Synthesis of Ψ[CH(RF)NH]Gly-peptides: The dramatic effect of a single fluorine atom on the diastereocontrol of the key aza-Michael reaction

Article abstract of DOI:10.1016/j.jfluchem.2008.06.018

We describe in full-detail the synthesis of new ψ[CH(R_F)NH]-peptidomimetics, having different fluoroalkyl groups R_F, as peptide bond surrogates. A key step in the synthesis is a stereoselective aza-Michael addition of chiral α-amino acid esters to β-fluoroalkyl-α-nitroethenes. The diastereoselection of the process was influenced by the electronegativity, rather than by the steric bulk, of the fluorinated residue R_F in the β-position of the nitroalkene acceptors. Replacement of a single F atom of R_F by a hydrogen or methyl group brings about a dramatic drop of stereocontrol, whereas Br, Cl and CF₃, albeit bulkier than F, provide inferior results in terms of stereocontrol. A mechanistic hypothesis is provided.

Full text of DOI:10.1016/j.jfluchem.2008.06.018

Journal of Fluorine Chemistry 129 (2008) 767–774
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis of
C[CH(RF)NH]Gly-peptides: The dramatic effect of a single
fluorine atom on the diastereocontrol of the key aza-Michael reaction
b,
Serena Bigotti a, Stefano V. Meille a, Alessandro Volonterio a, , Matteo Zanda
*
*
a Dipartimento di Chimica, Materiali ed Ingegneria Chimica ‘‘G. Natta’’ del Politecnico di Milano, via Mancinelli 7, I-20131 Milano, Italy
b C.N.R-Istituto di Chimica del Riconoscimento Molecolare, Sezione ‘‘A. Quilico’’, via Mancinelli 7, I-20131 Milano, Italy
A R T I C L E I N F O
A B S T R A C T
Article history:
We describe in full-detail the synthesis of new
c[CH(RF)NH]-peptidomimetics, having different
Received 12 May 2008
fluoroalkyl groups RF, as peptide bond surrogates. A key step in the synthesis is a stereoselective aza-
Michael addition of chiral -amino acid esters to -fluoroalkyl- -nitroethenes. The diastereoselection of
the process was influenced by the electronegativity, rather than by the steric bulk, of the fluorinated
residue RF in the -position of the nitroalkene acceptors. Replacement of a single F atom of RF by a
Received in revised form 17 June 2008
Accepted 17 June 2008
Available online 27 June 2008
a
b
a
b
hydrogen or methyl group brings about a dramatic drop of stereocontrol, whereas Br, Cl and CF3, albeit
bulkier than F, provide inferior results in terms of stereocontrol. A mechanistic hypothesis is provided.
ß 2008 Elsevier B.V. All rights reserved.
Keywords:
Peptidomimetics
Fluorine
Electronegativity
Peptide bond surrogate
Fluoroalkyl
Aza-Michael
The main drawback in the use of peptides as drugs is represented
by their low bioavailability and low metabolic stability. In order to
circumvent this problem, while maintaining the excellent biological
properties of peptidic structures, backbone modification is a popular
and effective strategy. In medicinal chemistry and drug discovery, a
viable and successful approach is the rational design of peptido-
mimetics in which a scissile peptide bond is replaced by a surrogate
function [1]. This strategy is particularly efficient when: (1) the
peptide bond surrogate is more stable to enzymatic hydrolysis than
the native peptide bond [2]; (2) it is able to mimic either the original
peptide bond or the transition state of amide bond hydrolysis at the
substrate cleavage site [3]; (3) it influences the conformational
preference of neighbouring residues; (4) by modifying the electronic
properties, the peptide bond surrogate affects significantly the
transport properties of the parent peptides [4].
analogue, as it combines some of the properties of a peptidyl –
CONH– group (very low NH basicity, a CH(CF3)–NH–CH backbone
angle close to 1208, a C–CF3 bond substantially isopolar with the
C
O) with properties of the tetrahedral intermediate of the
protease-mediated hydrolysis reaction of a peptide bond (high
electron density on the CF3 group, tetrahedral backbone carbon).
Moreover, the presence of the bulky CF3 group is probably the
driving force for the high stability of the turn-like conformation of
appropriately configured retro-peptides A both in low polarity
organic solvent solutions and in solid state. Recently, this concep-
tually new peptide bond surrogate has found the first validations
in drug discovery [8].
In order to gain a deeper understanding of the biomedicinal
properties of these peptide mimics, and to investigate further the
effect and the capacity of the fluorinated residue to induce and
stabilize secondary structures in peptide mimics, we undertook a
Recently, we proposed the trifluoroethylamino unit [5] as a
peptide bond replacement, and we described its incorporation into
partially modified retro- (PMR) peptides A [6] and into native
peptide chains B [7] (Fig. 1).
research program aimed at the synthesis of
C[CH(RF)NH]Gly-
peptides 1 (R = H) having different RF fluoroalkyl groups, namely
RF = CF2H, CF2CH3, CF2Cl, CF2Br, and C2F5. Moreover, following the
The trifluoroethylamine unit might be also seen as a hybrid
between a peptide bond mimic and a proteolytic transition state
same synthetic strategy used for the synthesis of C[CH(CF3)NH]Gly-
peptides B (RF = CF3) from the nitroalkene 2 (Table 2) [7], we decided
to investigate the role of the different fluorinated residues RF on the
diastereoselectivity of the key aza-Michael addition of
a-amino acid
esters 8 to -fluoroalkyl- -nitroethenes 3–7 (see Table 2) [9]. The
various RF groups differ from each other not only in terms of steric
bulk (quantified here by means of the Bondi volumes) and shape, but
b
a
* Corresponding author. Tel.: +39 0223993139; fax: +39 0223993080.
E-mail addresses: alessandro.volonterio@polimi.it (A. Volonterio),
matteo.zanda@polimi.it (M. Zanda).
0022-1139/$ – see front matter ß 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2008.06.018

768
S. Bigotti et al. / Journal of Fluorine Chemistry 129 (2008) 767–774
Fig. 1. Structure of
C[CH(RF)NH]-peptides 1.
Scheme 1. Synthesis of nitro-alkenes 2–7.
Table 1
Empirical electronegativities and Bondi volumes for X substituents (RF = CF2X).
10e–g (entries 5–7) whose stereochemistry could not be unam-
biguously assigned.
X substituent
Bondi volume (cm3 molꢀ1
)
Electronegativity
In these conditions the diastereoselection of the process
depends only on the nature of (1) the R amino acidic side chain
of 8, and (2) the fluorinated residue RF on the nitroethene acceptors
2–7. The results of the additions of 8a–d to the trifluoro derivative
2 (RF = CF3) were previously published [7], and are summarized for
the sake of comparison in entries 1–4 (Table 2).
H
3.3
13.7
5.8
2.28
2.30
3.95
3.03
2.80
3.35
CH3
F
Cl
12.0
15.1
21.3
Br
CF3
When RF = CF2H (nitroethene 3) (entries 5–8, Table 2), which is
both the least electronegative and the least bulky RF group among
those examined herein, a dramatic drop of diastereoselectivity was
alsointermsofelectronegativities (Table1)[10]. More specifically, if
one considers RF = CF2-X, then the difference between the six RF
groups studied herein depends on the X substituent. Thus, in terms
of electronegativity, the CF3 group(X = F)isthe mostelectronegative
RF group, followed by C2F5 (X = CF3), which in turn is more
electronegative than CF2Cl (X = Cl) and CF2Br (X = Br). The CF2CH3
(X = CH3) and CF2H (X = H) groups occupy the last positions of the
list. Sterically, the C2F5 group is the bulkiest, followed by CF2Br,
which in turn is only slightly bulkier than CF2CH3 and CF2Cl, but
remarkably bulkier than CF3 (X = F) and CF2H, respectively. One
should also note that the CF3 group is rotationally symmetrical
around the axis of its C–C bond, in analogy with the CH3 group,
whereas the C2F5, CF2Cl, CF2Br and CF2CH3 groups do not feature
such rotational symmetry. In terms of ‘‘effective bulk’’ the isotropic
CF3 is expected to occupy an even smaller volume than the
anisotropic C2F5, CF2Cl and CF2Br [11]. Thus, if steric bulk were the
dominating factor in the stereoselectivity of the aza-Michael
reaction, one would expect a much higher diastereocontrol when
RF is a C2F5 or CF2Br, rather than a CF3.
observed in comparison with 2 (RF = CF3). The additions of the
a-
amino esters 8a–d to 4 (RF = CF2CH3) (entries 9–12, Table 2) proved
to be only slightly more diastereoselective than those obtained
with 3 (RF = CF2H), and still much less diastereoselective than those
with 2 (RF = CF3). Generally higher diastereoselectivities were
observed with 5 (RF = CF2Cl) (entries 13–16, Table 2) as the Michael
acceptor, but still slightly worse when compared to those achieved
with 2 (RF = CF3). The results obtained with the nitroalkene 6
(RF = CF2Br) (entries 17–20, Table 2) were in all cases comparable
with those of the nitroalkene 5 (RF = CF2Cl). Surprisingly, even the
diastereoselectivity of the reactions performed with the
nitroethene 7 (RF = C2F5) (entries 21–24, Table 2), having the most
sterically demanding RF group (see Table 1), proved to be less
stereoselective than the reactions involving 2 (RF = CF3), and very
similar to those obtained with the nitroalkenes 5 and 6 (RF = CF2Cl
and CF2Br, respectively).
The experimental results above suggest that the diastereoselec-
tivity of the aza-Michael reaction is much more influenced by the
b
-Fluoroalkyl-a-nitroethenes 2–7, having respectively –CF3, –
CF2H, –CF2CH3, –CF2Cl, –CF2Br and –CF2CF3 as RF groups at the
b
electronegativity of the b-fluoroalkyl substituents RF, rather than by
position, were prepared in multigram amounts by reacting the
corresponding aldehyde hydrates or hemiacetals with nitro-
their steric bulk. In fact, the dramatic drop of diastereocontrol
observed with the nitroalkene 3 (RF = CF2H) and 4 (RF = CF2CH3) as
compared with that featured by 2 (RF = CF3) cannot be explained in
terms of steric bulk, as the CF2H group is quite close in size to the CF3
(their Bondi volumes are, respectively, 18.8 cm3 molꢀ1 vs.
21.3 cm3 molꢀ1) while the CF2CH3 group is much bigger (Bondi
volume = 29.2 cm3 molꢀ1). Thus, the striking effect on the stereo-
control observed by replacing a single F atom of the nitroalkene 2
with an H atom in 3 and a CH3 in 4, must be ascribed to the
considerably higher electronegativity of F with respect to H and CH3.
