of the amino acid functionality over compound (À)-10e.
chemoselective fashion over the iminic functionality. Cyclization
through an RCM reaction of the dienic products 15a,b in the
presence of second generation Grubbs catalyst 11 yielded the final
amino ester derivatives 16a,b attached to the fluorous tag. The last
step was thus the removal of the tag; this was carried out under
very mild conditions in a transesterification protocol involving
treatment with TBAF in the presence of an electrophile, i.e. benzyl
bromide (Scheme 6). It is worth noting that once the fluorous tag
had been anchored, the purifications of compounds 14, 15, and 16
were easily performed by means of fluorous solid-phase extraction
techniques (F-SPE), thus taking advantage of the special properties
of fluorous tags.
Fig. 1. Fluorous 2-(trimethylsilyl)ethanol 13: an efficient tag for the protection of
carboxylic acids.
results from treating 7a with NaI) in the presence of fluorous
trimethylsilylethanol 13 to furnish fluorous imino ester 14 in
moderate yield. Once the fluorous chain had been introduced, the
next step was the allylation process, which again occurred in a
Scheme 6. Fluorous synthesis of 5-membered ring amino esters 10.

946
S. Fustero et al. / Journal of Fluorine Chemistry 129 (2008) 943–950
3. Conclusions
JHH = 15.9 Hz, JHF = 10.8 Hz, 1H), 7.10 (d, JHH = 16.2 Hz, 1H), 7.33–
7.49 (m, 10H). 13C NMR (75.5 MHz, CDCl3)
59.1, 67.1, 76.9, 114.5
d
1
2
In conclusion, these results prove the versatility and usefulness
of our protocol in the preparation of fluorinated 1-amino-1-
cycloalkane carboxylic acid derivatives in enantiomerically pure
form. The chemoselective addition of allylzinc bromide derivatives
over the iminic functionality of imino esters 8 takes place very
efficiently, affording a single diastereoisomer when the methyl
ether of (R)-phenylglycinol is used as a chiral auxiliary. A
subsequent RCM reaction furnishes the final five-membered ring
amino acid derivatives 10 in moderate to good yields. This
methodology has now been successfully adapted to fluorous
chemistry, thus enhancing its scope. The incorporation of these
units into peptidic sequences is currently underway.
(t, JCF = 244.8 Hz), 119.8 (t, JCF = 25.4 Hz), 127.3, 127.4, 127.9,
3
128.6, 128.8, 129.4, 134.4, 136.2 (t, JCF = 9.0 Hz), 137.9, 140.2 (t,
2JCF = 37.6 Hz). 19F NMR (282.4 MHz, CDCl3)
JFF = 260.4 Hz, JFH = 10.7 Hz, 1F), À96.88 (dd, JFF = 259.5 Hz,
JFH = 11.3 Hz, 1F). HRMS calc. for C19H18NOClF2: 349.1045, found:
349.1049.
d
À95.90 (dd,
4.3. Preparation of fluorinated
a-imino esters 8 and 14
4.3.1. (2E,4E)-Ethyl 3,3-difluoro-2-(4-methoxyphenylimino)-5-
phenylpent-4-enoate (8a)
By means of the general procedure previously described [10], 8a
was obtained from 7a (236 mg) as an orange oil (126 mg) in 60%
yield after flash chromatography with toluene:dichloromethane
(20:1) as eluent. 1H NMR (300 MHz, CDCl3)
d 1.31 (t, J = 7.1 Hz, 3H),
4. Experimental
4.1. General experimental procedures
3.80 (s, 3H), 4.20 (q, J = 7.1 Hz, 2H), 6.54 (dt, JHH = 16.2 Hz,
JHF = 11.5 Hz, 1H), 6.86 (d, J = 8.9 Hz, 2H), 6.96 (d, J = 8.9 Hz, 2H),
7.13 (dt, JHH = 16.4 Hz, JHF = 2.5 Hz, 1H), 7.36–7.39 (m, 3H), 7.49–
Reactions were carried out under nitrogen atmosphere unless
otherwise indicated. The solvents were purified prior to use:
CH2Cl2 and CCl4 were distilled from calcium hydride; hexanes,
toluene and THF from sodium. All reagents were used as received.
The reactions were monitored with the aid of thin-layer
chromatography (TLC) on 0.25 mm E. Merck precoated silica gel
plates. Visualization was carried out with UV light and aqueous
ceric ammonium molybdate solution or potassium permanganate
stain. Flash column chromatography was performed with the
indicated solvents on silica gel 60 (particle size 0.040–0.063 mm).
Fluorous solid-phase extractions were performed on FluoroFlashTM
silica gel cartridges from Fluorous Technologies Inc. Optical
rotations were measured on a Jasco P-1020 polarimeter. 1H, 13C,
and 19F NMR spectra were recorded on a 300 MHz Bruker AC300
spectrometer and 400 MHz Bruker Avance. Chemical shifts are
7.52 (m, 2H). 13C NMR (75.5 MHz, CDCl3)
d 13.8, 55.4, 62.1, 114.1,
116.1 (t, JCF = 242.6 Hz), 120.2 (t, JCF = 25.2 Hz), 121.6, 127.4,
1
2
3
128.7, 129.3, 134.5, 135.7 (t, JCF = 9.2 Hz), 140.4, 155.4 (t,
2JCF = 35.1 Hz), 158.5, 162.3. 19F NMR (282.4 MHz, CDCl3)
d
À98.23 (dd, JFH1 = 11.5 Hz, JFH2 = 2.5 Hz, 2F). HRMS calc. for
C20H20F2NO3: 360.1411, found: 360.1403.
4.3.2. (2E,4E)-Benzyl 3,3-difluoro-2-(4-methoxyphenylimino)-5-
phenylpent-4-enoate (8b)
By means of the general procedure previously described [10],
8b was obtained from 7a (314 mg) as an orange oil (107 mg) in 35%
yield after flash chromatography with toluene:dichloromethane
(40:1) as eluent. 1H NMR (300 MHz, CDCl3)
d 3.79 (s, 3H), 5.18 (s,
2H), 6.55 (dt, JHH = 16.2 Hz, JHF = 11.5 Hz, 1H), 6.75 (d, J = 9.0 Hz,
2H), 6.90 (d, J = 9.0 Hz, 2H), 7.10–7.17 (m, 1H), 7.29–7.50 (m, 10H).
given in ppm (
d), and are referenced to the residual proton
resonances of the solvents or to fluorotrichloromethane in the 19
F
13C NMR (75.5 MHz, CDCl3)
d
55.3, 67.6, 114.1, 116.1 (t,
2
NMR experiments. Coupling constants (J) are given in Hertz (Hz).
