Synthesis of difluorinated carbocyclic analogues of 5-deoxypentofuranoses

Article abstract of DOI:10.1016/j.tetlet.2009.09.170

The synthesis of difluorinated carbocyclic analogues of 5-deoxypentofuranoses is described. The sequence involves an addition of PhSeCF₂TMS to carbohydrate-derived aldehydes followed by a radical cyclization, and provides a secure strategy for

Full text of DOI:10.1016/j.tetlet.2009.09.170

Tetrahedron Letters 50 (2009) 7048–7050
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Tetrahedron Letters
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Synthesis of difluorinated carbocyclic analogues of 5-deoxypentofuranoses
*
Gaëlle Fourrière, Jérôme Lalot, Nathalie Van Hijfte, Jean-Charles Quirion, Eric Leclerc
Université et INSA de Rouen, CNRS, UMR 6014 C.O.B.R.A.–IRCOF, 1 rue Tesnière, 76821 Mont Saint-Aignan Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of difluorinated carbocyclic analogues of 5-deoxypentofuranoses is described. The
sequence involves an addition of PhSeCF2TMS to carbohydrate-derived aldehydes followed by a radical
cyclization, and provides a secure strategy for a future synthesis of pentofuranoses and nucleoside
analogues.
Received 8 September 2009
Revised 25 September 2009
Accepted 29 September 2009
Available online 7 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Nucleosides
Carbasugars
Fluorine
Radical cyclization
In recent years, carbocyclic nucleosides (I, X = CH2, Scheme 1)
have acquired a growing importance in the field of drug discovery.
Their greater metabolic stability indeed imparts to these molecules
superior therapeutical properties compared to their natural coun-
terparts possessing a standard sugar backbone (I, X = O, Scheme
1).1 As powerful antiviral (mainly against HIV, hepatitis B, and her-
pes viruses) and antitumoral properties are exhibited by several
nucleosides (azidothymidine and gemcitabine) and carbonucleo-
sides (entecavir, abacavir, and aristeromycin), the need for new
analogues with greater activities and/or lowered side effects has
thus increased.
If the fluorination of various positions on the pentose backbone
has been widely studied,2 the synthesis of CF2-carbocyclic nucleo-
sides, in which the intracyclic oxygen atom is replaced by a CF2
group, is only scarcely described.3,4 The stereoelectronic properties
of the fluorine atom (strong electronegativity and small size) might
nevertheless reasonably impart to these surrogates better mimick-
ing abilities than the apolar CH2 group.2b Our current interest in
the synthesis of CF2-glycosides prompted us to devise a synthetic
plan for the preparation of fluorocarbocyclic analogues II
(X = CF2) of various pentoses using a general strategy.5
of PhSeCF2TMS on the pentose-derived aldehyde V. Overall, the
process would thus provide, in a limited number of steps, the cor-
responding CF2 surrogate II of the starting carbohydrate VI. We
wish to present herein our preliminary efforts and results in this
area, which allowed the preparation of several CF2-carbocyclic ana-
logues of 5-deoxypentoses.
Our first study was based on the reductive cyclization of the
difluoromethyl radical onto a terminal double bond. Aldehyde 1
was thus prepared according to a literature procedure6a and the
addition of PhSeCF2TMS was examined. The use of easily enolizable
a
-chiral aldehydes for the fluoride-promoted addition of
PhSeCF2TMS or PhSCF2TMS is poorly documented.7 Among the dif-
ferent methods reported in the literature for the addition to aro-
matic aldehydes (TBAF as a fluoride source,7a Cu(OAc)2/dppe as a
OH
HO
Y
HO
X
X
X
OP
Base
OH
X=CF2
PO
OP
OH
PO
OP
I
II
III
Our approach, as displayed in Scheme 1, is based on the use of
difluorocyclopentane III as the key intermediate. Compounds of
type III, which feature an exocyclic double bond or a phenylsela-
nylmethyl moiety at C-5, might indeed be obtained through a 5-
exo radical cyclization of a difluoromethyl radical onto a double
or triple bond, through an atom-transfer or reductive process.
The radical precursor IV would be readily prepared by addition
Y = H or SePh
X=CF2
X=O or CF2
X=O or CF2
PhSe
OH
X
O
OH
O
OP
PO
OP
PO
OP
PO
OP
VI
V
IV
* Corresponding author. Tel.: +33 235522901.
E-mail address: eric.leclerc@insa-rouen.fr (E. Leclerc).
Scheme 1. Retrosynthetic scheme.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.170

