Synthesis of exo-methylenedifluorocyclopentanes as precursors of fluorinated carbasugars by 5-exo-dig radical cyclization

Article abstract of DOI:10.1016/j.jfluchem.2011.02.015

The synthesis of polyhydroxylated 1,1-difluoro-5-methylenecyclopentanes is described. The sequence involves an addition of PhSeCF₂TMS to a tartrate-derived aldehyde or its corresponding tert-butanesulfinylimines followed by a radical cyclization. The use of a benzyl protected substrate led to an unproductive 1,5-hydrogen transfer after cyclization but the desired compound was eventually obtained from the unprotected substrate. A hydroboration/oxidation sequence was investigated on these 1,1-difluoro-5- methylenecyclopentanes as it would provide fluorinated carbasugars, a new and promising class of glycomimetics. Unfortunately, this reaction was poorly efficient and its regioselectivity not the expected one.

Full text of DOI:10.1016/j.jfluchem.2011.02.015

Journal of Fluorine Chemistry 134 (2012) 172–179
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis of exo-methylenedifluorocyclopentanes as precursors of fluorinated
carbasugars by 5-exo-dig radical cyclization
*
`
Gae¨lle Fourriere, Eric Leclerc , Jean-Charles Quirion, Xavier Pannecoucke
Universite´ et INSA de Rouen, CNRS, UMR 6014 C.O.B.R.A. – IRCOF, 1 rue Tesnie`re, 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 polyhydroxylated 1,1-difluoro-5-methylenecyclopentanes is described. The sequence
Received 11 January 2011
Received in revised form 8 February 2011
Accepted 27 February 2011
Available online 16 March 2011
involves an addition of PhSeCF2TMS to
a tartrate-derived aldehyde or its corresponding tert-
butanesulfinylimines followed by a radical cyclization. The use of a benzyl protected substrate led to
an unproductive 1,5-hydrogen transfer after cyclization but the desired compound was eventually
obtained from the unprotected substrate. A hydroboration/oxidation sequence was investigated on
these 1,1-difluoro-5-methylenecyclopentanes as it would provide fluorinated carbasugars, a new and
promising class of glycomimetics. Unfortunately, this reaction was poorly efficient and its
regioselectivity not the expected one.
Keywords:
Nucleosides
Carbasugars
Fluorine
ß 2011 Elsevier B.V. All rights reserved.
Radical cyclization
Fluorinated biomolecules and applications:
Presentation of the research group:
The group entitled ‘‘Synthesis of fluorinated biomolecules’’ is
part of the COBRA laboratory UMR-CNRS-6014 located in Mont-
Sain-Aignan. The group is headed by Xavier Pannecoucke (Pr.
INSA-Rouen), with 6 permanent co-workers: Jean-Philippe
Bouillon (Pr. Univ-Rouen), Dominique Cahard (DR CNRS), Sam-
uel Couve-Bonnaire (lecturer INSA-Rouen), Philippe Jubault (Pr.
INSA-Rouen), Eric Leclerc (CR CNRS) and Jean-Charles Quirion
(Pr. INSA-Rouen).
- Fluorinated glycomimetics (C-glycosides and carba-sugars).
- Fluoroalkene as amide bond mimic: Asymmetric synthesis of
fluorinated dipeptide analogues and synthesis of alkaloid
analogues.
- Fluorinated polyfunctional cyclopropanes as therapeutic
agents.
- Synthesis of trifluoromethylated heterocycles from perfluor-
oketene dithioacetals and g-ketothioesters, for pharmaceuti-
cal applications.
Our research interests are dealing with the development of new
methodologies in fluorine chemistry and their application to the
synthesis of fluorinated biomolecules.
Methodological studies:
Enantioselective electrophilic fluorination and trifluoromethyla-
tion (chiral reagents, organometallic catalysis and organocataly-
sis).
1. Introduction
The development of new nucleoside analogues remains a
productive approach for the development of antitumoral or
antiviral agents. Indeed, these agents may act as inhibitors of
various enzymes involved in the cell or viral replication processes.
Depending on their degree of phosphorylation, inhibition of
thymidilate synthetase, ribonucleotide reductase or DNA poly-
merases may occur, these nucleoside analogues acting either as
competitive inhibitors or alternate substrates [1]. The use of a
Diethylzinc/Ethyldibromofluoroacetate: an original association
for the synthesis of new fluorinated scaffolds.
* Corresponding author. Tel.: +33 2 35 52 29 01; fax: +33 2 35 52 29 59.
E-mail address: eric.leclerc@insa-rouen.fr (E. Leclerc).
0022-1139/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2011.02.015

G. Fourrie`re et al. / Journal of Fluorine Chemistry 134 (2012) 172–179
173
OH
HO
The fluorination of various positions on the base or on the
pentose backbone has been widely studied, especially the
replacement of the hydroxyl group in 2-position of the sugar
backbone which is known to slow down the metabolic cleavage of
the N-glycosidic bond and gave rise to efficient drugs (gemcitabine,
clorofarabine) [3]. We were to our part interested in the synthesis
of CF2-carbocyclic nucleosides III, in which the intracyclic oxygen
atom is replaced by a CF2 group. Such compounds were indeed only
scarcely described and no general method for their preparation
was provided (Scheme 1) [4,5]. The stereoelectronic properties of
the fluorine atom (strong electronegativity, small size) might
nevertheless reasonably impart to these surrogates better mim-
icking abilities than the apolar CH2 group [3b] The synthesis of
fluorinated carbanucleosides obviously required a general method
to prepare fluorocarbocyclic analogues of pentoses. We already
reported a synthetic route to 5-deoxy-CF2-carbasugars based on a
5-exo-trig reductive radical cyclization of a precursor obtained
from an addition of PhSeCF2TMS to the corresponding aldehyde
(Scheme 1) [6]. One of the ways to obtain exact analogues of sugars
using the same strategy was to perform a 5-exo-dig radical
cyclization on a similar substrate featuring a terminal triple bond.
The resulting exo-methylenedifluorocyclopentane could indeed be
adequately functionalized to provide the desired CF2-carbasugar
(Scheme 1). We wish to report herein the work which has been
achieved using such an approach.
X
Base
OH
I (X = O)
II (X = CH2)
III (X = CF2)
Fig. 1. Nucleoside and analogues.
F
F F
F
AIBN
(n-Bu)3SnH
PhSeCF2TMS
TMAF
PhSe
PO
OP
OP
O
OP
OP
PO
OP
PO
Previous work: 5-deoxy-D-arabinose analogues
F
F
F
F
OH
OP
OP
This work
Scheme 1. General retrosynthetic scheme.
OP
OP
O
PO
OP
PO
PO
standard sugar backbone (I, X = O, Fig. 1) with modifications either
on the base or on the substituents of the carbohydrate ring led to
several powerful anticancer or antiviral drugs (5-fluorouracil,
gemcitabine, azidothymidine, zalcitabine). Carbocyclic nucleo-
sides (II, X = CH2, Fig. 1) have more recently emerged in this field
and several lead compounds have been discovered (entecavir,
abacavir, aristeromycin) [2]. Unfortunately, all these compounds
may suffer from a lack of selectivity or bioavailability (and thus
from a certain toxicity) and the need for new analogues with
greater activities and/or lowered side effects has therefore
increased.
