Fluorination of tertiary alcohols derived from di-O- isopropylidenehexofuranose and O-isopropylidenepentofuranose

Article abstract of DOI:10.1016/j.jfluchem.2011.07.001

The stereo- and regioselectivity of the dehydroxyfluorination of various tertiary alcohols derived from di-O-isopropylidenehexofuranose and 1,2-O-isopropylidenepentofuranose has been studied. Reactions have been accomplished using DAST and PFPDEA (1,1,3,3

Full text of DOI:10.1016/j.jfluchem.2011.07.001

Journal of Fluorine Chemistry 132 (2011) 1232–1240
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Fluorination of tertiary alcohols derived from di-O-isopropylidenehexofuranose
and O-isopropylidenepentofuranose
*
Magdalena Rapp , Monika Bilska, Henryk Koroniak
Adam Mickiewicz University, Faculty of Chemistry, Grunwaldzka 6, 60780 Poznan´, Poland
A R T I C L E I N F O
A B S T R A C T
Article history:
The stereo- and regioselectivity of the dehydroxyfluorination of various tertiary alcohols derived from
di-O-isopropylidenehexofuranose and 1,2-O-isopropylidenepentofuranose has been studied. Reactions
have been accomplished using DAST and PFPDEA (1,1,3,3,3-pentafluoropropene-diethylamine adduct)
as fluorinating reagents. Dehydroxyfluorination of allylic alcohol 2a has occurred with an inversion of
configuration and allylic rearrangement leading to two ciral regioisomers 6a and 7a. Analogous reaction
of 2b has given allylic chiral fluoride 7b as the only product. In case of phenylacetylene, styryl and
benzylic alcohols 3a/3b-5a/5b the single diastereoisomers 8a/8b-10a/10b have been obtained.
Additionally, the participation of 1,2-O-substituent effect in carbocation stabilization during fluorination
have been discussed.
Received 30 March 2011
Received in revised form 1 July 2011
Accepted 4 July 2011
Available online 12 July 2011
In dedication to Professor Alain Tressaud
on the occasion of his 70th birthday.
Keywords:
ß 2011 Elsevier B.V. All rights reserved.
Hexofuranose
Pentofuranose
Fluorination
DAST
PFPDEA
Stereoselectivity
1. Introduction
as fluorinating reagents have been used. Application of 1,1,3,3,3-
pentafluoropropene diethylamine adduct (PFPDEA) as a dehy-
Placing a fluorine atom into molecules, due to its steric and
polar characteristic can have a remarkable effect upon the physical,
chemical and biological properties [1]. This effect is especially
apparent in a group of fluorinated carbohydrates and their
derivatives. Their numerous applications in medicinal chemistry
varies from radio labeled sugars used as sensors in medicinal
droxyfluorination reagent has also been studied [9]. Among
organic fluorine compounds, allylic and propargylic fluorides
constitute an important class of chiral building blocks essential for
organic synthesis [10]. A direct dehydroxyfluorination of allylic
alcohols using DAST (Scheme 1) can occurred with a retention or
an inversion of configuration. Additionally, transposition of the
double bond has been observed [6a,10–12]. Allylic substitution has
not been limited to DAST but also has occurred with other
fluorinating reagents [12a]. In general, fluorination of the
substituted with alkyl groups allylic alcohols leads to low
regioselectivity, while phenyl or conjugated double bonds sub-
stituents increase regioselectivity [11a,13a].
imaging (e.g. [18F]-2-fluoro-2-deoxy-
D-glucose – FDG [2]) to
building blocks for the synthesis of nucleosides with antiviral
and antitumor properties (e.g. 20,20-difluoro-20-deoxycytidine-
gemcitabine [3]; 20-fluoromethylene-20-deoxycytidine-tezacitabine
[4] – inhibitors of RNR) [Fig. 1].
Dehydroxyfluorination, effective with primary, secondary and
tertiary alcohols, is one of the methods of introducing a fluorine
into organic compounds. Regarding the direct conversion of
hydroxyl groups to fluorides, numerous reagents are available
[5]. Among the most useful, diethylaminosulfur trifluoride (DAST)
While regio- and stereoselectivity during fluorination of allylic
alcohols remain uncertain, several methodologies have been
´
proposed to solve this problem [14]. Gree et al. have achieved
the regio- and stereocontrol of fluorination by temporary
has been employed [6]. In alternative method
a
-fluoroamine and
complexation of the p-system with a transition metals [15].
a
-fluoroenamine derivatives have been applied [5,7–9]. Among
Moreover, Prakesch et al. demonstrated a complete regiocontrol
and good stereocontrol of dehydroxyfluorination of propargylic
alcohols followed by hydrometallation or hydrogenation [15c,16].
However, still preservation of the absolute configuration at the
fluorine-containing stereocenter was not complete. Furthermore,
Gouverneur et al. reported for the first time enantioselective
synthesis of propargylic fluorides using an electrophilic fluorine
them Yarovenko’s (diethylamine adduct of chlorotrifluoroethene)
[7] and Ishikawa’s (diethylamine adduct of hexafluoropropene) [8]
* Corresponding author. Tel.: +48 618291251; fax: +48 618291505.
E-mail address: magdrapp@amu.edu.pl (M. Rapp).
0022-1139/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2011.07.001

M. Rapp et al. / Journal of Fluorine Chemistry 132 (2011) 1232–1240
1233
NH2
NH2
NH
[4] analogues. In our approach, first we studied fluorination, using
PFPDEA and DAST, with carbohydrate precursors. In this paper we
report the results of our studies concerning the dehydroxyfluor-
ination of tertiary alcohols derived from O-isopropylidenehexo-
and -pentofuranose compounds, additionally modified at C-3 with
the vinyl, phenyl, styryl or phenylacetylene substituents. Resulting
stereocontrol strongly affected by neighboring 1,2-O-isopropyli-
dene groups in rigid pentofuranose rings would be also discussed.
OH
NH
O
O
HO
HO
O
HO
HO
N
N
O
O
OH
F
18 F
OH
F
OH
F
gemcitabine
FDG
tezacitabine
Fig. 1. Examples of fluorinated sugar derivatives.
2. Results and discussion
source [17]. Starting from highly enantioenriched allenylsilanes,
complete chirality transfer was achieved. Nevertheless, a disad-
vantage of this approach – extended and time-costly synthesis of
starting materials – limits its application on larger scales (Scheme
2).
Our synthesis were started from easily to handle diacetone
glucose and 5-O-benzyl-1,2-O-isopropylidenexylofuranose deri-
vatives. Treatment of 1,2;5,6-di-O-isopropylidene-
furanose-3-ulose 1a [20] and 5-O-benzyl-3-oxo-1,2-O-
isopropylidene- -erythro-pentofuranose 1b [21] with different
a-D-ribo-hexo-
a
-D
Recently, Jiang et al. reported successful synthesis of chiral
propargylic or secondary allylic fluorides with enantioselectivity
Grignard reagents or addition of lithium acetylide yield two series
of tertiary alcohols (Scheme 3). Treatment of ketones 1a and 1b
with vinyl magnesium bromide gave 2a [22] and 2b with 59% and
52% yields, respectively.
up to 99% ee [18]. This method involved organocatalytic
a-
fluorination of aldehyde and next homologation of the intermedi-
´
ate to obtain chiral fluorides (Scheme 2). Also, Gree et al. reported
Next, the prepared tertiary allylic alcohol 2a was examined
towards dehydroxyfluorination. Reaction of pentafluoropropene
diethyl amine adduct [PFPDEA, RT (48 h)] prepared in our
laboratory [9] with 2a gave, after isolation, only two products
6a and 7a with 31% and 34% yields, respectively (Scheme 4).
Corresponding reaction of 2a with DAST [ꢀ78 8C (1 h), RT (1 h)]
gave only 6a/7a with 1.6/1 ratio and lower yield (26%/16%).
an alternative method for fluorination dienic alcohols that are
complexed with iron tricarbonyl leading to nonracemic products
[15a]. However, fluorination of chiral secondary dienyl alcohol
complexes occurs with retention of configuration for one
enantiomer and with partial racemisation for the opposite one.