On the other hand, the CF3 group is ‘‘smaller’’ than the CF2Cl, CF2Br
and, in particular, the C2F5 groups (see Table 1 and discussion
thereof), therefore the decreased stereoselectivities observed with
nitroalkenes 5–7 as compared with the CF3-nitroalkene 2, cannot be
explained as well in terms of steric bulk. One should therefore notice
that, within the set of nitroalkenes 2–7, the trend of stereoselectivity
2 > 7 ꢁ 5 ꢁ 6 > 4 > 3 in the aza-Michael reaction matches quite
well the trend of electronegativity of the X group in RF (RF = CF2-X)
namely F > CF3 > Cl > Br > CH3 ꢁ H.
methane and a catalytic amount of Na2CO3 affording
b-nitro
alcohol intermediates that were dehydrated by refluxing in the
presence of P2O5 (Scheme 1) [12].
The aza-Michael reactions between nitroalkene acceptors 3–7
and a-aminoacid ester hydrochlorides 8a–d were performed using
the protocol previously optimized to achieve the best diastereos-
electivity with 2 [7], namely using 1.1 equiv. of DIPEA (the first
equiv. is needed to quench the hydrochloric acid of 8) in toluene at
rt, producing a mixture of syn-9 (major diastereoisomer) and anti-
10 (minor diastereoisomer), which proved to be easily separable by
simple flash chromatography (except for the CF2H derivatives 9,
10f,g which could not be separated), in excellent overall yields
(Table 2). The stereochemistry of the minor diastereoisomer 10z
(entry 25) was assessed by X-ray diffraction (Fig. 2) [13], whereas
the configuration of the other adducts 9 and 10 were confidentially
assigned on the basis of their spectroscopic features in comparison
with those of 9z and 10z [14], except for the CF2H compounds 9,

S. Bigotti et al. / Journal of Fluorine Chemistry 129 (2008) 767–774
769
Table 2
The aza-Michael reaction
Entry
Nitroethene
RF
a
-Aminoester
Major product
R
X
Ratio 9:10b
Yield %c
1a
2a
3a
4a
5
2
2
2
2
3
3
3
3
4
4
4
4
5
5
5
5
6
6
6
6
7
7
7
7
2
CF3
L
L
L
L
L
L
L
L
L
L
L
L
L
L
L
L
L
L
L
L
L
L
L
L
L
-8a
9a
9b
9c
9d
9e
9f
Me (Ala)
tert-Bu
Me
5.8:1.0
7.5:1.0
8.5:1.0
11.7:1.0
1.1:1.0d
1.4:1.0d,e
1.7:1.0d,e
2.5:1.0
2.3:1.0
3.3:1.0
2.5:1.0
4.2:1.0
4.0:1.0
8.8:1.0
4.8:1.0
10.0:1.0
4.2:1.0
8.1:1.0
6.5:1.0
10.3:1.0
3.5:1.0
8.1:1.0
5.9:1.0
10.2:1.0
11.2:1.0
60
75
60
65
77
96
68
85
80
82
63
74
74
69
75
76
77
65
70
93
70
66
74
90
79
CF3
-8b
-8c
-8d
-8a
-8b
-8c
-8d
-8a
-8b
-8c
-8d
-8a
-8b
-8c
-8d
-8a
-8b
-8c
-8d
-8a
-8b
-8c
-8d
-8e
sec-Bu (Ile)
Bn (Phe)
CF3
tert-Bu
tert-Bu
tert-Bu
Me
CF3
iso-Pr (Val)
Me (Ala)
CF2H
CF2H
CF2H
CF2H
CF2CH3
CF2CH3
CF2CH3
CF2CH3
CF2Cl
CF2Cl
CF2Cl
CF2Cl
CF2Br
CF2Br
CF2Br
CF2Br
CF2CF3
CF2CF3
CF2CF3
CF2CF3
CF3
6
sec-Bu (Ile)
Bn (Phe)
7
9g
9h
9i
tert-Bu
tert-Bu
tert-Bu
Me
8
iso-Pr (Val)
Me (Ala)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
9j
sec-Bu (Ile)
Bn (Phe)
9k
9l
tert-Bu
tert-Bu
tert-Bu
Me
iso-Pr (Val)
Me (Ala)
9m
9n
9o
9p
9q
9r
sec-Bu (Ile)
Bn (Phe)
tert-Bu
tert-Bu
tert-Bu
Me
iso-Pr (Val)
Me (Ala)
sec-Bu (Ile)
Bn (Phe)
9s
9t
tert-Bu
tert-Bu
tert-Bu
Me
iso-Pr (Val)
Me (Ala)
9u
9v
9w
9y
9z
sec-Bu (Ile)
Bn (Phe)
tert-Bu
tert-Bu
Bn
iso-Pr (Val)
iso-Pr (Val)
a
See Ref. [7].
b
c
Determined by 1H and 19F NMR.
Overall isolated yields.
d
e
Stereochemistry not assigned.
Inseparable mixture.
It clearly appears that very subtle differences such as the
assume that (1) the reaction is under kinetic control, (2) the
aminoester nucleophile reacts with a rigid conformation due to
the presence of an intramolecular N–Hꢂ ꢂ ꢂO C hydrogen bond, (3)
the fluorinated residue greatly stabilizes the LUMO of the nitro-
alkenes, making these Michael acceptorsmore electrophilic thanthe
parent unfluorinated compounds (4) the reaction involves a tight,
polar transition state, which is destabilized and disrupted in polar
solvents, decreasing the stereocontrol, (5) the base DIPEA appears to
play a fundamental catalytic role, presumably by promoting the
formation of a ternary transition state involving nucleophile,
Michael acceptor and amine base, in analogy with related processes
we have studied in the recent past [15]. Clearly, these results
demonstrate that electronic factors can overcome steric factors in
the control of the diastereoselectivity of aza-Michael reactions. A
possible transition state leading to the major diastereomers 9 is
portrayed in Fig. 3. According to this hypothesis the nitroalkenes
react in the dominant (E)-geometry from the Re diastereoface and
one amine proton of the nucleophile is hydrogen bonded both with
the C O and with a NO2 oxygen, whereas the H-transfer from the
presence of F instead of H, Cl or Br in the RF group of the nitroalkene
acceptor bring about a striking effect in terms of stereocontrol of
the process. Insufficient data exist at present to allow a detailed
mechanistic discussion on the stereolectronic effect of the RF group.
However, based on the current experimental data, we can reliably
NH2 grouptothe
a-nitropositionisassistedbyHunig’sbasecatalyst.
Elaboration of the major adducts 9 into the target
C[CH(RF)
NH]Gly-peptides 11 (Scheme 2) was addressed next. Reduction of
the nitro group of 9 was accomplished by using Perlman’s catalyst in
the presence of aqueous 1N HCl to trap the free amino function as
hydrochloride salt. Coupling with Boc(Cbz)-
EDC afforded Boc(Cbz)- -Phe- [CH(RF)NH]Gly-
very good yields.
L
-Phe-OH using HOBt/
L
C
L-Val-OtBu 11, in
In summary, we have reported on the synthesis of a new class of
peptidomimetics having diverse [CH(RF)NH] functions as surro-
Fig. 2. ORTEP view of 10z.

770
S. Bigotti et al. / Journal of Fluorine Chemistry 129 (2008) 767–774
1.2. Preparation of
b-fluoroalkyl-a-nitroethenes 2–7: typical
procedure (see also Ref. [12])
Fluoral hydrate (aq. solution 75%, 6.65 g, 43 mmol), nitro-
methane (7.87 g, 129 mmol) and sodium carbonate (280 mg,
2.64 mmol) were mixed at rt under vigorous stirring. The mixture
was heated at 60 8C (in a few minutes a red-orange coloration
appeared) for 3 h and then stirred at rt overnight. The mixture was
extracted in diethyl ether, the organic layer was dried with
anhydrous Na2SO4 and then filtered. The organic solvent was
carefully removed in vacuo at low temperature. The resulting light
orange oil was treated with P2O5 (6.5 g, 46 mmol) added in one
portion and the mixture submitted to fractional distillation at
atmospheric pressure. Nitroalkene 2 was obtained as a green-
yellow liquid distilled at 83–85 8C (3.75 g, 70%). Spectroscopic data
matched those reported in the literature.
Fig. 3. Possible transition state leading to the major diastereomers 9.
gates of the scissile peptide bond, namely
C[CH(RF)NH]Gly-pep-
tides. The aza-Michael addition of -aminoacid esters 8 to
a
fluoroalkyl nitroethenes 2–7 represents the key synthetic step.
The diastereoselectivity of this reaction, which was already known
to be dependent on the base and its stoichiometry, solvent, tem-
perature and R side chain of 8 [7], proved to be strongly influenced
also by the electronegativity, rather than the steric bulk, of the
1.3. Michael addition: typical procedure
fluorinated RF group in the b-position to the nitroethene acceptors.
To
(0.51 mmol, 92 mg) in toluene (7 ml) at rt, DIPEA was added
(0.56 mmol, 73 l). After half an hour at rt, the solvent was
a stirred solution of 2 (0.76 mmol, 107 mg) and 8
1. Experimental
m
removed in vacuo, the crude product was dissolved in EtOAc and
washed once with 1N HCl. The organic layer was dried over
anhydrous Na2SO4. The solvent was removed in vacuo, and the
crude product was purified by FC (hexane/diisopropyl ether 9:1)
affording 110 mg (75%) of the two pure diastereoisomers 9b
(Rf = 0.31, n-Hex/iPr2O 7:3) and 10b (Rf = 0.41, n-Hex/iPr2O 7:3), in
6.0:1.0 ratio.
1.1. General details
Commercially available reagent-grade solvents were employed
without purification. Melting points (m.p.) are uncorrected and
were obtained on a capillary apparatus. TLC were run on silica gel
60 F254 Merck. Flash chromatographies (FC) were performed with
silica gel 60 (60–200 m, Merck). 1H, 13C, and 19F NMR spectra were
run at 250, 400 or 500 MHz. Chemical shifts are expressed in ppm
1.4. Synthesis of the fluorinated tripeptide mimics 11: typical
procedure
(
d
), using tetramethylsilane (TMS) as internal standard for 1H and
C = 0.00), while C6F6 was used as external
13C nuclei (dH and
d
standard (dF ꢀ162.90) for 19F. 1H, 19F and 13C NMR spectral data of
nitroalkenes 2, 3, 5 and 7 were in agreement with those previously
reported [12].
A solution of 9m (0.11 mmol, 33 mg) and 1N HCl (0.11 mmol,
110
ml), in MeOH (2 ml), in the presence of a catalytic amount of
Scheme 2. Elaboration of the major aza-Michael adducts 9 into the target peptidomimetics 11.

