The influence of fluoroalkyl-group electronegativity on stereocontrol in the synthesis of ψ[CH(RF)NH]Gly peptides

Article abstract of DOI:10.1055/s-2008-1072653

New peptidomimetics featuring CH(R_F)NH units, having different degree of fluorination, as peptide-bond surrogates have been synthesized. The key step in the synthesis consists of a stereo-selective aza-Michael addition of chiral α-amino acid es

Full text of DOI:10.1055/s-2008-1072653

958
LETTER
The Influence of Fluoroalkyl-Group Electronegativity on Stereocontrol in the
Synthesis of Y[CH(RF)NH]Gly Peptides
Stereocontrol
e
S
ynth
r
esis of
Y
e
[CH(R )N
H
F n]Gly Peptid
a
es Bigotti,a Alessandro Volonterio,*a Matteo Zanda*b
a
Dipartimento di Chimica, Materiali ed Ingegneria Chimica ‘G. Natta’ del Politecnico di Milano, via Mancinelli 7, 20131 Milano, Italy
E-mail: alessandro.volonterio@polimi.it
b
C.N.R-Istituto di Chimica del Riconoscimento Molecolare, Sezione ‘A. Quilico’, via Mancinelli 7, 20131 Milano, Italy
Fax +39(02)23993080; E-mail: matteo.zanda@polimi.it
Received 19 January 2008
R2
CF3
O
R3
R2
O
R3
Abstract: New peptidomimetics featuring CH(RF)NH units, hav-
ing different degree of fluorination, as peptide-bond surrogates have
been synthesized. The key step in the synthesis consists of a stereo-
selective aza-Michael addition of chiral a-amino acid esters to b-
fluoroalkyl-a-nitroethenes. The diastereoselection of the process
was influenced by the electronegativity, rather than by the steric
bulk, of the fluorinated residue RF in b-position of the nitroalkene
acceptors. Replacement of a single F atom of RF by a hydrogen or
methyl group brings about a dramatic drop of stereocontrol, where-
as Br, Cl, and CF3, albeit bulkier than F, provide poorer results in
terms of stereocontrol.
H
N
*
*
N
N
N
H
N
H
H
H
R1
O
O
R1
O
O
parent peptide
PMR-Ψ[NHCH(CF3)]-peptide A
R2
RF
R3
R2
CF3 R3
H
H
N
N
*
*
N
N
N
H
N
H
H
H
R1
O
O
R1
O
O
Ψ[CH(CF3)NH]-peptide B
Ψ[CH(RF)NH]-peptide 1
Key words: peptidomimetics, fluorine, electronegativity, peptide
bond surrogate, fluoroalkyl
Figure 1 Structure of Y[CH(RF)NH] peptides
both in low polarity organic-solvent solutions and in solid
state. Recently, this conceptually new peptide bond surro-
gate has found the first validations in drug discovery.8
Replacement of a scissile peptide bond by a surrogate
function represents a viable and popular approach in the
rational design of peptidomimetics1 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 influ-
ences the conformational preference of contiguous resi-
dues; 4) modifying the electronic properties, the peptide-
bond surrogate affects significantly the transport proper-
ties of the parent peptides.4
To investigate further the biomedicinal properties, as well
as the effect and the capacity of the fluorinated residue to
induce and stabilize secondary structures in peptide mim-
ics, we undertook a research program aimed at the synthe-
sis of Y[CH(RF)NH]Gly peptides 1 (R = H) having
different degrees of fluorination, namely RF = CF2H,
CF2CH3, CF2Cl, CF2Br, and C2F5. Moreover, following
the same synthetic strategy used for the synthesis of
Y[CH(CF3)NH]Gly peptides B (RF = CF3) from the ni-
troalkene 2 (Table 2),7 we decided to investigate the role
of the different fluorinated residues RF on the diastereose-
lectivity of the key aza-Michael addition of a-amino acid
esters 8 to b-fluoroalkyl-a-nitroethenes 3–7 (see Table 2).