Although the influence of the structural features of the starting
allylic alcohols on the stereo- and regioselectivity of fluorination
has been extensively studied, there is a need for alternative,
efficient methodology for obtaining optically active alcohols. This
possibility could be achieved by applying carbohydrates as chiral
tools or blocks in an organic synthesis. In a search for novel
inhibitors of ribonucleoside reductases [19], we attempted the
synthesis of 20-fluoro-20-vinyl-20-deoxycytidine as a Tezacitabine
The signals in 19F NMR spectra for 6a appeared at
d
ꢀ181.3 (ddd,
3J = 31.5, 21.6, 11.5 Hz) whereas for product 7a they were located
at
d
ꢀ214.6 (tddd, 2J = 46.7 Hz, 3J = 13.2 Hz, 5J = 5.4, 2.5 Hz). The
larger values of coupling constants in 6a observed for fluorine and
vicinal hydrogen atom H-4 (trans, 3J = 31.5 Hz) as well as smaller
coupling constants between fluorine and H-2 (cis, 3J = 11.5 Hz)
supported the stereochemical assignment at C-3 as being 3R [23].
R
R
DAST
or
+
OH
F
R
OH
R
F
R = Me, Ph
R
R
R
F
DAST
+
*
R1
R1
R1
HO
F
R = C7H15
,
R1 =
threo / erythro = 2.5 / 1
OTr
NHC(O)C5H11
O CH3
R = CH2OBn, R1 =
3S,6R / 3S,6S
2.2 / 2.7
3R,4R / 3R,4S
O
CH3
1.5 / 1.0
Scheme 1.
Scheme 2.

1234
M. Rapp et al. / Journal of Fluorine Chemistry 132 (2011) 1232–1240
H3C
H3C
i, ii, iii or iv
H3C
H3C
SN1 component in this reaction. Fluorination seems to be strongly
O
O
affected by stabilization of planar allylic carbocation (derived from
transformation of hydroxyl group into good leaving group with
PFPDEA or DAST) by oxygen of 1,2-O-isopropylidene group
situated on bottom-side of ring as illustrated in Scheme 5.
Analogous stabilization was reported for chiral allylic and
propargylic alcohols by Bresciani et al. but modest regio- and
stereoselectivity during fluorination with similar yields (with a
range of reagents) comparing to our reactions would indicated
additional influence of a rigid pentofuranose ring [11c,27]. It is well
known that stereoselective bond formation especially in carbohy-
drates, could be achieved by various neighboring protecting groups
[28].
O
O
O
O
R
O
O
O
O
O
OH
CH3
CH3
H3C
H3C
2a R= CH=CH2
3a R= C C-Ph
4a R= CH=CHPh
5a R= Ph
1a
Reaction of 2a with DAST [1.5 eq, ꢀ78 8C (1 h), RT (1 h)] gave
only 6a/7a with ratio 1.6:1 and lower yields (26%/16%). In order to
obtain higher regioselectivity, we applied modified procedure of
fluorination. Thus, the problem with regiocontrol of DAST-induced
fluorination giving a mixture of primary and tertiary allylic
BnO
BnO
O
O
R
i, ii, iii or iv
O
O
O
O
O
OH
CH3
CH3
fluorides, in case of chiral 19-norwitamin D analogues, was solved
by a large excess of fluorinating reagents and/or changing of
solvent [29]. As a result, the reported reaction conditions afforded
considerably better results of terminal fluoride (61% and 81%) in
comparison to standard condition (1.5 eq of DAST) and no tertiary
fluoride as a rearrangement product. So, reaction of 2a with DAST
[10 eq, ꢀ78 8C (1 h), RT (1 h)] gave 6a/7a with 2:1 ratio and 45%
yield (both products).
H3C
H3C
2b R= CH=CH2
3b R= C C-Ph
4b R= CH=CHPh
5b R= Ph
1b
Scheme 3. Reagents and conditions (i) vinylmagnesium bromide, THF, RT,
overnight (ii) phenyl acetylene, n-BuLi, THF, ꢀ78 8C, then 1a or 1b, 4 h (iii) 3a or
3b, Et2O, 0 8C, then LiAlH4, 3.5 h (iv) phenylmagnesium bromide, THF, RT, overnight.
Surprisingly, reaction of 2b with DAST gave 7b with 51% yield as
the single product (Scheme 4). The position of the introduced
fluorine atom in 7b was deduced from 19F NMR and 1H NMR
spectra. 1H NMR spectra showed signals at
d 5.10 (dddd, H-b) and d
The fluorination leading to isomer 6a appears to have occurred
with an inversion of configuration and preferentially to the less
hindered top-face. This is in accordance with the stereoselective
face NaBH4 reduction of ulose 1a [24] as well as the addition of
magnesium vinyl bromide to 3-keto nucleoside analogue [22b].
Product 7a possesses characteristic up-field shielding of fluorine
5.12 (ddd, H-b0) of the methylene protons coupled with a fluorine
atom with large vicinal coupling constant 2J ꢁ 47 Hz. The fluorine
b
-
signals of 7b as for 7a appeared at
d
: ꢀ214.3 as a tddd with a
coupling constants 2J ꢁ 47 Hz. Analogous reaction of 2b with
PFPDEA gave mixture containing only 10% of 7b (19F NMR of crude
reaction mixture) while reaction with DAST [10 eq, ꢀ78 8C (1 h), RT
(1 h)] yields 7b (53%). The presence of one diastereoisomer 7b as
the only product would suggest influence of combination of steric
and electronic effects on planar allylic carbocation.
atom signal (
d
ꢀ214.6, tddd) typical for terminal CH2F group. It is
worth mentioning that the geminal CH2F protons are magnetically
nonequivalent. These protons have different chemical shifts and
coupling constants to each particular nucleus, i.e.
2J = 46.5 Hz, 2J = 1.9 Hz, 3J = 5.4 Hz, 5J = 0.5 Hz, H-b) and
2J = 47.2 Hz, 2J = 1.4 Hz, 3J = 7.5 Hz, H-b0), respectively [25]. Deter-
mining -gluco configuration in 6a with an inversion of configura-
tion could support proposed for fluorination by PFPDEA
mechanism as SNi [9]. On the other hand, Todoroki et al. during
a fluorination of chiral tertiary allylic system with conjugated
double bonds with DAST observed mainly retention of configura-
tion [26]. They also proposed SNi mechanism since the steric effect
in abscisic acid (ABA) derivatives would not allow to invert the
configuration at carbon C-10 during fluorination. In our case
d
5.03 (dddd,
Taking into account that conjugated system participates in
regioselectivity control in fluorination as well as substituent effect
determines its stereoselectivity [11a,13a], compounds 3a and 3b
were synthesized. Reaction of ketones 1a and 1b with lithium
phenyl acetylide gave 3a [30] and 3b with a 46% and 60% yields,
respectively [31]. Deoxyfluorination of compounds 3a/3b were
carried out with DAST yielding the single products 8a (84%) and 8b
(79%) without transposition of multiple bond during reaction time
(Scheme 6).
Analogous reaction of 3a/3b with PFPDEA gave chiral fluorides
8a and 8b with lower yields (29% and 20%, respectively).
Determination of configuration at C-3 was based on the analysis
of coupling constants of fluorine and vicinal H-4 and H-2 atoms.
d
5.19 (ddd,
D
however, the stereoselective fluorination occurring from the
a –
side as well as the presence of product 7a indicates a considerable
Scheme 4. (i) PFPDEA (6a/7a: 31%/34%; 7b: 10%), (ii) DAST (1.5eq, 6a/7a: 26%/16%, 7b: 51%), (iii) DAST (10 eq, 6a/7a: 2/1, 45%, 7b: 53%).

M. Rapp et al. / Journal of Fluorine Chemistry 132 (2011) 1232–1240
1235
Scheme 5. Stabilization of allylic carbocation intermediate by adjacent bottom-face ether oxygen causing regio- and stereocontrol of fluorination leading to 6a or 7a.