High-resolution mass spectra were carried out on a VGmAutospec
(VG Analytical, Micromass Instruments) by the Universidad de
Valencia Mass Spectrometry Service. Compound 6 was previously
described [8].
1JCF = 243.0 Hz), 120.1 (t, JCF = 25.2 Hz), 121.6, 127.4, 128.5,
3
128.5, 128.6, 128.7, 129.3, 134.0, 134.5, 135.8 (t, JCF = 9.1 Hz),
2
140.2, 154.9 (t, JCF = 35.6 Hz), 158.5, 162.1. 19F NMR (282.4 MHz,
CDCl3)
d
À98.00 (dd, JFH1 = 11.5 Hz, JFH2 = 2.5 Hz, 2F). HRMS calc.
for C25H21NO3F2: 421.1489, found: 421.1487.
4.2. Preparation of fluorinated imidoyl chlorides 7
4.3.3. (2E,4E)-2-(Trimethylsilyl)ethyl 3,3-difluoro-2-[(R)-2-methoxy-
1-phenylethylimino]-5-phenylpent-4-enoate (8c)
4.2.1. (1Z,3E)-2,2-Difluoro-N-(4-methoxyphenyl)-4-phenylbut-3-
enimidoyl chloride (7a)
By means of the general procedure previously described [10], 8c
was obtained from 7b (610 mg) as a yellow oil (344 mg) in 54%
yield after flash chromatography with toluene:dichloromethane
By means of the general procedure previously described [9], 7a
was obtained from 6 (1.50 g) as a yellow oil (1.22 g) in 50% yield
after flash chromatography with hexanes:diethyl ether (20:1) as
(30:1) as eluent. [
CDCl3) 0.05 (s, 9H), 1.04–1.09 (m, 2H), 3.33 (s, 3H), 3.67 (d,
a]
D
25 = +0.34 (c 1.0, CHCl3). 1H NMR (300 MHz,
d
eluent. 1H NMR (300 MHz, CDCl3)
d
3.83 (s, 3H), 6.51 (dt,
J = 6.4 Hz, 2H), 4.34–4.41 (m, 2H), 4.95 (d, J = 5.7 Hz, 1H), 6.46 (dt,
JHH = 16.2 Hz, JHF = 10.7 Hz, 1H), 7.06 (dt, JHH = 16.2 Hz, JHF = 2.7 Hz,
JHH = 16.2 Hz, JHF = 11.1 Hz, 1H), 6.93 (d, J = 9.0 Hz, 2H), 7.16 (dt,
J1 = 6.5 Hz, J2 = 3.6 Hz, 2H), 7.37–7.42 (m, 3H), 7.49–7.52 (m, 2H).
1H), 7.30–7.43 (m, 10H). 13C NMR (75.5 MHz, CDCl3)
d
À1.6, 17.4,
13C NMR (75.5 MHz, CDCl3)
d
55.3, 114.0, 114.7 (t, 1JCF = 245.0 Hz),
59.0, 64.6, 67.3, 77.0, 116.2 (t, JCF = 242.2 Hz), 120.8 (t,
2JCF = 25.9 Hz), 127.2, 127.3, 127.8, 128.5, 128.7, 129.1, 134.8,
1
119.6 (2JCF = 25.1 Hz), 123.2, 127.4, 128.7, 129.4, 134.3, 135.9 (t,
3JCF = 8.7 Hz), 136.9, 137.2 (t, JCF = 38.6 Hz), 158.5. 19F NMR
135.8 (t, JCF = 9.5 Hz), 138.9, 157.2 (t, JCF = 34.4 Hz), 161.3. 19F
2
3
2
(282.4 MHz, CDCl3)
2F). HRMS calc. for C17H14NOClF2: 321.0732, found: 321.0735.
d
À97.09 (dd, JFHA = 11.3 Hz, JFHB = 2.3 Hz,
NMR (282.4 MHz, CDCl3)
d
À96.13 (ddd, JFF = 268.6 Hz,
JFH1 = 10.7 Hz, JFH2 = 2.5 Hz, 1F), À97.14 (ddd, JFF = 268.6 Hz,
JFH1 = 10.4 Hz, JFH2 = 2.8 Hz, 1F). HRMS calc. for C25H31SiNO3F2:
459.2051, found: 459.2050.
4.2.2. (1Z,3E)-2,2-Difluoro-N-[(R)-2-methoxy-1-phenylethyl]-4-
phenylbut-3-enimidoyl chloride (7b)
By means of the general procedure previously described [9], 7b
was obtained from 6 (1.0 g) as a yellow oil (0.79 mg) in 45% yield
after flash chromatography with hexanes:ethyl acetate (30:1) as
4.3.4. (2E,4E)-2-[(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-
Heptadecafluoroundecyl)-dimethylsily])ethyl 3,3-difluoro-2-(4-
methoxyphenylimino)-5-phenylpent-4-enoate (14)
By means of the general procedure previously described [10],
14 was obtained from 8a (1.05 g) as a yellow oil (645 mg) in 30%
eluent. [
a
]
D
25 = À11.83 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3)
d
3.39 (s, 3H), 3.65–3.80 (m, 2H), 5.15–5.20 (m, 1H), 6.45 (dt,

S. Fustero et al. / Journal of Fluorine Chemistry 129 (2008) 943–950
947
yield after fluorous solid-phase extraction. 1H NMR (300 MHz,
CDCl3) 0.00 (s, 6H), 0.52–0.57 (m, 2H), 0.83–0.89 (m, 2H), 1.50–
1.61 (m, 2H), 1.97–2.15 (m, 2H), 3.79 (s, 3H), 4.18–4.24 (m, 2H),
6.54 (dt, JHH = 16.2 Hz, JHF = 11.5 Hz, 1H), 6.86 (d, J = 9.0 Hz, 2H),
6.97 (d, J = 9.0 Hz, 2H), 7.12 (dt, JHH = 16.2 Hz, JHF = 2.4 Hz, 1H),
2%. 1H NMR (300 MHz, CDCl3)
