Preparation of chiral sugar-derived fluorides using new nucleophilic fluorinating reagents

Article abstract of DOI:10.1016/j.jfluchem.2017.09.005

New fluorinating reagents, composed of (S)-2-(diphenylmethyl)pyrrolidine and 1,1,3,3,3-pentafluoropropene/hexafluoropropene, have been found to be an effective system for nucleophilic deoxyfluorination. Regio- and stereoselectivity of deoxyfluorination of sugar-derived allylic, benzylic and propargylic alcohols with new reagents have been studied.

Full text of DOI:10.1016/j.jfluchem.2017.09.005

Accepted Manuscript
Title: Preparation of chiral sugar-derived fluorides using new
nucleophilic fluorinating reagents
Authors: Monika Bilska-Markowska, Henryk Koroniak
PII:
S0022-1139(17)30263-4
DOI:
Reference:
http://dx.doi.org/10.1016/j.jfluchem.2017.09.005
FLUOR 9046
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Accepted date:
14-6-2017
5-9-2017
5-9-2017
Please cite this article as: Monika Bilska-Markowska, Henryk Koroniak, Preparation
of chiral sugar-derived fluorides using new nucleophilic fluorinating reagents, Journal
of Fluorine Chemistryhttp://dx.doi.org/10.1016/j.jfluchem.2017.09.005
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Preparation of chiral sugar-derived fluorides using new nucleophilic fluorinating
reagents
*
Monika Bilska-Markowska , Henryk Koroniak
Adam Mickiewicz University, Faculty of Chemistry, Umultowska 89b, 61-614 Poznan,
Poland
In dedication to Professor Antonio Togni, the winner of the ACS Award for Creative Work in
Fluorine Chemistry
Graphical abstract
Highlights


Synthesis of fluorides derived from carbohydrates has been studied.
Reactions has been accomplished by using DAST and new fluorinating reagents obtained
from (S)-2-(diphenylmethyl)pyrrolidine and 1,1,3,3,3-pentafluoropropene
/
hexafluoropropene.
1
9
1

Analysis of F NMR and H NMR has allowed assignment of syn/anti geometry of
products.

ABSTRACT
New fluorinating reagents, composed of (S)-2-(diphenylmethyl)pyrrolidine and 1,1,3,3,3-
pentafluoropropene/hexafluoropropene, have been found to be an effective system for
nucleophilic deoxyfluorination. Regio- and stereoselectivity of deoxyfluorination of sugar-
derived allylic, benzylic and propargylic alcohols with new reagents have been studied.
1
. INTRODUCTION
The replacement of a hydroxyl group by fluorine atom causes a minor change in the steric
arrangement of the molecule but such modification has profound impact on the
stereoelectronic properties and hence on the chemical properties [1]. As a result, fluorinated
compounds have attracted much interest in the areas of pharmaceutical, medicinal and
materials sciences due to their unique changes in properties (including biological activity)
exerted by small atom of fluorine [2]. Fluorine containing compounds have been also
considered as one of the most valuable building blocks in the organic synthesis. This is
because their incorporation/attachment into larger species give access to a new classes of
organic molecules [3].
Fluorination of carbohydrates is a quite common method to gain an information regarding
catalytic mechanism of various enzymatic transformations [4]. Fluorinated carbohydrate
analogues are often better enzyme inhibitors compared to the un-fluorinated analogues [5].
Among others, polyfluorinated sugars have become an interesting issue of studies related to
hydrophobicity effect, in which the hydrophobic domains are created by replacement of
CHOH groups on carbohydrate ring with CF
2
groups [6] and/or by introduction of CF group
3
into carbohydrate molecules [7].
A well-known procedure for preparation of alkyl fluorides, including fluorinated
carbohydrates, is the nucleophilic substitution (S ). The important strategy in this context is
N
deoxyfluorination reaction (Scheme 1). There are several examples of nucleophilic reagents
employed to construct the C-F bond, including bis(2-methoxyethyl) aminosulfur trifluoride
TM
(
Deoxo-Fluor ) [8], aminodifluorosulfinium salts (XtalFluor-E, XtalFluor-M) [9],
diethylaminosulfur trifluoride (DAST) and fluoroamino-reagents such as: 1,1,2,3,3,3-
hexafluoropropyl-N,N-diethylamine [10] (Ishikawa reagent), (2-chloro-1,1,2-trifluoroethyl)-
N,N-diethylamine (Yarovenko’s reagent) [11] and 1,1,2,2-tetrafluoroethyl-N,N-dimethylamine
(Petrov reagent) [12].
In this paper we would like to focus our attention on the synthesis of new fluorinating
reagents obtained from cyclic pyrrolidine derivative and two fluorinated olefins:
hexafluoropropene and 1,1,3,3,3-pentafluropropene. We report here the results of the regio-
and diastereoselectivity of fluorination reaction of several secondary alcohols obtained from
2
,3-O-isopropylideneglyceraldehyde. These alcohols are widely used in the organic synthesis,
including synthesis of unusual amino acids [13a] or biologically active alkaloids [13d]. Also,
propargylic and allylic fluorides in racemic or enantioenriched form are used for diverse
academic and industrial applications [3].