2. Results and discussion
The benzyl-protected ynal 3 was prepared from D-diethyltar-
trate 1 using modifications of the literature procedures (Scheme 2).
Aldehyde 2 was obtained, according to Marshall’s procedure, by
benzylation, complete reduction, monoprotection with a tert-
butyldimethylsilyl (TBS) group and oxidation with Dess–Martin
periodinane (DMP) of 1 [7]. The triple bond was introduced using
the Ohira–Bestmann reagent [8] and the remaining alcohol was
deprotected. Aldehyde 3 was obtained after another Dess–Martin
oxidation and subjected to the fluoride-promoted addition of
1- PhSeCF2TMS 2.4 eq.
TBAT 1 eq.
DMF, -60°C
PhSe
F
OTBS
F
O
EtO2C
HO
CO2Et
OH
1- NaH, BnBr, 62%
1- Ohira-Bestmann, 65%
2- TBAF, THF
O
OH
OBn
44% (2 steps), dr = 8:2
2- TBAF, 79%
3- DMP, 58%
2- LiAlH4, 73%
3- n-BuLi, TBSCl, 95%
4- DMP, 76%
BnO
OBn
BnO
OBn
BnO
1
2
3
4
Ac2O, NEt3
82%
PhSe
F
F
OAc
F
F
F
F
F
F
H
OAc
5-exo-dig
OAc
OBn
OAc
OBn
H
BnO
OBn
O
BnO
BnO
OBn
Ph
6
5
1,5-H transfer
Bu3SnH
AIBN
31%
F
F
F F
F
F
OAc
OAc
OBn
H
OAc
OBn
- PhCHO
O
OBn
Ph
7
Scheme 2. First synthesis with a benzyl-protected substrate.

174
G. Fourrie`re et al. / Journal of Fluorine Chemistry 134 (2012) 172–179
PhSe
O
F
OTBS
F
+
EtO2C
HO
CO2Et
OH
HO
OTBS
1- Me2C(OMe)2, H , 97%
1- IBX, 92%
1- TBAF, 91%
OH
2- Ohira-Bestmann, 62%
2- (i) IBX, AcOEt
(ii) PhSeCF2TMS 2.4 eq.
TBAT 1 eq.
2- LiAlH4, 84%
O
O
O
O
O
3- NaH, TBSCl, 67%
1
8
9
DMF, -60°C
10a
10b
(iii) TBAF, THF
31% (3 steps), dr = 1:1
TFA/H2O
93-96%
PhSe
F
F
F
F
OH
OH
OH
OH
Bu3SnH, AIBN
64%
HO
HO
for both diastereomers
12a
12b
11a
11b
Scheme 3. Synthesis of an exo-methylene-1,1-difluoro-2,3,4-tris(hydroxy)-cyclopentane.
PhSeCF2TMS [9]. The two-step sequence involving a subsequent
deprotection of the OH/OTMS mixture obtained from the addition
provided the desired compound 4 in moderate yield and with the
usual diastereoselectivity [6]. Up to that point, the only marked
difference compared to our previous work on enals concerns the
fluoride source that was used for the addition. Indeed, the addition
proceeded smoothly on most of the enals using TMAF in DCM
whereas this ynal required the use of TBAT in DMF as a promoter in
order to obtain satisfactory yields. The radical precursor 5 was
obtained after acetylation of 4 and subjected to the standard
reductive radical cyclization conditions [6,10]. Unfortunately,
compound 7 was obtained in 31% yield instead of the expected
5-exo-dig radical cyclization product 6. The formation of 7 can be
explained by a favorable 1,5-hydrogen transfer which takes place
after the cyclization and prevent the reduction to 6. The resulting
stabilized benzylic radical undergoes an irreversible fragmentation
reaction that yields benzaldehyde and an allylic radical. A final
reduction of the latter with tin hydride affords 7 through a process
that has already been reported on a non-fluorinated similar
substrate [11].
appeared that a simple switch in the protecting groups should
solve the problem. synthesis of the acetonide-protected
aldehyde was thus performed using a sequence similar to the
previous one [12]. Alcohol 8 was prepared according to the
literature procedure in three steps from 1 [12a,13]. The reported
synthesis of 9 was slightly modified, using an IBX oxidation instead
A
of the Swern reaction (Scheme 3) [12b,13].
A subsequent
deprotection and another IBX oxidation afforded a moderately
stable ynal which was not purified and directly subjected to the
PhSeCF2TMS addition/deprotection sequence. Compound 10 was
obtained in 31% yield over three steps from 9. Surprisingly, the
usual 8:2 diastereoselectivity dropped to 1:1 on this compound.
The reason for this loss of selectivity remains unclear but is
probably related to the conformational rigidity associated with an
acetonide protecting group for this particular C-2/C-3 relative
configuration [6]. The two diastereomers 10a and 10b could
however be separated and the acetonide group has been removed
on each one of them prior to cyclization. Compounds 11a and 11b
underwent an efficient radical cyclization to provide the expected
exo-methylenedifluorocyclopentanes 12a and 12b in 64% yield for
both compounds (Scheme 3).
This result was nonetheless encouraging since the targeted 5-
exo-dig radical cyclization did occur despite subsequent degrada-
tion reactions. As the benzyl-protecting group is responsible for
the hydrogen transfer and the fragmentation, it immediately
A similar sequence was applied to the tert-butanesulfinylimine
13 derived from the same aldehyde. Alcohol 9 was again oxidized
with IBX and the crude aldehyde condensed with Ellman’s
O
PhSe
F
F
PhSe
TMS
F
F
1- IBX, AcOEt
S
1-TFA/H2O, 86%
H
H
O
9
O
N
N
N
O
S
S
S
PhSeCF2TMS 2.4 eq.
TBAT 1 eq.
2- K2CO3, MeOH, 93%
H2N
2-
O
O
O
O
HO
OH
DMF, -60°C
65%, dr > 98:02
15
Ti(OEt)4, THF
48% (2 steps)
13
14
Bu3SnH, AIBN
56%
O
F
F
S
NH
OH
HO
16
Scheme 4. Synthesis of an exo-methylene-2-amino-3,4-bis(hydroxy)-1,1-difluorocyclopentane.

G. Fourrie`re et al. / Journal of Fluorine Chemistry 134 (2012) 172–179
175
F
F
F
F
F F
a failure. Poor yields and an unexpected regioselectivity were
indeed obtained and another route to fluorocarbocyclic analogues
of pentoses and nucleosides has thus to be disclosed. Work is
currently in progress in our laboratory to bring solutions to this
synthetic challenge.
OH
1- Borane, THF
0°C or RT
HO
OBn
OBn
OBn
OBn
+
2- NaOH, H2O2
OBn
OBn
BnO
BnO
BnO
17
18
19
9%
35%
4. Experimental
BH3.THF
thexylborane
9-BBN
3%
/
12%
/
4.1. General
All reactions were carried out under an argon atmosphere with
dry solvents under anhydrous conditions, unless otherwise noted.