d
2.85 (dd, J1 = 15.2 Hz, J2 = 7.9 Hz,
d
1H), 3.01 (dd, J1 = 14.8 Hz, J2 = 6.0 Hz, 1H), 3.66 (s, 3H), 4.58 (br s,
1H), 4.85 (d, J = 17.7 Hz, 1H), 4.87 (d, J = 10.5 Hz, 1H), 5.08 (d,
J = 12 Hz, 1H), 5.19 (d, J = 12 Hz, 1H), 5.33–5.47 (m, 1H), 6.17 (dt,
JHH = 16.2 Hz, JHF = 12.6 Hz, 1H), 6.66 (d, J = 9.0 Hz, 2H), 6.77 (d,
J = 9.0 Hz, 2H), 6.73–6.79 (m, 3H), 7.17–7.23 (m, 5H). 13C NMR
7.34–7.41 (m, 3H), 7.48–7.51 (m, 2H). 13C NMR (75.5 MHz, CDCl3)
d
2
À3.8, 14.6, 14.9, 15.5, 34.3 (t, JCF = 22.1 Hz), 55.2, 64.2, 114.2,
(75.5 MHz, CDCl3)
119.4, 120.4 (t, JCF = 24.8 Hz), 120.6 (t, JCF = 253.8 Hz), 120.9,
d
33.2, 55.5, 68.3, 70.5 (t, 2JCF = 26.8 Hz), 114.3,
1
2
2
1
116.2 (t, JCF = 242.6 Hz), 120.3 (t, JCF = 25.2 Hz), 121.8, 127.4,
3
128.7, 129.3, 134.6, 135.7 (t, JCF = 9.1 Hz), 140.4, 155.5 (t,
127.2, 128.5, 128.6, 128.6, 129.0, 131.4, 134.6, 134.7, 135.3 (t,
3JCF = 9.4 Hz), 137.6, 154.1, 170.4. 19F NMR (282.4 MHz, CDCl3)
d
2JCF = 35.6 Hz), 158.6, 162.6 (the signals from the C8F17 group
were obscured due to their low intensity). 19F NMR (282.4 MHz,
À101.42 (ddd, JFF = 241.3 Hz, JFH1 = 11.5 Hz, JFH2 = 2.3 Hz, 1F),
CDCl3)
d
À81.39 (t, J = 9.9 Hz, 3F), À98.18 (dd, JFH1 = 11.6 Hz,
À102.63 (dd, JFF = 241.4 Hz, JFH = 12.6 Hz, 1F). HRMS calc. for
JFH2 = 2.5 Hz, 2F), À115.09 (br s, 2F), À122.54 (br s, 6F), À122.54 (br
s, 2F), À123.35 (br s, 2F), À124.26 (br s, 2F), À126.74 (br s, 2F).
HRMS calc. for C33H31SiNO3F19: 878.1770, found: 878.1768.
C28H27NO3F2: 463.1959, found: 463.1957.
4.4.4. (E)-Benzyl 3,3-difluoro-2-(4-methoxyphenylamino)-2-(2-
methylallyl)-5-phenylpent-4-enoate (9d)
4.4. Preparation of the fluorinated dialkylated
a
-amino
By means of the general procedure previously described [4], 9d
was obtained from 8b (38 mg) as a colorless oil (34 mg) in 80%
yield after flash chromatography with hexane:diethyl ether (20:1)
as eluent, previously deactivated with a solution of n-hexane/Et3N
esters 9 and 15
4.4.1. (E)-Ethyl 2-allyl-3,3-difluoro-2-(4-methoxyphenylamino)-5-
phenylpent-4-enoate (9a)
2%. 1H NMR (300 MHz, CDCl3)
d 1.50 (s, 3H), 2.90 (dd, J1 = 24.6 Hz,
By means of the general procedure previously described [4], 9a
was obtained from 8a (35 mg) as a colorless oil (37 mg) in 92%
yield after flash chromatography with hexane:ethyl acetate (20:1)
as eluent, previously deactivated with a solution of n-hexane/Et3N
J2 = 16.2 Hz, 2H), 3.65 (s, 3H), 4.64 (br s, 1H), 4.68 (br s, 2H), 5.06 (d,
J = 12.1 Hz, 1H), 5.20 (d, J = 12.1 Hz, 1H), 6.08 (dt, JHH = 16.1 Hz,
JHF = 12.1 Hz, 1H), 6.65 (d, J = 9.1 Hz, 2H), 6.75 (d, J = 9.0 Hz, 2H),
6.67–6.74 (m, 1H), 7.11–7.15 (m, 2H), 7.19–7.22 (m, 3H), 7.26 (s,
2%. 1H NMR (300 MHz, CDCl3)
d
1.30 (t, J = 7.1 Hz, 3H), 2.93 (dd,
5H). 13C NMR (75.5 MHz, CDCl3)
d 24.0, 35.1, 55.5, 68.2, 70.0 (t,
5
J1 = 14.8 Hz, J2 = 8.1 Hz, 1H), 3.10 (dd, J1 = 14.8 Hz, J2 = 6.0 Hz, 1H),
3.76 (s, 3H), 4.23–4.31 (m, 2H), 4.70 (br s, 1H), 5.00 (d, J = 11.4 Hz,
1H), 5.01 (d, J = 15.6 Hz, 1H), 5.43–5.57 (m, 2H), 6.36 (ddd,
JHH = 16.2 Hz, JHF1 = 12.9 Hz, JHF2 = 11.2 Hz, 1H), 6.77 (d, J = 8.7 Hz,
2H), 6.88 (d, J = 8.7 Hz, 2H), 6.94 (dt, JHH = 16.2 Hz, JHF = 2.4 Hz, 1H),
2JCF = 26.3 Hz), 114.2, 114.4, 120.3 (t, JCF = 2.5 Hz), 120.4 (t,
1
2JCF = 24.8 Hz), 120.9 (t, JCF = 255.2 Hz), 127.2, 128.5, 128.5,
3
128.6, 129.0, 134.6, 135.1 (t, JCF = 8.8 Hz), 137.9, 139.8, 153.6,
170.6. 19F NMR (282.4 MHz, CDCl3)
d
À101.17 (d, JFH = 2.1 Hz, 1F),
À101.21 (d, JFH = 2.1 Hz, 1F). HRMS calc. for C29H29NO3F2:
7.33–7.39 (m, 5H). 13C NMR (75.5 MHz, CDCl3)
62.5, 70.3 (t, 2JCF = 26.7 Hz), 114.3, 119.3, 120.6 (t, 2JCF = 24.7 Hz),
d
14.1, 33.0, 55.5,
477.2115, found: 477.2112.
