Synthesis of Fluorinated Homo-C-Nucleoside Analogues from New Carbohydrate-Derived Acylsilanes

Article abstract of DOI:10.1055/s-2004-815403

Abstract: The stereocontrolled synthesis of new carbohydrate-derived acylsilanes with the silylcarbonyl moiety linked to the anomeric carbon via a methylene group is described. Reaction of these acylsilanes with perfluoroorganometallic reagents followed by treatment with hydrazines or amidines led to new polyfluorinated homo-C-nucleoside analogues, in a one-pot or two-step transformation, respectively.

Full text of DOI:10.1055/s-2004-815403

512
LETTER
Synthesis of Fluorinated Homo-C-Nucleoside Analogues from New Carbo-
hydrate-Derived Acylsilanes
Synthesis of
F
r
luorinate
é
d
homo-
C
-
d
N
ucleoside
A
é
nalogues ric Chanteau, Richard Plantier-Royon,* Charles Portella*
Laboratoire ‘Réactions Sélectives et Applications’, Associé au CNRS (UMR 6519), Université de Reims, Faculté des Sciences, B.P. 1039,
51687 Reims Cedex 2, France
Fax +33(3)26913166; E-mail: charles.portella@univ-reims.fr
Received 15 September 2003
Synthesis of the Acylsilanes
Abstract: The stereocontrolled synthesis of new carbohydrate-de-
rived acylsilanes with the silylcarbonyl moiety linked to the ano-
We have synthesized two acylsilane representatives of the
meric carbon via a methylene group is described. Reaction of these
D-ribofuranose and D-glucopyranose series. The strategy
acylsilanes with perfluoroorganometallic reagents followed by
was based on 1-C-formylglycosides as key intermediates.
Different routes were reported in the literature towards
these compounds starting from lactones (Scheme 1).9
treatment with hydrazines or amidines led to new polyfluorinated
homo-C-nucleoside analogues, in a one-pot or two-step transforma-
tion, respectively.
Key words: acylsilane, carbohydrate, heterocycles, organofluorine,
C-nucleoside
S
O
N
m (OBn)n
Ref 9a, 9b
The chemistry of C-nucleosides1 has received recently
considerable attention due to the biological activities of
naturally occurring compounds such as showdomycin,
formycin or oxazomycin.2 Homo-C-nucleosides are a
growing class of nucleosides3 which are structurally com-
posed of a sugar portion and an aglycon linked via a me-
thylene bridge between the anomeric carbon atom and a
carbon atom in the aglycon. The incorporation of one or
several fluorine atoms in biologically active molecules
has been shown to be of advantage both for improved ac-
tivity and higher bioavailability.4 Previous papers in this
series have demonstrated the versatility of the reaction of
perfluoro organometallic reagents with acylsilanes, lead-
ing to 1-(trialkylsilyl)perfluoroalkyl carbinols, 1-alkyl-1-
(trialkylsilyloxy)perfluoroalk-1-enes or the correspond-
ing hemifluorinated enones.5 Treatment of these com-
pounds with bis(nucleophiles) gave various nitrogen-
containing heterocycles such as imidazolidines/oxazo-
lidines and diazepines/thiazepines,6 pyrazoles7 and pyri-
midines.8 The synthesis of such heterocycles linked to a
carbohydrate moiety was also exemplified from carbohy-
drate-derived acylsilanes.7,8
Ref 9a, 9b
S
CHO
Ref 9c, 9d
Ref 9c, 9d
S
O
O
O
O
m
m
m
(OBn)n
(OBn)n
(OBn)n
Ph
Ref 9c
Ref 9c
O
m
(OBn)n
Scheme 1
The perbenzylated D-glucono-1,5-lactone 110 was con-
verted into the corresponding 1-C-formyl derivative 2 ac-
cording to a procedure reported by Genet’s group.9c In our
hands, the final aldehyde 2 was obtained as a 1:1 mixture
with its hydrate, and all attempts to improve the purity al-
lowed us to reach a 7:3 ratio in favor of the anhydrous
form as the best result. A similar reaction sequence was
applied to the perbenzylated D-ribonolactone 311 to give
the corresponding 1-C-formyl D-ribofuranoside 4, also
partially hydrated (Scheme 2).
In order to form fluorinated homo-C-nucleoside ana-
logues, we performed the synthesis of new compounds
bearing an acylsilane function linked to the anomeric car-
bon atom via a methylene group. This paper is devoted to
the account of this synthetic work and to the application
of these new carbohydrate derived acylsilanes to the syn-
thesis of fluorinated homo-C-nucleoside analogues.