S. Bigotti et al. / Journal of Fluorine Chemistry 129 (2008) 767–774
771
palladium hydroxide on carbon, was stirred at rt for 5 h, under
hydrogen atmosphere. Then, the mixture was filtered on a Celite
pad and the solvent was removed in vacuo. The crude product was
d = 5.99 (dt, J = 55.6, 3.4 Hz, 1H), 4.58 (dd, J = 13.1, 4.0 Hz, 1H), 4.44
(dd, J = 13.1, 8.6 Hz, 1H), 3.73 (s, 3H), 3.6 (m, 2H), 3.21 (d, J = 5.4 Hz,
1H), 1.7 (m, 1H), 1.4 (m, 1H), 1.11 (m, 1H), 0.87 (t, J = 7.7 Hz, 6H);
dissolved in 1 ml of dry DMF and Cbz-
L-Phe-OH, (0.11 mmol,
19F NMR (235.4 MHz, CDCl3):
d
= ꢀ124.3 (dd, J = 286.1, 55.6 Hz, 1F),
32.9 mg) followed by sym collidine (0.22 mmol, 30
m
l), HOAt
ꢀ139.8 (ddd, J = 286.1, 55.6, 15.6 Hz, 1H); ESI (m/z) 291.1 [M++Na,
(100)].
(0.11 mmol, 14.9 mg), HATU (0.11 mmol, 41.8 mg) were added at
rt. The mixture was stirred overnight, quenched with 1N HCl, and
extracted with Et2O. The organic layer was washed once with
water and then dried on Na2SO4. The solvent was removed in
vacuo, and the crude product purified by FC (hexane/AcOEt 70:30)
affording 50.6 mg of 11m (79%).
9g (stereochemistry not assigned, obtained in mixture with
10g): Rf = 0.34 (hexane:diisopropyl ether 8:2); 1H NMR (400 MHz,
CDCl3): d = 7.6–7.1 (m, 5H), 5.63 (td, J = 55.6, 3.21 Hz, 1H), 4.48 (dd,
J = 13.5, 4.5 Hz, 1H), 4.46 (dd, 13.5, 7.38 Hz, 1H), 3.57 (m, 1H), 2.68
(dd, J = 13.5, 5.46 Hz, 1H), 2.81 (dd, J = 13.5, 7.7 Hz, 1H), 1.42 (s,
4: 1H NMR (400 MHz, CDCl3):
7.10 (dt, J = 13.2, 10.9 Hz, 1H), 1.85 (t, J = 18.4 Hz, 3H); 19F NMR
d
= 7.29 (dt, J = 13.7, 1.9 Hz, 1H),
9H); 19F NMR (235.4 MHz, CDCl3):
d
= ꢀ124.0 (ddd, J = 285.9, 55.1,
7.7 Hz, 1F), ꢀ129.6 (ddd, J = 285.9, 55.1, 17.9 Hz, 1H); ESI (m/z)
345.1 [M++H, (13)], 367.0 [M++Na, (100)], 383.0 [M++K, (20)].
10g (stereochemistry not assigned, obtained in mixture with
9g): Rf = 0.34 (hexane:diisopropyl ether 8:2); 1H NMR (400 MHz,
(470.6 MHz, CDCl3):
d
= ꢀ92.27 (ddq, J = 252.8, 19.3, 9.2 Hz, 1F),
ꢀ92.36 (ddq, J = 252.8, 19.3, 12.3 Hz, 1F); 13C NMR (100.6 MHz,
CDCl3):
d = 142.66, 134.13 (t, J = 28.8 Hz), 118.72 (t, J = 239.1 Hz),
24.24 (t, J = 27.9 Hz); ESI (m/z) 283.0 [M++H, (100)], 305.0 [M++Na,
CDCl3): d = 7.6–7.1 (m, 5H), 5.96 (td, J = 55.6, 3.21 Hz, 1H), 4.48 (dd,
(11)].
J = 13.5, 5.1 Hz, 1H), 4.32 (dd, 13.5, 8.0 Hz, 1H), 3.51 (m, 1H), 2.92
(dd, J = 13.8, 6.1 Hz, 1H), 2.82 (dd, J = 13.5, 7.4 Hz, 1H), 1.44 (s, 9H);
6: 1H NMR (400 MHz, CDCl3):
d
= 7.31 (m, 2H); 19F NMR
(235.4 MHz, CDCl3):
d
= ꢀ51.41 (d, J = 2.3 Hz, 1F), ꢀ51.44 (d,
19F NMR (235.4 MHz, CDCl3):
d
= ꢀ123.9 (ddd, J = 288.5, 55.1,
J = 1.8 Hz, 1H); 13C NMR (100.6 MHz, CDCl3):
J = 27.1 Hz), 113.10 (t, J = 300.9 Hz).
d
= 141.85, 133.07 (t,
7.7 Hz, 1F), ꢀ129.7 (ddd, J = 288.5, 55.1, 16.7 Hz, 1H); ESI (m/z) 345.
[M++H, (5)], 367.0 [M++Na, (100)], 383.0 [M++K, (25)].
9b: Rf = 0.34 (hexane:diisopropyl ether 9:1); ½a D20
ꢃ
¼ ꢀ25:4ꢄ
9h: Rf = 0.34 (hexane: AcOEt 92:8); ½a D20
ꢃ
¼ ꢀ14ꢄ (c = 0.36,
(c = 0.56, CHCl3); 1H NMR (400 MHz, CDCl3):
d
= 4.66 (dd, J = 13.7,
CHCl3); 1H NMR (400 MHz, CDCl3):
d = 5.87 (dt, J = 55.6, 3.4 Hz,
4.6 Hz, 1H), 4.56 (dd, J = 13.3, 7.1 Hz, 1H), 3.90 (m, 1H), 3.37 (dd,
J = 8.8, 5.6 Hz, 1H), 1.80 (m, 2H), 1.48 (m, 2H), 1.47 (s, 9H), 1.40 (m,
1H), 0.92 (d, J = 5.6 Hz, 3H), 0.90 (d, J = 5.6, 3H); 19F NMR
1H), 4.66 (dd, J = 13.7, 4.3 Hz, 1H), 4.55 (dd, J = 13.7, 6.8 Hz, 1H),
3.57 (m, 1H), 3.11 (d, J = 4.8 Hz, 1H), 2.03 (s, 1H), 1.99 (m, 1H), 1.47
(s, 9H), 0.97 (d, J = 6.8 Hz, 3H), 0.86 (d, J = 6.8 Hz, 3H); 19F NMR
(235.4 MHz, CDCl3):
(100.6 MHz, CDCl3):
d
= ꢀ76.45 (d, J = 7.01 Hz, 1F);13
C
NMR
(235.4 MHz, CDCl3):
d
= ꢀ123.8 (ddd, J = 285.4, 55.6, 7.8 Hz, 1F),
d
= 174.26, 126.15 (q, J = 282.2 Hz), 81.99,
ꢀ130.0 (ddd, J = 285.4, 55.6, 18.0 Hz, 1H); 13C NMR (100.6 MHz,
74.49, 60.04, 57.92, (q, J = 29.7), 43.21, 27.91, 24.64, 24.35, 21.81;
ESI (m/z) 353.1 [M++Na, (100)], 369.1 [M++K, (19)].
CDCl3): d = 174.17, 115.81 (t, J = 247.2 Hz), 82.26, 74.40, 58.52 (t,
J = 22.04 Hz), 32.31, 18.37, 19.67, 17.62; ESI (m/z) 319.1 [M++Na,
10b: Rf = 0.35 (hexane:diisopropyl ether 9:1); ½a D23
ꢃ
¼ þ6:5ꢄ
(100)], 335.1 [M++K, (35)].
(c = 0.25, CHCl3); 1H NMR (400 MHz, CDCl3):
d
= 4.60 (dd, J = 20.9,
10h: Rf = 0.33 (hexane:AcOEt 92:8); ½a D20
ꢃ
¼ þ9ꢄ (c = 0.2, CHCl3);
6.0 Hz, 1H), 4.38 (dd, J = 20.9, 16.1 Hz, 1H), 3.96 (m, 1H), 3.23 (dd,
J = 25.8, 11.2 Hz, 1H), 2.11 (m, 1H), 1.67 (m, 2H), 1.55 (br s, 1H),
1.48 (s, 9H), 0.88 (d, J = 8.64 Hz, 3H), 0.86 (d, J = 8.6, 3H); 19F NMR
1H NMR (400 MHz, CDCl3):
d = 6.00 (dt, J = 55.6, 3.4 Hz, 1H), 4.58
(dd, J = 13.1, 4.3 Hz, 1H), 4.44 (dd, J = 13.1, 8.6, 1H), 3.56 (m, 1H),
2.99 (d, J = 5.1 Hz, 1H), 1.91 (m, 2H), 1.48 (s, 9H), 0.91 (d, J = 6.8 Hz,
3H), 0.83 (d, J = 0.83 Hz, 3H); 19F NMR (235.4 MHz, CDCl3):
(235.4 MHz, CDCl3):
d
= ꢀ74.92 (d, J = 7.01 Hz, 3F); ESI (m/z) 351.2
[M++Na, (100)], 367.1 [M++K, (35)].
d
= ꢀ124.2 (ddd, J = 288.9, 55.5, 8.2 Hz, 1F), ꢀ130.2 (ddd,
9e (stereochemistry not assigned): Rf = 0.34 (hexane:diisopro-
J = 288.9, 55.6, 17.9 Hz, 1F); ESI (m/z) 319.1 [M++Na, (100)],
pyl ether 7:3); ½a D20
ꢃ
¼ þ3ꢄ (c = 0.25, CHCl3); 1H NMR (400 MHz,
335.1 [M++K, (15)].
CDCl3):
d
= 6.06 (dt, J = 55.4, 3.1 Hz, 1H), 4.60 (dd, J = 13.1, 4.0 Hz,
9i: Rf = 0.33 (hexane:diisopropyl ether 85:15); ½a D20
ꢃ
¼ ꢀ32:3ꢄ
1H), 4.45 (dd, J = 13.1, 8.3 Hz, 1H), 3.65 (m, 1H), 3.35 (q, J = 7.4 Hz,
1H), 1.95 (br s, 1H), 1.46 (s, 9H), 1.25 (d, J = 7.1 Hz, 1H); 19F NMR
(c = 2.8, CHCl3); 1H NMR (400 MHz, CDCl3):
d = 4.69 (dd, J = 13.7,
4.8 Hz, 1H), 4.48 (dd, J = 13.7, 7.3 Hz, 1H), 3.63 (m, 1H), 3.38 (q,
J = 7.0 Hz, 1H), 1.92 (br s, 1H), 1.69 (t, J = 19.1 Hz, 3H), 1.44 (s, 9H),
(235.4 MHz, CDCl3):
d
= ꢀ124.0 (ddd, J = 290.5, 55.4, 7.4 Hz, 1F),
ꢀ131.1 (ddd, J = 290.5, 55.4, 20.0 Hz, 1H); 13C NMR (100.6 MHz,
1.26 (d, J = 7.0 Hz, 3H); 19F NMR (470.6 MHz, CDCl3):
d
= ꢀ96.2
(ddq, J = 249.7, 19.4, 5.0 Hz, 1F), ꢀ104.2 (dquint, J = 249.7, 18.8 Hz,
1F); 13C NMR (100.6 MHz, CDCl3):
= 174.74, 124.13 (t,
CDCl3):
d = 174.95, 115.35 (t, J = 245.8 Hz), 82.14, 74.81, 57.91 (t,
J = 21.2), 56.85, 28.34, 20.07; ESI (m/z) 291.1 [M++Na, (100)].