1
5
120.6 (t, JCF = 249.5 Hz), 120.9 (d, JCF = 2.3 Hz), 127.2, 128.7,
129.0, 131.5, 134.5, 135.1 (t, 3JCF = 9.5 Hz), 137.6, 154.0, 170.5. 19
NMR (282.4 MHz, CDCl3)
4.4.5. (S,E)-2-(Trimethylsilyl)ethyl 2-allyl-3,3-difluoro-2-[(R)-2-
methoxy-1-phenylethylamino]-5-phenylpent-4-enoate [(S)-9e]
By means of the general procedure previously described [4], (S)-
9e was obtained from 8c (150 mg) as a colorless oil (152 mg) in 92%
yield after flash chromatography with hexane:ethyl acetate (20:1)
as eluent, previously deactivated with a solution of n-hexane/Et3N
F
d
À101.57 (ddd, JFF = 241.1 Hz,
JFH1 = 11.1 Hz, JFH2 = 2.5 Hz, 1F), À103.14 (dd, JFF = 240.9 Hz,
JFH = 12.9 Hz, 1F). HRMS calc. for C23H25NO3F2: 401.1802, found:
401.1820.
2%. [
a
]
25 = À4.53 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3)
d 0.00
D
4.4.2. (E)-Ethyl 3,3-difluoro-2-(4-methoxyphenylamino)-2-(2-
methylallyl)-5-phenylpent-4-enoate (9b)
(s, 9H), 0.87–0.93 (m, 2H), 2.46 (dd, J1 = 14.7 Hz, J2 = 6.3 Hz, 1H),
2.68 (dd, J1 = 14.7 Hz, J2 = 7.5 Hz, 1H), 2.93 (s, 1H), 3.33 (s, 3H),
3.44–3.55 (m, 2H), 3.97–4.12 (m, 2H), 4.32 (br s, 1H), 4.89 (d,
J = 7.8 Hz, 1H), 4.91 (d, J = 18.3 Hz, 1H), 5.48–5.61 (m, 1H), 6.44 (dt,
JHH = 15.9 Hz, JHF = 12.3 Hz, 1H), 6.88 (dt, JHH = 15.9 Hz,
By means of the general procedure previously described [4], 9b
was obtained from 8a (35 mg) as a colorless oil (36 mg) in 89%
yield after flash chromatography with hexane:ethyl acetate (20:1)
as eluent, previously deactivated with a solution of n-hexane/Et3N
JHF = 2.4 Hz, 1H), 7.23–7.36 (m, 10H). 13C NMR (75.5 MHz, CDCl3)
2%. 1H NMR (300 MHz, CDCl3)
d
1.20 (t, J = 7.1 Hz, 3H), 1.53 (br s,
d
À1.7, 17.2, 34.6, 56.5, 58.9, 63.9, 69.8 (t, JCF = 24.7 Hz), 77.9,
2
2
1
3H), 2.90 (dd, J1 = 28.2 Hz, J2 = 16.2 Hz, 2H), 3.65 (s, 3H), 4.12–4.23
(m, 2H), 4.66 (br s, 1H), 4.69 (br s, 2H), 6.18 (dt, JHH = 16.1 Hz,
JHF = 12.0 Hz, 1H), 6.66 (d, J = 9.0 Hz, 2H), 6.75 (d, J = 9.0 Hz, 2H),
6.80 (dt, JHH = 16.2 Hz, JHF = 2.4 Hz, 1H), 7.22–7.26 (m, 5H). 13C
118.2, 121.2 (t, JCF = 24.1 Hz), 121.5 (t, JCF = 255.0 Hz), 127.1,
3
127.2, 127.7, 128.1, 128.6, 128.8, 132.6, 134.6 (t, JCF = 9.6 Hz),
135.0, 142.7, 170.4. 19F NMR (282.4 MHz, CDCl3)
JFF = 247.9 Hz, JFH = 12.7 Hz, 1F), À101.86 (JFF = 246.8 Hz,
JFH = 11.9 Hz, 1F). HRMS calc. for C29H40SiNO3F2: 502.2589, found:
502.2573.
d
À98.87 (dd,
NMR (75.5 MHz, CDCl3)
d 13.9, 24.5, 34.9, 55.5, 62.5, 69.7 (t,
2
2JCF = 26.3 Hz), 114.2, 120.2, 120.6 (t, JCF = 25.2 Hz), 120.9 (t,
1JCF = 255.7 Hz), 127.2, 128.7, 129.0, 134.7, 135.0 (t, JCF = 9.3 Hz),
138.1, 139.8, 153.5, 170.7. 19F NMR (282.4 MHz, CDCl3)
(ddd, JFF = 240.0 Hz, JFH1 = 11.7 Hz, JFH2 = 2.4 Hz, 1F), À102.00 (ddd,
JFF = 240.1 Hz, JFH1 = 12.3 Hz, JFH2 = 1.8 Hz, 1F). HRMS calc. for
3
d
À101.06
4.4.6. (S,E)-2-(Trimethylsilyl)ethyl 3,3-difluoro-2-((R)-2-methoxy-1-
phenylethylamino)-2-(2-methylallyl)-5-phenylpent-4-enoate [(S)-9f]
By means of the general procedure previously described [4], (S)-
9f was obtained from 8c (30 mg) as a colorless oil (29 mg) in 86%
yield after flash chromatography with hexane:ethyl acetate (30:1)
as eluent, previously deactivated with a solution of n-hexane/Et3N
C24H27NO3F2: 415.1959, found: 415.1960.