Two different pathways were explored to convert the al-
dehydes into the targeted acylsilanes. The first one, de-
scribed by Yoshida and co-workers for simple
aldehydes,12 was applied to the D-gluco-derivative 2. Nu-
cleophilic addition of the lithio derivative of bis(trimeth-
ylsilyl)methoxymethane to the aldehyde gave, via a
Peterson reaction, the expected enol ether 5 and unreacted
starting material which were isolated in 49% and 31%
yield respectively. Then, acidic hydrolysis of 5 led to the
acylsilane 6. All attempts to improve the conversion rate
of this reaction were unsuccessful even using an excess
(1.5 equiv) of the nucleophile, due to the partially hydrat-
ed character of the intermediate aldehyde 2 (Scheme 3).
SYNLETT 2004, No. 3, pp 0512–0516
1
8.
0
2.
2
0
0
4
Advanced online publication: 12.01.2004
DOI: 10.1055/s-2004-815403; Art ID: D23103ST.pdf
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Fluorinated Homo-C-Nucleoside Analogues
513
BnO
BnO
were displaced by the silylcarbonyl equivalent. De-
thioketalization was efficiently performed with iodine/
CaCO3 in aqueous THF to give the acylsilanes 6 and 7 in
good yields (Scheme 4).14
Ref 9c
X
O
O
3 steps
H
O
OBn
OBn
42 %
BnO
BnO
OBn
O
OBn
X = O or
X = OH, OH
2
1
Synthesis of Polyfluorinated Homo-C-Nucleoside
Analogues
X
Ref 9c
H
BnO
BnO
3 steps
O
O
46 %
The multistep process to convert acylsilanes into fluori-
nated heterocycles may be performed sequentially by
treating the isolated hemifluorinated enone intermediates
with a bis (nucleophile) or in a one-pot operation from the
acylsilanes.6–8 The enone itself is the result of a multistep
sequence starting by the reaction of the acylsilane with an
in situ generated perfluoroorganolithium reagent, and in-
volving a Brook rearrangement.5 The direct precursor of
the enone is a silylenolether, the conversion of which is
generally activated by addition of triethylamine. For the
synthesis presented here, no triethylamine was added and
the conversion into the enone occurred under the unique
action of the fluoride ion released subsequently to the
Brook rearrangement.
OBn OBn
OBn OBn
3
4
Scheme 2
BnO
OMe
1) BuLi (1.5 eq.)
THF, –78 °C
O
SiMe3
OMe
SiMe3
OBn
2) 0 °C, 30 min.
Me3Si
BnO
3) 2, THF, –78 °C
OBn
49 %
5
HCl conc. THF/H2O
85 %
The treatment of an ethereal solution of the pyranosic
acylsilane 6 and perfluorobutyl iodide with methyllithium
at low temperature then at room temperature led to the
corresponding hemifluorinated enone 8 (b-anomer exclu-
sively) and the a-hydroperfluorobutyl ketone 9 as an in-
separable 75/25 mixture (total yield = 84%; Scheme 5).15
The ketone 9 results from the hydrolysis of the remaining
silylenolether. The complete stereoselectivity of the reac-
tion seems to rule out the opening of the pyranose ring al-
though the ring closure of the proposed enone
intermediate would probably occur preferentially towards
the all equatorial compound.16 It was not necessary to op-
timize the reaction conditions in order to improve the
enone content. The a-hydroperfluorobutyl ketone 9 is in-
deed a synthetic equivalent of the enone 8 owing to the
easy HF elimination under the basic conditions used for
heterocycles synthesis (vide infra). Hence the presence of
9 has not to be considered here as a drawback, and the
subsequent reactions leading to heterocycles were
performed on the mixture.
BnO
O
O
SiMe3
OBn
BnO
OBn
6
Scheme 3
To overcome the problematic addition of an organometal-
lic species to a partially hydrated aldehyde, we developed
another method based on the sequence: nucleophilic
substitution by 2-lithio-2-trimethylsilyl-1,3-dithiane-de-
thioketalization, well known in our laboratory.13 The
formyl derivatives 2 and 4 were quantitatively reduced
under standard conditions. The resulting primary alcohols
were converted into the corresponding triflates, which
S
S
OTf
2
or
1) NaBH4/EtOH
SiMe3
Li
O
F
O
BnO
2) Tf2O
THF, –78 °C
O
4
C2F5
m
2,6-lutidine
CH2Cl2, 0 °C
(OBn)n
81–86%
OBn
F
BnO
91–94%
OBn
+
1) C4F9I (1.2 equiv)
Et2O, –78 °C
8
6
6
O
S
2) MeLi, –78 °C, 30 min.