In general, the obtained fluorinated analogues prepared in the course of these studies are
new, not known in literature, and can be employed as valuable building blocks in the
synthesis of a larger systems.
2
. RESULTS AND DISCUSSION
Our synthesis have started from easy to be handled 1,2:5,6-di-O-isopropylidene-D-
mannitol 1 and, as a result of an oxidative cleavage of diol, (R)-2,3-O-
isopropylideneglyceraldehyde 2 has been obtained. This molecule is synthetically useful
chiral starting material for the construction of optically active organic compounds. As shown
in Scheme 2, the chiral alcohols have been simply prepared, by treatment of 2 with
corresponding Grignard reagents (3a-4a, 3b-4b) or lithium phenylacetylene (5a, 5b), with
good yields (Table 1).
The mixture of two propargylic derivatives (5a/5b) has been subsequently transformed
by reduction using LiAlH
4
to the corresponding allylic alcohols 6a/6b (Scheme 3) with
4
4/56 (threo/erythro) ratio (82% yield).
Diastereoselectivity (Table 1) of Grignard reaction has been determined by analysis of the
H NMR spectra and can be understood by the concept of Felkin–Ahn model (Scheme 4). The
1
absolute configuration of the newly created stereogenic centers of compounds 3a/3b–6a/6b
has been established on the basis of appropriate values of coupling constant (JH1-H2) and
compared with literature data [13]. In each of these reactions, the erythro-stereoisomers has
been formed predominantly.
Next step, the synthesis of fluorinating reagents has employed the reactions of chiral
secondary amine, cyclic pyrrolidine derivative 7, with commercially available fluorinated
olefins 1,1,3,3,3-pentafluoropropene (PFP) or hexafluoropropene (HFP). (S)-2-
(Diphenylmethyl)-pyrrolidine 7 has been obtained from L-proline, according to the described
procedure [14]. The reaction, in the case of PFP, has given the tetrafluorinated enamine 8
1
9
(
Scheme 5) with a 73% yield (determined by F NMR spectrum) [15]. Analogous reaction of
chiral amine 7 with HFP has given a mixture of enamine and fluorinated tertiary amine 9a/9b
with a 65% total yield (the ratio of enamine/amine 9a/9b was 1:32) (Scheme 5) [15]. The
1
9
crude reaction enamine–amine mixtures 9a/9b, after the previous F NMR analysis, were
directly used to fluorination without further purification and separation.
The next stage of our studies was to apply new reagents (8 and mixture 9a/9b) in
dehydroxyfluorination reaction of previously obtained alcohols. As a standard procedure of
deoxyfluorination reaction with DAST has been carried out (Scheme 6).
Reaction of PFP and (S)-2-(diphenyl-methyl)pyrrolidine adduct 8 with alcohols 3a/3b
has given mixture of two secondary fluorides 10a/10b and primary fluoride 11 in 1/2/9.5 ratio
and with 28% and 60% yields, respectively (Scheme 7, Table 2). Diastereoisomers 10a/10b