4.4.3. (E)-Benzyl 2-allyl-3,3-difluoro-2-(4-methoxyphenylamino)-5-
phenylpent-4-enoate (9c)
By means of the general procedure previously described [4], 9c
was obtained from 8b (40 mg) as a colorless oil (37 mg) in 85%
yield after flash chromatography with hexane:diethyl ether (20:1)
as eluent, previously deactivated with a solution of n-hexane/Et3N
2%. [
a
]
25 = À68.35 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3)
d 0.00
D
(s, 9H), 0.97 (t, J = 8.7 Hz, 2H), 1.48 (s, 3H), 2.25 (d, J = 15.6 Hz, 1H),
2.65 (d, J = 15.6 Hz, 1H), 2.87 (br s, 1H), 3.29 (s, 3H), 3.54 (d, J = 6 Hz,
2H), 4.08–4.25 (m, 2H), 4.36 (d, J = 4.2 Hz, 1H), 4.75 (s, 2H), 6.15–
6.29 (m, 1H), 6.77 (dt, J1 = 16.2 Hz, J2 = 2.1 Hz, 2H), 7.22–7.32 (m,

948
S. Fustero et al. / Journal of Fluorine Chemistry 129 (2008) 943–950
10H). 13C NMR (75.5 MHz, CDCl3)
d
À1.6, 17.2, 23.7, 38.4, 56.7,
J1 = 17.6 Hz, J2 = 8.4 Hz, J3 = 2.4 Hz, 1H), 3.55–3.66 (m, 1H), 3.67 (s,
2
2
58.9, 69.0 (t, JCF = 24.6 Hz), 78.2, 114.3, 121.5 (t, JCF = 24.0 Hz),
3H), 4.15–4.25 (m, 2H), 4.58 (br s, 1H), 5.84 (dt, J1 = 6.0 Hz,
J2 = 2.1 Hz, 1H), 6.42 (dd, J1 = 5.9 Hz, J2 = 2.3 Hz, 1H), 6.55 (dd,
J1 = 6.6 Hz, J2 = 2.4 Hz, 2H), 6.76 (dd, J1 = 6.6 HZ, J2 = 2.4 Hz, 2H). 13
C
1
121.9 (t, JCF = 257.0 Hz), 126.8, 127.2, 127.8, 127.9, 128.5, 128.7,
3
134.3 (t, JCF = 9.7 Hz), 135.1, 139.9, 143.4, 171.6. 19F NMR
(282.4 MHz, CDCl3)
1F), À102.36 (dd, JFF = 248.5 Hz, JFH = 13.0 Hz, 1F). HRMS calc. for
29H40SiNO3F2: 516.2745, found: 516.2755.
d
À96.69 (dd, JFF = 248.2 Hz, JFH = 11.4 Hz,
NMR (75.5 MHz, CDCl3) d 14.4, 40.2, 56.0, 62.6, 69.8, 115.1,
2
3
116.9, 124.7 (t, JCF = 25.9 Hz), 142.1 (t, JCF = 11.7 Hz), 138.6,
153.7. 19F NMR (282.4 MHz, CDCl3)
C
d
À90.72 (ddd, JFF = 256.8 Hz,
JFH1 = 8.4 Hz, JFH2 = 3.9 Hz, 1F), À105.59 (dd, JFF = 256.8 Hz,
JFH = 6.6 Hz). HRMS calc. for C15H17NO3F2: 297.1176, found:
297.1163.
4.4.7. (E)-2-[(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-
Heptadecafluoroundecyl) dimethylsilyl]ethyl 2-allyl-3,3-difluoro-2-
(4-methoxyphenylamino)-5-phenylpent-4-enoate (15a)
By means of the general procedure previously described [4], 15a
was obtained from 14 (100 mg) as a colorless oil (65 mg) in 60%
yield after fluorous solid-phase extraction. 1H NMR (300 MHz,
4.5.2. Ethyl 2,2-difluoro-1-(4-methoxyphenylamino)-4-
methylcyclopent-3-enecarboxylate (10b)
By means of the general procedure previously described [4],
10b was obtained from 9b (33 mg) as a brown oil (16 mg) in 65%
yield after flash chromatography with hexane:ethyl acetate (20:1)
as eluent, previously deactivated with a solution of n-hexane/Et3N
CDCl3)
d 0.05 (s, 6H), 0.57–0.62 (m, 2H), 1.03–1.06 (m, 2H), 1.53–
1.64 (m, 2H), 1.99–2.16 (m, 2H), 2.92 (dd, J1 = 15.0 Hz, J2 = 8.1 Hz,
1H), 3.09 (dd, J1 = 15.0 Hz, J2 = 6.0 Hz, 1H), 3.75 (s, 3H), 4.20–4.34
(m, 2H), 4.68 (s, 1H), 4.99 (d, J = 11.9 Hz, 2H), 5.43–5.56 (m, 1H),
6.35 (ddd, JHH = 16.2 Hz, JHF1 = 12.9 Hz, JHF2 = 11.1 Hz, 1H), 6.76 (d,
J = 9.0 Hz, 2H), 6.86 (d, J = 9.0 Hz, 2H), 6.92 (dt, JHH = 16.2 Hz,
2%. 1H NMR (300 MHz, CDCl3)
d 1.14 (t, J = 7.1 Hz, 3H), 1.88 (br s,
3H), 2.70 (d, J = 17.2 Hz, 1H), 3.53 (d, J = 17.2 Hz, 1H), 3.74 (s, 3H),
4.13–4.24 (m, 2H), 4.60 (br s, 1H), 5.52 (d, J = 1.6 Hz, 1H), 6.54 (d,
JHF = 2.4 Hz, 1H), 7.31–7.39 (m, 5H). 13C NMR (75.5 MHz, CDCl3)
d
J = 9.0 Hz, 2H), 6.76 (d, J = 9.2 Hz, 2H). 13C NMR (100 MHz, CDCl3)
d
2
À3.6, 14.7, 15.0, 15.9, 33.1, 34.4 (t, JCF = 22.3 Hz), 55.5, 64.7, 70.2
13.9, 17.3, 43.7, 55.6, 62.0, 70.3 (dd, 2JCF1 = 28.1 Hz, 2JCF2 = 16.4 Hz),
2
2
2
2
(t, JCF = 26.5 Hz), 114.3, 119.3, 120.6 (t, JCF = 24.7 Hz), 120.9,
114.7, 116.4, 118.7 (dd, JCF1 = 28.6 Hz, JCF2 = 25.7 Hz), 130.2 (dd,
3
1
127.2, 128.7, 129.1, 131.6, 134.7, 135.1 (t, JCF = 10.9 Hz), 137.8,
1JCF1 = 255.6, JCF2 = 244.6 Hz), 138.3, 153.2, 170.6. 19F NMR
154.0, 170.6 (the signals from the CF2 and C8F17 groups were
(282.4 MHz, CDCl3)
JFF = 253.3 Hz, 1F). HRMS calc. for C16H19NO3F2: 311.1333, found:
d
À88.13 (d, JFF = 253.6 Hz, 1F), À103.10 (d,
obscured due to their low intensity). 19F NMR (282.4 MHz, CDCl3)
d
À81.42 (t, J = 9.9 Hz, 3F), À101.61 (ddd, JFF = 240.9 Hz, JFH1
=
311.1339.