3) r.t. 72 h
or
O
S
BnO
I2/CaCO3
C3F7
O
BnO
SiMe3
O
O
SiMe3
84%
THF/H2O 4/1
OBn
m
F
78–84%
(OBn)n
8/9 = 75/25
BnO
OBn OBn
OBn
7
9
Scheme 4
Scheme 5
Synlett 2004, No. 3, 512–516 © Thieme Stuttgart · New York

514
F. Chanteau et al.
LETTER
When submitted to the same reaction conditions, the D-ri- 12 is an inseparable mixture of anomers in a ratio (b/a =
bofuranosic acylsilane 7 was quantitatively converted into 80:20) corresponding to the starting mixture.
the expected enone 10, but some epimerization took place
The pyrazole derivatives 13 and 14, each as a single regio-
at the anomeric carbon, as already observed in a similar
isomer,8 were prepared conveniently in high overall yield
‘furanose’ situation (Scheme 6).7,17
by simply adding methylhydrazine to the crude mixture
from the reaction of acylsilanes 6 and 7, respectively
(Scheme 8).20 Compound 14 was obtained as an insepara-
ble anomeric mixture (b/a = 75:25) comparable to the
corresponding enone mixture.
O
F
1) C4F9I (1.2 equiv)
Et2O, –78 °C
BnO
C2F5
O
7
F
2) MeLi, –78 °C, 30 min.
3) r.t. 72 h
OBn OBn
N
N
72%
α/β = 20/80
10
BnO
C2F5
1) C4F9I (1.2 equiv)
Et2O, –78 °C
O
Scheme 6
6
F
OBn
2) MeLi, –78 °C, 30 min.
3) r.t. 72 h
BnO
This epimerization probably occurred via a retro-Michael
type process. The two epimeric enones were obtained in a
80/20 ratio, the major one having the b-configuration
OBn
4) MeNH-NH2
13
83%
3
according to a coupling constant J3¢,4¢ similar to those
N
N
reported for 2,3-O-isopropylidene-a-D-ribofuranosyl-C-
glycosides.18 Several experiments gave a constant epimer-
ic ratio (b/a = 80:20 by 19F NMR), therefore assumed to
represent the thermodynamic equilibrium. The b-configu-
ration was attributed to the major isomer after comparison
of the coupling constants 3J3¢,4¢ with those reported for 2,3-
O-isopropylidene-a-D-ribofuranosyl-C-glycosides.18
C2F5
1) C4F9I (1.2 equiv)
Et2O, –78 °C
BnO
O
F
7
2) MeLi, –78 °C, 30 min.
3) r.t. 72 h
α/β = 20/80
OBn OBn
14
4) MeNH-NH2
79%
Pyrimidine (from acetamidine) and pyrazole (from meth-
ylhydrazine) derivatives were chosen to exemplify the
preparation of polyfluorinated homo-C-nucleosides.
Whereas the pyrazole derivatives were achieved via a
one-pot procedure from acylsilanes, we operated sequen-
tially via the isolated enones to obtain satisfactory yields
of the pyrimidine derivatives, as previously observed with
other substrates.7
Scheme 8
In summary, we have developed two new routes for the
synthesis of new carbohydrates-derived acylsilanes with
the COSiMe3 group linked to the anomeric carbon via a
methylene group. These unprecedented C-glycosides
were converted, by a sequential or a one-pot reaction with
perfluoroorganolithium reagent and acetamidinium salt or
methylhydrazine, into the respective pyrimidine or pyra-
zole derivatives. These compounds may be considered as
homo-C-nucleoside analogues having a fluorine and a
pentafluoroethyl group on vicinal positions of the base
moiety. All reactions were carried out in mild and effec-
tive conditions, and the high overall yields generally ob-
tained deserve to be emphasized owing to the multi-step
process, especially for the pyrazoles one-pot synthesis.
Isolated enones 8 (as a mixture with the ketone 9, vide su-
pra) and 10 (mixture of epimers) were reacted with aceta-
midine (released from its hydrochloride) to give excellent
yields of the pyrimidine derivatives 11 and 12 respective-
ly (Scheme 7).19 The D-ribofuranose derived pyrimidine
N
N
Cl-
+
H2N
BnO
(5 equiv)
NH2
C2F5
O
Acknowledgment
8
+
9
F
OBn
KOH (3 equiv)
We thank the MENRT for a PhD research grant (F. C.), H. Baillia
for his help in the NMR spectrometry and ATOFINA company for
the generous gift of the perfluoroalkyliodides.
BnO
CH2Cl2
OBn
79%
11
References
N
N
Cl-
+
H2N
(5 equiv)
NH2
(1) (a) Watanabe, K. A. The Chemistry of C-Nucleosides, In
Chemistry of Nucleosides and Nucleotides, Vol. 3;
Townsend, L. B., Ed.; Plenum Press: New York, 1994, 421–
535. (b) Postema, M. H. D. In C-Glycoside Synthesis; Rees,
C. W., Ed.; CRC Press: Boca Raton, 1995, Chap. 11, 303–
344.