10e (stereochemistry not assigned): Rf = 0.33 (hexane:diiso-
d
J = 243.3 Hz), 82.09, 75.32, 60.61 (t, J = 25.4 Hz), 56.83, 28.27,
20.91 (t, J = 26.3 Hz) 20.41 1; ESI (m/z) 305.2 [M++Na, (100)], 321.0
[M++K, (23)].
propyl ether 7:3); ½a D20
ꢃ
¼ ꢀ12:0ꢄ (c = 0.58, CHCl3); 1H NMR
(400 MHz, CDCl3):
d = 5.90 (dt, J = 55.6, 3.4 Hz, 1H), 4.66 (dd,
J = 13.4, 4.6 Hz, 1H), 4.55 (dd, J = 13.4, 6.8 Hz, 1H), 3.63 (m, 1H),
3.43 (q, J = 6.8 Hz, 1H), 1.98 (br s, 1H), 1.47 (s, 9H), 1.28 (d,
10i: Rf = 0.32 (hexane:diisopropyl ether 9:1); ½a D20
ꢃ
¼ ꢀ3:7ꢄ
(c = 0.55, CHCl3); 1H NMR (400 MHz, CDCl3):
d = 4.62 (dd, J = 13.0,
J = 7.1 Hz, 3H); 19F NMR (235.4 MHz, CDCl3):
d
= ꢀ124.5 (ddd,
4.1 Hz, 1H), 4.36 (dd, J = 13.0, 8.6 Hz, 1H), 3.74 (m, 1H), 3.35 (q,
J = 7.0 Hz, 1H), 1.98 (br, 1H), 1.70 (t, J = 19.1 Hz, 3H), 1.47 (s, 9H),
J = 288.3, 55.6, 19 Hz, 1F), ꢀ129.6 (ddd, J = 288.0, 56.7, 19 Hz, 1F);
ESI (m/z) 291.1 [M++Na, (100)].
1.23 (d, J = 6.7 Hz, 3H); 19F NMR (470.6 MHz, CDCl3):
d
= ꢀ95.2
9f (stereochemistry not assigned, obtained in mixture with
10f): Rf = 0.34 (hexane:AcOEt 9:1); 1H NMR (400 MHz, CDCl3):
(ddq, J = 251.2, 26.1, 7.0 Hz, 1F), ꢀ101.3 (dquint, J = 251.2, 15.3 Hz,
1F); ESI (m/z) 305.2 [M++Na, (100)], 321.0 [M++K, (4)].
d
= 5.84 (dt, J = 55.6, 3.4 Hz, 1H), 4.60 (dd, J = 13.7, 4.3 Hz, 1H), 4.52
9j: Rf = 0.34 (hexane:AcOEt 9:1); ½a D20
ꢃ
¼ ꢀ26:0ꢄ (c = 2.8, CHCl3);
(dd, J = 13.7, 6.8 Hz, 1H), 3.71 (s, 3H), 3.55 (m, 2H), 3.28 (d,
J = 5.1 Hz, 1H), 1.72 (m, 1H), 1.45 (m, 1H), 1.1 (m, 1H), 0.92 (d,
J = 6.8 Hz, 3H), 0.86 (d, J = 9.7 Hz, 3H); 19F NMR (235.4 MHz,
1H NMR (400 MHz, CDCl3):
d = 4.68 (dd, J = 13.4, 4.4 Hz, 1H), 4.42
(dd, J = 13.4, 7.3 Hz, 1H), 3.69 (s, 3H), 3.57 (m, 1H), 3.29 (br s, 1H),
1.85 (br s, 1H), 1.70 (m, 1H), 1.99 (t, J = 19.1 Hz, 3H), 1.45 (m, 1H),
1.17 (m, 1H), 0.92 (d, J = 7.0 Hz, 3H), 0.88 (t, J = 7.6 Hz, 3H); 19F
CDCl3):
d
= ꢀ124.4 (dd, J = 287.2, 55.6 Hz, 1F), ꢀ130.0 (ddd,
J = 287.2, 55.6, 16.7 Hz, 1H); ESI (m/z) 291.1 [M++Na, (100)].
10f (stereochemistry not assigned, obtained in mixture with
9f): Rf = 0.34 (hexane:AcOEt 9:1); 1H NMR (400 MHz, CDCl3):
NMR (470.6 MHz, CDCl3):
d
= ꢀ95.3 (ddq, J = 250.2, 19.3, 4.9 Hz,
1F), ꢀ103.8 (dquint, J = 250.2, 19.2 Hz, 1F); 13C NMR (100.6 MHz,
CDCl3):
d = 175.24, 124.07 (t, J = 243.3 Hz), 75.44, 66.03, 61.60 (t,

772
S. Bigotti et al. / Journal of Fluorine Chemistry 129 (2008) 767–774
J = 26.3 Hz), 52.13, 39.43, 25.23, 20.89 (t, J = 26.3 Hz), 16.13, 11.73;
ESI (m/z) 283.0 [M++Na, (100)], 305.0 [M++K, (14)].
d
= ꢀ60.21 (dd, J = 166.8, 8.2 Hz, 1F), ꢀ61.04 (dd, J = 166.8, 6.8 Hz,
1F); 13C NMR (100.6 MHz, CDCl3):
d
= 172.93, 136.89, 129.90,
10j: Rf = 0.33 (hexane:AcOEt 9:1);
CHCl3); 1H NMR (400 MHz, CDCl3):
½
a 2D0
ꢃ
¼ þ20:0ꢄ (c = 0.2,
129.44 (t, J = 298.4 Hz), 128.76, 127.29, 82.65, 75.73, 63.25 (t,
J = 25.43 Hz), 62.67, 40.52, 28.26; ESI (m/z) 401.0 [M++Na, (100)],
413.2 [M++K, (21)].
d
= 4.59 (dd, J = 12.7, 4.2 Hz,
1H), 4.35 (dd, J = 12.7, 8.9 Hz, 1H), 3.73 (s, 3H), 3.71 (s br, 1H), 3.24
(s br, 1H), 1.97 (s br, 1H), 1.67 (t, J = 19.3 Hz, 3H), 1.70 (m, 1H) 1.65
(m, 1H), 1.43 (m, 1H), 1.14 (m, 1H), 0.87 (t, J = 7.5 Hz, 3H), 0.85 (d,
10n: Rf = 0.34 (hexane:diisopropylether 85:15): ½a D20
ꢃ
¼ ꢀ26:7ꢄ
(c = 0.3, CHCl3); 1H NMR (400 MHz, CDCl3):
4.71 (dd, J = 13.2, 2.9 Hz, 1H), 4.29 (dd, J = 13.2, 9.3 Hz, 1H), 4.04 (m,
1H), 3.56 (7, J = 7.1 Hz, 1H), 2.99 (dd, J = 13.5, 6.1 Hz, 1H), 2.81 (dd,
J = 13.5, 6.1 Hz, 1H), 1.39 (s, 9H); 19F NMR (235.4 MHz, CDCl3):
d = 7.3–7.15 (m, 5H),
J = 6.7 Hz, 3H); 19F NMR (470.6 MHz, CDCl3):
d
= ꢀ96.0 (ddq,
J = 252.8, 19.3, 9.2 Hz, 1F), ꢀ98.8 (ddq, J = 252.8, 19.3, 12.3 Hz, 1F);
ESI (m/z) 283.0 [M++Na, (100)], 305.0 [M++K, (11)].
9k: Rf = 0.36 (hexane:AcOEt 9:1);
CHCl3); 1H NMR (400 MHz, CDCl3):
½
a 2D0
ꢃ
¼ ꢀ22:4ꢄ (c = 0.9,
d
= ꢀ58.811 (d, J = 169.3 Hz, 1F), ꢀ60.63 (dd, J = 169.3, 9.4 Hz, 1F);
d
= 7.3–7.1 (m, 5H), 4.66 (dd,
ESI (m/z) 401.0 [M++Na, (100)], 413.2 [M++K, (34)].
9o: Rf = 0.33 (hexane:diisopropylether 9:1):
(c = 3.8, CHCl3); 1H NMR (400 MHz, CDCl3):
J = 13.7, 4.8 Hz, 1H), 4.44 (dd, J = 13.7, 7.0 Hz, 1H), 3.67 (m, 2H),
3.00 (dd, J = 13.7, 5.4 Hz, 1H), 2.75 (dd, J = 13.7, 8.3 Hz, 1H), 1.84 (br
s, 1H), 1.42 (s, 9H), 1.39 (t, J = 19.1 Hz, 3H); 19F NMR (470.6 MHz,
½
a 2D0
ꢃ
¼ ꢀ11:9ꢄ
d
= 4.71 (dd, J = 13.2,
4.2 Hz, 1H), 4.52 (dd, J = 13.5, 7.7 Hz, 1H), 3.93 (m, 1H), 3.71 (s, 3H),
3.38 (d, J = 5.1 Hz, 1H), 2.34 (t, J = 9.9 Hz, 1H), 1.73 (m, 1H), 1.45 (m,
1H), 1.17 (m, 2H), 0.92 (d, J = 6.7 Hz, 3H), 0.88 (t, J = 7.4 Hz, 3H); 19
F
CDCl3):
d
= ꢀ95.3 (ddq, J = 250.0, 19.1, 4.1 Hz, 1F), ꢀ104.5 (dquint,
= 173.92,
J = 250.0, 19.1 Hz, 1F); 13C NMR (100.6 MHz, CDCl3):
d
137.79, 129.82, 128.70, 127.10, 124.12 (t, J = 243.3 Hz), 82.54,
75.38, 63.23, 61.25 (t, J = 25.4 Hz), 41.11, 28.28, 20.64 (t,
J = 26.3 Hz); ESI (m/z) 381.0 [M++Na, (100)], 397.0 [M++K, (31)].
NMR (235.4 MHz, CDCl3):
d
= ꢀ60.22 (dd, J = 166.9, 7.7 Hz, 1F),
ꢀ61.1 (dd, J = 166.9, 6.7 Hz, 1F); 13C NMR (100.6 MHz, CDCl3):
d
= 174.93, 129.40 (t, J = 296.7 Hz), 75.80, 66.27, 63.57 (t,
10k: Rf = 0.35 (hexane:AcOEt 9:1);
CHCl3); 1H NMR (400 MHz, CDCl3):
½
a 2D0
ꢃ
¼ þ32:3ꢄ (c = 0.6,
J = 26.3 Hz), 52.29, 39.02, 25.12, 16.04, 11.73; ESI (m/z) 270.1
d
= 7.4–7.1 (m, 5H), 4.51 (dd,
[M++Na, (100)].