Thus, tertiary propargylic fluoride 8a had coupling constants
3J = 25.3 Hz (F – H-4, trans), slightly different from this in 6a, but
3J = 11.1 Hz (F – H-2, cis) analogous to 6a, while its fluoride signal
the inversion of configuration at C-3 (D-gluco, D-xylo). The products
9a/9b were obtained with yields 74% and 64%, respectively. The
chemical shift of fluorine and protons were shielded comparing to
8a. The stereochemical assignment for 9a and 9b (3R) was
confirmed by coupling constants between fluorine and protons H-
4 (trans, 3J = 21.4 Hz) and H-2 (cis, 3J = 11.5 Hz) for 9a, while for 9b
was located at
constants 3J = 24.6 Hz (F – H-4, trans), and 3J = 11.0 Hz (F-H-2, cis)
while in 19F NMR the signal of fluorine appeared at
: ꢀ165.0.
d
: ꢀ163.9 (dd). Similarly compound 8b had coupling
d
3
3
´
Parallel results were presented by Gree and co-workers [16a,32].
They fluorinated non terminal enentioenriched propargylic
alcohols at low temperature (ꢀ75 8C, ꢀ95 8C) with DAST. While
reaction of one enantiomer gave fluoride with high ee (96%) and
yield (85%), the other enantiomer underwent temperature-
dependent reaction to give fluoride with 55% yield but lower ee
(75%). Another method to diastereoselectively synthesize enan-
tioenriched propargylic fluorides was developed via SN1 type
reaction of DAST with diastereomeric propargylic alcohol cobalt–
carbonyl complexes [33]. This approach resulted fluorides with
good yields and moderate to high diastereoselectivities.
coupling constants were J4-F = 27.2 Hz and J2-F = 11.1 Hz. More-
over, examination of 13C NMR spectra of 9a allowed to distinguish
besides 1J = 184.1 Hz for C-3 and fluorine (
d
101.6, d), the smaller
81.6 (d, 2J = 19.6 Hz, C-4), as well
121.3 (d, 2J = 17.9 Hz, C-a) [23].
Analogously, in 13C NMR spectra of 9b signals for C-3 appeared
2J = 37.8 Hz at
as for vinylic carbon at
d 85.5 (d, C-2) and d
d
at
at
d
d
: 101.6 as dublet with 1J = 185.0 Hz, while for C-2 were located
85.3 (d, J = 37.3 Hz,), for C-4 at 81.3 (d, J = 19.4 Hz,) as well as
121.1 (d, J = 17.6 Hz). Fluorination of 4a/
d
for vinylic carbon C-a at
d
4b using PFPDEA gave 9a/9b with yields 47%/30%. The regioselec-
tivity of reaction 4a/4b with DAST or PFPDEA is in accordance with
literature data. Thus, fluorination of phenyl substituted or
conjugated double bonds substituents alcohols increase regios-
electivity towards more conjugated products [11a,13a].
To compare the fluorination stereoselectivity, benzylic type
alcohols 5a and 5b were obtained (Scheme 3). In both cases the
only one diastereoisomeric alcohol 5a and 5b were isolated after
Grignard reaction of ketone 1a/1b with phenyl magnesium
Next, study on regioselectivity of deoxyfluorination was
provided on compounds 4a and 4b, obtained by treatment of
3a/3b with LiAlH4 (96% and 80%) [34] (Scheme 3). Analysis of 1H
NMR spectra of 4a and 4b confirmed E-alkene configuration at
double bond. Consequently, the fluorination of 4a/4b using
PFPDEA and DAST was carried out (Scheme 7).
As a result, the single chiral fluorides 9a/9b were isolated with
19F NMR
d
: ꢀ178.8 (ddd, 3J = 31.0, 21.4, 11.5 Hz) for 9a, while for 9b
bromide (besides a few percent of second diastereoisomer
the signals in 19F NMR were located at
d
: ꢀ181.6 (ddd, 3J = 27.2,
reported by Fisher and Horton for 1a) [35]. Fluorination of
compounds 5a/5b carried out with DAST gave the single products
10a/10b with yields 58%/28% (Scheme 8).
21.4, 11.1 Hz). So, the introduction of fluorine atom afforded with
R1
R1
b
Ph
O
O
i or ii
F
a
O
O
O
O
OH
CH3
CH3
Ph
H3C
H3C
4 a, b
9 a, b
H3C
H3C
O
O
a
Series : R1 =
b
Series : R1 = BnOCH2-
Scheme 6. (i) DAST (8a: 84%; 8b: 79%;), (ii) PFPDEA (8a: 29%; 8b: 20%).
Scheme 7. (i) DAST (9a: 74%; 9b: 64%), (ii) PFPDEA (9a: 47%; 9b: 30%).

1236
M. Rapp et al. / Journal of Fluorine Chemistry 132 (2011) 1232–1240
Bruker. Optical rotations were measured using a 243 B Perkin-
Elmer polarimeter [ ] D values are determined at 589 nm and
a
25 8C. Reagent grade chemicals were used and solvents were dried
by refluxing with sodium metal-benzophenone (THF), with CaCl2
(CH2Cl2) and distilled under an argon atmosphere. All moisture
sensitive reactions were carried out under an argon atmosphere
using oven-dried glassware. Reaction temperatures below 0 8C
were performed using a cooling bath (liquid N2/hexane or CO2/iso-
propanol). TLC was performed on Merck Kieselgel 60-F254 with
EtOAc/hexane as developing systems, and products were detected
by inspection under UV light (254 nm) and with a solution
phosphomolybdenic acid. Merck Kieselgel 60 (230–400 mesh) was
used for column chromatography. DAST was obtained from
Aldrich. PFPDEA was prepared as reported [9], distilled under
reduced pressure and the purity of PFPDEA was conveniently
evaluated by 19F NMR in CDCl3. Carbohydrate substrates have to be
well dried prior to use. Compounds 1a [20], 1b [21], 2a [22], 3a
[30], 5a [35] were prepared as described.
Scheme 8. (i) DAST (10a: 58%, 10b: 28%), (ii) PFPDEA (10a: 22%; 10b: 15%).
The 1H NMR as well as 19F NMR spectra confirmed that 10a/10b
had C-3 gluco/xylo configurations. The signals of fluorine atom in
10a appeared at
benzylic fluorides while for 10b were located at
Their chemical shifts could be compared to this of 8a (
1H NMR spectra of compound 10a/10b, the coupling constants for
the fluorine atoms and protons H-4 were larger, (3J = 30.2 Hz,
3J = 28.1 Hz), while between fluorines and protons H-2 were
smaller (3J = 11.5 Hz, 3J = 11.6 Hz).
d
ꢀ175.4 (dd) – the value typical for tertiary
ꢀ176.5 (dd).
: ꢀ178.8). In
d
3.2. Preparation of 5-O-benzyl-1,2-O-isopropylidene-C-3-vinyl-a-D-
ribofuranose 2b
d
To the magnetically stirred suspension of magnesium turnings
(41 mg, 1.72 mmol) and a few crystals of I2 in dry THF (2 mL) in
Carius tube at ꢀ20 8C vinyl bromide (207 mg, 1.94 mmol) was
added. The reaction mixture was refluxed for 2 h. Next, the solution
of ketone 1b (120 mg, 0.43 mmol) in anhydrous THF (1 mL) at 0 8C
was added and the reaction was stirred at room temperature
overnight. Then, the resulting mixture was partitioned (1 N HCl/
H2O//Et2O). The combined extracts were washed with water, brine,
dried (MgSO4), evaporated and was carefully column chromato-
graphed (10% EtOAc/hexane) to give 2b (68 mg, 52%) as slightly
This observation is in accordance with data concerning more
stable orthogonal conformation of benzylic fluoride which benefits
from a
p–s* C–F interaction, which narrows the C–C–F angle and
lengthens the C–F bond relative to the planar conformer [1e,36].