have been inseparable by using silica gel chromatography. Corresponding reaction of 3a/3b
with HFP and (S)-2-(diphenylmethyl)pyrrolidine adducts 9a/9b has led to the same products
1
0a/10b/11 in 1/2/10 ratio and with higher 33% and 62% yields, respectively. As mentioned
before, we have carried out deoxofluorination of alcohols 3a/3b with DAST to compare the
efficiency and stereoselectivity of new fluorinating reagents. In this case we also obtained two
secondary fluorides 10a/10b and primary fluoride 11 in 1/2/9.5 ratio and with 27% and 52%
yields, respectively. Allylic fluorides 10a/10b and 11 are stable after isolation (as stored at
low temperature). We didn’t observe decomposition of these products under chromatography
and there was no difference in stability of the branched (10a/10b) and linear allylic fluorides.
The ratio of the obtained products depends only on the fluorination reaction mechanism.
As it was reported before [16], in the reaction of analogous allylic alcohol derived
from di-O-isopropylidenehexofuranose with various fluorinating reagents two fluorides have
been formed: 3-deoxy-3-fluoro-1,2;5,6-di-O-isopropylidene-C-3-(R)-vinyl-α-D-glucofuranose
and
3-deoxy-C-3-(2-fluoroethylidene)-1,2;5,6-di-O-isopropylidene-α-D-ribohexofuranose
(Fig. 1) with 31% and 34% yields, respectively. On the other hand, the deoxyfluorination of
compounds derived from O-isopropylidenepentofuranose with DAST has given primary
fluoride with 51% yield as the single product (Fig. 1).
The chemical structures of the obtained products have been determined by the NMR
19
spectroscopy. The signal in F NMR spectrum for 10a has appeared at -186.3 ppm (dtd,
J=48.1, 14.3, 3.6 Hz) whereas for fluoride 10b has been found at -190.1 ppm (dtd, J=47.6,
1
2.9, 3.1 Hz). The higher value of observed coupling constant in 10a is due to coupling of
3
fluorine and vicinal hydrogen nuclei H-2 (Fig. 2) (anti, J=14.3 Hz). Similarly lower value of
coupling constant between fluorine and H-2 nuclei in 10b (syn, J=12.9 Hz) have supported
3
the stereochemical absolute configuration assignment at carbon atom directly attached to the
fluorine atom as being R for 10a and S for 10b, respectively [17].
The product 11 has possessed characteristic up-field shift of fluorine atom signal (δ -
2
4
15.2, tddd) typical for terminal CH
.89 ppm and the following values of coupling constants ( J=46.6 Hz, J=5.3 Hz, J=1.3 Hz).
2
F group. These protons have the same chemical shift
2
3
5
These results are in contrast with those observed in previously reported systems [16]. The
geminal CH F protons in 3-deoxy-C-3-(2-fluoroethylidene)-1,2;5,6-di-O-isopropylidene-α-D-
2
ribohexofuranose (Fig. 1) have been magnetically nonequivalent (δ 5.03 and 5.19,
respectively).
We would suggest that the mechanism of this nucleophilic deoxyfluorination, after an
activation of hydroxyl group, involves formation of allylic carbocation as the key intermediate
in the synthesis (Scheme 7). An analogous mechanism and similar regioselectivity has been
recently demonstrated [16] by our group during fluorination of various tertiary alcohols
derived from di-O-isopropylidenehexofuranose and O-isopropylidenepentofuranose using
DAST or PFPDEA [18] (1,1,3,3,3-pentafluoropropene-diethylamine adduct). O’Hagan and
coworkers in their work have also proposed a similar stabilization for chiral allylic and
propargylic alcohols [19]. It must be noted that the formation of compound 11 (Scheme 7), as