C2F5
BnO
O
F
10
KOH (3 equiv)
α/β = 20/80
CH2Cl2
99%
OBn OBn
12
(2) Hanessian, S.; Pernet, A. G. Adv. Carbohydr. Chem.
Biochem. 1976, 33, 111.
Scheme 7
Synlett 2004, No. 3, 512–516 © Thieme Stuttgart · New York

LETTER
Synthesis of Fluorinated Homo-C-Nucleoside Analogues
515
(3) (a) Sallam, M. A. E.; Townsend, L. B. Nucleosides
Nucleotides 1998, 17, 1215. (b) Doboszewski, B.
Nucleosides Nucleotides 1997, 16, 1049. (c) Van
Calenbergh, S.; De Bruyn, A.; Schraml, J.; Blaton, N.;
Peeters, O.; De Keukeleire, D.; Busson, R.; Herdewijn, P.
Nucleosides Nucleotides 1997, 16, 291. (d) Pino Gonzalez,
M. S.; Lopez Herrera, F. J.; Pabon Aguas, R.; Uraga Baelo,
C. Nucleosides Nucleotides 1990, 9, 51; and references cited
therein.
(15) Experimental Procedure for the Synthesis of Enone 8. To
a solution, under Ar, of the acylsilane 6 (100 mg, 0.16 mmol)
and perfluorobutyl iodide (32 mL, 0.19 mmol) in anhydrous
Et2O (10 mL) was added dropwise, at –78 °C, a solution of
MeLi 1 M in Et2O (190 mL, 0.19 mmol). After 30 min at
–78 °C, the resulting mixture was stirred at r.t. for 3 d. The
reaction was then washed with a sat. NaCl solution and the
aqueous layer extracted twice with Et2O. The organic layer
was dried over MgSO4, filtered and Et2O was evaporated.
The residue was purified by a silica gel column
(4) Welsh, J. T.; Eswarakrishnan, S. Fluorine in Bioorganic
Chemistry; Wiley: New York, 1991.
chromatography (petroleum ether/EtOAc: 95:5) to afford 99
mg (84%) of an unseparable mixture of enone 8 (75%) and
the corresponding hydroperfluoroketone 9 (25%). Selected
data of the mixture of enone 8 and the corresponding
hydroperfluoroketone 9. Enone 8: 1H NMR (250 MHz,
CDCl3): d = 7.43–7.16 (m, 20 H, H-aromatic), 5.03 (d, 1 H,
J = 12.5 Hz, H-benzyl), 4.97 (d, 1 H, J = 11.5 Hz, H-benzyl),
4.91 (d, 1 H, J = 11.0 Hz, H-benzyl), 4.84 (d, 1 H, J = 11.0
Hz, H-benzyl), 4.64 (d, 1 H, J = 11.5 Hz, H-benzyl), 4.63 (d,
1 H, J = 12.0 Hz, H-benzyl), 4.54 (d, 1 H, J = 12.5 Hz, H-
benzyl), 4.48 (d, 1 H, J = 12.0 Hz, H-benzyl), 3.88 (ddd, 1
H, J1¢,2¢ = 9.3 Hz, J1¢,1 = 7.9 Hz, J1¢,1 = 4.4 Hz, H-1¢), 3.79–
3.66 (m, 4 H, H-3¢, H-4¢, H-6¢, H-6¢), 3.50 (m, 1 H, H-5¢),
3.38 (t, 1 H, J2¢,3¢ = J2¢,1¢ = 9.3 Hz, H-2¢), 2.93 (ddd, 1 H,
J1,2 = 17.1 Hz, J1,1¢ = 4.4 Hz, 4J1,F = 2.0 Hz, H-1), 2.85 (ddd,
1 H, J1,2 = 17.1 Hz, J1,1¢ = 7.9 Hz, 4J1,F = 2.0 Hz, H-1) ppm.
13C NMR (62.5 MHz, CDCl3): d = 188.7 (dd, 2JC,F = 17.7 Hz,
3JC,F = 3.2 Hz, C=O), 138.7–138.1 (C-q aromatic), 129.0–
128.2 (CH aromatic), 87.7 (C-3¢), 80.7 (C-2¢), 79.4 (C-5¢),
78.6 (C-4¢), 76.1 (CH2 benzyl), 75.4 (CH2 benzyl), 75.3
(CH2 benzyl), 74.5 (C-1¢), 73.9 (CH2 benzyl), 68.9 (C-6¢);
42.7 (d, 3JC,F = 1.6 Hz, C-1) ppm. 19F NMR (235.4 MHz,
CDCl3): d = –84.6 (m, 3 F, CF3), –121.6 (dm, 2 F,
(5) (a) Portella, C.; Dondy, B. Tetrahedron Lett. 1991, 32, 83.
(b) Dondy, B.; Doussot, P.; Portella, C. Synthesis 1992, 995.
(c) Dondy, B.; Portella, C. J. Org. Chem. 1993, 58, 6671.