Clearly, the differences among the various RF groups do
not arise only from the different steric bulk (quantified
here by means of the Bondi volumes) and shape of the RF
groups, but also from their electronegativities (Table 1).9
More specifically, if one considers RF = CF2X, then the
difference between the six RF groups studied herein de-
pends on the X substituent. Thus, in terms of electronega-
tivity, the CF3 group (X = F) is the most electronegative
RF group, followed by the C2F5 (X = CF3), which in turn
is more electronegative than the CF2Cl (X = Cl) and
CF2Br (X = Br). The CF2CH3 (X = CH3) and CF2H
(X = H) occupy the last positions of the list. Sterically, the
C2F5 group is the bulkiest, followed by the CF2Br, which
in turn is only slightly bulkier than CF2CH3 and CF2Cl,
but remarkably bulkier than the CF3 (X = F) and CF2H, re-
spectively. One should also note that the CF3 is rotation-
ally symmetrical around the axis of its C–C bond, in
Recently, we proposed the trifluoroethylamino unit5 as a
peptide bond replacement, and we described its incorpo-
ration into partially modified retro (PMR)-peptides A6
and into native peptide chains B7 (Figure 1).
We also suggested that this unit might be seen as a hybrid
between a peptide-bond mimic and a proteolytic transi-
tion-state analogue, as it combines some of the properties
of a peptidyl CONH group [very low NH basicity, a
CH(CF3)NHCH backbone angle close to 120°, a C–CF3
bond substantially isopolar with the C=O] with properties
of the tetrahedral intermediate involved in the protease-
mediated hydrolysis reaction of a peptide bond (high elec-
tron density on the CF3 group, tetrahedral backbone car-
bon). Moreover, the presence of the bulky CF3 group is
probably the driving force for the high stability of turnlike
conformation of appropriately configured retropeptides A
SYNLETT 2008, No. 7, pp 0958–0962
x
x.
x
x.
2
0
0
8
Advanced online publication: 28.03.2008
DOI: 10.1055/s-2008-1072653; Art ID: D02808ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Stereocontrol in the Synthesis of Y[CH(RF)NH]Gly Peptides
959
Under these conditions the diastereoselection of the pro-
cess depends only on the nature of the R amino acidic side
chain of 8, and the fluorinated residue RF on the nitro-
ethene acceptors 2–7. The results of the additions of 8a–d
to the trifluoro derivative 2 (RF = CF3) have been previ-
ously published,7 and are summarized for the sake of com-
parison in entries 1–4 (Table 2).
Table 1 Empirical Electronegativities and Bondi Volumes for X
Substituents (RF = CF2X)
X Substituent
Electronegativity
Bondi volume (cm3 mol–1)
H
2.28
2.30
3.95
3.03
2.80
3.35
3.3
13.7
5.8
CH3
F
When RF = CF2H (nitroethene 3, entries 5–8, Table 2),
which is both the less electronegative and the least bulky
RF group among those examined herein, a dramatic drop
of diastereoselectivity was 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) resulted in only
slighly more diastereoselectivity than those obtained with
Cl
12.0
15.1
21.3
Br
CF3
analogy with the CH3 group, whereas the C2F5, CF2Cl, 3 (RF = CF2H), and still much less diastereoselective than
CF2Br, and CF2CH3 groups do not feature such rotational those with 2 (RF = CF3). Generally higher diastereoselec-
symmetry. In terms of ‘effective bulk’ the isotropic CF3 is tivities were observed with 5 (RF = CF2Cl, entries 13–16,
expected to occupy an even smaller volume than the Table 2) as the Michael acceptor, but still slightly worse
anisotropic C2F5, CF2Cl, and CF2Br.10 Thus, if steric bulk as compared with those achieved with 2 (RF = CF3). The
would be the dominating factor in the stereoselectivity of results obtained with the nitroalkene 6 (RF = CF2Br, en-
the aza-Michael reaction, one would expect a much higher tries 17–20, Table 2), were in all cases comparable with
diastereocontrol when RF is a C2F5 or CF2Br, rather than those of the nitroalkene 5 (RF = CF2Cl). To our surprise,
CF3.