Fluorination occurring preferentially from one side is in contrast to
the results obtained by reaction of racemic phenyl substituted
hydroxy ester with DAST [37]. Starting from racemic mixture
Takeuchi et al. received racemic tertiary fluoroacetate derivatives
but with excellent yield. Fluorination of 5a/5b using PFPDEA gave
10a/10b with 22%/15% yields.
a-
yellow oil. Compound 2b had: [
3463, 3028, 2989, 2930, 2878, 1640, 1592, 1423, 1386, 1373,
1284, 1192, 1167, 1111, 1008, 928, 877, 725 cmꢀ1; 1H NMR:
1.36
(3H, s, i-Pr), 1.60 (3H, s, i-Pr), 2.78 (1H, d, J = 1.1 Hz, OH), 3.49 (1H,
a] D 25 +108 (c 0.3, CHCl3); IR (KBr)
n
d
In summary, the study towards a dehydroxyfluorination of
tertiary alcohols derived from 1,2;5,6-di-O-isopropylidenegluco-
furanose and 5-O-benzyl-1,2-O-isopropylidenexylofuranose deri-
vatives were presented. Fluorination of allylic alcohol 2a occurs
with an inversion of configuration from the less hindered top- face
and allylic rearrangement to give two chiral regioisomers 6a and
7a. Analogous reactions of 2b with DAST or PFPDEA yield only 7b.
The stereoselectivity of 2a, 2b–5a, 5b fluorinations was strongly
affected by stabilization of intermediate carbocation by neighbor-
ing 1,2-O-isopropylidene groups in rigid hexofuranose or pento-
furanose rings and was also demonstrated for chiral fluorides 6a,
6b–10a, 10b. The synthesis of tertiary fluorides derived from
sugars has been accomplished using DAST and PFPDEA as
dehydroxyfluorination reagents. In comparison to DAST, fluorina-
tion of 2a with PFPDEA, gave compounds 6a/7a with better yield.
Fluorination of 3a,b–5a,b provided with DAST gave better results
comparing to this with PFPDEA. The stereo- and regioselectivity of
fluorine introduction was determined by 19F NMR and 1H NMR
spectroscopy.
0
0
0
dd, J5-5 = 10.7 Hz, J5-4 = 7.5 Hz, H-5), 3.57 (1H, dd, J5 -5 = 10.7 Hz, J5 -
4 = 3.3 Hz, H-50), 4.10 (1H, dd, J4-5 = 7.4 Hz, J4-5 = 3.3 Hz, H-4), 4.21
(1H, d, J2-1 = 3.8 Hz, H-2), 4.50 (1H, d, J = 12.1 Hz, Bn), 4.60 (1H, d,
0
0
J = 12.1 Hz, Bn), 5.26 (1H, dd, Jb-a = 10.8 Hz, Jb-b = 1.7 Hz, H-b), 5.51
(1H, dd, Jb -a = 17.3 Hz, Jb -b = 1.7 Hz, H-b0), 5.73 (1H, ddd, Ja-
0
0
b0
= 17.3 Hz, Ja-b = 10.8 Hz, Ja-OH = 0.9 Hz, H-a), 5.86 (1H, d, J1-
2 = 3.8 Hz, H-1), 7.27–7.38 (5H, m, Ph); 13C NMR:
d 26.5, 26.6, 68.9,
73.4, 79.6, 81.4, 83.1, 103.9, 112.8, 116.1, 127.6, 128.3, 133.7,
137.9; MS m/z (rel. int.) 91 [C7H7]+ (100), 291 [MꢀMe]+ (7), 306
[M]+ (5); HRMS (EI) Calcd for C17H22O5 [M]+: 306.14673; Found:
306.14728.
3.3. Preparation of 5-O-benzyl-1,2-O-isopropylidene-C-3-
phenylethynyl-a-D-ribofuranose 3b
To a stirred solution of phenyl acethylene (0.44 mL, 408 mg,
4.0 mmol) in dry THF (3 mL) at ꢀ78 8C, n-BuLi (2 mL, 4.0 mmol, 2 M
in n-hexane) was added. After stirring at ꢀ78 8C for 2 h, a solution
of ketone 1b (556 mg, 2.0 mmol) in THF (2 mL) was added
dropwise and the reaction was stirred for additional 4 h at ꢀ78 8C.
Then, the reaction mixture was poured into saturated aqueous
NH4Cl (10 mL). Next, water (40 mL) was added and then reaction
was extracted with Et2O. The combined organic layers were
washed with H2O, brine, dried (MgSO4), evaporated and carefully
column chromatographed (CHCl3 ! 1% MeOH/CHCl3) to give
acethylenic product (461 mg, 60%) as white solid. Compound 3b
3. Experimental
3.1. General procedures
1H (Me4Si) NMR spectra were determined with solutions in
CDCl3 at 400 MHz, 13C (Me4Si) at 100.6 MHz and 19F NMR (CCl3F) at
376.4 MHz. Elementar analysis were performed using EuroScience
Elementar Analyser Euro EA apparatus. Low-resolution and high-
resolution mass spectra were recorded by electron impact (MS-EI)
techniques using AMD-402 spectrometer unless otherwise noted.
IR spectra were performed using spectrometer FT-IR IFS 66/s from
had: [
a
] D 25 ꢀ208 (c 0.5, CHCl3); IR (KBr)
n 3469, 2989, 2930, 2865,
2228, 1487, 1455, 1444, 1382, 1375, 1165, 1133, 1097, 1052, 1038,
884, 754, 698, 691 cmꢀ1; 1H NMR:
Pr), 3.08 (1H, s, OH), 3.86 (1H, dd, J5-5 = 10.2 Hz, J5-4 = 7.0 Hz, H-5),
d
1.39 (3H, s, i-Pr), 1.61 (3H, s, i-
0

M. Rapp et al. / Journal of Fluorine Chemistry 132 (2011) 1232–1240
1237
3.95 (1H, dd, J5 -5 = 10.2 Hz, J5 -4 = 4.5 Hz, H-50), 4.20 (1H, dd, J4-
(10% EtOAc/hexane) to give 5b (62 mg, 52%) as slightly yellow oil.
Compound 5b had: [ ] D 25 +48 (c 0.2, CHCl3); IR (KBr) 3368, 3063,
0
0
0
5 = 6.9 Hz, J4-5 = 4.5 Hz, H-4), 4.57 (1H, d, J = 12.0 Hz, Bn), 4.64 (1H,
a
n
d, J2-1 = 3.8 Hz, H-2), 4.68 (1H, d, J = 12.0 Hz, Bn), 5.94 (1H, d, J1-
3031, 2989, 2933, 2869, 1605, 1498, 1450, 1383, 1375, 1257, 1216,
1102, 1078, 1023, 873, 763, 697 cmꢀ1; 1H NMR:
d 1.40 (3H, s, i-Pr),
2 = 3.7 Hz, H-1), 7.26–7.42 (10H, m, Ph); 13C NMR:
d
26.6, 26.7, 69.5,
0
73.7, 75.6, 80.7, 83.7, 84.9, 88.0, 104.3, 113.4, 121.6, 127.7, 127.8,
128.3, 128.9, 131.8, 137.7; MS m/z (rel. int.) 91 [C7H7]+ (100), 365
[M-Me]+ (5), 380 [M]+ (3); Anal. Calcd for C23H24O5 ꢂ 0.25 H2O: C,
71.76; H, 6.42. Found: C, 71.79; H, 6.41.
1.65 (3H, s, i-Pr), 3.09 (1H, dd, J5-5 = 10.8 Hz, J5-4 = 7.9 Hz, H-5), 3.28
(1H, s, OH), 3.34 (1H, dd, J5 -5 = 10.8 Hz, J5 -4 = 3.1 Hz, H-50), 4.29 (1H,
dd, J4-5 = 7.8 Hz, J4-5 = 3.1 Hz, H-4), 4.32 (1H, d, J = 11.9 Hz, Bn), 4.40
(1H, d, J2-1 = 4.0 Hz, H-2), 4.46 (1H, d, J = 11.9 Hz, Bn), 6.12 (1H, d, J1-
2 = 4.0 Hz, H-1), 7.27–7.42 (10H, m, Ph); 13C NMR:
d 26.5, 26.6, 69.2,
0
0
0
3.4. Preparation of 1,2;5,6-di-O-isopropylidene-C-3-(E)-styryl-
a
-
D
-
73.3, 80.0, 83.3, 84.4, 92.9, 105.1, 112.8, 124.3, 125.0, 126.6, 127.5,
127.6, 127.7, 128.2, 137.9, 138.7; MS m/z (rel. int.) 91 [C7H7]+ (100),
341 [MꢀMe]+ (6), 356 [M]+ (5); HRMS (EI) Calcd for C21H24O5 [M]+:
356.16238; Found: 356.16451.