(d) Doussot, P.; Portella, C. J. Org. Chem. 1993, 58, 6675.
(6) Dondy, B.; Doussot, P.; Iznaden, M.; Muzard, M.; Portella,
C. Tetrahedron Lett. 1994, 35, 4357.
(7) Chanteau, F.; Didier, B.; Dondy, B.; Plantier-Royon, R.;
Portella, C. Eur. J. Org. Chem., accepted for publication.
(8) Bouillon, J.-P.; Didier, B.; Dondy, B.; Doussot, P.; Plantier-
Royon, R.; Portella, C. Eur. J. Org. Chem. 2001, 187.
(9) (a) Dondoni, A.; Scherrmann, M.-C. Tetrahedron Lett. 1993,
34, 7319. (b) Dondoni, A.; Schermann, M.-C. J. Org. Chem.
1994, 59, 6404. (c) Sanchez, M. E. L.; Michelet, V.;
Besnier, I.; Genet, J.-P. Synlett 1994, 705. (d) Labeguere,
F.; Lavergne, J.-P.; Martinez, J. Tetrahedron Lett. 2002, 43,
7271.
(10) Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1979, 20, 399.
(11) Martin, O. R. Carbohydr. Res. 1987, 171, 211.
(12) Yoshida, J.; Matsunaga, S.; Ishichi, Y.; Isoe, S. J. Org.
Chem. 1991, 56, 1307.
(13) (a) Plantier-Royon, R.; Portella, C. Synlett 1994, 527.
(b) Plantier-Royon, R.; Portella, C. Tetrahedron Lett. 1996,
37, 6113.
3JF,F = 14.7 Hz, CF2), –151.8 (dm, 1 F, 3JF,F = 134.5 Hz, CF2-
CF), –152.6 (dm, 1 F, 3JF,F = 134.5 Hz, CO-CF) ppm.
Hydroperfluoroketone 9 (50:50 mixture of two
(14) Selected data for the acylsilanes 6 and 7. Compound 6:
yellow syrup. 1H NMR (250 MHz, CDCl3): d = 7.37–7.20
(m, 20 H, H-aromatic), 4.96–4.85 (m, 4 H, H-benzyl), 3.88
(ddd, 1 H, J1¢,2¢ = 9.2 Hz, J1¢,2 = 7.6 Hz, J1¢,2 = 3.6 Hz, H-1¢),
3.79–3.63 (m, 4 H, H-3¢, H-4¢, H-6¢, H-6¢), 3.47 (m, 1 H, H-
5¢), 3.37 (t, 1 H, J2¢,1¢ = J2¢,3¢ = 9.2 Hz, H-2¢), 2.87 (dd, 1 H,
diastereomers): 19F NMR (235.4 MHz, CDCl3): d = –81.2
(m, 3 F, CF3), –120.3 (dm, 2 F, 2JF,F = 282.0 Hz, CHF-CF2),
–126.7 (m, 2 F, CF2-CF2), –205.3 (dm, 1 F, 2JH,F = 45.7 Hz,
CHF) ppm.
J2,2 = 15.6 Hz, J2,1¢ = 7.6 Hz, H-2), 2.79 (dd, 1 H, J2,2 = 15.6
(16) Dawe, R. D.; Fraser-Reid, B. J. Org. Chem. 1984, 49, 522.
(17) Selected data for the mixture of enones 10. Enone b-10: 1H
NMR (250 MHz, CDCl3): d = 7.41–7.26 (m, 15 H, H-
aromatic), 4.79 (d, 1 H, J = 11.5 Hz, H-benzyl), 4.67 (d, 1 H,
J = 11.8 Hz, H-benzyl), 4.63 (d, 1 H, J = 11.8 Hz, H-benzyl),
4.58 (d, 1 H, J = 11.8 Hz, H-benzyl), 4.54–4.43 (m, 2 H, H-
1¢, H-benzyl), 4.39 (d, 1 H, J = 11.5 Hz, H-benzyl), 4.24
(ddd, 1 H, J4¢,5¢ = 4.1 Hz, J1¢,1 = 3.5 Hz, J1¢,1 = 3.4 Hz, H-4¢),
3.96 (dd, 1 H, J3¢,2¢ = 5.3 Hz, J3¢,4¢ = 3.4 Hz, H-3¢), 3.71 (dd,
1 H, J2¢,1¢ = 6.9 Hz, J2¢,3¢ = 5.3 Hz, H-2¢), 3.59 (dd, 1 H,