J = 13.2, 4.7 Hz, 1H), 4.20 (dd, J = 13.2, 8.0 Hz, 1H), 3.71 (m, 1H),
3.52 (t, J = 6.6 Hz, 1H), 2.92 (dd, J = 13.6, 6.1 Hz, 1H), 2.79 (dd,
J = 13.6, 7.1 Hz, 1H), 1.94 (br s, 1H), 1.64 (t, J = 19.3 Hz, 3H), 1.40 (s,
10o: Rf = 0.35 (hexane:diisopropylether 9:1): ½a D20
ꢃ
¼ þ35:3ꢄ
(c = 0.3, CHCl3); 1H NMR (400 MHz, CDCl3):
d = 4.69 (dd, J = 12.7,
3.3 Hz, 1H), 4.41 (dd, J = 12.7, 9.9 Hz, 1H), 4.06 (m, 1H), 3.74 (s, 3H),
3.27 (dd, J = 8.0, 5.2 Hz, 1H), 1.61 (m, 1H), 1.39 (m, 2H), 1.13 (m,
1H), 0.88 (t, J = 7.5 Hz, 3H), 0.84 (d, J = 7.1 Hz, 3H); 19F NMR
9H); 19F NMR (470.6 MHz, CDCl3):
d
= ꢀ95.7 (ddq, J = 252.2, 19.3,
7.7 Hz, 1F), ꢀ100.7 (ddq, J = 252.2, 19.3, 15.5 Hz, 1F); ESI (m/z)
381.0 [M++Na, (100)], 397.0 [M++K, (6)].
(235.4 MHz, CDCl3):
d
= ꢀ58.45 (dd, J = 169.5, 3.9 Hz, 1F), ꢀ60.8
9l: Rf = 0.35 (hexane:AcOEt 97:3);
CHCl3); 1H NMR (400 MHz, CDCl3):
½
a 2D0
ꢃ
¼ ꢀ27:3ꢄ (c = 4.3,
(dd, J = 169.5, 10.4 Hz, 1F); ESI (m/z) 270.1 [M++Na, (100)], 292.0
d
= 4.69 (dd, J = 13.7, 4.8 Hz,
[M++K, (28)].
1H), 4.45 (dd, J = 13.7, 6.7 Hz, 1H), 3.55 (d, 1H), 3.09 (br s, 1H), 1.96
(m, 1H), 1.83 (br s, 1H), 1.72 (t, J = 19.2 Hz, 3H), 1.44 (s, 9H), 0.96 (d,
J = 7.0 Hz, 3H), 0.85 (d, J = 7.0 Hz, 3H); 19F NMR (470.6 MHz,
9p: Rf = 0.33 (hexane:diisopropyl ether 9:1); ½a D23
ꢃ
¼ ꢀ29:5ꢄ
(c = 1.8, CHCl3); 1H NMR (400 MHz, CDCl3):
d = 4.72 (dd, J = 13.7,
4.2 Hz, 1H), 4.56 (dd, J = 13.7, 7.0 Hz, 1H), 3.95 (m, 1H), 3.18 (dd,
J = 8.3, 4.5 Hz, 1H), 1.97 (m, 1H), 1.95 (s br, 1H), 1.47 (s, 9H), 0.98 (d,
J = 6.8 Hz, 3H), 0.88 (d, J = 6.8, 3H); 19F NMR (235.4 MHz, CDCl3):
CDCl3):
d
= ꢀ95.1 (ddq, J = 251.5, 19.0, 3.7 Hz, 1F), ꢀ104.7 (dquint,
= 174.39,
J = 251.5, 20.3 Hz, 1F); 13C NMR (100.6 MHz, CDCl3):
d
124.26 (t, J = 243.3 Hz), 82.20, 75.35, 67.09, 61.85 (t, J = 25.4 Hz),
32.66, 28.32, 21.15 (t, J = 26.3 Hz) 19.81, 17.62 1; ESI (m/z) 333.0
[M++Na, (100)], 349.0 [M++K, (21)].
d
= ꢀ60.6 (dd, J = 166.2, 7.5 Hz, 1F), ꢀ61.5 (dd, J = 166.2, 6.7 Hz,
1F);13
C
NMR (100.6 MHz, CDCl3): = 173.52, 129.14 (t,
d
J = 296.7 Hz), 82.04, 75.53, 67.13, 63.55 (t, J = 26.28 Hz) 33.00,
28.00, 19.26, 17.39; ESI (m/z) 353.1 [M++Na, (100)], 369.1 [M++K,
(9)].
10l: Rf = 0.34 (hexane:AcOEt 97:3); ½a D20
ꢃ
¼ þ21:1ꢄ (c = 0.6,
CHCl3); 1H NMR (400 MHz, CDCl3):
d = 4.57 (dd, J = 12.7, 4.1 Hz,
1H), 4.32 (dd, J = 12.7, 8.9 Hz, 1H), 3.69 (m, 1H), 3.03 (d, J = 5.1 Hz,
1H), 1.85 (m, 1H), 1.66 (t, J = 19.1 Hz, 3H), 1.61 (s, 9H), 0.89 (d,
J = 6.7 Hz, 3H), 0.84 (d, J = 6.7 Hz, 3H); 19F NMR (470.6 MHz,
10p: Rf = 0.34 (hexane:diisopropyl ether 9:1); ½a D23
ꢃ
¼ þ16:0ꢄ
(c = 0.25, CHCl3); 1H NMR (400 MHz, CDCl3):
3.4 Hz, 1H), 4.32 (dd, J = 12.8, 10 Hz, 1H), 3.95 (m, 1H), 3.00 (d,
J = 4.5 Hz, 1H), 2.24 (s br, 1H), 1.81 (m, 1H), 1.32 (s, 9H), 0.80 (d,
J = 6.8 Hz, 3H), 0.74 (d, J = 7.4, 3H); 19F NMR (235.4 MHz, CDCl3):
d = 4.61 (dd, J = 12.8,
CDCl3):
d
= ꢀ95.6 (ddq, J = 252.6, 19.1, 9.2 Hz, 1F), ꢀ95.7 (ddq,
J = 252.6, 19.1, 10.8 Hz, 1F); ESI (m/z) 333.0 [M++Na, (100)], 349.0
[M++K, (11)].
d
= ꢀ58.2 (dd, J = 168.4, 4.3 Hz, 1F), ꢀ60.8 (dd, J = 168.4, 8.5 Hz, 1F);
9m: Rf = 0.35 (hexane:AcOEt 95:5); ½a D20
ꢃ
¼ ꢀ25:4ꢄ (c = 0.56,
ESI (m/z) 353.1 [M++Na, (100)], 369.1 [M++K, (20)].
CHCl3); 1H NMR (400 MHz, CDCl3):
d
= 4.71 (dd, J = 13.4, 4.3 Hz,
9q: Rf = 0.35 (hexane:AcOEt 7:3):
½
a 2D0
ꢃ
¼ ꢀ40:1ꢄ (c = 0.91,
1H), 4.54 (dd, J = 13.4, 7.7 Hz, 1H), 4.06 (m, 1H), 3.49 (m, 1H), 1.98
(br, 1H), 1.4 (s, 9H), 1.29 (d, J = 6.8, 2H); 19F NMR (235.4 MHz,
CHCl3); 1H NMR (400 MHz, CDCl3):
1H), 4.54 (dd, J = 13.4, 7.7 Hz, 1H), 3.98 (m, 1H), 3.50 (q, J = 7.1 Hz,
1H), 1.97 (br s, 1H), 1.44 (s, 9H), 1.31 (d, J = 6.8 Hz, 3H); 19F NMR
(235.4 MHz, CDCl3):
J = 163.8, 7.8 Hz, 1H); 13C NMR (100.6 MHz, CDCl3):
d = 4.72 (dd, J = 13.4, 4.3 Hz,
CDCl3):
d
= ꢀ61.0 (dd, J = 166.7, 7.6 Hz, 1F), ꢀ61.5 (dd, J = 166.7,
= 174.14, 129.12 (t,
6.7 Hz, 1F);13C NMR (100.6 MHz, CDCl3):
d
d
= ꢀ54.3 (dd, J = 163.8, 8.2 Hz, 1F), ꢀ55.4 (dd,
= 174.17,
J = 297.5 Hz), 75.46, 62.74 (t, J = 26.3 Hz), 56.74, 30.80, 29.67,
19.92; ESI (m/z) 325.1 [M++Na, (100)], 341.0 [M++K, (8)].
d
124.18 (t, J = 311.1 Hz), 82.31, 76.26, 64.35 (t, J = 23.7 Hz), 57.06,
28.29, 20.09; ESI (m/z) 369.1 [M++Na, (100)], 387.0 [M++K, (21)].
10m: Rf = 0.36 (hexane:AcOEt 95:5); ½a D20
ꢃ
¼ þ25:4ꢄ (c = 0.26,
CHCl3); 1H NMR (400 MHz, CDCl3):
d
= 4.70 (dd, J = 12.6, 3.2 Hz,
10q: Rf = 0.33 (hexane:AcOEt 7:3): ½a D20
ꢃ
¼ þ20ꢄ (c = 0.3, CHCl3);
1H), 4.42 (dd, J = 12.6, 9.7 Hz, 1H), 4.11 (m, 1H), 3.44 (m, 1H), 1.46
(s, 9H), 2.45 (br s, 1H), 1.24 (d, 3H); 19F NMR (235.4 MHz, CDCl3):
1H NMR (400 MHz, CDCl3):
d = 4.70 (dd, J = 13.1, 3.4 Hz, 1H), 4.38
(dd, J = 13.1, 9.4 Hz, 1H), 4.44 (m, 1H), 3.45 (m, 1H), 2.47, (br s, 1H),
1.47 (s, 9H), 1.24 (d, J = 7.1 Hz, 2H); 19F NMR (235.4 MHz, CDCl3):
d
= ꢀ58.7 (dd, J = 168.8, 4.3Hz, 1F), ꢀ60.4 (dd, J = 168.8, 8.8 Hz, 1F);
ESI (m/z) 325.1 [M++Na, (100)], 341.0 [M++K, (17)].
d
= ꢀ52.0 (dd, J = 166.5, 4.4 Hz, 1F), ꢀ54.4 (dd, J = 166.5, 10.2 Hz,
9n: Rf = 0.33 (hexane:diisopropylether 85:15): ½a D20
ꢃ
¼ ꢀ44:0ꢄ
1F); ESI (m/z) 369.1 [M++Na, (100)].