allofuranose 4a
To the solution of 3a (114 mg, 0.32 mmol) in Et2O (7 mL), a
suspension of LiAlH4 (16 mg, 0.41 mmol) in Et2O (8 mL) at 0 8C was
added. The reaction mixture was stirred at room temperature for
3.7. Preparation of 3-deoxy-3-fluoro-1,2;5,6-di-O-isopropylidene-C-
3.5 h and then was quenched by addition of water (24
m
L), 10%
3(R)-vinyl-a-D-glucofuranose 6a and 3-deoxy-C-3-(2-
aqueous solution of KOH (48 L) and water (72 L). The mixture
m
m
fluoroethylidene)-1,2;5,6-di-O-isopropylidene-a-D-ribohexofuranose
was filtered and the precipitate was washed with Et2O. The
combined organic layers were dried (MgSO4) and the product was
column chromatographed (20% EtOAc/hexane) to give alcohol 4a
7a
PFPDEA (156 mg, 0.84 mmol) in anhydrous CH2Cl2 (2 mL) was
added dropwise to the solution of 2a (120 mg, 0.42 mmol) in
CH2Cl2 (4 mL), and the mixture was stirred for 18 h at room
temperature. Then solvent was evaporated to give crude mixture of
6a/7a (ꢃ60%, 1:1; 1H NMR and 19F NMR). The reaction mixture was
partitioned (H2O//CH2Cl2) and the separated inorganic layer was
extracted (CH2Cl2), dried (MgSO4), evaporated and carefully
column chromatographed (0 ! 30% EtOAc/hexane) to give 6a
(38 mg, 31%) and 7a (41 mg, 34%) as slightly yellow oils.
Compound 6a [less polar than 7a and 2a on TLC (EtOAc/hexane,
(110 mg, 96%) as an oil. Compound 4a had [
CHCl3); IR (KBr) 3461, 3085, 3060, 3028, 2997, 2986, 2972, 2945,
2936, 2895, 2887, 1382, 1372, 1212, 1166, 1156, 973, 878, 855,
750, 691 cmꢀ1; 1H NMR:
1.29 (3H, s, i-Pr), 1.37 (3H, s, i-Pr), 1.44
a] D 25 –168 (c 0.3,
n
d
(3H, s, i-Pr), 1.65 (3H, s, i-Pr), 2.95 (1H, s, OH), 3.91–4.06 (3H, m, H-
60, H-6, H-5), 4.17 (1H, q, J4-5/6/6 = 6.1 Hz, H-4), 4.36 (1H, d, J2-
0
1 = 3.6 Hz, H-2), 5.87 (1H, d, J1-2 = 3.6 Hz, H-1), 6.14 (1H, d, Ja-
b=16.1 Hz, H-a), 6.92 (1H, d, Jb-a=16.1 Hz, H-b), 7.22–7.49 (5H, m,
Ph); 13C NMR:
d 25.3, 26.4, 26.6, 26.7, 66.8, 73.9, 80.4, 81.6, 83.8,
103.8, 109.4, 113.2, 125.7, 126.6, 127.9, 128.7, 131.3, 136.2; MS m/z
(rel. int.) 91 [C7H7]+(25), 347 [M-Me]+ (8), 362 [M]+ (1); HRMS (EI)
Calcd for C19H23O6 [MꢀMe]+: 347.14948; Found: 347.14768.J4-5/
6/60 = 6.1 Hz,
2:8)] had [
2899, 1456, 1417, 1384, 1375, 1252, 1218, 1165, 1080, 1012,
875 cmꢀ1; 1H NMR:
1.33 (3H, s, i-Pr), 1.34 (3H, s, i-Pr), 1.42 (3H, s,
a] D 25 +778 (c 0.3, CHCl3); IR (KBr/neat) n 2989, 2937,
d
0
0
0
i-Pr), 1.54 (3H, s, i-Pr), 3.99 (1H, ddd, J6 -6 = 8.7 Hz, J6 -5 = 6.4 Hz, J6 -
b = 1.9 Hz, H-60), 4.06 (1H, dd, J6-6 = 8.9 Hz, J6-5 = 5.7 Hz, H-60), 4.24
0
0
3.5. Preparation of 5-O-benzyl-1,2-O-isopropylidene-C-3-(E)-styryl-
(1H, q, J5-4/6/6 = 5.5 Hz, H-5), 4.25 (1H, dd, J4-F = 31.5 Hz, J4-
a
-D
-ribofuranose 4b
5 = 5.1 Hz, H-4), 4.43 (1H, dd, J2-F = 11.4 Hz, J2-1 = 3.7 Hz, H-2),
0
0
5.41 (1H, ddd, Jb-a = 11.3 Hz, Jb-6 = 2.1 Hz, Jb-b = 1.2 Hz, H-b), 5.53
0
0
Analogous treatment of 3b (122 mg, 0.32 mmol) in Et2O (7 mL),
(1H, dd, Jb -a = 17.5 Hz, Jb -b = 1.2 Hz, H-b0), 5.94 (1H, d, J1-2 = 3.7 Hz,
0
with a suspension of LiAlH4 (16 mg, 0.41 mmol) in Et2O (8 mL,
3.5 h) gave after isolation compound 4b (98 mg, 80%) as a white
H-1), 5.99 (1H, ddd, Ja-F = 21.6 Hz, Ja-b = 17.5 Hz, Ja-b = 11.3 Hz, H-
a); 13C NMR:
d 25.4 (i-Pr), 26.5 (i-Pr), 26.9 (i-Pr), 29.7 (i-Pr), 65.8 (d,
solid. Compound 4b had [
3441, 3028, 2993, 2934, 2904, 2868, 1600, 1577, 1495, 1386, 1166,
1146, 1099, 999, 880, 753, 696 cmꢀ1; 1H NMR:
1.63 (3H, s, i-Pr), 2.93 (1H, s, OH), 3.55 (1H, dd, J5-5 = 10.7 Hz, J5-
4 = 7.2 Hz, H-5), 3.64 (1H, dd, J5 -5 = 10.7 Hz, J5 -4 = 3.5 Hz, H-50),
4.17 (1H, dd, J4-5 = 7.2 Hz, J4-5 = 3.5 Hz, H-4), 4.30 (1H, d, J2-
1 = 3.8 Hz, H-2), 4.46 (1H, d, J = 12.1 Hz, Bn), 4.59 (1H, d, J = 12.1 Hz,
Bn), 5.94 (1H, d, J1-2 = 3.8 Hz, H-1), 6.09 (1H, d, Ja-b = 16.0 Hz, H-a),
6.87 (1H, d, Jb-a = 16.0 Hz, H-b), 7.24–7.41 (10H, m, Ph); 13C NMR:
a
] D 25 –178 (c 0.5, CHCl3); IR (KBr)
n
J = 5.1 Hz, C-5), 72.4 (d, J = 4.7 Hz, C-6), 81.4 (d, J = 19.5 Hz, C-4),
85.5 (d, J = 37.7 Hz, C-2), 101.2 (d, J = 184.1 Hz, C-3), 104.8 (C-1),
109.0 (i-Pr), 113.0 (i-Pr), 117.9 (d, J = 12.0 Hz, C-b), 130.5 (d,
d
1.37 (3H, s, i-Pr),
J = 19.5 Hz, C-a); 19F NMR:
d
ꢀ181.3 (ddd, JF-4 = 31.5 Hz, JF-
0
a = 21.6 Hz, JF-2 = 11.5 Hz, 1F); MS (APCI) m/z 289.2 [M+ H]+; HRMS
(EI) Calcd for C13H18O5F [MꢀMe]+: 273.11383; Found: 273.11422.
Compound 7a [more polar than 6a and less polar than 2a on TLC
0
0
0
(EtOAc/hexane, 2:8)] had [
n
a
] D 25 +528 (c 0.2, CHCl3); IR (KBr/neat)
d
3093, 2990, 2940, 2901, 1457, 1417, 927, 875, 845, 802 cmꢀ1; 1H
26.5, 26.6, 69.8, 73.5, 79.8, 81.8, 83.4, 103.9, 112.9, 124.9, 126.5,
127.6, 127.7, 127.9, 128.3, 128.6, 130.6, 136.3, 137.8; MS m/z (rel.
int.) 91 [C7H7]+ (100), 367 [MꢀMe]+(2); Anal. Calcd for C23H26O5: C,
72.23; H, 6.85. Found: C, 72.10; H, 7.05.