11.0 Hz, JFH2 = 2.3 Hz, 1F), À103.29 (dd, JFF = 240.9 Hz,
JFH = 12.7 Hz, 1F), À115.09 (t, J = 14.4 Hz, 2F), À122.57 (br s, 6F),
À123.57 (br s, 2F), À124.28 (br s, 2F), À126.77–(À126.82) (m, 2F).
HRMS calc. for C36H36SiNO3F19: 920.2239, found: 920.2226.
4.5.3. Benzyl 2,2-difluoro-1-(4-methoxyphenylamino) cyclopent-3-
enecarboxylate (10c)
By means of the general procedure previously described [4], 10c
was obtained from 9c (35 mg) as a brown oil (23 mg) in 86% yield
after flash chromatography with hexane:ethyl acetate (20:1) as
eluent, previously deactivated with a solution of n-hexane/Et3N
4.4.8. (E)-2-[(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-
Heptadecafluoroundecyl) dimethylsilyl] ethyl 3,3-difluoro-2-(4-
methoxyphenylamino)-2-(2-methylallyl)-5-phenylpent-4-enoate
(15b)
By means of the general procedure previously described [4],
15b was obtained from 14 (100 mg) as a colorless oil (66 mg) in
60% yield after fluorous solid-phase extraction. 1H NMR (300 MHz,
2%. 1H NMR (300 MHz, CDCl3)
d 2.72–2.83 (m, 1H), 3.50–3.59 (m,
1H), 3.66 (s, 3H), 4.53 (d, J = 4.1 Hz, 1H), 5.07 (dd, J1 = 15.2 Hz,
J2 = 12.2 Hz, 2H), 5.77 (dt, J1 = 6.0 Hz, J2 = 2.2 Hz, 1H), 6.34 (dd,
J1 = 6.0 Hz, J2 = 2.3 Hz, 1H), 6.43 (dd, J1 = 6.6 Hz, J2 = 2.2 Hz, 2H),
6.63 (dd, J1 = 6.8 Hz, J2 = 2.2 Hz, 2H), 7.01–7.04 (m, 2H), 7.17–7.19
CDCl3)
d
0.05 (s, 6H), 0.57–0.63 (m, 2H), 1.01–1.06 (m, 2H), 1.54–
(m, 3H). 13C NMR (75.5 MHz, CDCl3)
d
39.9, 55.6, 67.7, 69.5 (t,
2
1.65 (m, 2H), 1.62 (s, 3H), 1.99–2.14 (m, 2H), 2.98 (dd, J1 = 26.7 Hz,
J2 = 16.5 Hz, 2H), 3.75 (s, 3H), 4.19–4.36 (m, 2H), 4.76 (d, J = 9.7,
3H), 6.27 (dt, JHH = 16.1 Hz, JFH = 12.0 Hz, 1H), 6.75 (d, J = 9.0 Hz,
2H), 6.83 (d, J = 9.0 Hz, 2H), 6.89 (dt, JHH = 16.2 Hz, JHF = 2.4 Hz, 1H),
2JCF1 = 28.2 Hz, JCF2 = 16.1 Hz), 114.7, 116.4, 124.2, 128.1, 130.0
1
1
(dd, JCF1 = 259.3 Hz, JCF2 = 247.8 Hz), 133.4, 135.1, 141.6 (t,
3JCF = 11.5 Hz), 153.3, 170.4. 19F NMR (282.4 MHz, CDCl3)
d
À89.80 (ddd, JFF = 256.7 Hz, JFH1 = 8.6 Hz, JFH2 = 3.4 Hz), À105.26
7.33 (s, 5H). 13C NMR (75.5 MHz, CDCl3)
d
À3.6, 15.0, 15.7, 24.1,
(dtd, JFF = 256.7 Hz, JFH1 = 4.3 Hz, JFH2 = 2.6 Hz). HRMS calc. for
2
2
34.4 (t, JCF = 27.9 Hz), 34.9, 55.5, 64.6, 69.7 (t, JCF = 27.9 Hz),
C20H19NO3F2: 359.1333, found: 359.1337.
2
114.2, 120.2, 120.6 (t, JCF = 28.5 Hz), 127.2, 128.7, 129.1, 134.7,
135.0 (t, 3JCF = 9.6 Hz), 138.1, 139.8, 153.6, 170.9 (the signals from
4.5.4. Benzyl 2,2-difluoro-1-(4-methoxyphenylamino)-4-
methylcyclopent-3-enecarboxylate (10d)
the CF2 and C8F17 groups were obscured due to their low intensity).
19F NMR (282.4 MHz, CDCl3)
d
À81.44 (t, J = 9.9 Hz, 3F), À101.22
By means of the general procedure previously described [4],
10d was obtained from 9d (35 mg) as a brown oil (22 mg) in 67%
yield after flash chromatography with hexane:ethyl acetate (20:1)
as eluent, previously deactivated with a solution of n-hexane/Et3N
(ddd, JFF = 239.8 Hz, JFH1 = 11.7 Hz, JFH2 = 2.3 Hz, 1F), À102.19 (dd,
JFF = 240.0 Hz, JFH = 12.3 Hz, 1F), À115.09 (br s, 2F), À122.57 (br s,
6F), À123.38 (br s, 2F), À124.29 (br s, 2F), À126.78 (br s, 2F). FAB-
MS (m/z): 934 (M+1+, 4), 850 (7), 780 (42), 752 (100).
2%. 1H NMR (300 MHz, CDCl3)
d 1.80 (br s, 3H), 2.64 (dd,
J1 = 17.1 Hz, J2 = 7.8 Hz, 1H), 3.48 (d, J = 16.8 Hz, 1H), 3.67 (s,
3H), 4.56 (d, J = 4.5 Hz, 1H), 5.06 (dd, J1 = 14.7 Hz, J2 = 12.3 Hz,
2H), 5.45 (s, 1H), 6.43 (d, J = 9.0 Hz, 2H), 6.64 (d, J = 9.0 Hz, 2H), 7.02
(dd, J1 = 6.5 Hz, J2 = 3.0 Hz, 2H), 7.18 (dd, J1 = 5.3 Hz, J2 = 1.6 Hz,
4.5. Preparation of the fluorinated cyclic dialkylated
a-amino
esters 10 and 16
4.5.1. Ethyl 2,2-difluoro-1-(4-methoxyphenylamino)cyclopent-3-
enecarboxylate (10a)
3H). 13C NMR (75.5 MHz, CDCl3)
d 12.3, 43.8, 55.6, 67.7, 70.4
2
2
(dd, JCF1 = 28.3 Hz, JCF2 = 16.4 Hz), 114.7, 116.3, 118.7 (dd,
2JCF1 = 28.8 Hz, 2JCF2 = 25.7 Hz), 128.1, 128.3, 130.2 (dd,
By means of the general procedure previously described [4], 10a
was obtained from 9a (64 mg) as a brown oil (38 mg) in 80% yield
after flash chromatography with hexane:ethyl acetate (20:1) as
eluent, previously deactivated with a solution of n-hexane/Et3N
1
1JCF1 = 257.4 Hz, JCF2 = 246.2 Hz), 135.2, 138.3, 153.2, 170.6. 19F
NMR (282.4 MHz, CDCl3)
(d, JFF = 253.4 Hz, 1F). HRMS calc. for C20H19NO3F2: 373.1489,
d
À87.92 (d, JFF = 253.4 Hz, 1F), À103.48
2%. 1H NMR (300 MHz, CDCl3)
d
1.08 (t, J = 7.2 Hz, 3H), 2.84 (ddd,
found: 373.1489.