Dry THF, DMF, or CH2Cl2 were obtained by drying over Na/
benzophenone (THF) or barium oxide (DMF) or P2O5 (CH2Cl2) and
distillation. All reagents were purchased from commercial sources
and used without further purification. Reactions were monitored
by thin-layer chromatography (TLC) carried out on 0.25 mm silica
gel plates using UV light as a visualizing agent and an ethanolic
solution of phosphomolybdic acid, p-anisaldehyde or potassium
permanganate, and heat as developing agents. Chromatographic
purifications were carried out using silica gel columns (60, particle
size 0.040–0.063 mm or 0.070–0.200 mm) or automated equip-
Scheme 5. Hydroboration of an exo-methylenedifluorocyclopentane.
auxiliary to afford 13 in 48% overall yield. The PhSeCF2TMS
addition was performed according to the reported procedure [10f]
to afford 14 in 65% yield and as a single diastereomer (Scheme 4).
The silylation of the triple bond was not anticipated and might
result from the weak stability of the N–Si bond of the first
intermediate: an equilibration and a transfer of the silicon group
from the sulfinamide to the alkyne might take place. The higher
stability of the O–Si bond prevent this side-reaction in the case of 4
and 10. This high diastereoselectivity (matched case) is in
agreement with the previously reported results obtained on
eneimines [6b]. The triple bond was however silylated during the
process and a complete deprotection was thus performed prior to
the cyclization which proceeded smoothly to afford 16 in 56% yield
(Scheme 4).
Having in hand functionalized exo-methylenedifluorocyclo-
pentanes, our next move was to investigate the hydroboration/
oxidation of the double bond in order to prepare fluorocarbocyclic
analogues of arabinose. The hydroboration of the unprotected
compounds 12 with BH3.THF either led to incomplete conversion
or to degradation of the starting material when an excess of
reagent was used. Both diastereomers were thus benzylated and
compounds 17 were subjected to a hydroboration/oxidation
sequence which provided alcohols 18 and 19 in low yields
(Scheme 5). Surprisingly, a Markovnikov-type regioselectivity was
observed for this reaction since 19 was the major compound. The
use of sterically hindered boranes such as thexylborane or 9-BBN
only led to a loss of reactivity without improving the regioselec-
tivity. It has already been reported in the literature that a CF2 group
ment with pre-packed silica cartridges. 1H NMR, 13C NMR and 19
F
NMR spectra were recorded on a 300 MHz instrument and
calibrated using residual undeuterated solvent as an internal
reference. The following abbreviations were used to explain the
multiplicities: s = singlet, d = doublet, t = triplet, q = quadruplet,
m = multiplet, app = apparent. Mass spectrometry (MS) experi-
ments were performed using electrospray ionization (ESI). IR
spectra were recorded on a FT-IR Spectrometer. Optical rotations
were measured at 20 8C and with
expressed in cg mLÀ1
l = 589 nm; concentrations are
.
4.2. (2S,3R)-2,3-Bis(benzyloxy)pent-4-ynal (3)
To a flask containing 2 [7] (522 mg, 1.26 mmol) were added
Bestmann–Ohira reagent (362 mg, 1.89 mmol, 1.5 equiv.), MeOH
(20 mL) and K2CO3 (348 mg, 2.52 mmol, 2 equiv.) in one portion.
The resulting suspension was stirred at room temperature
overnight where after saturated aqueous NH4Cl was added. The
resulting solution was extracted with Et2O, and the combined
extracts were dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude residue was then purified by flash
column chromatography (cyclohexane/EtOAc 95:05) to afford
(2S,3R)-2,3-bis(benzyloxy)-4-{[tert-butyl(dimethyl)silyl]oxy}-
pent-1-yne (336 mg, 65%) as a colorless oil. Rf = 0.51 (5% EtOAc in
a
to the double bond could favor this type of regioselectivity and
that the Markovnikov regioisomer could even be the exclusive one
when electrophilic boranes such as HBCl2 are used [14]. However,
the steric hindrance of C-4 and the boranes which were used
should have led to a classical anti-Markovnikov regioselectivity
and this result remains puzzling, even in light of the literature
reports.
cyclohexane). 1H NMR (300 MHz, CDCl3)
d 7.40–7.28 (m, 10H), 4.84
(d, J = 11.7 Hz, 1H), 4.78 (dd, J = 16.7 Hz, J = 11.6 Hz, 2H), 4.55 (d,
J = 11.7 Hz, 1H), 4.30 (dd, J = 10.7 Hz, J = 2.11 Hz, 1H), 3.93–3.88 (m,
1H), 3.81–3.71 (m, 1H), 3.65 (dd, J = 10.3 Hz, J = 5.3 Hz, 1H), 2.51 (d,
J = 2.1 Hz, 1H), 0.88 (s, 9H), 0.03 (s, 6H). 13C NMR (75.5 MHz, CDCl3)
3. Conclusion
d
138.9, 138.0, 128.7, 128.6, 128.5, 128.3, 128.0, 127.8, 81.7, 80.9,
An efficient preparation of polyfunctionalized 1,1-difluoro-5-
methylenecyclopentanes has thus been carried out. The synthetic
pathway involves an addition of PhSeCF2TMS to tartrate-derived
aldehydes or tert-butanesulfinylimines featuring a terminal triple
bond followed by a reductive 5-exo-dig radical cyclization. The
PhSeCF2TMS addition proceeded in agreement with our previous
reports except for the aldehyde derived from 9 for which no
diastereoselectivity was observed. The reductive 5-exo-dig radical
cyclization was efficient in all cases despite an undesired 1,5-
hydrogen transfer in the case of 6 which changed the course of the
reaction to afford 7 instead of the expected compound. These exo-
methylenedifluorocyclopentanes appeared as a nice entry to
fluorocarbocyclic analogues of pentoses but, to our disappoint-
ment, the final and crucial hydroboration/oxidation sequence was
75.5, 74.0, 71.3, 69.0, 63.3, 26.2, 18.6, À5.1. IR (neat) nmax 3306,
2929, 1094 cmÀ1. MS (ESI+): m/z = 428.13 ([M+H2O]+). Anal. Calcd.
for C25H34O3Si: C, 73.13; H, 8.35. Found: C, 72.78; H, 8.29. To a
solution of (2S,3R)-2,3-bis(benzyloxy)-4-{[tert-butyl(dimethyl)si-
lyl]oxy}pent-1-yne (1.5 g, 3.7 mmol) in dry THF (45 mL) was added
a solution of TBAF (1 M in THF, 4.5 mL, 4.5 mmol, 1.2 equiv.). The
mixture was then stirred at room temperature for 1 h, then water
was added and the product was extracted with CH2Cl2. The organic
phase was dried over MgSO4, filtered and concentrated under
reduced pressure. The crude residue was then purified by flash
column chromatography (cyclohexane/EtOAc 90:10 then 85:15) to
afford (2R,3R)-2,3-bis(benzyloxy)pent-4-yn-1-ol (840 mg, 91%) as
a colorless oil. Rf = 0.33 (20% EtOAc in cyclohexane). 1H NMR
(300 MHz, CDCl3) d 7.38–7.27 (m, 10H), 4.87 (d, J = 8.4 Hz, 1H), 4.84

176
G. Fourrie`re et al. / Journal of Fluorine Chemistry 134 (2012) 172–179
(d, J = 8.4 Hz, 1H), 4.66 (d, J = 11.8 Hz, 1H), 4.55 (d, J = 11.8 Hz, 1H),
4.33 (dd, J = 5.9 Hz, J = 2.2 Hz, 1H), 3.94–3.86 (m, 1H), 3.83–3.78
(m, 1H), 3.76–3.70 (m, 1H), 2.58 (d, J = 2.1 Hz, 1H), 2.07 (dd,
reduced pressure. The crude residue was then purified by flash
chromatography using cyclohexane/EtOAc (95:05) as eluent to
afford the desired product 5 (430 mg, 82%) as a pale yellow oil.