Hz, J2,1¢ = 3.6 Hz, H-2), 0.31 (s, 9 H, SiMe3) ppm. 13C NMR
(62.5 MHz, CDCl3): d = 247.0 (C=O), 138.4–137.9 (C-q
aromatic), 128.4–127.5 (CH aromatic), 87.2 (C-3¢), 81.0 (C-
2¢), 78.7 (C-5¢), 78.2 (C-4¢), 75.5 (CH2 benzyl), 74.9 (CH2
benzyl), 74.8 (CH2 benzyl), 74.6 (C-1¢), 73.3 (CH2 benzyl),
68.6 (C-6¢), 49.5 (C-2), –3.4 (SiMe3) ppm. MS (EI): m/z
(%) = 638 (16) [M+], 623 (32) [M – 15], 522, 517, 439 (100),
372, 279. Compound 7: yellow syrup. 1H NMR (250 MHz,
CDCl3): d = 7.27–7.10 (m, 15 H, H-aromatic), 4.51–4.32 (m,
7 H, 6 H-benzyl, H-1¢), 4.05 (dt, 1 H, J4¢,3¢ = 5.2 Hz,
J
J
J
5¢,5¢ = 10.6 Hz, J5¢,4¢ = 3.5 Hz, H-5¢), 3.49 (dd, 1 H,
5¢,5¢ = 10.6 Hz, J5¢,4¢ = 4.1 Hz, H-5¢), 2.96 (dm, 1 H,
1,1 = 17.9 Hz, H-1), 2.87 (dm, 1 H, J1,1 = 17.9 Hz, H-1)
J
4¢,5¢ = J4¢,5¢ = 3.9 Hz, H-4¢), 3.77 (t, 1 H, J3¢,2¢ = J3¢,4¢ = 5.2 Hz,
H-3¢), 3.49 (t, 1 H, J2¢,3¢ = J2¢,1¢ = 5.2 Hz, H-3¢), 3.40 (dd, 1 H,
J5¢,5¢ = 10.5 Hz, J5¢,4¢ = 3.9 Hz, H-5¢), 3.35 (dd, 1 H,
5¢,5¢ = 10.5 Hz, J5¢,4¢ = 3.9 Hz, H-5¢), 2.71 (dd, 1 H,
ppm. 13C NMR (62.5 MHz, CDCl3): d = 188.5 (dd,
J
2JC,F = 17.2 Hz, 3JC,F = 2.7 Hz, C=O), 137.9–137.5 (C-q
aromatic), 128.4–127.6 (CH aromatic), 82.2 (C-4¢), 80.4 (C-
2¢), 77.2 (C-3¢), 75.5 (C-1¢), 73.4 (CH2 benzyl), 72.1 (CH2
J2,2 = 16.5 Hz, J2,1¢ = 7.0 Hz, H-2), 2.56 (dd, 1 H, J2,2 = 16.5
Hz, J2,1¢ = 5.5 Hz, H-2), 0.20 (s, 9 H, SiMe3) ppm. 13C NMR
(62.5 MHz, CDCl3): d = 247.2 (C=O), 138.7–138.3 (C-q
aromatic), 128.8–128.0 (CH aromatic), 81.5 (C-4¢), 80.8 (C-
2¢), 77.2 (C-3¢), 76.7 (C-1¢), 73.8 (CH2 benzyl), 72.2 (CH2
benzyl), 72.1 (CH2 benzyl), 70.5 (C-5¢), 52.2 (C-2), –2.8
(SiMe3) ppm. MS (EI): m/z (%) = 518 (26) [M+], 427 (100),
337, 261, 179.
benzyl), 71.7 (CH2 benzyl), 70.0 (C-5¢), 44.2 (C-1) ppm. 19
F
NMR (235.4 MHz, CDCl3): d = –84.6 (m, 3 F, CF3), –121.6
(dm, 2 F, 3JF,F = 15.3 Hz, CF2), –151.7 (dm, 1 F, 3JF,F = 137.3
Hz, CO-CF), –152.4 (dm, 1 F, 3JF,F = 137.3 Hz, CF2-CF)
ppm. Enone a-10: 13C NMR (62.5 MHz, CDCl3): d = 188.4
(dd, 2JC,F = 17.2 Hz, 3JC,F = 2.7 Hz, C=O), 138.0–137.7 (C-q
aromatic), 128.4–127.6 (CH aromatic), 80.1 (C-4¢), 79.3 (C-
2¢), 77.2 (C-3¢), 75.4 (C-1¢), 73.6 (CH2 benzyl), 72.7 (CH2
benzyl), 71.7 (CH2 benzyl), 69.9 (C-5¢), 41.6 (C-1) ppm. 19
NMR (235.4 MHz, CDCl3): d = –84.6 (m, 3 F, CF3) ppm.
F
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F. Chanteau et al.
LETTER
(18) (a) Lopez Herrera, F. J.; Uraga Baelo, C. Carbohydr. Res.
1985, 139, 95. (b) Lopez Herrera, F. J.; Uraga Baelo, C.