S. Fustero et al. / Journal of Fluorine Chemistry 129 (2008) 943–950
949
4.5.5. (S)-2-(Trimethylsilyl)ethyl 2,2-difluoro-1-((R)-2-methoxy-1-
4.5.8. 2-[(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-
phenylethylamino) cyclopent-3-enecarboxylate [(S)-10e]
Heptadecafluoroundecyl) dimethylsilyl]ethyl 2,2-difluoro-1-(4-
By means of the general procedure previously described [4],
(S)-10e was obtained from (S)-9e (110 mg) as a brown oil
(76 mg) in 88% yield after flash chromatography with hexa-
ne:ethyl acetate (20:1) as eluent, previously deactivated with a
methoxyphenylamino)-4-methylcyclopent-3-enecarboxylate (16b)
By means of the general procedure previously described [4],
16b was obtained from 15b (38 mg) as a brown oil (26 mg) in 76%
yield after fluorous solid-phase extraction. 1H NMR (300 MHz,
solution of n-hexane/Et3N 2%. [
NMR (300 MHz, CDCl3)
a
]
25 = À58.6 (c 1.0, CHCl3). 1H
CDCl3) d 0.01 (s, 6H), 0.51–0.57 (m, 2H), 0.88–0.94 (m, 2H), 1.55 (s,
D
d
0.00 (s, 9H), 0.75 (ddd, J1 = 13.7 Hz,
3H), 1.86–1.89 (m, 3H), 1.96–2.14 (m, 2H), 2.64–2.73 (m, 1H), 3.53
(d, J = 17.0 Hz, 1H), 3.73 (s, 3H), 4.10–4.30 (m, 2H), 4.59 (d,
J = 4.5 Hz, 1H), 5.52 (d, J = 1.5 Hz, 1H), 6.52 (d, J = 8.9 Hz, 2H), 6.75
J2 = 11.4 Hz, J3 = 5.6 Hz, 1H), 0.86 (ddd, J1 = 13.7 Hz, J2 = 11.6 Hz,
J3 = 6.1 Hz, 1H), 2.43–2.53 (m, 1H), 2.94 (br s, 1H), 3.11–3.22 (m,
1H), 3.32 (s, 3H), 3.36 (dd, J1 = 9.8 Hz, J2 = 5.3 Hz, 1H), 3.45 (dd,
J1 = 9.8 Hz, J2 = 7.9 Hz, 1H), 3.77 (td, J1 = 11.2 Hz, J2 = 11.1 Hz,
J3 = 5.6 Hz, 1H), 3.88 (br s, 1H), 4.05 (td, J1 = 11.1 Hz, J2 = 11.1 Hz,
J3 = 6.1 Hz, 1H), 5.83 (dt, J1 = 6.1 Hz, J2 = 2.0 Hz, 1H), 6.23
(dd, J1 = 5.8 Hz, J2 = 2.7 Hz, 1H), 7.24–7.30 (m, 5H). 13C NMR
(d, J = 8.9 Hz, 2H). 13C NMR (75.5 MHz, CDCl3)
d
À3.6, 15.0, 15.5,
2
17.3, 34.4 (t, JCF = 21.8 Hz), 43.7, 55.6, 64.1, 70.2 (dd,
2
2JCF1 = 28.3 Hz, JCF2 = 16.5 Hz), 99.5, 114.7, 116.3, 118.7 (dd,
2
2JCF1 = 28.7 Hz, JCF2 = 25.6 Hz), 138.2, 153.2, 170.8 (the signals
from the CF2 and C8F17 groups were obscured due to their low
(75.5 MHz, CDCl3)
d
À1.6, 16.7, 37.1, 57.8, 58.9, 63.9, 71.1
intensity). 19F NMR (282.4 MHz, CDCl3)
d
À81.39 (t, J = 10.0 Hz, 3F),
2
2
2
(dd, JCF1 = 27.0 Hz, JCF2 = 18.4 Hz), 125.0 (dd, JCF1 = 29.1 Hz,
À88.17 (d, JFF = 253.4 Hz, 1F), À103.20 (d, JFF = 253.4 Hz, 1F),
À115.09 (br s, 2F), À122.56 (br s, 6F), À123.37 (br s, 2F), À124.28
2JCF2 = 24.5 Hz), 127.4, 127.5, 128.3, 129.2 (dd, JCF1 = 257.8 Hz,
1
1JCF2 = 247.7 Hz), 141.1 (t, JCF = 11.8 Hz), 142.0, 170.1. 19F NMR
(br s, 2F), À126.75 (br s, 2F). HRMS calc. for C29H31SiNO3F19
:
3
(282.4 MHz, CDCl3)
d
À91.32 (ddd, JFF = 258.1 Hz, JFH1
=
=
830.1725, found: 830.1729.
7.1 Hz, JFH2 = 4.8 Hz, 1F), À108.40 (dd, JFF = 257.8 Hz, JFH
2.5 Hz, 1F). HRMS calc. for C20H30SiNO3F2: 398.1963, found:
398.1943.