J = 6.8 Hz, J = 5.5 Hz, 1H). 13C NMR (75.5 MHz, CDCl3)
d
138.3,
137.6, 128.8, 128.3, 128.2, 80.6, 77.6, 76.6, 73.9, 71.4, 70.2, 62.6. IR
(neat)
max 3418, 3287, 2874, 1072 cmÀ1. MS (ESI+): m/z = 314.43
Rf = 0.12 (5% EtOAc in cyclohexane). [
a
]
D = À41.7 (c 1.3, CHCl3). 1H
NMR (300 MHz, CDCl3)
d
7.71 (d, J = 8.3 Hz, 2H), 7.44–7.28 (m,
n
13H), 5.78 (td, J = 10.8 Hz, J = 2.1 Hz, 1H), 4.94–4.75 (m, 3H), 4.47
(d, J = 11.4 Hz, 1H), 4.25 (dd, J = 7.3 Hz, J = 2.1 Hz, 1H), 4.15 (dd,
J = 7.3 Hz, J = 2.1 Hz, 1H), 2.54 (d, J = 2.1 Hz, 1H), 2.14 (s, 3H). 19F
([M+H2O]+1,30), 615.00 ([2M+Na]+). Anal. Calcd. for C19H20O3: C,
77.00; H, 6.80. Found: C, 77.09; H, 7.03. To a solution of (2R,3R)-2,3-
bis(benzyloxy)pent-4-yn-1-ol (1.0 g, 3.4 mmol) in CH2Cl2 (10 mL)
at room temperature was added Dess–Martin reagent (15 wt% in
CH2Cl2, 8.5 mL, 3.9 mmol, 1.1 equiv.). After 1 h the reaction
mixture was diluted with ether and a solution of Na2S2O3 in
saturated aqueous NaHCO3 was poured into the flask. After 10 min
stirring, the two layers were separated and the ether layer was
washed with saturated aqueous NaHCO3. The combined aqueous
phases were extracted twice with ether, and the combined ether
extracts were dried over MgSO4 and concentrated. The crude
residue was then purified by flash column chromatography
(cyclohexane/EtOAc 90:10 then 80:20) to afford the desired
product 3 (862 mg, 87%) as a colorless oil. 1H NMR (300 MHz,
NMR (282.5 MHz, CDCl3)
d
À76.7 (dd, J = 215.9 Hz, J = 11.0 Hz, 1F),
À78.1 (dd, J = 215.9 Hz, J = 11.0 Hz, 1F). 13C NMR (75.5 MHz, CDCl3)
d
169.6, 137.9, 137.8, 137.7, 137.5, 137.0, 129.9, 129.4, 129.0,
128.7, 128.6, 128.4, 128.3, 128.2, 124.8 (t, J = 300.0 Hz), 124.0, 79.3,
77.6, 77.0, 75.4, 72.5 (t, J = 25.7 Hz), 71.6, 70.1, 21.2. IR (neat) nmax
3285, 3063, 2871, 1760, 1217, 1071 cmÀ1. MS (ESI+): m/z = 562.07
([M+H2O]+). Anal. Calcd. for C28H26F2O4Se: C, 61.88; H, 4.82.
Found: C, 61.63; H, 5.07.
4.5. (4S,5R)-5-(O-Acetyl)-4-(O-benzyl)-1,1-difluoro-2-
methylcyclopent-2-en-4,5-diol (7)
CDCl3)
d
9.69 (s, 1H), 7.39–7.27 (m, 10H), 4.86–4.75 (m, 3H), 4.55
To a solution of compound 5 (100 mg, 0.18 mmol) in t-BuOH
(4 mL) was added AIBN (9 mg, 0.06 mmol, 0.3 equiv.). The mixture
was then degassed, heated at 80 8C and a degassed solution of
(d, J = 15.6 Hz, 1H), 4.45 (dd, J = 4.3 Hz, J = 2.3 Hz, 1H), 3.94 (dd,
J = 4.4 Hz, J = 1.5 Hz, 1H), 2.63 (d, J = 2.3 Hz, 1H).
Bu3SnH (74
mL, 0.28 mmol, 1.5 equiv.) in t-BuOH (2 mL) was added
4.3. (2R,3S,4S)-3,4-Bis(O-benzyl)-1,1-difluoro-1-(phenylselanyl)-
dropwise via a syringe pump over 45 min. After 1 h, the solvent
was evaporated and the crude residue was purified by flash
chromatography using cyclohexane/EtOAc (99:01 then 98:02) as
eluent to afford product 7 (16 mg, 31%) as a pale yellow oil.
hex-5-yn-2,3,4-triol (4)
To
a solution of aldehyde 3 (862 mg, 2.93 mmol) and
PhSeCF2TMS (1.96 g, 7.03 mmol, 2.4 equiv.), with suspended MS
Rf = 0.41 (10% EtOAc in cyclohexane). [
NMR (300 MHz, CDCl3) 7.39–7.27 (m, 5H), 5.91 (s, 1H), 5.32 (ddd,
J = 11.4 Hz, J = 5.2 Hz, J = 3.1 Hz, 1H), 4.60 (dd, 2H), 4.48–4.45 (m,
1H), 2.15 (s, 3H), 1.60 (s, 1H). 19F NMR (282.5 MHz, CDCl3)
À97.0
(ddd, J = 259.0 Hz, J = 10.7 Hz, J = 9.0 Hz, 1F), À110.8 (dd,
J = 257.8 Hz, J = 3.1 Hz, 1F). 13C NMR (75.5 MHz, CDCl3)
169.9,
a]
D = +72.0 (c 0.7, CHCl3). 1H
˚
4 A, in dry DMF (20 mL) at À60 8C was added TBAT (1.57 g,
d
2.93 mmol, 1 equiv.). The reaction mixture was allowed to stir at
À60 8C for 1 h. Water was then added and the aqueous layer was
extracted with CH2Cl2. The combined organic layers were then
washed with brine, dried over MgSO4, filtered and concentrated
under reduced pressure. To a solution of the crude residue in dry
THF (50 mL) was added a solution of TBAF (1 M in THF, 5.86 mL,
5.86 mmol, 2 equiv.). The mixture was then stirred at room
temperature for 1 h. Water was then added and the aqueous layer
was extracted with CH2Cl2. The combined organic layers were
dried over MgSO4, filtered and concentrated under reduced
pressure. The crude residue was then purified by flash chroma-
tography using cyclohexane/EtOAc (gradient from 99:01 to 90:10)
and the two diastereomers could be separated to afford 4 (486 mg)
and the minor (2R,3R,4R) diastereomer (156 mg, 44% overall) as
d
d
137.7, 133.4 (t, J = 8.7 Hz), 128.9, 128.4, 128.2, 124.8 (t,
J = 249.6 Hz), 82.0 (d, J = 4.4 Hz), 78.4 (dd, J = 27.3 Hz,
J = 19.3 Hz), 72.3, 20.9, 10.6. IR (neat) nmax 2925, 1757, 1234,
1096 cmÀ1. MS (ESI+): m/z = 300.13 ([M+H2O]+). Anal. Calcd. for
C15H16F2O3: C, 63.82; H, 5.71. Found: C, 63.79; H, 6.05.