(c = 2.3, CHCl3); 1H NMR (400 MHz, CDCl3):
d
= 7.3–7.15 (m, 5H),
9r: Rf = 0.33 (hexane:diisopropyl ether 75:25): ½a D20
ꢃ
¼ ꢀ31:5ꢄ
4.65 (dd, J = 13.5, 4.5 Hz, 1H), 4.47 (dd, J = 13.5, 7.7 Hz, 1H), 4.05 (m,
1H), 3.69 (q, J = 6.7 Hz, 1H), 2.99 (dd, J = 13.5, 5.8 Hz, 1H), 2.88 (dd,
J = 13.5, 7.4 Hz, 1H), 1.37 (s, 9H); 19F NMR (235.4 MHz, CDCl3):
(c = 3.8, CHCl3); 1H NMR (400 MHz, CDCl3):
d = 4.73 (dd, J = 13.7,
3.8 Hz, 1H), 4.53 (dd, J = 13.7, 8.0 Hz, 1H), 3.39 (m, 1H), 3.75 (s, 3H),
3.39 (dd, J = 9.4, 5.6 Hz, 1H), 1.94 (t, J = 8 Hz, 1H), 1.75 (m, 1H), 1.46

S. Bigotti et al. / Journal of Fluorine Chemistry 129 (2008) 767–774
773
(m, 1H), 1.92 (m, 1H), 0.94 (d, J = 7.1 Hz, 3H), 0.89 (t. J = 7.5 Hz, 3H);
19F NMR (235.4 MHz, CDCl3): 13C NMR (100.6 MHz, CDCl3):
= 174.78, 124.09 (t, J = 311.10 Hz), 76.31, 66.17, 64.71 (t,
J = 23.74 Hz), 52.29, 39.03, 30.03, 25.16, 16.12, 11.75;
9v: Rf = 0.35 (hexane:diisopropylether 9:1):
(c = 0.4, CHCl3); 1H NMR (400 MHz, CDCl3):
4.5 Hz, 1H), 4.61 (dd, J = 14.1, 6.7 Hz, 1H), 4.03 (m, 1H), 3.70 (s, 3H),
3.31 (q, J = 4.8 Hz, 1H), 1.86 (t, J = 9.6 Hz, 1H), 1.72 (m, 1H), 1.39 (m,
2H), 1.14 (m, 1H), 0.89 (d, J = 7.1 Hz, 3H), 0.86 (t, J = 7.4 Hz, 2H); 19
F
½
a 2D0
ꢃ
¼ ꢀ41:9ꢄ
d
= 4.72 (dd, J = 14.1,
d
d
= ꢀ51.7
(dd, J = 167.9, 3.8 Hz, 1F), ꢀ54.9 (dd, J = 167.9, 11.1Hz, 1H); ESI (m/
z) 370.9 [M++Na, (100)], 386.8 [M++K, (32)].
NMR (235.4 MHz, CDCl3):
d
= ꢀ81.52 (s, 3F), ꢀ117.81 (dd, J = 276.8,
10r: Rf = 0.36 (hexane:diisopropyl ether 75:25): ½a D20
ꢃ
¼ þ13:4ꢄ
4.8 Hz, 1F), ꢀ127.06 (dd, J = 276.8, 18.9 Hz, 1F); 3C NMR
(c = 1.0, CHCl3); 1H NMR (400 MHz, CDCl3):
d
= 4.72 (dd, J = 12.7,
(100.6 MHz, CDCl3): d = 173.96, 119.00 (qt, J = 286.52, 39.7 Hz),
3.3 Hz, 1H), 4.40 (dd, J = 12.7, 9.9 Hz, 1H), 3.98 (m, 1H), 3.74 (s, 3H),
3.27 (dd, J = 8.5, 5.6 Hz, 1H), 2.35 (t, J = 9.4 Hz, 1H), 1.61 (m, 1H),
1.40 (m, 1H), 1.14 (m, 1H), 0.86 (t, J = 7.5 Hz, 3H), 0.84 (d, J = 7.1 Hz,
114.34 (tq, J = 261.24, 39.7 Hz), 74.91, 65.17, 58.01 (t, J = 22.89 Hz),
52.18, 39.88, 30.04, 25.60, 21.61; ESI (m/z) 337.0 (M+H(+, 359.0
[M++Na, (100)], 374.9 [M++K, (14)].
3H); 19F NMR (235.4 MHz, CDCl3):
d
= ꢀ51.7 (dd, J = 167.9, 3.8 Hz,
10v: Rf = 0.34 (hexane:diisopropylether 9:1):
½
a 2D0
ꢃ
¼ þ4:7ꢄ
1F), ꢀ54.9 (dd, J = 167.9, 11.1Hz, 1H); ESI (m/z) 370.9 [M++Na,
(c = 4.2, CHCl3); 1H NMR (400 MHz, CDCl3):
d = 4.62 (dd, J = 13.2,
(100)], 386.8 [M++K, (16)].
3.3 Hz, 1H), 4.42 (dd, J = 13.2, 9.9 Hz, 1H), 4.11 (m, 1H), 3.43 (s, 3H),
3.28 (t, J = 7.1 Hz, 1H), 2.31 (t, J = 8.9 Hz, 1H), 1.71 (m, 1H), 1.41 (m,
2H), 1.14 (m, 1H), 0.92 (t, J = 7.5 Hz, 2H), 0.83 (t, J = 7.1 Hz, 3H); 19
F
9s: Rf = 0.36 (hexane:diisopropyl ether 75:25); ½a D20
ꢃ
¼ ꢀ23:1ꢄ
(c = 2.0, CHCl3); 1H NMR (400 MHz, CDCl3):
d
= 7.3–7.2 (m, 5H),
4.66 (dd, J = 13.7, 4.3 Hz, 1H), 4.47 (dd, J = 13.7, 7.7 Hz, 1H), 3.91 (m,
1H), 3.70 (q, J = 6.8 Hz, 1H), 2.00 (dd, J = 13.7, 6.0 Hz, 1H), 2.88 (dd,
J = 13.7, 7.1 Hz, 1H), 1.99 (br s, 1H), 1.41 (s, 9H); 19F NMR
NMR (235.4 MHz, CDCl3):
d
= ꢀ82.61 (s, 3F), ꢀ120.81 (dd, J = 278.8,
9.4 Hz, 1F), ꢀ123.57 (dd, J = 278.8, 15.1 Hz, 1F); ESI (m/z) 337.0
(M+H(+, 359.0 [M++Na, (100)], 374.9 [M++K, (9)].
(235.4 MHz, CDCl3):
d
= ꢀ53.7 (dd, J = 164.7, 8.5 Hz, 1F), ꢀ54.7 (dd,
= 172.9,
9w: Rf = 0.35 (hexane:diisopropyl ether 9:1); ½a D20
ꢃ
¼ ꢀ4:2ꢄ
J = 164.7, 6.5 Hz, 1F); 13C NMR (100.6 MHz, CDCl3):
d
(c = 0.25, CHCl3); 1H NMR (400 MHz, CDCl3):
d = 7.3–7.1 (m, 5H),
136.78, 129.87, 128.75, 127.08, 124.13 (t, J = 370.5 Hz), 82.63,
76.15, 64.27 (t, J = 24.05 Hz), 62.51, 40.39, 28.19; ESI (m/z) 445.0
[M++Na, (100)].
4.69 (dd, J = 14.6, 4.8 Hz, 1H), 4.61 (dd, J = 14.6, 6.6 Hz, 1H), 4.09 (m,
1H), 3.62 (dt, J = 9.1, 6.3 Hz, 1H), 2.93 (d, J = 6.3 Hz, 1H), 1.83 (br s,
1H), 1.39 (s, 9H); 19F NMR (235.4 MHz, CDCl3):
d
= ꢀ81.6 (s, 3F),
ꢀ117.6 (dd, J = 275.7, 5.9 Hz, 1F), ꢀ127.8 (dd, J = 275.7, 19.7 Hz,
1F); 13C NMR (100.6 MHz, CDCl3):
= 173.25, 136.46, 129.43,
10s: Rf = 0.38 (hexane:diisopropyl ether 75:25); ½a D20
ꢃ
¼ þ21:3ꢄ
(c = 0.20, CHCl3); 1H NMR (400 MHz, CDCl3):
d
= 7.4–7.2 (m, 5H),
d
4.61 (dd, J = 13.1, 3.7 Hz, 1H), 4.28 (dd, J = 13.1, 9.4 Hz, 1H), 3.92 (m,
1H), 3.55 (m, 1H), 2.88 (dd, J = 13.7, 5.7 Hz, 1H), 2.80 (dd, J = 13.7,
7.1 Hz, 1H), 2.39 (br s, 1H), 1.38 (s, 9H); 19F NMR (235.4 MHz,
128.28, 126.87, 125.43, 118.62 (qt, J = 34.8, 283.96 Hz), 113.96 (tq,
J = 34.8, 236.4 Hz), 82.41, 74.12, 62.83, 57.21 (t, J = 20.4 Hz), 40.39,
27.80; ESI (m/z) 413.3 [M++H, (100)].
CDCl3):
d
= ꢀ52.9 (dd, J = 167.3, 3.9 Hz, 1F), ꢀ54.5 (dd, J = 167.3,
10w: Rf = 0.34 (hexane:diisopropyl ether 9:1); ½a D20
ꢃ
¼ þ16ꢄ
10.2Hz, 1H); ESI (m/z) 445.0 [M++Na, (100)].
(c = 0.20, CHCl3); 1H NMR (400 MHz, CDCl3):
d = 7.3–7.1 (m, 5H),
9t: Rf = 0.34 (hexane:diisopropyl ether 9:1); ½a D20
ꢃ
¼ ꢀ30:6ꢄ
4.59 (dd, J = 13.4, 4.6 Hz, 1H), 4.47 (dd, J = 13.7, 7.7 Hz, 1H), 3.95 (m,
1H), 3.65 (t, J = 6.6 Hz, 1H), 2.98 (dd, J = 13.7, 5.9 Hz, 1H), 2.88 (dd,
J = 13.7, 7.1 Hz, 1H), 1.52 (br s, 1H), 1.37 (s, 9H); 19F NMR
(c = 4.5, CHCl3); 1H NMR (400 MHz, CDCl3):
d = 4.72 (dd, J = 13.9,
4.3 Hz, 1H), 4.56 (dd, J = 13.9, 7.4 Hz, 1H), 3.86 (m, 1H), 3.19 (d,
J = 5.1 Hz, 1H), 1.98 (m, 1H), 1.44 (s, 9H), 0.98 (d, J = 6.5 Hz, 3H),
(235.4 MHz, CDCl3):
d
= ꢀ82.7 (s, 3F), ꢀ122.8 (dd, J = 278.3, 6.3 Hz,
0.89 (d, J = 6.5 Hz, 3H); 19F NMR (235.4 MHz, CDCl3):
d
= ꢀ53.9 (dd,
1F), ꢀ130.2 (dd, J = 278.3, 18.8 Hz, 1F); ESI (m/z) 413.3 [M++H,
J = 163.8, 8.3 Hz, 1F), ꢀ130.2 (dd, J = 163.8, 6.7 Hz, 1F); 13C NMR
(100)].