NMR: d 1.36 (3H, s, i-Pr), 1.38 (3H, s, i-Pr), 1.44 (3H, s, i-Pr), 1.48
(3H, s, i-Pr), 3.95 (1H, dd, J6 -6 = 7.3 Hz, J6 -5 = 4.7 Hz, H-60), 4.00–
4.06 (1H, m, H-6), 4.06–4.10 (1H, m, H-5), 4.64 (1H, tdd, J4-
F = 5.0 Hz, J4-5 = 3.4 Hz, J4-6/a = 1.9 Hz, H-4), 5.03 (1H, dddd, Jb-
0
0
0
F = 46.5 Hz, Jb-a = 5.4 Hz, Jb-b = 1.9 Hz, Jb-2 = 0.5 Hz, H-b), 5.14 (1H,
0
3.6. Preparation of 5-O-benzyl-1,2-O-isopropylidene-C-3-phenyl-
-ribofuranose 5b
a-
tdd, J2-1 = 4.0 Hz, J2-F = 2.5 Hz, J2-b = 0.5 Hz, H-2), 5.19 (1H, ddd, Jb -
0
0
D
F = 47.2 Hz, Jb -b = 1.4 Hz, Jb -a = 7.5 Hz, H-b0), 5.85 (1H, d, J1-
2 = 4.3 Hz, H-1), 6.14 (1H, dddt, Ja-F = 12.9 Hz, Ja-b = 5.5 Hz, Ja-
b0
To the magnetically stirred suspension of magnesium turnings
(24 mg, 1.0 mmol) and a few crystals of I2 in dry THF (1.5 mL) in
L, 104 mg, 0.66 mmol)
was added. The reaction mixture was refluxed for 2 h. Next, the
solution of ketone 1b (93 mg, 0.33 mmol) in anhydrous THF (1 mL)
at 0 8C was added and the reaction was stirred at room temperature
overnight. Then, the resulting mixture was partitioned (1 N HCl/
H2O//Et2O). The combined extracts were washed with water, brine,
dried (MgSO4), evaporated and carefully column chromatographed
= 7.2 Hz, Ja-4/5 = 1.9 Hz, H-a); 13C NMR:
d 25.4 (i-Pr), 26.6 (i-Pr),
27.2 (i-Pr), 27.3 (i-Pr), 60.4 (C-6), 66.9 (C-5), 78.4 (C-4), 79.9 (d,
J = 161.0 Hz, C-b), 79.9 (C-2), 104.9 (C-1), 109.9 (i-Pr), 112.7 (i-Pr),
123.2 (d, J = 19.7 Hz, C-a), 142.7 (d, J = 10.7 Hz, C-3); 19F NMR:
d
Carius tube at ꢀ20 8C bromobenzene (69
m
0
ꢀ214.6 (tddd, JF-b/b = 46.7 Hz, JF-a = 13.2 Hz, JF-4 = 5.4 Hz, JF-
2 = 2.5 Hz, 1F); MS (APCI) m/z 289.2 [M+ H]+; HRMS (EI) Calcd
for C13H18O5F [MꢀMe]+: 273.11383; Found: 273.11403.
Note 1: Analogous treatment of 2a in CH2Cl2 with DAST (1.5 eq,
1 h, ꢀ78 8C; 1 h, RT) gave 6a/7a (1.6:1) with 26%/16% yields.

1238
M. Rapp et al. / Journal of Fluorine Chemistry 132 (2011) 1232–1240
Note 2: Analogous treatment of 2a in CH2Cl2 with DAST (10 eq,
1 h, ꢀ78 8C; 1 h, RT) gave 6a/7a (2:1) with 45% yield.
Note: Analogous treatment of 3a in CH2Cl2 with PFPDEA (48 h,
RT) gave 8a with 29% yield.
3.10. Preparation of 5-O-benzyl-3-deoxy-3-fluoro-1,2-O-
isopropylidene-C-3(R)- phenylethynyl- -xylofuranose 8b
3.8. Preparation of 5-O-benzyl-3-deoxy- C-3-(2-fluoroethylidene)-
a
-D
1,2-O-isopropylidene-
a
-D-erythropentofuranose 7b
Analogous treatment of 3b (103 mg, 0.27 mmol) with DAST
(65 mg, 53
L, 0.4 mmol) in dry CH2Cl2 (2 mL) at ꢀ78 8C (1 h), and
next at room temperature (1 h) gave a fluoride 8b (82 mg, 79%) as an
oil. Compound 8b had [ ] D 25 +848 (c 0.8, CHCl3); IR (KBr/neat)
To a mixture of DAST (58 mg, 60
m
L, 0.45 mmol) in dry CH2Cl2
m
(2 mL) at ꢀ78 8C, a solution of alcohol 2b (93 mg, 0.3 mmol) in
CH2Cl2 (2 mL) was added dropwise. The mixture was stirred at
ꢀ78 8C for 2 h, and then additional 1 h at room temperature. Then,
the reaction mixture was poured into saturated NaHCO3 contain-
ing ice chips and extracted with CH2Cl2. The combined organic
layer were washed with H2O, dried (Na2SO4), filtered and
evaporated under reduced pressure. The product was purified
on a silica gel (5% EtOAc/hexane) to give a fluoride 7b (48 mg, 51%)
a
n,
3063, 3032, 2990, 2935, 2869, 2237, 1598, 1491, 1453, 1384, 1375,
1216, 1065, 1104, 1028, 1004, 876, 758, 692 cmꢀ1; 1H NMR:
d 1.38
0
(3H, s, i-Pr) 1.57 (3H, s, i-Pr), 3.79 (1H, ddd, J5-5 = 10.9 Hz, J5-
0
0
4 = 7.0 Hz, J5-F = 0.9 Hz, H-5), 3.99 (1H, dd, J5 -5 = 10.9 Hz, J5 -
4 = 3.8 Hz, H-50), 4.53 (1H, ddd, J4-F = 24.6 Hz, J4-5 = 6.9 Hz, J4-
50
= 3.8 Hz, H-4), 4.60 (1H, d, J = 11.9 Hz, Bn), 4.65 (1H, dd, J2-
as an oil. Compound 7b had [
neat) 3065, 3030, 2989, 2938, 2868, 1725, 1654, 1636, 1603,
1586, 1497, 1455, 1384, 1245, 1216, 1162, 1079, 877, 755 cmꢀ1; 1H
NMR: 1.39 (3H, s, i-Pr), 1.46 (3H, s, i-Pr), 3.56 (1H, dd, J5-
= 10.3 Hz, J5-4 = 4.4 Hz, H-5), 3.67 (1H, dd, J5 -5 = 10.3 Hz, J5 -
a] D 25 +748 (c 1.8, CHCl3); IR (KBr/
F = 11.0 Hz, J2-1 = 3.8 Hz, H-2), 4.68 (1H, d, J = 11.9 Hz, Bn), 6.03 (1H,
d, J1-2 = 3.7 Hz, H-1), 7.28–7.40 (10H, m, Ph); 13C NMR:
26.7 (i-Pr),
n
d
26.8 (i-Pr), 67.3 (d, J = 6.3 Hz, C-5), 73.5 (CH2), 79.9 (d, J = 27.1 Hz,
C-b), 82.6 (d, J = 21.7 Hz, C-4), 84.2 (d, J = 38.4 Hz, C-2), 91.5
(d, J = 9.5 Hz, C-a), 95.2 (d, J = 178.9 Hz, C-3), 105.0 (C-1), 113.2
(i-Pr), 124.4 (d, J = 4.1 Hz, Ph),127.7(Ph),128.2(Ph),128.3(Ph), 129.3
d
0
0
50
4 = 3.7 Hz, H-50), 4.55 (1H, d, J = 12.2 Hz, Bn), 4.60 (1H, d,
J = 12.1 Hz, Bn), 4.87-4.82 (1H, m, H-4), 5.10 (1H, ddd, Jb-
(Ph), 132.1 (d, J = 2.8 Hz, Ph), 137.8 (Ph); 19F NMR:
d
ꢀ165.0
0
F = 46.3 Hz, Jb-a = 5.9 Hz, Jb-b = 1.3 Hz, H-b), 5.11–5.16 (1H, m, H-
(dd, JF-4 = 24.6 Hz, JF-2 = 10.9 Hz, 1F); MS m/z (rel. int.) 91 [C7H7]+
(100), 382 [M]+ (16); HRMS (EI) Calcd for C23H23O4F [M]+:
382.15805; Found: 382.15707.