one of the products in the deoxyfluorination process can be explained assuming the S 1’ type
N
of the mechanism. Substantially, each new fluorinating agent has reacted with alcohols
yielding corresponding fluorides, 1-((S)-2-benzhydrylpyrrolidin-1-yl)-3,3,3-trifluoropropan-1-
one 15 or 1-((S)-2-benzhydryl-pyrrolidin-1-yl)-(R/S)-2,3,3,3-tetrafluoro-propan-1-one 16
(Scheme 7) as byproduct and hydrogen fluoride.
Another effective method via S 1 mechanism to synthesize diastereoselectively
N
enantioenriched propargylic fluorides, using diastereomeric propargyl alcohol cobalt-carbonyl
complexes has been presented by Zhang et al. [20]. This approach provided preparation of
fluorides with good yields, as well as moderate to high diastereoselectivities.
In our case, dehydroxyfluorination reactions have been conducted on all obtained alcohols
mixtures using our new fluorinating reagents and DAST, and the resultant ratios and yields
have been summarized in Table 2.
Using “chiral pyrrolidine derivative” as starting material for the synthesis of fluorinating
reagent we have considered it to be a chiral auxiliary in deoxofluorination. Such derivatives
are often used in asymmetric synthesis [21]. Compounds 8 and 9a/9b were found to be an
efficient fluorinating agents replacing hydroxyl groups in alcohols into fluorine. In general,
they react with alcohols yielding corresponding fluorides. However, it should be pointed out
that the experimental data presented in our work explained that the regio- and stereoselectivity
of fluorination depended only on the structure (substituents) of the starting alcohols, not on
the structure of the fluorinating reagents. The comparison of compounds 8 and 9a/9b with the
results of DAST (Table 2) shows close similarity in efficiency of these two different systems.
DAST is a common nucleophilic reagent employed to construct the C-F bond, that is why it
was used as a reference.
Designed in our laboratory reagent consisting of a chiral pyrrolidine and fluorinated olefin
(hexafluoropropene) is an analogue of Ishikawa’s reagent [10]. There is a little information
available on the mechanism of conversion of alcohols into the corresponding fluorides using
α-fluoroamines (example: Ishikawa’s reagent and compound 9b) as fluorinating reagents. It is
known that the key step in the deoxofluorination is the nucleophilic attack of fluoride anion
on the carbon atom bearing the hydroxyl group. There are doubts if the process goes through a
mechanism of nucleophilic substitution S
N
1 or a mechanism of nucleophilic substitution S 2.
N
The first mechanism of the fluorination of alcohols was suggested by Ishikawa. It shows all
possible ways for the transformation of the intermediate [10]. A different approach was
suggested by Petrov [12]. He has suggested that this reaction proceeds through two-step
process (Scheme 8):
1
) Formation of an intermediate as a result of the reaction between the alcohol
and α-fluoroamine
) Decomposition of this intermediate with the formation of products
Mechanism of nucleophilic substitution S 2 presented above would suggest obtaining the
2
N
corresponding fluorides 12a/12b in 56:44 ratio. We therefore assume that the structure of
substrate and both steric and electronic factors probably strongly affect the mechanism of
fluorination and lead to formation of 12a/12b in 34:66 ratio. The mechanism above also
suggests that the presence of even traces of HF would trigger the fluorination.

The combination of electronic and steric effects is the main reason for the formation of the
diastereoisomers in different amounts. In reactions where the substrate was a mixture of
alcohols with a phenyl group 4a/4b, the erythro-stereoisomers has been formed
predominantly. Replacing the phenyl group with larger phenylethynyl group 5a/5b or styryl
group 6a/6b has resulted in obtaining the threo-stereoisomers as the main products. This can
be explained by a steric factor. The more remote large phenyl group is from the chiral carbon
atom, the less steric congestion is observed and the access of the fluoride anion to the
carbocation is facilitated. Only effect of the oxygen atom from the opposite side might have
an influence on intermediate stability.
Dehydroxyfluorination reactions of the 6a/6b alcohols mixture have been regioselective.
Only the more conjugated compounds 14a/14b have been formed (Table 2). Assuming
carbocation as an intermediate in the reaction, no rearrangement causing formation of
product(s) having fluorine atom at the α position to the phenyl group has not been observed.
This can be easily understood by resonance stabilization effect of phenyl group. Only a more
conjugated and therefore thermodynamically more stable system has been created and has led
to the formation of the single regioisomer. However, it should be mentioned that the reaction
of cinnamyl alcohol 17 with DAST yields a 34:66 mixture of primary/secondary fluorides
1
8/19 (Scheme 9) [22]. It is worth to note that compound 19 is very sensitive and decomposes
during column chromatography[22].
Hence, presented work results indicate that the regio- and stereoselectivity of nucleophilic
deoxofluorination using the chiral pyrrolidine derivatives or DAST as fluorinating agents
were strongly influenced by the nature (substituents) of the starting alcohols, not by the
fluorinating reagents structure. The tested deoxyfluorinating system, i.e. amine-PFP
or amine-HFP adducts are of similar reactivity compared to DAST.
3
. CONCLUSIONS
In summary, we have synthesized the new fluorinating reagents which were composed of
(S)-2-(diphenylmethyl)pyrrolidine and 1,1,3,3,3-pentafluoropropene or hexafluoropropene.
These compounds have been successfully applied in the synthesis of sugar-derived fluorides.
The conversion of the alcohols into corresponding fluorides gave us an access to new
fluorinated derivatives that might represent useful starting material for the synthesis of
biologically interesting molecules.
4
. EXPERIMENTAL
.1. General procedures
4
1
13
19
H NMR, C NMR, F NMR spectra were performed on Varian GEMINI 300 (300
MHz), Varian 400 (400 MHz), Bruker Avance 400 (400 MHz) or Bruker Avance 600 (600