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), resulted 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, re-
spectively).
b-Fluoroalkyl-a-nitroethenes 2–7, having CF3, CF2H,
CF2CH3, CF2Cl, CF2Br, and CF2CF3 as RF groups at the b-
position, respectively, were prepared in multigram
amounts by reacting the corresponding aldehyde hydrates
or hemiacetals with nitromethane and a catalytic amount
of Na2CO3 affording b-nitro alcohol intermediates that
were dehydrated by refluxing in the presence of P2O5 All these experimental results suggest that the diastereo-
(Scheme 1).11
selectivity of the aza-Michael reaction is much more in-
fluenced by the electronegativity of the b-fluoroalkyl
substituents RF, rather than by their steric bulk. In fact, the
dramatic drop of diastereocontrol observed with the ni-
troalkene 3 (RF = CF2H) and 4 (RF = CF2CH3) as com-
pared 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
18.8 vs. 21.3 cm3 mol–1, respectively) while the CF2CH3
group is much bigger (Bondi volume = 29.2 cm3 mol–1).
Thus, the striking effect on the stereocontrol 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 consid-
erably 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 com-
pared 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 stere-
oselectivity 2 > 7 ª 5 ª 6 > 4 > 3 in the aza-Michael reac-
tion matches quite well the trend of electronegativity of
the X group in RF (RF = CF2-X) namely F > CF3 > Cl > Br
> CH3 ª H.
The aza-Michael reactions between nitroalkene acceptors
3–7 and a-amino acid ester hydrochlorides 8a–d were
performed using the protocol previously optimized to
achieve the best diastereoselectivity with 2,7 namely using
1.1 equivalents of DIPEA (the first equivalent is needed to
quench the hydrochloric acid of 8) in toluene at room tem-
perature, producing a mixture of syn-9 (major diastereo-
isomer) and anti-10 (minor diastereoisomer),12 which
resulted to be easily separable by simple flash chromatog-
raphy, in excellent overall yields (Table 2).
Na2CO3
60 °C to r.t.
OH
OR
MeNO2
OH
+
RF
16–18 h
R = H, Et
P2O5
NO2
NO2
RF
∆
RF
2: RF = CF3, 70%; 3: RF = CF2H, 40%;
4: RF = CF2Me, 44%; 5: RF = CF2Cl, 39%;
6: RF = CF2Br, 48%; 7: RF = CF2CF2, 37%
Scheme 1 Synthesis of nitroalkenes 2–7
Synlett 2008, No. 7, 958–962 © Thieme Stuttgart · New York

960
S. Bigotti et al.
LETTER
Table 2 The Aza-Michael Reaction
R
RF
R
RF
R
DIPEA, toluene
r.t.
NO2
O2N
O2N
+
+
–Cl+H3N
CO2X
RF
N
CO2X
N
CO2X
H
H
2–7
8
major 9
minor 10
Entry
1a
Nitroethene RF
CF3
CF3
a-Amino ester Major product
R
X
Ratio 9/10b
5.8:1.0
7.5:1.0
8.5:1.0
11.7:1.0
1.1:1.0
1.4:1.0
1.7:1.0
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
Yield (%)c
2
2
2
2
3
3
3
3
4
4
4
4
5
5
5
5
6
6
6
6
7
7
7
7
L-8a
L-8b
L-8c
L-8d
L-8a
L-8b
L-8c
L-8d
L-8a
L-8b
L-8c
L-8d
L-8a
L-8b
L-8c
L-8d
L-8a
L-8b
L-8c
L-8d
L-8a
L-8b
L-8c
L-8d
9a
9b
9c
9d
9e
9f
Me (Ala)
s-Bu (Ile)
Bn (Phe)
i-Pr (Val)
Me (Ala)
s-Bu (Ile)
Bn (Phe)
i-Pr (Val)
Me (Ala)
s-Bu (Ile)
Bn (Phe)
i-Pr (Val)
Me (Ala)
s-Bu (Ile)
Bn (Phe)
i-Pr (Val)
Me (Ala)
s-Bu (Ile)
Bn (Phe)
i-Pr (Val)
Me (Ala)
s-Bu (Ile)
Bn (Phe)
i-Pr (Val)
t-Bu
Me
60
75
60
65
77
96
68
85
80
82
63
74
74
69
75
76
77
65
70
93
70
66
74
90
2a
3a
CF3
t-Bu
t-Bu
t-Bu
Me
4a
CF3
5
CF2H
6
CF2H
7
CF2H
9g
9h
9i
t-Bu
t-Bu
t-Bu
Me
8
CF2H
9
CF2CH3
CF2CH3
CF2CH3
CF2CH3
CF2Cl
CF2Cl
CF2Cl
CF2Cl
CF2Br
CF2Br
CF2Br
CF2Br
CF2CF3
CF2CF3
CF2CF3
CF2CF3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
9j
9k
9l
t-Bu
t-Bu
t-Bu
Me
9m
9n
9o
9p
9q
9r
9s
t-Bu
t-Bu
t-Bu
Me
t-Bu
t-Bu
t-Bu
Me
9t
9u
9v
9w
9y
t-Bu
t-Bu
a See ref. 7.