G. Fourrière et al. / Tetrahedron Letters 50 (2009) 7048–7050
7049
F
F
F
F
F F
F
F
PhSe
O
PhSe
O
OAc
OAc
1. PhSeCF2TMS 1.5 equiv.
(n-Bu)3SnH, AIBN
OAc
F
OH
O
TMAF 1 equiv., CH2Cl2, -78 °C
+
t-BuOH, 80 °C
89%, dr = 50:50
2. TBAF, THF, rt.
48%, dr = 80:20
O
O
O
O
O
O
O
O
10b
10a
9
1
2
F
F
F
F
PhSe
F
OAc
(n-Bu)3SnH, AIBN
PhSe
BnO
OAc
PhSeCF2TMS 1.5 equiv.
TMAF 1 equiv., CH2Cl2
OH
O
OBn
t-BuOH, 80 °C
48%, dr = 90:10
BnO
OBn
BnO
OBn
F
-78 °C to rt
11
F
12
BnO
OBn
78%, dr = 80:20
3
4
F
F
PhSe
F
(n-Bu)3SnH, AIBN
OAc
F
OAc
PhSe
HO
t-BuOH, 80 °C
43%, dr = 80:20
1. PhSeCF2TMS 1.5 equiv.
TMAF 1 equiv., CH2Cl2, -78 °C
OH
O
BzO
OBz
BzO
OBz
2. TBAF, TH F, rt.
59%, dr =95:05
13
F
14
TBSO
BzO
OTBS
OH
F
F
F
6
F
5
7
F
PhSe
(n-Bu)3SnH, AIBN
OAc
OAc
PhSe
BzO
t-BuOH, 80 °C
70%, dr = 90:10
1. PhSeCF2TMS 3 equiv.
TBAT 1.5 equiv., THF, -78 °C
OH
OBz
O
AcO
HO
OAc
AcO
OAc
16
15
F
2. TBAF, THF, rt.
27%, dr =75:25
OBz
F
F
F
8
PhSe
(n-Bu)3SnH, AIBN
OH
OH
Scheme 2. Addition of PhSeCF2TMS to carbohydrate-derived aldehydes.
t-BuOH, 80 °C
52%, dr = 90:10
OH
HO
OH
6
17
Lewis acid activator,7detc.), the use of TMAF as a promoter led, in
our hands, to the best and most reproducible results.7c The require-
ment of a two-step procedure to convert the OH/OTMS mixture ini-
tially obtained to the free alcohol 2 is the only drawback of this
method (Scheme 2). The yield and the diastereoselectivity are
however satisfactory and similar conditions were also applied to
aldehydes 3, 5, and 7.6 Worthy of note is the fact that, for ben-
zyl-protected aldehydes such as 3, a warm-up to room tempera-
ture is sufficient to directly afford alcohol 4 in high yield. The
TBS-protected arabinose derivative 5 led to the fully deprotected
addition product 6 in appreciable yield, thanks to the two-step pro-
cedure mentioned earlier. Finally, the benzoyl-protected arabinose
derivative 7 required the use of TBAT as the fluoride source to iso-
late the addition product 8, unfortunately in low yield (Scheme 2).
Each major diastereomer obtained from these reactions was
afterwards acetylated and engaged in a classical tin hydride-med-
iated radical cyclization (Scheme 3).3a,b,8 The cyclized compounds
were generally obtained within 2 h in moderate to high yields.
The reaction conditions appeared compatible with all protecting
Scheme 3. Synthesis of the 5-deoxypentose CF2-carbocyclic analogues.
groups including none, as illustrated by the successful cyclization
of the unprotected arabinose derivative 8 (Scheme 3).
The relative configurations of the cyclized compounds were
easily determined from NOESY NMR experiments, providing infor-
mations on the stereochemical outcome of both the PhSeCF2TMS
addition and the radical cyclization (Scheme 4). The latter proceeds
according to the classical Beckwith–Houk transition state.9
A
strong diastereoselectivity was therefore observed in the reaction
of the xylose and arabinose derivatives 11 and 15. On the other
hand, an equimolar mixture of the two C-5 epimers 10a and 10b
was obtained from the ribose derivative 9. Both transition states
leading to these compounds indeed suffer from at least one non-
bonding 1,3-diaxial interaction (Scheme 4). More puzzling is the
stereochemical outcome in the addition of PhSeCF2TMS to alde-
hydes 1, 3, 5, and 7, for which anti-Felkin adducts are obtained
Me
Me
TBSO
O
O
F
OBn
F
O
BnO
O
H
F
F
O
H
H
F
F
H
H
O
O
AcO
BnO
AcO
11
TBSO
.
.
Nu
Minor diastereomer
Me
H
H
O
F
F
Me
H
H
H
BnO
O
Felkin TS
14
10b
9
Me
O
H
OTBS
O
F
AcO
OAc
O
Me
H
O
F
Me
H
O
H
H
H
AcO
AcO
O
O
.
F
15
.
Nu
F
F
F
OTBS
H
AcO
H
H
F
O
F
OAc
16
H
O
TS leading to major diastereomer
10a
Scheme 4. Stereoselectivity of the PhSeCF2TMS addition and of the radical cyclization.