1
MHz) spectrometers. Chemical shifts of H NMR were expressed in parts per million
downfield from tetramethylsilane (TMS) as an internal standard (δ = 0) in CDCl . Chemical
as an internal
standard (δ = 77.0). Chemical shifts of F NMR were expressed in parts per million upfield
from CFCl as an internal standard (δ = 0) in CDCl . Mass spectra were recorded by electron
impact (MS-EI) techniques using AMD-402. Reagent grade chemicals were used and solvents
were dried by refluxing with sodium metal-benzophenone (THF), with CaH (CH Cl ) and
3
13
shifts of C NMR were expressed in parts per million downfield from CDCl
3
19
3
3
2
2
2
distilled under an argon atmosphere. All moisture sensitive reactions were carried out under
o
argon atmosphere using oven-dried glassware. Reaction within temperatures below 0 C were
performed using a bath cooling (dry ice/iso-propanol). Thin-layer chromatography (TLC) was
performed on Merck Kieselgel 60-F254 with EtOAc/hexane as developing systems.
Visualization of the reactions products was achieved using UV light (254 nm) and a standard
procedure (solution of phosphomolybdenic acid or KMnO
mesh) was used for column chromatography. DAST was obtained from Apollo Scientific,
,1,3,3,3-pentafluoropropene (PFP) and hexafluoropropene (HFP) were provided to us by
4
). Merck Kieselgel 60 (230-400
1
SynQuest Laboratories Ltd. (S)-2-(Diphenylmethyl)pyrrolidine 7 was prepared according to
known literature method [14]. Compounds 2 [23], 3a/3b [13a], 4a/4b [13b], 5a/5b [20], 6a/6b
[
13c] were prepared as described in the literature and the NMR data were in a good agreement
with those reported in the literature.
4
.2. Preparation and spectral data of new compounds
4
.2.1. (R)-4-((R)-1-fluoroallyl)-2,2-dimethyl-1,3-dioxolane 10a, (R)-4-((S)-1-fluoroallyl)-2,2-
dimethyl-1,3-dioxolane 10b and (S,E)-4-(3-fluoroprop-1-en-1-yl)-2,2-dimethyl-1,3-
dioxolane 11
DAST
To the solution of DAST (1.07 ml, 1.31 g, 8.15 mmol) in dry CH
solution of alcohols 3a/3b (515 mg, 3.26 mmol) in CH Cl (7 mL) was added dropwise. The
mixture was stirred at -78 °C for 1 h, and then additional 1 h at room temperature. Then, the
reaction mixture was poured into saturated NaHCO containing ice chips and extracted with
CH Cl . The combined organic extracts were washed with water, dried (Na SO ), filtered and
2
Cl
2
(8 mL) at -78 °C the
2
2
3
2
2
2
4
evaporated under reduced pressure. The crude product was purified by column
chromatography (2% EtOAc/hexane) to give a mixture of fluorides 10a/10b and 11 as
colorless oils, in 1:2:9.5 ratio (10a/10b: 141 mg, 27% yield; 11: 271 mg, 52%).
1
1
0a: H NMR (400 MHz, CDCl3) δ 1.40 (3H, s, C(CH
3
)
2
), 1.47 (3H, s, C(CH
3
2
) ), 3.81 (1H,
dd, J=8.6 Hz, J=6.4 Hz, OCHH), 4.04 (1H, ddd, J=8.3 Hz, J=6.7 Hz, J=1.4 Hz, OCHH),
.26 (1H, dq, J=14.5 Hz, J=6.4 Hz, OCH), 4.86 (1H, ddt, J=48.1 Hz, J=6.1 Hz, J=1.3 Hz,
CHF), 5.40 (1H, dt, J=10.4 Hz, J=1.2 Hz, CH=CH ), 5.49 (1H, ddt, J=17.3 Hz, J=3.5 Hz,
J=1.3 Hz, CH=CH ), 5.90 (1H, ddd, J=17.4 Hz, J=10.4 Hz, J=3.9 Hz, CH=CH ),
13C NMR (101 MHz, CDCl
3) δ 25.29 (i-Pr), 26.35 (i-Pr), 65.00 (d, J=5.5 Hz, OCH ), 76.69
d, J=23.0 Hz, OCH), 93.09 (d, J=174.2 Hz, CHF), 110.27 (i-Pr), 120.04 (d, J=11.7 Hz,
4
2
2
2
2
(