b Determined by 1H NMR and 19F NMR.
c Overall isolated yields.
It is, in our opinion, quite remarkable that very subtle dif- making these Michael acceptors more electrophilic than
ferences such as the presence of F instead of H, Cl, or Br the parent unfluorinated compounds, 4) the reaction in-
in the RF group of the nitroalkene acceptor bring about a volves a tight, polar transition state, which is destabilized
striking effect in terms of stereocontrol of the process. In- and disrupted in polar solvents, decreasing the stereocon-
sufficient data exist at present to allow a detailed mecha- trol, and 5) the base DIPEA appears to play a fundamental
nistic discussion. However, based on the current catalytic role, presumably by promoting the formation of
experimental data, we can reliably assume that 1) the re- a ternary transition-state-involving nucleophile, Michael
action is under kinetic control, 2) the amino ester nucleo- acceptor and amine base, in analogy with related process-
phile reacts with a rigid conformation due to the presence es we have studied in the recent past.13 Clearly, these re-
of an intramolecular hydrogen bond, 3) the fluorinated sults demonstrate that electronic factors can overcome
residue greatly stabilizes the LUMO of the nitroalkenes,
Synlett 2008, No. 7, 958–962 © Thieme Stuttgart · New York

LETTER
Stereocontrol in the Synthesis of Y[CH(RF)NH]Gly Peptides
961
Pr2O, 7:3) and 10b (Rf = 0.41, n-hexane–i-Pr2O, 7:3), in a ratio of
7.5:1.0.
Ph
O
RF
RF
i
H
O2N
N
N
COOt-Bu ii
PG
N
N
COOt-Bu
H
H
H
Typical Procedure for the Synthesis of the Fluorinated Tripep-
tide Mimics 11
9h,p
11h: RF = CF2H, PG = Boc, 86%
11p: RF = CF2Cl, PG = Cbz, 79%
A solution of 9p (0.11 mmol, 33 mg) and 1 N HCl (0.11 mmol, 110
mL), in MeOH (2 mL) and in the presence of a catalytic amount of
Pd(OH)2/C, was stirred at r.t. for 5 h under hydrogen atmosphere.
Then, the mixture was filtered on a Celite pad, the solvent removed
in vacuo. The crude was dissolved in 1 mL of dry DMF and Cbz-L-
Phe-OH, (0.11 mmol, 32.9 mg) followed by sym-collidine (0.22
mmol, 30 mL), HOAt (0.11 mmol, 14.9 mg), HATU (0.11 mmol,
41.8 mg) were added at r.t. The mixture was stirred overnight,
quenched with 1 N HCl, and extracted with Et2O. The organic layer
was washed once with H2O and then dried on Na2SO4. The solvent
was removed in vacuo, and the crude purified by flash chromatog-
raphy (hexane–EtOAc, 70:30) affording 50.6 mg of 11p (79%).