(100.6 MHz, CDCl3):
d
= 173.8, 124.18 (t, J = 311.9 Hz), 82.38, 76.34,
9y: Rf = 0.34 (hexane:diisopropyl ether 9:1); ½a D20
ꢃ
¼ ꢀ28:7ꢄ
65.00 (t, J = 23.7 Hz), 32.48, 28.34, 19.66, 17.81; ESI (m/z) 397.0
(c = 2.1, CHCl3); 1H NMR (400 MHz, CDCl3):
d = 4.73 (dd, J = 14.5,
[M++Na, (100)], 413.2 [M++K, (8)].
4.8 Hz, 1H), 4.65 (dd, J = 14.5, 5.7 Hz, 1H), 4.04 (m, 1H), 3.14 (dd,
J = 9.9, 4.3 Hz, 1H), 2.05 (br s, 1H), 2.00 (m, 1H), 1.46 (s, 9H), 0.97
(d, J = 6.8 Hz, 3H), 0.84 (d, J = 6.8 Hz, 3H); 19F NMR (235.4 MHz,
10t: Rf = 0.35 (hexane:diisopropyl ether 9:1); ½a D20
ꢃ
¼ þ33ꢄ
(c = 0.20, CHCl3); 1H NMR (400 MHz, CDCl3):
d = 4.69 (dd,
J = 12.8, 3.4 Hz, 1H), 4.38 (dd, J = 12.8, 9.9 Hz, 1H), 3.93 (m, 1H),
3.06 (dd, J = 7.7, 4.6 Hz, 1H), 1.83 (m, 1H), 1.46 (s, 9H), 0.86 (d,
J = 6.8 Hz, 3H), 0.80 (d, J = 6.8 Hz, 3H); 19F NMR (235.4 MHz,
CDCl3):
d
= ꢀ81.2 (s, 3F), ꢀ117.1 (dd, J = 276.4, 5.1 Hz, 1F),
ꢀ127.9 (dd, J = 276.4, 19.5 Hz, 1F); 13C NMR (100.6 MHz, CDCl3):
d
= 171.53, 122.81 (qt, J = 283.96, 34.81 Hz), 111.47 (tq,
CDCl3):
d
= ꢀ51.4 (dd, J = 167.1 both Hz, 1F), ꢀ55.1 (dd, J = 167.1,
256.48, 34.8 Hz), 79.55, 71.55, 64.49, 55.39 (t, J = 22.2 Hz),
29.50, 25.27, 16.56, 14.21; ESI (m/z) 364.3 [M++H, (100)], 386.2
[M++Na, (10)].
11.0 Hz, 1H); ESI (m/z) 376.3 [M++H, (23)], 397.0 [M++Na, (100)],
413.2 [M++K, (28)].
9u: Rf = 0.35 (hexane:diisopropyl ether 9:1); ½a D20
ꢃ
¼ ꢀ12:8ꢄ
10y: Rf = 0.33 (hexane:diisopropyl ether 9:1); ½a D20
ꢃ
¼ þ10:0ꢄ
(c = 0.25, CHCl3); 1H NMR (400 MHz, CDCl3):
d
= 4.74 (dd, J = 14.0,
(c = 0.3, CHCl3); 1H NMR (400 MHz, CDCl3):
d = 4.60 (dd, J = 13.4,
4.6 Hz, 1H), 4.66 (dd, J = 14.0, 6.6 Hz, 1H), 4.09 (m, 1H), 3.39 (m,
1H), 1.98 (m, 1H), 1.45 (s, 9H), 1.27 (d, J = 7.1 Hz, 3H); 19F NMR
3.7 Hz, 1H), 4.41 (dd, J = 13.4, 9.9 Hz, 1H), 4.02 (m, 1H), 3.06 (dd,
J = 9.9, 4.6 Hz, 1H), 2.00 (m, 1H), 1.61 (br s, 1H), 1.47 (s, 9H), 0.97 (d,
J = 7.1 Hz, 3H), 0.87 (d, J = 7.1 Hz, 3H); 19F NMR (235.4 MHz,
(235.4 MHz, CDCl3):
d
= ꢀ81.7 (s, 3F), ꢀ117.9 (dd, J = 274.7,
5.5 Hz, 1F), ꢀ128.1 (dd, J = 274.7, 19.4 Hz, 1F); 13C NMR
CDCl3):
d
= ꢀ82.6 (s, 3F), ꢀ120.2 (dd, J = 276.6, 9.5 Hz, 1F), ꢀ124.2
(100.6 MHz, CDCl3):
d
= 174.46, 118.73 (qt, J = 35.1, 286.68 Hz),
(dd, J = 276.6, 15.3 Hz, 1F); ESI (m/z) 364.3 [M++H, (100)].
114.39 (tq, J = 35.1, 258.94 Hz), 82.06, 74.15, 57.21, 56.77 (t,
J = 22.2 Hz), 27.83, 19.92; ESI (m/z) 360.3 [M++Na, (100)], 376.3
[M++K, (5)].
9z: ½a 2D3
ꢃ
¼ ꢀ17:2ꢄ (c = 1.2, CHCl3); FT IR (film):
n
max = 3363,
2966, 1732, 1566, 1382 cmꢀ1; 1H NMR (500 MHz, CDCl3):
d
= 7.41–
7.33 (m, 5H), 5.18 (d, J = 12.2 Hz, 1H), 5.15 (d, J = 12.2 Hz, 1H), 4.64
(dd, J = 13.5, 4.3 Hz, 1H), 4.52 (dd, J = 13.5, 7.5 Hz, 1H), 3.91 (m, 1H),
3.32 (d, J = 5.3 Hz, 1H), 2.04 (m, 1H), 1.94 (br s, 1H), 0.97 (d,
J = 6.5 Hz, 3H), 0.87 (d, J = 6.5 Hz, 3H); 19F NMR (470.6 MHz,
10u: Rf = 0.33 (hexane:diisopropyl ether 9:1); ½a D20
ꢃ
¼ þ24:0ꢄ
(c = 0.63, CHCl3); 1H NMR (400 MHz, CDCl3):
d = 4.65 (dd, J = 13.7,
7.4 Hz, 1H), 4.43 (dd, J = 13.7, 9.1 Hz, 1H), 4.18 (m, 1H), 3.39 (m,
1H), 1.64 (br s, 1H), 1.46 (s, 9H), 1.23 (d, J = 6.8 Hz, 3H); 19F NMR
CDCl3):
d
= ꢀ75.8 (d, J = 7.7 Hz); 13C NMR (125.7 MHz, CDCl3):
(235.4 MHz, CDCl3):
d
= ꢀ82.54 (s, 3F), ꢀ121.5 (dd, J = 277.6,
d = 174.1, 135.4, 128.62, 128.60, 128.5, 124.5 (q, J = 281.7 Hz), 74.3,
11.4 Hz, 1F), ꢀ123.3 (dd, J = 277.5, 12.4 Hz, 1F); ESI (m/z) 360.3
67.1, 66.6, 58.29 (q, J = 29.8 Hz), 31.9, 19.1, 17.3; MS (70 eV): e/z
(%): 349 [M++1] (20), 213 (100), 91 (40).
[M++Na, (100)], 376.3 [M++K, (23)].

774
S. Bigotti et al. / Journal of Fluorine Chemistry 129 (2008) 767–774
10z: ½a 2D3
ꢃ
¼ þ22:9ꢄ (c = 1.0, CHCl3); FT IR (film):
n
max = 3345,
1H), 5.11 (d, J = 12.4 Hz, 1H), 5.00 (d, J = 12.4 Hz, 1H), 4.49 (br s,
1H), 3.63 (dt, J = 13.9, 4.4 Hz, 1H), 3.31 (m, 1H), 3.13 (dd, J = 6,
13.7 Hz, 1H), 3.19 (dd, J = 13.7, 5.9 Hz, 1H), 3.00 (br m, 2H), 2.93
(dd, J = 13.7, 6 Hz, 1H), 2.93 (dd, J = 13.7, 7 Hz, 1H), 1.58 (br s, 1H),
2967, 2919, 1733, 1567, 1382 cmꢀ1 1H NMR (500 MHz, CDCl3):
;
d
= 7.41–7.31 (m, 5H), 5.15 (s, 2H), 4.59 (dd, J = 12.9, 3.6 Hz, 1H),
4.40 (dd, J = 12.9, 10.1 Hz, 1H), 3.94 (m, 1H), 3.20 (d, J = 4.6 Hz, 1H),
2.20 (br s, 1H), 1.90 (m, 1H), 0.86 (d, J = 6.5 Hz, 3H), 0.80 (d,
1.41 (s, 9H); 19F NMR (470.6 MHz, CDCl3):
d
= ꢀ82.0 (s, 1F), ꢀ143.7
J = 6.5 Hz, 3H); 19F NMR (470.6 MHz, CDCl3):
d
= ꢀ74.8 (d,
(dd, J = 277.7, 12.9 Hz, 1F), ꢀ121.9 (dd, J = 277.7, 9.7 Hz, 1F); 13C
J = 7.6 Hz); 13C NMR (62.9 MHz, CDCl3):
d
= 173.5, 135.4, 128.6,
NMR (100.6 MHz, CDCl3): d = 174.99, 171.81, 156.12, 137.66,
124.7 (q, J = 285.5 Hz), 74.7, 67.1, 66.3, 59.4 (q, J = 29.5 Hz), 32.7,
19.0, 17.2; MS (70 eV): e/z (%): 349 [M++1] (20), 213 (100), 91 (40).
137.10, 136.84, 129.71, 128.89, 128.47, 128.38, 127.37, 127.24,
119.47 (qt, J = 286.53, 35.6 Hz), 114.94 (tq, J = 257.7, 36.4 Hz),
67.38, 61.74, 57.92 (t, J = 22.4 Hz), 57.26, 56.66, 40.99, 40.18, 39.14,
38.46, 28.19; ESI (m/z) 664.1 [M++H, (32)], 686.1 [M++Na, (100)],
702.1 [M++K, (5)].
11h: Rf = 0.30 (hexane:AcOEt 8:2):
CHCl3); 1H NMR (400 MHz, CDCl3):
½
a 2D0
ꢃ
¼ þ16:5ꢄ (c = 2.1,
d
= 7.35–7.15 (m, 5H), 5.51
(td, J = 56.1, 4.8 Hz, 1H), 5.22 (s br, 1H), 4.45 (s br, 1H), 3.43 (m, 1H),
3.27 (dt, J = 13.8, 3.9 Hz, 1H), 3.18 (dd, J = 13.8, 6.1 Hz, 1H), 3.00 (m,
1H), 2.65 (m, 1H), 1.96 (m, 1H), 1.61 (s br, 1H), 1.47 (s, 9H), 1.37 (s,
9H), 0.96 (d, 3H), 0.84 (d, 3H); 19F NMR (235.4 MHz, CDCl3):
Acknowledgements
d
= ꢀ53.3 (d, J = 163.4 Hz, 1F), ꢀ53.8 (d, J = 163.4 Hz, 1H); 13C NMR
We thank MIUR (PRIN 2004 project ‘‘Polipeptidi Bioattivi e
Nanostrutturati’’), Politecnico di Milano, and C.N.R. for economic
support. We thank Dr. M. Molteni for preliminary experiments.