1
9
CH=CH
2
), 131.98 (d, J=19.1 Hz, CH=CH ), F NMR (376 MHz, CDCl3) δ -186.27 (dtd,
2
J=48.1 Hz, J=14.3 Hz, J=3.6 Hz, 1F),
1
1
0b: H NMR (400 MHz, CDCl3) δ 1.37 (3H, s, C(CH
3
)2), 1.45 (3H, s, C(CH )2), 3.98 (1H,
3
ddd, J=8.6 Hz, J=5.4 Hz, J=1.1 Hz, OCHH), 4.08 (1H, ddd, J=7.7 Hz, J=6.5 Hz, J=1.3 Hz,
OCHH), 4.15 (1H, dt, J=12.8 Hz, J=6.0 Hz, OCH), 4.85 (1H, dtt, J=47.9 Hz, J=5.6 Hz,
J=1.4 Hz, CHF), 5.37 (1H, dt, J=10.8 Hz, J=1.3 Hz, CH=CH
J=3.0 Hz, J=1.4 Hz, CH=CH ), 5.95 (1H, dddd, J=17.3 Hz, J=16.0 Hz, J=10.8 Hz, J=5.6
), C NMR (101 MHz, CDCl3) δ 25.20 (i-Pr), 26.41 (i-Pr), 65.43 (d, J=4.1 Hz,
), 76.53 (d, J=26.9 Hz, OCH), 92.07 (d, J=174.1 Hz, CHF), 109.96 (i-Pr), 118.95 (d,
J=12.1 Hz, CH=CH ), 132.74 (d, J=18.7 Hz, CH=CH
), 19F NMR (376 MHz, CDCl3)
2
), 5.45 (1H, ddt, J=17.4 Hz,
2
1
3
Hz, CH=CH
2
OCH
2
2
2
δ -190.12 (dtd, J=47.6 Hz, J=12.9 Hz, J=3.1 Hz, 1F),
+
HRMS (EI) calcd for C7H10O2F [M - Me] : 145.06648; found 145.06695.
1
1
1: H NMR (400 MHz, CDCl3): δ 1.42 (3H, s, C(CH
3
)2), 1.46 (3H, s, C(CH )2), 3.64 (1H,
3
dd, J=8.2 Hz, J=7.5 Hz, CHH), 4.15 (1H, dd, J=8.2 Hz, J=6.2 Hz, CHH), 4.57 (1H, qd,
J=7.0 Hz, J=2.3 Hz, CHO), 4.89 (2H, ddd, J=46.6 Hz, J=5.3 Hz, J=1.3 Hz, CH F), 5.84
1H, dddt, J=15.5 Hz, J=6.8 Hz, J=3.9 Hz, J=1.4 Hz, CH=CH), 5.99 (1H, ddtd, J=15.1 Hz,
2
(
1
3
J=14.0 Hz, J=5.3 Hz, J=0.9 Hz, CH=CH), C NMR (101 MHz, CDCl3) δ 25.83 (i-Pr), 26.62
i-Pr), 69.27 (d, J=2.7 Hz, CH O), 75.97 (d, J=1.2 Hz, CHO), 82.29 (d, J=164.4 Hz, CH F),
09.58 (i-Pr), 128.11 (d, J=16.9 Hz, CHCH F), 131.65 (d, J=11.4 Hz, CH), F NMR (376
(
1
2
2
1
9
2
MHz, CDCl3) δ -215.20 (tddd, J=46.7 Hz, J=14.2 Hz, J=3.7 Hz, J=2.6 Hz, 1F),
+
HRMS (EI) calcd for C7H10O2F [M - Me] : 145.06648; found 145.06947.
Note 1. Analogous treatment of 3a/3b (50 mg, 0.32 mmol) in CH
2
Cl with HFP and (S)-2-
2
(diphenylmethyl)pyrrolidine adducts (0.48 mmol, 18 h, RT) gave a mixture of 10a/10b and 11
with 1:2:10 ratio and 10a/10b: 16.7 mg, 33% yield; 11: 31.4 mg, 62% yield. (Determined
after product isolation).
Note 2. Analogous treatment of 3a/3b (35 mg, 0.22 mmol) in CH
2
Cl with PFP and (S)-2-
2
(diphenylmethyl)pyrrolidine adducts (0.33 mmol, 18 h, RT) gave a mixture of 10a/10b and 11
with 1:2:9.5 ratio and 10a/10b: 9.9 mg, 28% yield; 11: 21.3 mg, 60% yield (Determined after
product isolation).
4.2.2. (R)-4-((R)-fluoro(phenyl)methyl)-2,2-dimethyl-1,3-dioxolane 12a and (R)-4-((S)-
fluoro(phenyl)methyl)-2,2-dimethyl-1,3-dioxolane 12b
DAST
To the solution of DAST (0.17 ml, 208 mg, 1.29 mmol) in dry CH
solution of alcohols 4a/4b (90 mg, 0.43 mmol) in CH Cl (1 mL) was added dropwise. The
mixture was stirred at -78 °C for 1 h, and then additional 1 h at room temperature. Then, the
reaction mixture was poured into saturated NaHCO containing ice chips and extracted with
CH Cl . The combined organic extracts were washed with water, dried (Na SO ), filtered and
evaporated under reduced pressure. The crude product was purified by column
2
Cl
2
(4 mL) at -78 °C the
2
2
3
2
2
2
4