Ph
RF
H
RF
i
O2N
N
ii
N
H
COOMe
PG
N
N
COOMe
H
H
O
9j,r
11j: RF = CF2Me, PG = Boc, 88%
11r: RF = CF2Br, PG = Boc, 93%
Ph
Ph
Ph
i
RF
RF
H
O2N
N
ii
N
H
COOt-Bu
PG
N
N
COOt-Bu
Compound 11p
H
H
Rf = 0.35 (hexane–EtOAc, 8:2); [a]D20 +9 (c 1.1, CHCl3). 1H NMR
(400 MHz, CDCl3): d = 7.40–7.10 (m, 10 H), 5.52 (br s, 1 H), 5.11
(d, J = 12.3 Hz, 1 H), 5.00 (d, J = 12.3 Hz, 1 H), 4.56 (br s, 1 H),
3.49 (dt, J = 13.6, 4.3 Hz, 1 H), 3.39 (m, 1 H), 3.25 (d, J = 3.7 Hz,
1 H), 3.19 (dd, J = 13.7, 5.9 Hz, 1 H), 3.06 (br m, 1 H), 2.94 (br m,
1 H), 2.03 (m, 1 H), 1.55 (br s, 1 H), 1.46 (s, 9 H), 0.99 (d, J = 6.8
Hz, 3 H), 0.83 (d, J = 6.8 Hz, 3 H). 19F NMR (470.6 MHz, CDCl3):
d = –60.2 (dd, J = 177.3, 6.0 Hz, 1 F), –60.8 (dd, J = 177.3, 8.6 Hz,
1 F). 13C NMR (100.6 MHz, CDCl3): d = 175.86, 172.01, 137.08,
136.76, 130.90 (t, J = 296.7 Hz), 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-MS: m/z (%) = 582.3 (15) [M+ + H], 604.3 (100) [M+ +
Na], 620.2 (23) [M+ + K].
O
9w
11w: RF = CF2CF3, PG = Cbz, 94%
Scheme 2 Elaboration of the aza-Michael adducts 9 into the targets
peptidomimetics 11. Reagents and conditions: i) H2, Pd(OH)2/C, aq
HCl–MeOH; ii) PG-LPhe-OH, HATU and HOAt, TMP, DMF.
steric factors in the control of the diastereoselectivity of
aza-Michael reactions.
Elaboration of the major adducts 9 into the target
Y[CH(RF)NH]Gly peptides 11 (Scheme 2) was addressed
next. Reduction of the nitro group of 9 was accomplished
by using Parlman’s catalyst in the presence of aqueous 1
N HCl to trap the free amino function as hydrochloride
salt. Coupling with Boc(Cbz)-L-Phe-OH using HOBt and
EDC afforded Boc(Cbz)-L-Phe-Y[CH(RF)NH]Gly-L-
Val-Ot-Bu (11), in very good yields.
Acknowledgment
We thank MIUR (PRIN 2004 project ‘Polipeptidi Bioattivi e Nano-
strutturati’), Politecnico di Milano, and C.N.R. for economic sup-
port. We thank Dr. M. Molteni for preliminary experiments.
In summary, a new class of peptidomimetics having di-
verse [CH(RF)NH] functions as surrogates of the scissile
peptide bond, namely Y[CH(RF)NH]Gly peptides are
now available. The aza-Michael addition of a-amino acid
esters 8 to 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, temperature, and R side chain
of 8, resulted to be strongly influenced also by the elec-
tronegativity, rather than the steric bulk, of the fluorinated
RF group in b-position to the nitroethene acceptors. The
synthesis of more complex Y[CH(RF)NH] peptides and
the study of their conformation in solution, as well as cal-
culations and mechanistic studies, are currently being ad-
dressed.
References and Notes
(1) (a) Olson, G. L.; Bolin, D. R.; Bonner, M. P.; Bös, M.; Cook,
C. M.; Fry, D. C.; Graves, B. J.; Hatada, M.; Hill, D. E.;
Kahn, M.; Madison, V. S.; Rusiecki, V. K.; Sarabu, R.;
Sepinwall, J.; Vincent, G. P.; Voss, M. E. J. Med. Chem.
1993, 36, 3039. (b) Gante, J. Angew. Chem., Int. Ed. Engl.
1994, 33, 1699. (c) Leung, D.; Abbenante, G.; Fairlie, D. P.
J. Med. Chem. 2000, 43, 305.
(2) Fauchère, J.-L.; Thurieau, C. Adv. Drug Res. 1992, 23, 127.
(3) Spatola, A. F. In Chemistry and Biochemistry of Amino
Acids, Peptides and Proteins, Vol. 7; Weinstein, B., Ed.;
Marcel Dekker: New York, 1983, 267–357.
(4) (a) Morley, J. S.; Hennessey, T. D.; Payne, J. W. Biochem.