2), 5.12 (1H, ddd, Jb -F = 47.1 Hz, Jb -a = 7.5 Hz, Jb -b = 1.3 Hz, H-b0),
0
0
0
0
5.80 (1H, dddt, Ja-F = 12.6 Hz, Ja-b = 7.4 Hz, Ja-b = 5.5 Hz, Ja-4/
2 = 1.9 Hz, H-a), 5.93 (1H, d, J1-2 = 3.5 Hz, H-1), 7.20–7.49 (5H, m,
Ph); 13C NMR:
d 27.3 (i-Pr), 27.4 (i-Pr), 71.9 (d, J = 2.5 Hz, C-4), 73.4
Note: Analogous treatment of 3b in CH2Cl2 with PFPDEA (48 h,
RT) gave 8b with 20% yield.
(Bn), 78.4 (d, J = 1.4 Hz, C-5), 79.3 (d, J = 1.4 Hz, C-2), 79.8 (d,
J = 161.4 Hz, C-b), 105.2 (C-1), 112.5 (i-Pr), 121.5 (d, J = 19.8 Hz, C-
a), 127.6 (Ph), 127.7 (Ph), 128.4 (Ph), 137.8 (Ph), 143.2 (d,
0
3.11. Preparation of 3-deoxy-3-fluoro-1,2;5,6-di-O-isopropylidene-
C-3(R)-(E)-styryl-a-D-glucofuranose 9a
J = 10.9 Hz, C-3); 19F NMR:
d -214.30 (tddd, JF-b/b = 46.6 Hz, JF-
a = 12.2 Hz, JF-2/4 = 5.5, 2.6 Hz, 1F); MS m/z (rel. int.) 91 [C7H7]+
(100), 293 [MꢀMe]+ (14), 308 [M]+ (10); HRMS (EI) Calcd for
To a mixture of DAST (65 mg, 0.4 mmol) in dry CH2Cl2 (2 mL) at -
78 8C, a solution of alcohol 4a (97 mg, 0.27 mmol) in CH2Cl2 (2 mL)
was added dropwise. The mixture was stirred at ꢀ78 8C for 2 h, and
then additional 1 h at room temperature. Then, the reaction mixture
was poured into saturated NaHCO3 containing ice chips and
extracted with CH2Cl2 The combined organic layer were washed
with H2O, dried (Na2SO4), filtered and evaporated under reduce
pressure. The product was purified on a silica gel (5% EtOAc/hexane)
C
17H21O4F [M]+: 308.14240; Found: 308.14359.
Note 1: Analogous treatment of 2b in CH2Cl2 with PFPDEA (48 h,
RT) gave 7b with 10% yield.
Note 2: Analogous treatment of 2b in CH2Cl2 with DAST (10eq,
1 h, ꢀ78 8C; 1 h, RT) gave 7b with 53% yield.
3.9. Preparation of 3-deoxy-3-fluoro-1,2;5,6-di-O-isopropylidene- C-
to give a fluoride 9a (72 mg, 74%) as an oil. Compound 9a had [
25 +1428 (c 0.3, CHCl3); IR (KBr) 3062, 3051, 3031, 2995, 2985,
2933, 2901, 1656, 1600, 1492, 1448, 1379, 1369, 1247, 1219, 1065,
1053, 1036, 1008, 972, 945, 902, 874, 751, 735, 694 cmꢀ1; 1H NMR:
1.32 (3H, s, i-Pr), 1.34 (3H, s, i-Pr), 1.41 (3H, s, i-Pr), 1.58 (3H, s, i-Pr),
a] D
3(R)- phenylethynyl-a- D-glucofuranose 8a
n
To a mixture of DAST (77 mg, 0.48 mmol) in dry CH2Cl2 (2 mL)
at ꢀ78 8C, a solution of alcohol 3a (114 mg, 0.32 mmol) in CH2Cl2
(2 mL) was added dropwise. The mixture was stirred at ꢀ78 8C for
2 h, and then additional 1 h at room temperature. Then, the
reaction mixture was poured into saturated NaHCO3 containing ice
chips and extracted with CH2Cl2. The combined organic layer were
washed with H2O, dried (Na2SO4), filtered and evaporated under
reduced pressure. The product was purified on a silica gel (5%
EtOAc/hexane) to give a fluoride 8a (96 mg, 84%) as an oil.
d
4.05 (1H, dd, J6 -6 = 8.6 Hz, J6 -5 = 6.6 Hz, H-60), 4.11 (1H, dd, J6-
0
0
60
= 8.7 Hz, J6-5 = 5.5 Hz, H-6), 4.31 (1H, ddd, J5-4 = 4.3 Hz, J5-
0
6 = 5.4 Hz, J5-6 = 6.7 Hz, H-5), 4.38 (1H, dd, J4-F = 31.0 Hz, J4-
5 = 4.6 Hz, H-4), 4.50 (1H, dd, J2-F = 11.5 Hz, J2-1 = 3.6 Hz, H-2),
5.99 (1H, d, J1-2 = 3.6 Hz, H-1), 6.31 (1H, dd, Ja-F = 21.4 Hz, Ja-
b = 16.3 Hz, H-a), 6.82 (1H, d, Jb-a = 16.3 Hz, H-b), 7.19–7.55 (5H, m,
Ph); 13C NMR:
d 25.3 (i-Pr), 26.4 (i-Pr), 26.6 (i-Pr), 27.1 (i-Pr), 65.9 (d,
Compound 8a had [
3057, 2989, 2936, 2903, 2239, 1599, 1574, 1491, 1455, 1444, 1382,
1373, 1075, 1047, 1028, 1004, 874, 844, 691 cmꢀ1; 1H NMR:
1.43
a] D 25 +858 (c 0.2, CHCl3); IR (KBr/neat) n
J = 4.8 Hz, C-5), 72.6 (d, J = 4.5 Hz, C-6), 81.6 (d, J = 19.6 Hz, C-4), 85.5
(d, J = 37.8 Hz, C-2), 101.6 (d, J = 184.1 Hz, C-3), 104.9 (C-1), 108.9 (i-
Pr), 113.0 (i-Pr), 121.3 (d, J = 17.9 Hz, C-a), 126.8 (Ph), 128.2 (Ph),
128.6 (Ph), 132.1 (d, J = 11.5 Hz, C-b), 135.91 (Ph); 19F NMR:
d -178.8
(ddd, JF-4 = 31.0 Hz, JF-a = 21.4 Hz,JF-2 = 11.5 Hz,1F);MSm/z(rel. int.)
364 [M]+ (10), 349 [M-Me]+ (20); HRMS (EI) Calcd for C20H25O5F
[M]+: 364.16861; Found: 364.16728.