chromatography (5% EtOAc/hexane) to give a mixture of fluorides 12a/12b as colorless oil,
in 41:59 ratio (55 mg, 60% yield).
1
1
2a: H NMR (300 MHz, CDCl3) δ 1.39 (3H, s, C(CH
3
)2), 1.48 (3H, s, C(CH )2), 3.79 (1H,
3
ddd, J=8.5 Hz, J=6.7 Hz, J=1.6 Hz, CHH), 4.04 (1H, ddd, J=8.7 Hz, J=6.5 Hz, J=1.2 Hz,
CHH), 4.47 (1H, dtd, JH-F=14.8 Hz, J=6.8 Hz, J=6.8 Hz, CH), 5.32 (1H, dd, J=47.6 Hz,
1
3
J=7.0 Hz, CHF), 7.21-7.50 (m, 5H, Ph), C NMR (75 MHz, CDCl3) δ 25.26 (i-Pr), 26.52 (i-
Pr), 65.49 (d, J=4.0 Hz, CH2), 77.77 (d, J=29.2 Hz, CH), 92.88 (d, J=176.3 Hz, CHF), 110.05
(
i-Pr), 126.08 (d, J=7.2 Hz, Ph), 128.51 (Ph), 128.75 (d, J=1.5 Hz, Ph), 136.78 (d, J=19.7 Hz,
1
9
Ph), F NMR (282 MHz, CDCl3) δ -179.34 (dd, J=47.5 Hz, J=14.8 Hz, 1F),
1
1
2b: H NMR (300 MHz, CDCl3) δ 1.34 (3H, s, C(CH
3
)2), 1.45 (3H, s, C(CH )2), 3.66 (1H,
3
ddd, J=8.7 Hz, J=6.7 Hz, J=0.9 Hz, CHH), 4.14 (1H, ddd, J=8.8 Hz, J=5.2 Hz, J=1.5 Hz,
CHH), 4.34 (1H, dtd, JH-F=13.5 Hz, J=6.2 Hz, J=5.2 Hz, CH), 5.39 (1H, dd, J=46.9 Hz,
13
J=6.0 Hz, CHF), 7.21-7.50 (m, 5H, Ph), C NMR (75 MHz, CDCl3) δ 25.45 (i-Pr), 26.52 (i-
Pr), 65.27 (d, J=6.2 Hz, CH2), 78.03 (d, J=23.1 Hz, CH), 94.68 (d, J=176.7 Hz, CHF), 110.61
(
i-Pr), 126.70 (d, J=6.1 Hz, Ph), 128.66 (Ph), 129.29 (d, J=1.8 Hz, Ph), 135.93 (d, J=20.1 Hz,
1
9
Ph), F NMR (282 MHz, CDCl3) δ -188.40 (dd, J=46.9 Hz, J=13.5 Hz, 1F),
HRMS (EI) calcd for C11H12O2F [M - Me] : 195.08214; found 195.08293.
+
Note 1. Analogous treatment of 4a/4b (17 mg, 0.08 mmol) in CH
2
Cl
2
with HFP and (S)-2-
(
3
diphenylmethyl)pyrrolidine adducts (0.12 mmol, 18 h, RT) gave a mixture of 12a/12b with
4:66 ratio and 53% yield (Determined by F NMR analysis, using m-fluorotoluene as an
1
9
internal standard).
Note 2. Analogous treatment of 4a/4b (8.5 mg, 0.04 mmol) in CH
2
Cl with PFP and (S)-2-
2
(
4
diphenylmethyl)pyrrolidine adducts (0.08 mmol, 18 h, RT) gave a mixture of 12a/12b with
4:56 ratio and 39% yield (Determined by F NMR analysis, using m-fluorotoluene as an
1
9
internal standard).
4.2.3. (R)-4-((R)-1-fluoro-3-phenylprop-2-yn-1-yl)-2,2-dimethyl-1,3-dioxolane 13a and (R)-4-
((S)-1-fluoro-3-phenylprop-2-yn-1-yl)-2,2-dimethyl-1,3-dioxolane 13b
DAST
To the solution of DAST (43 μl, 53 mg, 0.33 mmol) in dry CH
solution of alcohols 5a/5b (25 mg, 0.11 mmol) in CH Cl (0.5 mL) was added dropwise. The
mixture was stirred at -78 °C for 1 h, and then additional 1 h at room temperature. Then, the
reaction mixture was poured into saturated NaHCO containing ice chips and extracted with
CH Cl . The combined organic extracts were washed with water, dried (Na SO ), filtered and
2
Cl (2 mL) at -78 °C the
2
2
2
3
2
2
2
4
evaporated under reduced pressure. The crude product was purified by column
chromatography (5% EtOAc/hexane) to give a mixture of fluorides 13a/13b as colorless oil,
in 76:24 ratio (25 mg, 99% yield).
1
1
3a: H NMR (300 MHz, CDCl3) δ 1.34 (3H, s, C(CH
3
)2), 1.43 (3H, s, C(CH )2), 4.11 (1H,
3
ddd, J=7.8 Hz, J=6.3 Hz, J=1.0 Hz, CHH), 4.12 (1H, ddd, J=8.5 Hz, J=6.6 Hz, J=1.1 Hz,
CHH), 4.32 (1H, dtd, JH-F=16.3 Hz, J=6.0 Hz, J=4.4 Hz, CH), 5.25 (1H, dd, J=48.8 Hz,