4.6. (2R,3S,4S) and (2S,3S,4S)-3,4-(O-isopropylidene)-1,1-difluoro-1-
(phenylselanyl)-hex-5-yn-2,3,4-triol (10)
To a solution of compound 9 (1.6 g, 5.9 mmol) in dry THF
(50 mL) was added a solution of TBAF (1 M in THF, 7.1 mL,
7.1 mmol, 1.2 equiv.) and the mixture was stirred at room
temperature for 1 h. Water was then added and the product
was extracted with CH2Cl2. The organic phase was dried over
MgSO4, filtered and concentrated under reduced pressure. The
crude residue was then purified by flash column chromatography
(cyclohexane/EtOAc 90:10 then 80:20) to afford (2R,3R)-2,3-(O-
isopropylidene)pent-4-yn-1-ol(840 mg, 91%) as a colorless oil.
yellow oils. Rf = 0.30 (10% EtOAc in cyclohexane). [
a
]
D = À11.5 (c
1.2, CHCl3). 1H NMR (300 MHz, CDCl3)
d
7.74 (d, J = 7.3 Hz, 2H),
7.43–7.28 (m, 13H), 4.94 (d, J = 10.7 Hz, 1H), 4.87 (d, J = 11.9 Hz,
1H), 4.71 (d, J = 10.7 Hz, 1H), 4.56 (d, J = 11.9 Hz, 1H), 4.36 (dd,
J = 8.0 Hz, J = 2.2 Hz, 1H), 4.34–4.24 (m, 1H), 4.07 (d, J = 8.0 Hz, 1H),
3.24 (d, J = 10.7 Hz, 1H), 2.57 (d, J = 2.2 Hz, 1H). 19F NMR
(282.5 MHz, CDCl3)
d
À79.3 (dd, J = 209.0 Hz, J = 8.1 Hz, 1F),
À82.7 (dd, J = 209.5 Hz, J = 15.6 Hz, 1F). 13C NMR (75.5 MHz,
CDCl3)
d
137.7, 137.5, 129.8, 129.5, 128.8, 128.7, 128.4, 128.3,
Rf = 0.22 (20% EtOAc in cyclohexane). [
NMR (300 MHz, CDCl3) 4.58 (dd, J = 7.6 Hz, J = 2.2 Hz, 1H), 4.18
a]
D = +13.8 (c 1.3, CHCl3). 1H
128.2, 127.3 (t, J = 300.2 Hz), 124.0, 79.5, 77.6, 75.5, 73.3 (dd,
J = 26.2 Hz, J = 23.8 Hz), 71.9, 71.3. Anal. Calcd. for C26H24F2O3Se: C,
62.28; H, 4.82. Found: C, 61.95; H, 5.07.
d
(dt, J = 6.6 Hz, J = 2.7 Hz, 1H), 3.90 (dd, J = 12.4 Hz, J = 3.1 Hz, 1H),
3.68 (dd, J = 12.4 Hz, J = 3.7 Hz, 1H), 2.55 (d, J = 2.2 Hz, 1H), 1.90 (br
s, 1H), 1.50 (s, 3H), 1.44 (s, 3H). 13C NMR (75.5 MHz, CDCl3)
d 111.0,
4.4. (2R,3S,4R)-2-Acetoxy-3,4-bis(benzyloxy)-1,1-difluoro-1-
82.2, 80.9, 75.2, 66.5, 61.0, 27.0, 26.3. IR (neat) nmax 3434, 3290,
2990, 2937, 1384, 1216, 1068 cmÀ1. MS (EI): m/z = 141.1 ([M-
CH3]+). Anal. Calcd. for C8H12O3: C, 61.52; H, 7.74. Found: C, 61.51;
H, 7.85. (2R,3R)-2,3-(O-Isopropylidene)pent-4-yn-1-ol (200 mg,
1.28 mmol) was dissolved in EtOAc (8 mL). IBX (1.08 g, 3.84 mmol,
3 equiv.) was added and the mixture was refluxed for 7 h (TLC
cyclohexane/EtOAc 80:20). The reaction was filtered through a
sintered glass funnel to remove the excess IBX and its byproducts
and washed with EtOAc. The solvent was removed under reduced
phenylselanyl-hex-5-yne (5)
To a solution of compound 4 (486 mg, 0.97 mmol) in dry CH2Cl2
(20 mL) was added triethylamine (0.23 mL, 1.68 mmol, 1.7 equiv.),
DMAP (15 mg, 0.12 mmol, 0.1 equiv.) and Ac2O (0.18 mL,
1.94 mmol, 2 equiv.). The mixture was stirred at room temperature
for 1 h, then water was added and the organic layer was washed
with brine, dried over MgSO4, filtered and concentrated under

G. Fourrie`re et al. / Journal of Fluorine Chemistry 134 (2012) 172–179
177
pressure to give the crude aldehyde (217 mg, quantitative yield) as
a colorless oil. This unstable aldehyde was used for the next step
without further purification. To a solution of aldehyde (200 mg,
1.28 mmol) and PhSeCF2TMS (859 mg, 3.07 mmol, 2.4 equiv.), with
131.0, 130.9, 130.8, 129.8 (t, J = 299.8 Hz), 127.1, 85.1, 75.9 (t,
J = 22.1 Hz), 75.2, 75.0, 64.1. IR (neat) nmax 3296, 1061 cmÀ1. MS
(EI): m/z = 322.0 ([M]+). Anal. Calcd. for C12H12F2O3Se: C, 44.87; H,
3.77. Found: C, 45.02; H, 3.80.
˚
suspended MS 4 A, in dry DMF (20 mL) at À60 8C was added TBAT
(685 mg, 1.28 mmol, 1 equiv.). The reaction mixture was allowed
to stir at À60 8C for 1 h. Water was then added and the aqueous
layer was extracted with CH2Cl2. The combined organic layers
were then washed with brine, dried over MgSO4, filtered and
concentrated under reduced pressure. To a solution of the crude
residue in dry THF was added a solution of TBAF (1 M in THF,
2.56 mL, 2 equiv.). The mixture was then stirred at room
temperature for 1 h. Water was then added and the aqueous layer
was extracted with CH2Cl2. The combined organic layers were
dried over MgSO4, filtered, and concentrated under reduced
pressure. The crude residue was then purified by flash chroma-
tography using cyclohexane/EtOAc (gradient from 99:01 to 90:10)
as eluent to afford the separated (2S,3R,4R) and (2R,3R,4R)
diastereomers 10a and 10b (63 mg and 71 mg respectively, 31%
overall) as yellow oils. 10a: Rf = 0.19 (10% EtOAc in cyclohexane).