(100.6 MHz, CDCl3):
d = 175.78, 172.47, 137.42, 129.77, 128.84,
127.10, 117.35 (t, J = 241.14 Hz), 82.21, 80.27, 66.39, 59.24 (t,
J = 21.19 Hz), 39.24, 38.81, 31.94, 30.04, 28.63, 19.77, 17.83; 19F
NMR (235.4 MHz, CDCl3):
d
= ꢀ125.08 (ddd, J = 8.8, 56.1, 285.0 Hz,
1F), ꢀ126.46 (ddd, J = 11.4, 56.1, 285.0 Hz, 1F); ESI (m/z) 515.0 1
[M++H, (100)], 537.1 [M++Na, (41)].
References
11j: Rf = 0.34 (hexane:AcOEtr 7:3):
CHCl3); 1H NMR (400 MHz, CDCl3):
½
a 2D0
ꢃ
¼ þ6:5ꢄ (c = 2.5,
[1] (a) G.L. Olson, D.R. Bolin, M.P. Bonner, M. Bo¨s, C.M. Cook, D.C. Fry, B.J. Graves, M.
Hatada, D.E. Hill, M. Kahn, V.S. Madison, V.K. Rusiecki, R. Sarabu, J. Sepinwall, G.P.
Vincent, M.E. Voss, J. Med. Chem. 36 (1993) 3039–3049;
(b) J. Gante, Angew. Chem. Int. Ed. Engl. 33 (1994) 1699–1720;
(c) D. Leung, G. Abbenante, D.P. Fairlie, J. Med. Chem. 43 (2000) 305–341.
[2] J.-L. Fauche`re, C. Thurieau, Adv. Drug Res. 23 (1992) 127–159.
[3] A.F. Spatola, in: B. Weinstein (Ed.), Chemistry and Biochemistry of Amino Acids,
Peptides and Proteins, vol. 7, Marcel Dekker, New York, 1983, pp. 267–357.
[4] (a) J.S. Morley, T.D. Hennessey, J.W. Payne, Biochem. Soc. Trans. 11 (1983) 798–
800;
d
= 7.3–7.15 (m, 5H), 6.87 (s,
1H), 5.22 (s br, 1H), 4.43 (s br, 1H), 3.71 (s, 3H), 3.33 (d, J = 5.1 Hz,
1H), 3.27 (m, 1H), 3.15 (s br, 1H), 3.03 (s br, 1H), 2.58 (m, 1H), 1.68
(m, 1H), 1.57 (t, J = 19.3 Hz, 3H), 1.36 (s, 9H), 1.13 (m, 1H), 0.90 (d,
J = 7.1 Hz, 3H), 0.86 (t, J = 7.4 Hz, 2H); 19F NMR (235.4 MHz, CDCl3):
d
= ꢀ94.78 (dd, J = 248.7, 9.1 Hz, 1F), ꢀ97.99 (ddd, J = 248.7, 18.3,
7.6 Hz, 1F); 13C NMR (100.6 MHz, CDCl3):
d
= 177.30, 172.54,
137.53, 129.62, 128.78, 127.03, 125.42 (t, J = 241.59 Hz), 65.86,
65.50, 61.69, 56.30, 52.20, 39.74, 39.72, 39.68, 30.03, 28.61, 25.24,
19.49 (t, J = 25.4 Hz), 16.38, 11.83; ESI (m/z) 500.2 [M++H, (100)],
[M++Na, (11)].
(b) A.B. Smith III, R. Hirschmann, A. Pasternak, M.C. Guzman, A. Yokoyama, P.A.
Sprengeler, P.L. Darke, E.A. Emini, W.A. Schleif, J. Am. Chem. Soc. 117 (1995)
11113–11123.
[5] For a review on the trifluoroethylamine unit, see: M. Sani, A. Volonterio, M. Zanda,
ChemMedChem, 2 (2007) 1693–1700.
11p: Rf = 0.35 (hexane:AcOEt 8:2); ½a D20
ꢃ
¼ þ9ꢄ (c = 1.1, CHCl3);
´
[6] A. Volonterio, S. Bellosta, F. Bravin, M.C. Bellucci, L. Bruche, G. Colombo, L.
Malpezzi, S. Mazzini, S.V. Meille, M. Meli, C. Ramirez de Arellano, M. Zanda,
Chem. Eur. J. 9 (2003) 4510–4522, and references cited therein.
1H NMR (400 MHz, CDCl3):
d = 7.4–7.1 (m, 10H), 5.52 (br s, 1H),
5.11 (d, J = 12.3 Hz, 1H), 5.00 (d, J = 12.3 Hz, 1H), 4.56 (br s, 1H),
3.49 (dt, J = 13.6, 4.3 Hz, 1H), 3.39 (m, 1H), 3.25 (d, J = 3.7 Hz, 1H),
3.19 (dd, J = 13.7, 5.9 Hz, 1H), 3.06 (br m, 1H), 2.94 (br m, 1H), 2.03
(m, 1H), 1.55 (br s, 1H), 1.46 (s, 9H), 0.99 (d, J = 6.8 Hz, 3H), 0.83 (d,
[7] M. Molteni, A. Volonterio, M. Zanda, Org. Lett. 5 (2003) 3887–3890.
[8] (a) W.C. Black, C.I. Bayly, D.E. Davies, S. Desmarais, J.-P. Falgueyret, S. Le´ger, C.S. Li,
´
F. Masse, D.J. McKay, J.T. Palmer, M.D. Percival, J. Robichaud, N. Tsou, R. Zamboni,
Bioorg. Med. Chem. Lett. 15 (2005) 4741–4744;
(b) C.S. Li, D. Deschenes, S. Desmarais, J.-P. Falgueyret, J.Y. Gauthier, D.B. Kimmel,
S. Le´ger, F. Masse´, M.E. McGrath, D.J. McKay, M.D. Percival, D. Riendeau, S.B. Rodan,
M. The´rien, V.-L. Truong, G. Wesolowski, R. Zamboni, W.C. Black, Bioorg. Med.
Chem. Lett. 16 (2006) 1985–1989;
J = 6.8, 3H); 19F NMR (470.6 MHz, CDCl3):
d
= ꢀ60.2 (dd, J = 177.3,
6.0 Hz, 1F), ꢀ60.8 (dd, J = 177.3, 8.6 Hz, 1F); 13C NMR (100.6 MHz,
CDCl3):
d = 175.86, 172.01, 137.08, 136.76, 130.90 (t, J = 296.7 Hz),
(c) W.C. Black, M.D. Percival, ChemBioChem 7 (2006) 1525–1535.
[9] For a preliminary report of this work see: S. Bigotti, A. Volonterio, M. Zanda,
Synlett, (2008) 958–962.
[10] For the electronegativities see: F.A. Carey, R.J. Sundberg, Advanced Organic
Chemistry, 3rd ed., Plenum Press, New York, 1990;
129.75, 129.59, 129.19, 128.84 (d, J = 4.2 Hz), 128.45 (d, J = 8.5 Hz),
127.22, 82.63, 67.27, 66.45, 64.11 (t, J = 24.5 Hz), 56.66, 40.10,
40.06, 31.86, 28.48, 19.83, 17.59; ESI (m/z) 582.3 [M++H, (15)],
604.3 [M++Na, (100)], 620.2 [M++K, (23)].
For the Bondi volume values see: R.E. Banks, J.C. Talow, B.E. Smart, Organofluorine
Chemistry: Principles and Commercial Applications, Plenum Press, New York,
1994.
11r: Rf = 0.34 (hexane:AcOEt 8:2): ½a D20
ꢃ
¼ ꢀ3:4ꢄ (c = 1.7, CHCl3);
1H NMR (400 MHz, CDCl3):
d = 7.35–7.1 (m, 5H), 4.72 (dd, J = 12.7,
[11] For a recent analysis of this issue see: K. Mu¨ ller, C. Faeh, F. Diederich, Science, 317
(2007) 1881–1886.
[12] Nitro-alkene 2 was prepared starting from a commercially available aqueous
solution of fluoral hydrate, whereas nitro-alkenes 3–7 were synthetized from
fluoro-acetaldehyde hemiacetals prepared by reduction of the corresponding
esters:
3.3 Hz, 1H), 6.97 (s, 1H), 5.17 (s br, 1H), 4.43 (s br, 1H), 3.73 (s, 3H),
3.51 (dt, J = 13.8, 3.9 Hz, 1H), 3.37 (s br, 1H), 3.15 (s br, 1H), 3.02 (s br,
1H), 2.77 (s br, 1H), 1.74 (m, 2H), 1.36 (s, 9H), 1.15 (m, 2H), 0.95 (d,
J = 6.7 Hz, 3H), 0.88 (t, J = 7.7 Hz, 3H); 19F NMR (235.4 MHz, CDCl3):
= ꢀ53.3 (d, J = 163.4 Hz, 1F), ꢀ53.8 (d, J = 163.4 Hz, 1H); 13C NMR
M. Molteni, R. Consonni, T. Giovenzana, L. Malpezzi, M. Zanda, J. Fluorine Chem.
127 (2006) 901–908.
d
(100.6 MHz, CDCl3):
d = 176.77, 172.53, 137.49, 129.81, 129.69,
[13] CCDC 687809.
[14] For example, the 19F NMR signals of the fluorinated group of the major diaster-
oisomers 9 were always observed at higher fields than those of the minor
diastereoisomer 10 (see Experimental Section).
127.07, 126.18, 123.09 (t, 311.1 Hz), 65.61 (t, J = 25.4 Hz), 56.3,
52.36, 40.61, 39.37, 38.81, 30.04, 28.62, 25.17, 16.42, 11.91, 11.81;
ESI (m/z) 564.0 [M++H, (42)], 586.0 [M++Na, (100)].
[15] For a recent mechanistic investigation on a related Michael reaction involving
fluorinated acrylamide acceptors: S. Fustero, G. Chiva, J. Piera, A. Volonterio, M.
Zanda, J. Gonzalez, A.M. Ramallal, Chem. Eur. J. 13 (2007) 8530–8542.
11w: Rf = 0.35 (hexane:AcOEt 85:15); ½a D20
ꢃ
¼ þ12:3ꢄ (c = 3.3,
CHCl3); 1H NMR (400 MHz, CDCl3):
d = 7.4–7.1 (m, 15H), 5.43 (br s,