Soc. Trans. 1983, 11, 798. (b) Smith, A. B. III; Hirschmann,
R.; Pasternak, A.; Guzman, M. C.; Yokoyama, A.;
Sprengeler, P. A.; Darke, P. L.; Emini, E. A.; Schleif, W. A.
J. Am. Chem. Soc. 1995, 117, 11113.
Typical Procedure for the Michael Addition
To a stirred solution of 2 (0.76 mmol, 107 mg) and 8b (0.51 mmol,
92 mg) in toluene (7 mL) at r.t., DIPEA was added (0.56 mmol, 73
mL). After 30 min at r.t., the solvent was removed in vacuo, the
crude residue was dissolved in EtOAc, and washed once with 1 N
HCl. The organic layer was dried over anhydrous Na2SO4. The sol-
vent was removed in vacuo, and the crude was purified by flash
chromatography (hexane–diisopropyl ether, 9:1) affording 110 mg
(75%) of the two pure diastereoisomers 9b (Rf = 0.31, n-hexane–i-
(5) For a review on the trifluoethylamine unit, see: Sani, M.;
Volonterio, A.; Zanda, M. ChemMedChem 2007, 2, 1693.
(6) Volonterio, A.; Bellosta, S.; Bravin, F.; Bellucci, M. C.;
Bruché, L.; Colombo, G.; Malpezzi, L.; Mazzini, S.; Meille,
S. V.; Meli, M.; Ramirez de Arellano, C.; Zanda, M. Chem.
Eur. J. 2003, 9, 4510; and references cited therein.
(7) Molteni, M.; Volonterio, A.; Zanda, M. Org. Lett. 2003, 5,
3887.
Synlett 2008, No. 7, 958–962 © Thieme Stuttgart · New York

962
S. Bigotti et al.
LETTER
(8) (a) Black, W. C.; Bayly, C. I.; Davies, D. E.; Desmarais, S.;
Falgueyret, J.-P.; Léger, S.; Li, C. S.; Massé, F.; McKay, D.
J.; Palmer, J. T.; Percival, M. D.; Robichaud, J.; Tsou, N.;
Zamboni, R. Bioorg. Med. Chem. Lett. 2005, 15, 4741.
(b) Li, C. S.; Deschenes, D.; Desmarais, S.; Falgueyret, J.-P.;
Gauthier, J. Y.; Kimmel, D. B.; Léger, S.; Massé, F.;
McGrath, M. E.; McKay, D. J.; Percival, M. D.; Riendeau,
D.; Rodan, S. B.; Thérien, M.; Truong, V.-L.; Wesolowski,
G.; Zamboni, R.; Black, W. C. Bioorg. Med. Chem. Lett.
2006, 16, 1985. (c) Black, W. C.; Percival, M. D.
(10) For a recent analysis of this issue, see: Müller, K.; Faeh, C.;
Diederich, F. Science 2007, 317, 1881.
(11) Nitroalkene 2 was prepared starting from a commercially
available aqueous solution of fluoral hydrate, whereas
nitroalkenes 3–7 were synthetized from fluoroacetaldehyde
hemiacetals prepared by reduction of the corresponding
esters: Molteni, M.; Consonni, R.; Giovenzana, T.;
Malpezzi, L.; Zanda, M. J. Fluorine Chem. 2006, 127, 901.
(12) The stereochemistry of the diastereoisomers was assessed by
X-ray diffraction of a Michael adduct and on the basis of
their spectroscopic and analytical features. Full details will
be given in a full paper.
(13) For a recent mechanistic investigation on a related Michael
reaction involving fluorinated acrylamide acceptors:
Fustero, S.; Chiva, G.; Piera, J.; Volonterio, A.; Zanda, M.;
Gonzalez, J.; Ramallal, A. M. Chem. Eur. J. 2007, 13, 8530.
ChemBioChem 2006, 7, 1525.
(9) (a) For the electronegativities, see: Carey, F. A.; Sundberg,
R. J. Advanced Organic Chemistry, 3th ed.; New York:
Plenum Press, 1990. (b) For the Bondi volume values, see:
Banks, R. E.; Talow, J. C.; Smart, B. E. Organofluorine
Chemistry: Principles and Commercial Applications;
Plenum Press: New York, 1994.
Synlett 2008, No. 7, 958–962 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.