4.8. (2R,3S,4S) and (2S,3S,4S)-1,1-difluoro-5-
methylenecyclopentane-2,3,4-triol (12)
The same procedure as for the preparation of 7 was applied to
11a and 11b. In each case, the crude residue was purified by flash
chromatography using CH2Cl2/MeOH (95:05 then 80:20) as eluent
to afford 12a or 12b (64%) as a pale yellow oil. 12a: Rf = 0.24 (5%
MeOH in CH2Cl2). [
MeOD) 5.81 (dt, J = 5.9 Hz, J = 3.0 Hz, 1H), 5.66 (dt, J = 5.3 Hz,
a]
D = +84.5 (c 1.2, MeOH). 1H NMR (300 MHz,
d
J = 2.7 Hz, 1H), 4.20–4.17 (m, 1H), 3.83 (td, J = 11.9 Hz, J = 9.2 Hz,
1H), 3.63 (td, J = 8.4 Hz, J = 2.5 Hz, 1H). 19F NMR (282.5 MHz,
MeOD)
J = 252.4 Hz, J = 11.5 Hz, J = 3.7 Hz, 1F). 13C NMR (75.5 MHz, MeOD)
147.5 (dd, J = 21.0 Hz, J = 19.7 Hz), 120.5 (t, J = 251.1 Hz), 118.0,
d
À104.5 (dd, J = 251.7 Hz, J = 12.2 Hz, 1F), À106.0 (ddt,
d
81.0 (d, J = 6.3 Hz), 78.2 (dd, J = 23.7 Hz, J = 19.7 Hz), 74.8 (t,
J = 3.7 Hz). IR (neat) nmax 3271, 1045 cmÀ1. MS (CI+): m/z = 167
([M+H]+). Anal. Calcd. for C6H8F2O3: C, 43.38; H, 4.85. Found: C
[a] d 7.73 (d,
D = +27.9 (c 1.4, CHCl3). 1H NMR (300 MHz, CDCl3)
J = 7.7 Hz, 2H), 7.46–7.33 (m, 3H), 4.61 (dd, J = 7.7 Hz, J = 2.1 Hz,
1H), 4.40 (dd, J = 7.7 Hz, J = 1.5 Hz, 1H), 3.96–3.85 (m, 1H), 2.91 (d,
43.54; H, 4.82. 12b: Rf = 0.23 (10% MeOH in CH2Cl2). [
a]D = +20.3 (c
5.77 (dt, J = 5.3 Hz,
J = 10.7 Hz, 1H), 2.57 (d, J = 1.8 Hz, 1H), 1.52 (s, 3H), 1.47 (s, 3H). 19
F
0.8, MeOH). 1H NMR (300 MHz, MeOD)
d
NMR (282.5 MHz, CDCl3)
d
À79.6 (dd, J = 212.9 Hz, J = 8.2 Hz, 1F),
J = 2.7 Hz, 1H), 5.63 (dt, J = 5.3 Hz, J = 2.7 Hz, 1H), 4.45–4.41 (m,
1H), 4.02 (q, J = 4.7 Hz, 1H), 3.79 (dt, J = 8.7 Hz, J = 4.4 Hz, 1H). 19F
À81.6 (dd, J = 213.1 Hz, J = 14.3 Hz, 1F). 13C NMR (75.5 MHz, CDCl3)
d
137.8, 130.0, 129.6, 126.3 (t, J = 168.5 Hz), 112.3, 79.6, 77.6, 76.0,
NMR (282.5 MHz, MeOD)
d
À96.2 (d, J = 259.0 Hz, 1F), À110.9 (d,
148.8 (t,
72.2 (t, J = 25.0 Hz), 67.8, 26.8, 26.6. Anal. Calcd. for C15H16F2O3Se:
C, 49.87; H, 4.46. Found: C, 50.10; H, 4.34. 10b: Rf = 0.13 (10%
J = 258.0 Hz, 1F). 13C NMR (75.5 MHz, MeOD)
d
J = 20.9 Hz), 122.6 (dd, J = 258.0 Hz, J = 245.5 Hz), 118.6, 77.5,
76.9 (t, J = 2.7 Hz), 75.0 (dd, J = 30.7 Hz, J = 18.1 Hz). Anal. Calcd. for
C6H8F2O3: C, 43.38; H, 4.85. Found: C 43.41; H, 4.79.
EtOAc in cyclohexane).
(300 MHz, CDCl3) 7.73 (d, J = 8.3 Hz, 2H), 7.46–7.33 (m, 3H),
[a]
D = +9.4 (c 1.1, CHCl3). 1H NMR
d
4.90 (dd, J = 5.9 Hz, J = 2.1 Hz, 1H), 4.50 (t, J = 5.0 Hz, 1H), 4.18–4.08
(m, 1H), 2.67 (d, J = 4.7 Hz, 1H), 2.53 (d, J = 2.1 Hz, 1H), 1.52 (s, 3H),
4.9. N-{[(4R,5R)-5-Ethynyl-2,2-dimethyl-1,3-dioxolan-4-
1.45 (s, 3H). 19F NMR (282.5 MHz, CDCl3)
d
À78.5 (dd, J = 215.1 Hz,
yl]methylene}-2-methylpropane-2-sulfinamide (13)
J = 7.9 Hz, 1F), À82.8 (dd, J = 214.9 Hz, J = 15.5 Hz, 1F). 13C NMR
(75.5 MHz, CDCl3)
d
137.8, 130.1, 129.9, 129.8, 129.6, 129.5, 123.7
Compound 9 (156 mg, 1.0 mmol) was dissolved in EtOAc
(6.5 mL). IBX (839 mg, 3.0 mmol, 3 equiv.) was added and the
mixture was refluxed for 7 h (TLC cyclohexane/EtOAc 80:20). The
reaction was filtered through a sintered glass funnel to remove the
excess IBX and its byproducts and washed with EtOAc. The solvent
was removed under reduced pressure to give the crude aldehyde
(217 mg, quantitative yield) as a colorless oil. This unstable
aldehyde was used in the next step without further purification. To
a solution of aldehyde (154 mg, 1.00 mmol) and Ti(OEt)4 (0.50 mL,
2.00 mmol, 2 equiv.) in 5 mL of anhydrous THF was added (S)-2-
methyl-2-propanesulfinamide (121 mg, 1.00 mmol, 1 equiv.) and
the mixture was refluxed for 1 h. Saturated aqueous NaCl (5 mL)
was then added under vigorous stirring, and the suspension
formed was filtered through celite and washed with EtOAc. The
filtrate was then washed with 10 mL of saturated aqueous NaCl
and the aqueous layer extracted with EtOAc. The combined organic
layers were dried over MgSO4, filtered and concentrated under
reduced pressure. The crude residue was then purified by flash
chromatography (cyclohexane/EtOAc85:15) to afford the desired
product 13 (123 mg, 48% over 2 steps) as a yellow oil. Rf = 0.42 (40%
(t, J = 149.3 Hz), 111.4, 82.1, 80.4, 74.7, 74.3 (dd, J = 26.7 Hz,
J = 22.5 Hz), 66.3 (d, J = 2.7 Hz), 27.0, 25.9. IR (neat) nmax 3435,
3299, 1060 cmÀ1. MS (EI): m/z = 362.0 ([M]+), 347.0 ([MÀCH3)+].