Carbohydr. Res. 1985, 143, 161. (c) Lopez Herrera, F. J.;
Pino Gonzalez, M. S.; Pabon Aguas, R. J. Chem. Soc.,
Perkin Trans. 1 1989, 2401.
72.6 (CH2 benzyl), 72.0 (CH2 benzyl), 70.0 (C-5¢), 25.1
(CH3) ppm.19F NMR (235.4 MHz, CDCl3): d = –117.5 (dm,
2 F, 4JF,F = 21.5 Hz, CF2), –139.2 (m, 1 F, CF) ppm.
(20) Experimental Procedure for the Synthesis of the
Pyrazoles 13 and 14. To a solution, under Ar, of the
acylsilane 6 or 7 (1 mmol) and perfluorobutyl iodide (1.2
mmol) in anhydrous Et2O (15 mL) was added dropwise, at
–78 °C, a solution of MeLi 2.2 M in Et2O (1.2 mmol). After
30 min at –78 °C, the resulting mixture was stirred at r.t. for
3 d. Methylhydrazine (5 mmol) was then added and the
reaction was monitored by TLC (petroleum ether/EtOAc
85:15). After 18 h at r.t., the reaction was washed with a sat.
NaCl solution and the aqueous layer extracted twice with
Et2O. The organic layer was dried over MgSO4, filtered and
ether was evaporated. The residue was purified by a silica
gel column chromatography (petroleum ether/EtOAc:
90:10). Selected data of pyrazole 13: yellow syrup (83%). 1H
NMR (250 MHz, CDCl3): d = 7.33–7.04 (m, 20 H, H-
aromatic), 4.92–4.67 (m, 4 H, H-benzyl), 4.59–4.35 (m, 4 H,
H-benzyl), 3.72 (s, 3 H, NCH3), 3.70–3.45 (m, 6 H, H-1¢, H-
3¢, H-4¢, H-5¢, H-6¢, H-6¢), 3.32 (t, 1 H, J2¢,3¢ = J2¢,1¢ = 8.7 Hz,
H-2¢), 3.04 (dd, 1 H, J1,1 = 14.8 Hz, J1,1¢ = 3.3 Hz, H-1), 2.77
(dd, 1 H, J1,1 = 14.8 Hz, J1,1¢ = 7.3 Hz, H-1) ppm. 13C NMR
(62.5 MHz, CDCl3): d = 146.9 (d, 1JC,F = 260.6 Hz, C-4),
138.4–138.1 (C-q aromatic), 137.9 (d, 2JC,F = 9.7 Hz, C-5),
135.2 (d, 2JC,F = 9.7 Hz, C-3), 128.5–127.9 (CH aromatic),
117.5 (tq, 1JC,F = 287.4 Hz, 2JC,F = 35.6 Hz, CF3), 87.2 (C-
3¢), 81.3 (C-2¢), 79.2 (C-5¢), 78.5 (C-4¢), 77.4 (C-1¢), 75.6
(CH2 benzyl), 75.0 (CH2 benzyl), 74.9 (CH2 benzyl), 73.4
(19) Experimental Procedure for the Synthesis of the
Pyrimidines 11 and 12. To a suspension of acetamidinium
chloride (5 equiv) and KOH (3 equiv) in CH2Cl2 (15 mL)
stirred for 1 h, was added a solution of the mixture of enone
8 and the corresponding hydroperfluoroketone 9 or the
mixture of enones 10 (1 equiv) in CH2Cl2 (2 mL). After 24 h
at r. t., the reaction was washed with a sat. NaCl solution and
the aqueous layer extracted twice with CH2Cl2. The organic
layer was dried over MgSO4, filtered and the solvent was
evaporated. The residue was purified by a silica gel column
chromatography (petroleum ether/EtOAc: 90:10). Selected
data of pyrimidine 11: yellow syrup (79%). 1H NMR (250
MHz, CDCl3): d = 7.35–7.00 (m, 20 H, H-aromatic), 4.95–
4.35 (m, 8 H, H-benzyl), 3.70–3.40 (m, 6 H, H-1¢, H-3¢, H-
4¢, H-5¢, H-6¢, H-6¢), 3.33 (t, 1 H, J2¢,3¢ = J2¢,1¢ = 9.3 Hz, H-2¢),
3.00 (dd, 1 H, J1,1 = 15.1 Hz, J1,1¢ = 3.0 Hz, H-1), 2.80 (dd, 1
H, J1,1 = 15.1 Hz, J1,1¢ = 6.9 Hz, H-1), 2.68 (s, 3 H, CH3)
ppm. 19F NMR (235.4 MHz, CDCl3): d = –83.9 (m, 3 F,
CF3), –117.4 (dm, 2 F, 4JF,F = 19.0 Hz, CF2), –139.8 (m, 1 F,
CF) ppm. Selected data of pyrimidine 12: yellow syrup
(99%, a/b = 20:80), b-anomer 12: 1H NMR (250 MHz,
CDCl3): d = 7.38–7.23 (m, 15 H, H-aromatic), 4.63–4.45 (m,
7 H, 6 H-benzyl, H-1¢), 4.20 (ddd, 1 H, J4¢,3¢ = 4.2 Hz,
J
J
J
4¢,5¢ = 4.1 Hz, J4¢,5¢ = 3.5 Hz, H-4¢), 3.95 (t, 1 H,
3¢,2¢ = J3¢,4¢ = 4.2 Hz, H-3¢), 3.81 (dd, 1 H, J2¢,1¢ = 5.9 Hz,
2¢,3¢ = 4.2 Hz, H-2¢), 3.56 (dd, 1 H, J5¢,5¢ = 10.7 Hz, J5¢,4¢ = 3.5
(CH2 benzyl), 68.8 (C-6¢), 39.7 (CH2), 29.7 (NCH3) ppm. 19
F
NMR (235.4 MHz, CDCl3): d = –85.5 (m, 3 F, CF3), –113.3
(dm, 2 F, 4JF,F = 11.7 Hz, CF2), –166.9 (m, 1 F, CF) ppm.