Note: Analogous treatment of 4a in CH2Cl2 with PFPDEA (48 h,
RT) gave 9a with 47% yield.
d
(3H, s, i-Pr), 1.45 (3H, s, i-Pr), 1.55 (3H, s, i-Pr), 1.63 (3H, s, i-Pr),
4.14–4.20 (2H, m, H-6/60), 4.46 (1H, dd, J4-F = 25.3 Hz, J4-5 = 5.8 Hz,
0
H-4), 4.53 (1H, q, J5-4/6/6 = 5.3 Hz, H-5), 4.72 (1H, dd, J2-F = 11.1 Hz,
J2-1 = 3.7 Hz, H-2), 6.06 (1H, d, J1-2 = 3.6 Hz, H-1), 7.34–7.64 (5H, m,
Ph); 13C NMR:
d 25.2 (i-Pr), 26.7 (i-Pr), 26.7 (i-Pr), 26.9 (i-Pr), 65.9
(d, J = 3.8 Hz, C-5), 72.7 (d, J = 3.5 Hz, C-6), 80.2 (d, J = 27.4 Hz, C-a),
83.0 (d, J = 22.3 Hz, C-4), 84.6 (d, J = 38,7 Hz, C-2), 91.7 (d, J = 9.6 Hz,
C-b), 95.1 (d, J = 178.8 Hz, C-3), 104.9 (C-1), 109.3 (i-Pr), 113.2 (i-
Pr), 121.3 (Ph), 128.2 (Ph), 129.3 (Ph), 131.9 (Ph); 19F NMR:
3.12. Preparation of 5-O-benzyl-3-deoxy-3-fluoro-1,2-O-
isopropylidene-C-3(R)- (E)-styryl-a-D-ribofuranose 9b
d
ꢀ163.9 (dd, JF-4 = 25.3 Hz, JF-2 = 11.1 Hz, 1F); MS m/z (rel. int.) 347
[M-Me]+ (99); HRMS (EI) Calcd for C19H20O5F [MꢀMe]+:
347.12949; Found: 347.12930.
Analogous treatment of 4b (70 mg, 0.18 mmol) with DAST
(45 mg, 36 L, 0.27 mmol) in dry CH2Cl2 (2 mL) at -78 8C (1 h), and
m

M. Rapp et al. / Journal of Fluorine Chemistry 132 (2011) 1232–1240
1239
next at room temperature (1 h) gave a fluoride 9b (45 mg, 64%) as
an oil. Compound 9b had [ ] D 25 +1028 (c 0.7, CHCl3); IR (KBr)
6.11 (1H, d, J1-2 = 3.4 Hz, H-1), 7.15–7.51 (10H, m, Ph); 13C NMR:
d
a
n
26.4 (i-Pr), 26.9 (i-Pr), 67.6 (d, J = 7.8 Hz, C-5), 73.4 (Bn), 81.8 (d,
J = 18.7 Hz, C-4), 85.0 (d, J = 40.7 Hz, C-2), 102.0 (d, J = 180.2 Hz, C-
3), 105.3 (C-1), 113.1 (i-Pr), 126.0 (d, J = 10.1 Hz, Ph), 127.5 (d,
J = 1.5 Hz, Ph), 128.2 (Ph), 128.3 (Ph), 128.6 (Ph), 133.6 (d,
3061, 3029, 2989, 2934, 2869, 1655, 1601, 1496, 1453, 1379, 1383,
1375, 1248, 1215, 1165, 1102, 1069, 1008, 971, 876, 749,
696 cmꢀ1
;
1H NMR:
d 1.35 (3H, s, i-Pr), 1.58 (3H, s, i-Pr), 3.72
(1H, ddd, J5-5 = 10.8 Hz, J5-4 = 6.8 Hz, J5-F = 0.9 Hz, H-5), 3.78 (1H,
J = 21.0 Hz, Ph), 137.9 (Ph); 19F NMR:
d
ꢀ176.50 (dd, JF-
0
dd, J5 -5 = 10.8 Hz, J5 -4 = 4.1 Hz, H-50), 4.44 (1H, ddd, J4-F = 27.2 Hz,
4 = 28.3 Hz, JF-2 = 11.4 Hz, 1F); MS m/z (rel. int.) 91 [C7H7]+ (100),
358 [M]+ (16); HRMS (EI) Calcd for C21H23O4F [M]+: 358.15805;
Found: 358.15816.
0
0
0
J4-5 = 6.7 Hz, J4-5 = 4.0 Hz, H-4), 4.50 (1H, dd, J2-F = 11.4 Hz, J2-
1 = 3.4 Hz, H-2), 4.53 (1H, d, J = 11.9 Hz, Bn), 4.59 (1H, d, J = 11.9 Hz,
Bn), 6.04 (1H, d, J1-2 = 3.6 Hz, H-1), 6.32 (1H, dd, Ja-F = 21.5 Hz, Ja-
b = 16.3 Hz, H-a), 6.80 (1H, d, Jb-a = 16.4 Hz, H-b), 7.23–7.45 (10H,
Note: Analogous treatment of 5b in CH2Cl2 with PFPDEA (48 h,
RT) gave 10b with 15% yield.
m, Ph); 13C NMR:
d 26.4 (i-Pr), 26.9 (i-Pr), 67.1 (d, J = 7.9 Hz, C-5),
73.4 (CH2), 81.3 (d, J = 19.4 Hz, C-4), 85.3 (d, J = 37.3 Hz, C-2), 101.6
(d, J = 185.0 Hz, C-3), 104.9 (C-1), 112.9 (i-Pr), 121.1 (d, J = 17.6 Hz,
C-a), 126.8 (Ph), 127.5 (Ph), 127.6 (Ph), 128.2 (Ph), 128.3 (Ph), 128.6
References
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d -
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(EI) Calcd for C23H25O4F [M]+: 384.17368; Found: 384.17172.
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3.13. Preparation of 3-deoxy-3-fluoro-1,2;5,6-di-O-isopropylidene-
C-3(R)-phenyl-a-D-glucofuranose 10a
To the solution of DAST (81 mg, 0.5 mmol) in dry CH2Cl2 (3 mL)
at -78 8C the solution of alcohol 5a (113 mg, 0.34 mmol) in CH2Cl2
(3 mL) was added dropwise. The mixture was stirred at ꢀ78 8C for
2 h, and then additional 1 h at room temperature. Then, the
reaction mixture was poured into saturated NaHCO3 containing ice
chips and extracted with CH2Cl2 The combined organic extracts
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[
a
] D 25 +878 (c 0.3, CHCl3); IR (KBr/neat)
n 3062, 2988, 2935, 1499,
1450, 1382, 1373, 1257, 1215, 1165, 1076, 1048, 1039, 1023, 872,
847, 763, 697, 674 cmꢀ1; 1H NMR:
d 1.24 (3H, s, i-Pr), 1.28 (3H, s, i-
Pr), 1.31 (3H, s, i-Pr), 1.62 (3H, s, i-Pr), 3.97-4.06 (1H, m, H-60), 4.15
0
(1H, dd, J6-6 = 8.4 Hz, J6-5 = 5.7 Hz, H-6), 4.20 (1H, ddd, J5-4 = 4.4 Hz,
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0
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1 = 3.7 Hz, H-2), 4.76 (1H, dd, J4-F = 30.2 Hz, J4-5 = 4.4 Hz, H-4), 6.07
(1H, d, J1-2 = 3.5 Hz, H-1), 7.31–7.59 (5H, m, Ph); 13C NMR:
d 25.0 (i-
Pr), 25.1 (i-Pr), 26.2 (i-Pr), 26.9 (i-Pr), 65.5 (d, J = 5.8 Hz, C-5), 72.8
(d, J = 4.6 Hz, C-6), 82.1 (d, J = 19.1 Hz, C-4), 85.0 (d, J = 40.9 Hz, C-
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´
´
´
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(d, J = 21.0 Hz, Ph); 19F NMR:
d
ꢀ175.4 (dd, JF-4 = 30.2 Hz, JF-
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´
´
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´
´
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Analogous treatment of 5b (35 mg, 0.1 mmol) with DAST
(32 mg, 26
L, 0.2 mmol) in dry CH2Cl2 (2 mL) at ꢀ78 8C (1 h), and
next at room temperature (1 h) gave a fluoride 10b (10 mg, 28%) as
an oil. Compound 10b had [ ] D 25 +608 (c 0.2, CHCl3); IR (KBr/
neat) 3063, 3031, 2988, 2933, 2869, 1604, 1586, 1497, 1450,
m
(c) V. Madiot, D. Gre´e, R. Gre´e, Tetrahedron Lett. 40 (1999) 6403–6406;
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a
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n
1384, 1373, 1257, 1216, 1165, 1102, 1078, 1050, 1021, 872, 763,
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4113–4115.
697 cmꢀ1; 1H NMR:
d
1.32 (3H, s, i-Pr), 1.61 (3H, s, i-Pr), 3.64 (1H,
0
0
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0
2), 4.84 (1H, ddd, J4-F = 28.1 Hz, J4-5 = 6.9 Hz, J4-5 = 3.5 Hz, H-4),

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