Anal. Calcd. for C15H16F2O3Se: C, 49.87; H, 4.46. Found: C, 49.96; H,
4.57.
4.7. 1,1-Difluoro-1-(phenylselanyl)-hex-5-yne-2,3,4-triol (11)
A solution of compound 10 (204 mg, 0.56 mmol) in a mixture of
TFA (0.47 mL) and H2O (0.12 mL) was stirred at room temperature
for 3 h. The mixture was then concentrated under reduced
pressure, co-evaporated twice with CHCl3 and lyophilized
overnight. The crude residue was then purified by flash chroma-
tography using CH2Cl2/MeOH (gradient from 100:00 to 98:2) as
eluent to afford the desired product 11 (174 mg, 96%) as a white
solid. 11a: Rf = 0.19 (5% MeOH in CH2Cl2). [
a
]
D = À14.6 (c 1.2,
MeOH). 1H NMR (300 MHz, CD3OD)
d
7.74 (d, J = 6.9 Hz, 2H), 7.47–
7.35 (m, 3H), 4.35 (dd, J = 8.3 Hz, J = 2.2 Hz, 1H), 4.22 (t, J = 11.0 Hz,
2H), 3.89 (d, J = 8.2 Hz, 1H), 2.92 (d, J = 2.2 Hz, 1H). 19F NMR
(282.5 MHz, CD3OD)
d
À79.4 (dd, J = 210.5 Hz, J = 10.9 Hz, 1F),
EtOAc in cyclohexane). 1H NMR (CDCl3, 300 MHz):
d 8.06 (d,
À80.5 (dd, J = 210.2 Hz, J = 11.2 Hz, 1F). 13C NMR (75.5 MHz,
J = 3.8 Hz, 1H), 4.84–4.76 (m, 2H), 2.60 (d, J = 2.1 Hz, 1H), 1.46 (s,
3H), 1.42 (s, 3H), 1.23 (s, 9H).
CD3OD)
d
139.3, 131.2, 130.9, 129.6 (t, J = 298.1 Hz), 126.5, 84.0,
77.0, 75.0 (t, J = 24.2 Hz), 74.4 (d, J = 2.9 Hz), 65.5. Anal. Calcd. for
C
12H12F2O3Se: C, 44.87; H, 3.77. Found: C, 45.11; H, 3.75. 11b:
4.10. (SS,2R,3R,4S)-2-tert-Butanesulfinamido-3,4-(O-
isopropylidene)-6-trimethylsilyl-1,1-difluoro-1-phenylselanyl-hex-5-
yne (14)
Rf = 0.29 (5% MeOH in CH2Cl2). [
(300 MHz, CD3OD)
a
]
D = À12.0 (c 1.4, MeOH). 1H NMR
d
7.74 (d, 2H), 7.43–7.30 (m, 3H), 4.66 (t,
J = 2.1 Hz, 1H), 4.07 (q, J = 10.0 Hz, 1H), 3.83 (dd, J = 8.5 Hz,
J = 2.2 Hz, 1H), 2.83 (d, J = 2.3 Hz, 1H). 19F NMR (282.5 MHz,
To a solution of 13 (709 mg, 2.76 mmol) and PhSeCF2TMS
˚
CD3OD)
d
À77.6 (dd, J = 205.0 Hz, J = 10.9 Hz, 1F), À81.0 (dd,
139.3,
(1.85 g, 6.62 mmol, 2.4 equiv.), with suspended MS 4 A, in dry DMF
J = 206.3 Hz, J = 10.2 Hz, 1F). 13C NMR (75.5 MHz, CD3OD)
d
(22 mL) at À60 8C was added TBAT (1.49 g, 2.76 mmol, 1 equiv.).

178
G. Fourrie`re et al. / Journal of Fluorine Chemistry 134 (2012) 172–179
The reaction mixture was allowed to stir at À60 8C for 2 h. A
saturated solution of NH4Cl and water were then added and the
aqueous layer was extracted with EtOAc. The combined organic
layers were then washed with water, dried over MgSO4, filtered
and concentrated under reduced pressure. The crude residue was
then purified by flash chromatography using cyclohexane/EtOAc
(gradient from 99:01 to 90:10) as eluent to afford product 14
(960 mg, 65%) as a yellow oil. Rf = 0.52 (30% EtOAc in cyclohexane).
n
max 3394, 1681, 1044 cmÀ1. MS (EI): m/z = 269 ([M]+). Anal. Calcd.
for C10H17F2NO3S: C, 44.60; H, 6.36; N, 5.20; S, 11.91. Found: C,
44.57; H, 6.38; N, 5.24; S, 11.93.
4.13. (2R,3S,4S) and (2S,3S,4S)-2,3,4-tris(O-benzyl)1,1-difluoro-5-
methylenecyclopentane-2,3,4-triol (17)
To a solution of 12 (20 mg, 0.11 mmol) in DMF (2 mL) were
added NaH (95% in mineral oil, 11 mg, 0.46 mmol), (n-Bu)4NI
(4 mg, 0.01 mmol) and BnBr (0.070 mL, 0.55 mmol) and the
mixture was stirred overnight. A saturated solution of NH4Cl
was added and the aqueous phases were extracted three times
with Et2O. The combined organics were washed with water, dried
over MgSO4 and evaporated. Purification by column chromatogra-
phy (10% EtOAc in cyclohexane) afforded 17 as a colorless oil
[a] d 7.70 (d,
D = +40.3 (c 1.6, CHCl3). 1H NMR (300 MHz, CDCl3)
J = 7.0 Hz, 2H), 7.45–7.32 (m, 3H), 4.88 (d, J = 8.5 Hz, 1H), 4.44 (d,
J = 8.1 Hz, 1H), 4.32 (d, J = 8.3 Hz, 1H), 3.84–3.74 (m, 1H), 1.50 (s,
3H), 1.46 (s, 3H), 1.30 (s, 9H), 0.16 (s, 9H). 19F NMR (282.5 MHz,
CDCl3)
d
À76.7 (dd, J = 207.3 Hz, J = 10.3 Hz, 1F), À78.1 (dd,
137.7,
J = 208.3 Hz, J = 12.4 Hz, 1F). 13C NMR (75.5 MHz, CDCl3)
d
135.3 (t, J = 386.5 Hz), 129.9, 129.5, 124.0, 111.8, 99.9, 93.5, 77.4,
68.1, 60.9 (t, J = 24.2 Hz), 57.4, 27.0, 26.9, 23.0, 0.1. IR (neat) nmax
(21 mg, 42%). 1H NMR (300 MHz, CDCl3)
d 7.40–7.25 (m, 15H),
3295, 2961, 2186, 1171, 1077 cmÀ1
.