4.6. Release of the amino acid functionality
4.6.1. (S)-2,2-Difluoro-1-[(R)-2-methoxy-1-phenylethylamino]
4.5.6. (S)-2-(Trimethylsilyl)ethyl 2,2-difluoro-1-((R)-2-methoxy-1-
phenylethylamino)-4-methylcyclopent-3-enecarboxylate [(S)-10f]
By means of the general procedure previously described [4],
(S)-10f was obtained from (S)-9f (59 mg) as a brown oil (26 mg)
in 55% yield after flash chromatography with hexane:
ethyl acetate (20:1) as eluent, previously deactivated with a
cyclopent-3-enecarboxylic acid [(À)-12]
By means of the general procedure previously described [4],
(À)-12 was obtained from (S)-10e (100 mg) as a brown oil (65 mg)
in 87% yield after flash chromatography with hexane:ethyl acetate
(3:1) with 2% AcOH as eluent. [
NMR (300 MHz, CDCl3)
a
]
25 = À68.85 (c 1.0, CHCl3). 1H
D
d
2.50 (d, J = 17.3, 1H), 2.95 (d, J = 17.3 Hz,
solution of n-hexane/Et3N 2%. [
NMR (300 MHz, CDCl3)
a
]
25 = À68.85 (c 1.0, CHCl3). 1H
1H), 3.33 (s, 3H), 3.39 (dd, J1 = 9.9 Hz, J2 = 4.3 Hz, 1H), 3.51 (dd,
J1 = 9.9 Hz, J2 = 4.3 Hz, 1H), 4.00 (dd, J1 = 8.8 Hz, J2 = 4.3 Hz, 1H),
5.81 (d, J = 6.2 Hz, 1H), 6.24 (d, J = 6.1 Hz, 1H), 7.05 (br s, 1H), 7.25–
7.27 (m, 5H). 13C NMR (75.5 MHz, CDCl3)
D
d
À0.06 (s, 9H), 0.67–0.88 (m, 2H), 1.57
(br s, 3H), 2.20 (dd, J1 = 17.4 Hz, J2 = 6.9 Hz, 1H), 3.01 (d,
J = 22.8 Hz, 2H), 3.23–3.39 (m, 2H), 3.26 (s, 3H), 3.74–3.87 (m,
2H), 4.02 (td, J1 = 11.0 Hz, J2 = 6.2 Hz, 1H), 5.43 (br s, 1H), 7.19–
d 36.6, 58.6, 58.8, 71.1
2
2
2
(dd, JCF1 = 25.2 Hz, JCF2 = 19.5 Hz), 76.6, 124.8 (t, JCF = 26.6 Hz),
7.23 (m, 5H). 13C NMR (75.5 MHz, CDCl3)
d
À1.6, 16.8, 17.2, 40.9,
127.5, 128.2, 128.6, 129.2 (dd, JCF1 = 254.6 Hz, JCF2 = 251.4 Hz),
139.4, 141.7 (t, 3JCF = 11.7 Hz), 171.9. 19F NMR (282.4 MHz, CDCl3)
1
2
2
2
57.8, 58.8, 63.9, 72.1 (dd, JCF1 = 26.9 Hz, JCF2 = 18.8 Hz), 77.9,
d
2
2
119.5 (dd, JCF1 = 29.1 Hz, JCF2 = 24.2 Hz), 127.5, 128.3, 129.6
(dd, 1JCF1 = 256.3 Hz, 1JCF2 = 247.0 Hz), 142.1, 152.7 (t,
À95.70 (d, JFF = 255.7 Hz, 1F), À100.12 (d, JFF = 255.7 Hz, 1F). HRMS
calc. for C15H17NO3F2: 298.1255, found: 298.1256.
3JCF = 11.8 Hz), 170.2. 19F NMR (282.4 MHz, CDCl3)
d
À88.79
(ddd, JFF = 254.4 Hz, JFH1 = 11.6 Hz, JFH2 = 5.4 Hz, 1F), À106.58 (d,
JFF = 254.4 Hz, 1F). HRMS calc. for C21H32SiNO3F2: 412.2119,
found: 412.2104.
4.6.2. (S)-1-Amino-2,2-difluorocyclopentanecarboxylic acid [(À)-5]
By means of the general procedure previously described [4],
(À)-5 was obtained from (À)-12 (38 mg) as white solid (10 mg) in
47% yield after filtration and washing with dichloromethane and
4.5.7. 2-[(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-
diethyl ether. [
a
]
25 = À6.57 (c 1.0, H2O). 1H NMR (400 MHz,
D
Heptadecafluoroundecyl) dimethylsilyl]ethyl 2,2-difluoro-1-(4-
methoxyphenylamino)cyclopent-3-enecarboxylate (16a)
By means of the general procedure previously described [4],
16a was obtained from 15a (60 mg) as a brown oil (48 mg) in 90%
yield after fluorous solid-phase extraction. 1H NMR (300 MHz,
DMSO-d6) d 1.67–1.85 (m, 4H), 2.08–2.21 (m, 1H), 2.33–2.45 (m,
1H). 13C NMR (100 MHz, DMSO-d6)
d
18.0, 32.9, 65.6, 128.2, 169.5.
19F NMR (282.4 MHz, DMSO-d6)
À119-10 (d, J = 228.5 Hz, 1F).
d
À111.80–(À114.08) (m, 1F),
CDCl3)
d 0.00 (s, 6H), 0.52–0.58 (m, 2H), 0.88–0.95 (m, 2H), 1.51–
Acknowledgements
1.62 (m, 2H), 1.97–2.14 (m, 2H), 2.78–2.88 (m, 1H), 3.55–3.66 (m,
1H), 3.73 (s, 3H), 4.12–4.31 (m, 2H), 4.57 (d, J = 4.3 Hz, 1H), 5.84
(dt, JHH = 6.0 Hz, JHF = 2.1 Hz, 1H), 6.40–6.44 (m, 1H), 6.54 (d,
J = 8.9 Hz, 2H), 6.76 (d, J = 8.9 Hz, 2H). 13C NMR (75.5 MHz, CDCl3)
´
We thank the Ministerio de Educacion y Ciencia (CTQ2007-
61462) of Spain for their financial support. V.R. expresses her
thanks for a predoctoral fellowship, M.S.-R. for a postdoctoral
3
2
d
À3.6, 14.7 (t, JCF = 4.0 Hz), 15.0, 15.5, 34.4 (t, JCF = 22.0 Hz),
´
contract and C.P. for a Ramon y Cajal contract.
2 2
39.7, 55.5, 64.2, 69.3 (dd, JCF1 = 28.2 Hz, JCF2 = 16.7 Hz), 114.7,
2
2
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116.4, 124.2 (dd, JCF1 = 28.8 Hz, JCF2 = 25.7 Hz), 138.1, 141.7,
153.3, 170.6 (the signals from the CF2 and C8F17 groups were
obscured due to their low intensity). 19F NMR (282.4 MHz, CDCl3)
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