7050
G. Fourrière et al. / Tetrahedron Letters 50 (2009) 7048–7050
as the major diastereomers.10 A chelated transition state can be
claimed for Cu(II)-mediated reactions,7d but is of course ruled out
for fluoride-promoted additions. Similar results were observed in
the addition of fluoroalkylsilane reagents to other carbohydrate-
derived aldehydes by Portella’s team.11 The exceptional bulkiness
of the postulated hypervalent fluorosilicon intermediate was in-
voked by the authors to explain this unusual selectivity. In the ab-
sence of relevant calculation studies regarding such reactions, a
transition state similar to Portella’s is therefore proposed in
Scheme 4. It accounts for the observed selectivity and allows the
minimization of steric interactions despite an unusual gauche
conformation.
In summary, we have devised a general synthetic route to diflu-
orinated carbocyclic 5-deoxypentofuranose analogues which
should be applicable to the preparation of pentofuranose and
nucleoside surrogates. The sequence involves an addition of
PhSeCF2TMS to carbohydrate-derived aldehydes featuring a termi-
nal double bond followed by a reductive 5-exo-trig radical cycliza-
tion. Several extensions of this work are currently under
investigation. A similar sequence using tert-butanesulfinylimines
derived from aldehydes V (Scheme 1) could for example allow us
to control at will the configuration of the pseudo-anomeric center.
The phenylselanyl group transfer radical cyclization of the same
substrates and the reductive 5-exo-dig radical cyclization of similar
precursors featuring a terminal triple bond are also studied. These
last strategies would indeed provide access to pentofuranose and
nucleoside analogues. Results in these areas will be reported in
due course.
2. (a) Meier, C.; Knispel, T.; Marquez, V. E.; Siddiqui, M. A.; De Clercq, E.; Balzarini,
J. J. Med. Chem. 1999, 42, 1615–1624; (b) Kirsch, P. Modern Fluoroorganic
Chemistry; Wiley-VCH: Weinheim, Germany, 2004; (c) Wang, J.; Jin, Y.; Rapp, K.
L.; Bennett, M.; Schinazi, R. F.; Chu, C. K. J. Med. Chem. 2005, 48, 3736–3748. and
references cited therein.
3. For the synthesis of fluorinated carbocyclic analogues of deoxypentofuranoses,
see: (a) Barth, F.; O-Yang, C. Tetrahedron Lett. 1991, 32, 5873–5876; (b) Arnone,
A.; Bravo, P.; Cavicchio, G.; Frigerio, M.; Viani, F. Tetrahedron 1992, 48, 8523–
8540; (c) Yang, Y.-Y.; Meng, W.-D.; Qing, F.-L. Org. Lett. 2004, 6, 4257–4259.
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(a) Jiang, S.; Singh, G.; Batsanov, A. S. Tetrahedron: Asymmetry 2000, 11, 3873–
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Sardinha, J.; Guieu, S.; Deleuze, A.; Fernández-Alonso, M. C.; Rauter, A. P.; Sinaÿ,
P.; Marrot, J.; Jiménez-Barbero, J.; Sollogoub, M. Carbohydr. Res. 2007, 342,
1689–1703; (e) Sardinha, J.; Rauter, A. P.; Sollogoub, M. Tetrahedron Lett. 2008,
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G.; Bundgaard, E.; Madsen, R. J. Org. Chem. 2005, 70, 10139–10142; (c) Uenishi,
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7. For the addition to aromatic or poorly functionalized aliphatic aldehydes, see:
(a) Qin, Y.-Y.; Qiu, X.-L.; Yang, Y.-Y.; Meng, W.-D.; Qing, F.-L. J. Org. Chem. 2005,
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Morikawa, T.; Kodama, Y.; Uchida, J.; Takano, M.; Washio, Y.; Taguchi, T.
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Acknowledgments
We thank the Centre National de la Recherche Scientifique
(CNRS) and the Région Haute-Normandie for a PhD grant to G.F.
We also thank Dr. Pedro Lameiras, Sophie Guillard, and Pr. Hassan
Oulyadi (LRMN, COBRA UMR 6014, Mont Saint-Aignan, France) for
the NOESY experiments.
9. (a) Beckwith, A. L. J. Tetrahedron 1981, 37, 3073–3100; (b) Spellmeyer, D. C.;
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Rev. 2003, 32, 251–263.
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a-chiral aldehydes is often poorly
diastereoselective except for -dibenzylaminoaldehydes for which a Felkin
a
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