MS (ESI+): m/z = 537.8
5.95–5.90 (m, 1H), 5.67–5.64 (m, 1H), 4.88 (d, J = 12.1 Hz, 1H),
([M+H]+), 1074.8 ([2M+H]+). Anal. Calcd. for C22H33F2NO3SSeSi:
C, 49.24; H, 6.20; N, 2.61; S, 5.98. Found: C, 49.30; H, 6.22; N, 2.69;
S, 5.96.
4.62–4.47 (m, 6H), 4.12–4.05 (m, 1H), 3.96–3.90, 5.95–5.90 (m,
1H). 19F NMR (282.5 MHz, CDCl3)
d
À90.7 (ddd, J = 255.8 Hz,
J = 8.2 Hz, J = 4.1 Hz, 1F), À111.4 (ddd, J = 255.8 Hz, J = 5.2 Hz,
J = 3.1 Hz, 1F).
4.11. N-{(2R,3R)-1-[Difluoro(phenylseleno)methyl]-2,3-
dihydroxypent-4-yn-1-yl}-2-methylpropane-2-sulfinamide (15)
4.14. Representative procedure for the hydroboration reactions
A solution of compound 14 (870 mg, 1.62 mmol) in a mixture of
TFA (1.44 mL) and H2O (0.36 mL) was stirred at room temperature
for 3 h. The mixture was then concentrated under reduced
pressure, co-evaporated twice with CHCl3 and lyophilized
overnight. The crude residue was then purified by flash chroma-
tography using CH2Cl2/MeOH (97:03) as eluent to afford the
desired product (690 mg, 86%) as a yellow oil. To a solution of this
compound (657 mg, 1.32 mmol) was added K2CO3 (274 mg,
1.99 mmol, 1.5 equiv.) in MeOH (9 mL). After 1 h at room
temperature, a saturated solution of NH4Cl was added and the
aqueous phases were extracted three times with EtOAc. The
combined organic phases were then washed with water, brine,
dried over MgSO4 filtered and concentrated under reduced
pressure to give the desired product 15 (520 mg, 93%) as a solid.
To a solution of 17 (11 mg, 0.03 mmol) in THF (1 mL) at 0 8C was
added dropwise a solution of BH3.THF (1 M in THF, 0.08 mL,
0.08 mmol). The reaction was monitored by TLC (20% EtOAc in
cyclohexane) and three more equivalents of BH3.THF were added if
necessary. The reaction was usually complete in 1 h 30 min after
which time NaOH (3 M in water, 0.06 mL, 0.18 mmol) and
hydrogen peroxide (35% in water, 0.03 mL, 0.03 mmol) were
added and the mixture stirred for 45 mn. Extraction with CH2Cl2,
drying over MgSO4 and filtration afforded the crude mixture that
was purified by column chromatography (gradient from 1 to 15%
EtOAc in cyclohexane) to yield 19 (4 mg, 35%) and 18 (1 mg, 9%).
19: 1H NMR (300 MHz, CDCl3)
d 7.38–7.22 (m, 15H), 4.88 (d,
J = 11.9 Hz, 1H), 4.72–4.59 (m, 4H), 4.47 (d, J = 11.9 Hz, 1H), 4.04–
3.92 (m, 2H), 3.84–3.76 (m, 1H), 1.30 (d, J = 3.2 Hz, 1H). 19F NMR
Rf = 0.40 (4% MeOH in CH2Cl2). [
(300 MHz, CD3OD)
a
]
D = À41.9 (c 0.8, MeOH). 1H NMR
(282.5 MHz, CDCl3)
J = 4.1 Hz, 1F), À125.8 (ddd, J = 243.4 Hz, J = 11.3 Hz, J = 6.2 Hz,
1F). 18: 1H NMR (300 MHz, CDCl3)
7.38–7.24 (m, 15H), 4.87 (d,
d
À110.1 (ddd, J = 243.4 Hz, J = 7.2 Hz,
d
7.73–7.70 (m, 2H), 7.48–7.37 (m, 3H), 4.43
(dd, J = 9.0 Hz, J = 2.1 Hz, 1H), 4.09 (t, J = 11.3 Hz, 1H), 4.02 (d,
J = 9.0 Hz, 1H), 2.98 (d, J = 2.1 Hz, 1H), 1.33 (s, 9H). 19F NMR
d
J = 12.1 Hz, 1H), 4.65–4.44 (m, 5H), 4.24–4.19 (m, 1H), 4.05–3.88
(m, 4H), 2.97–2.89 (m, 1H), 1.9 (bs, 1H). 19F NMR (282.5 MHz,
(282.5 MHz, CD3OD)
d
À77.1 (dd, J = 207.3 Hz, J = 11.3 Hz), À77.9
139.3,
(dd, J = 207.3 Hz, J = 11.3 Hz). 13C NMR (75.5 MHz, CD3OD)
d
CDCl3)
d
À105.6 to À105.8 (m, 2F).
131.5, 131.1, 129.0 (t, J = 299.8 Hz), 126.2, 83.8, 77.8, 73.3, 65.5,
65.2 (t, J = 23.1 Hz), 59.2, 23.9. IR (neat) nmax 3372, 3264,
1048 cmÀ1. MS (ESI+): m/z = 426.1 ([M+H]+), 870.7 ([2M+Na]+).
Anal. Calcd. for C16H21F2NO3SSe: C, 45.28; H, 4.99; N, 3.30; S, 7.56.
Found: C, 45.32; H, 4.97; N, 3.24; S, 7.63.
Acknowledgements
We thank the Centre National de la Recherche Scientifique
´
(CNRS) and the Region Haute-Normandie for a PhD grant to G. Fand
´
the Region Haute-Normandie (CRUNCH network) for funding.
4.12. (SS,2R,3R,4S)-2-tert-Butanesulfinamido-1,1-difluoro-5-
methylenecyclopentane-3,4-diol (16)
Appendix A. Supplementary data
The same procedure as for the preparation of 7 was applied to
15. Purification of the crude material by flash chromatography
using CH2Cl2/MeOH (gradient from 96:04 to 70:30) as eluent to
afford 16 (56%) as a pale yellow solid. Rf = 0.38 (10% MeOH in
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.jfluchem.2011.02.015.
CH2Cl2). [a] d
D = +90.2 (c 1.3, MeOH). 1H NMR (300 MHz, CD3OD)
References
5.82 (dt, J = 4.5 Hz, J = 2.6 Hz, 1H), 5.69 (dt, J = 5.1 Hz, J = 2.6 Hz,
1H), 4.27 (dt, J = 2.6 Hz, J = 2.3 Hz, 1H), 3.74 (td, J = 10.0 Hz,
J = 1.5 Hz, 1H), 3.58 (td, J = 14.1 Hz, J = 11.3 Hz, 1H), 1.31 (s, 9H).
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