Selected data of pyrazole 14: yellow syrup (100%, a/
b = 25:75). b-Anomer: 1H NMR (250 MHz, CDCl3): d =
7.42–7.20 (m, 15 H, H-aromatic), 4.65–4.42 (m, 7 H, 6 H-
benzyl, H-1¢), 4.23 (m, 1 H, H-4¢), 3.90 (t, 1 H,
Hz, H-5¢), 3.51 (dd, 1 H, J5¢,5¢ = 10.7 Hz, J5¢,4¢ = 4.1 Hz, H-5¢),
3.16 (dd, 1 H, J1,1 = 14.0 Hz, J1,1¢ = 7.1 Hz, H-1), 3.11 (dd, 1
H, J1,1 = 14.0 Hz, J1,1¢ = 5.4 Hz, H-1), 2.70 (s, 3 H, CH3)
ppm. 13C NMR (62.5 MHz, CDCl3): d = 163.4 (d, 2JC,F = 9.9
Hz, C-4), 158.5 (d, 2JC,F = 15.3 Hz, C-6), 153.2 (d,
1JC,F = 273.8 Hz, C-5), 138.0–137.8 (C-q aromatic), 128.3–
127.5 (CH aromatic), 118.1 (tq, 1JC,F = 287.4 Hz,
J
3¢,2¢ = J3¢,4¢ = 5.6 Hz, H-3¢), 3.73 (t, 1 H, J2¢,3¢= J2¢,1¢ = 5.6 Hz,
H-2¢), 3.70 (s, 3 H, NCH3), 3.56 (dd, 1 H, J5¢,5¢ = 10.9 Hz,
5¢,4¢ = 3.4 Hz, H-5¢), 3.48 (dd, 1 H, J5¢,5¢ = 10.9 Hz, J5¢,4¢ = 5.3
2JC,F = 35.6 Hz, CF3), 82.0 (C-4¢), 80.6 (C-2¢), 78.3 (C-1¢),
77.0 (C-3¢), 73.3 (CH2 benzyl), 72.0 (CH2 benzyl), 71.8
J
Hz, H-5¢), 2.92 (dm, 1 H, J1,1 = 14.9 Hz, H-1), 2.85 (dm, 1
H, J1,1 = 14.9 Hz, H-1) ppm. 19F NMR (235.4 MHz, CDCl3):
d = –85.4 (m, 3 F, CF3), –113.2 (dm, 2 F, 4JF,F = 12.5 Hz,
CF2), –167.3 (m, 1 F, CF) ppm. a-Anomer: 19F NMR (235.4
MHz, CDCl3): d = –85.1 (m, 3 F, CF3), –113.1 (dm, 2 F,
4JF,F = 12.5 Hz, CF2), –167.7 (m, 1 F, CF) ppm.
(CH2 benzyl), 70.2 (C-5¢), 35.2 (CH2), 25.0 (CH3) ppm. 19
F
NMR (235.4 MHz, CDCl3): d = –83.5 (m, 3 F, CF3), –117.4
(d, 2 F, 4JF,F = 21.5 Hz, CF2), –139.4 (m, 1 F, CF) ppm. a-
Anomer 12: 13C NMR (62.5 MHz, CDCl3): d = 163.2 (d,
2JC,F = 9.2 Hz, C-4), 160.0 (d, 2JC,F = 14.5 Hz, C-6), 80.5 (C-
4¢), 79.1 (C-3¢), 77.9 (C-1¢), 77.8 (C-2¢), 73.0 (CH2 benzyl),
Synlett 2004, No. 3, 512–516 © Thieme Stuttgart · New York