1
3
J=4.3 Hz, CHF), 7.21-7.45 (m, 5H, Ph), C NMR (75 MHz, CDCl3) 25.36 (i-Pr), 29.69 (i-
Pr), 65.09 (d, J=3.9 Hz, CH2), 76.92 (d, J=24.6 Hz, CH), 82.13 (d, J=175.9 Hz, CHF), 82.35
(
d, J=24.9 Hz, C≡CPh), 89.47 (d, J=10.4 Hz, C≡CPh), 110.64 (i-Pr), 121.37 (Ph), 128.35
1
9
(Ph), 129.22 (Ph), 131.99 (Ph), F NMR (282 MHz, CDCl3) δ -185.66 (dd, J=48.8 Hz, J
=16.3 Hz, 1F),
1
1
3b: H NMR (300 MHz, CDCl3) δ 1.19 (3H, s, C(CH
3
)2), 1.44 (3H, s, C(CH )2), 3.97 (1H,
3
ddd, J=8.8 Hz, J=5.6 Hz, J=0.5 Hz, CHH), 4.08 (1H, ddd, J=8.8 Hz, J=5.7 Hz, J=0.7 Hz,
CHH), 4.39 (1H, dtd, JH-F=11.1 Hz, J=6.8 Hz, J=5.7 Hz, CH), 5.21 (1H, dd, J=49.0 Hz,
1
3
J=7.0 Hz, CHF), 7.21-7.45 (m, 5H, Ph), C NMR (75 MHz, CDCl3) δ 25.32 (i-Pr), 29.65 (i-
Pr), 65.70 (d, J=3.9 Hz, CH2), 76.86 (d, J=25.0 Hz, CH), 81.95 (d, J=24.9 Hz, C≡CPh), 83.75
(
1
1
d, J=173.6 Hz, CHF), 89.67 (d, J=10.3 Hz, C≡CPh), 111.02 (i-Pr), 121.24 (Ph), 128.39 (Ph),
29.30 (Ph), 131.95 (Ph), F NMR (282 MHz, CDCl3) δ -179.66 (dd, J=48.9 Hz, J =10.9 Hz,
1
9
F),
+
HRMS (EI) calcd for C13H12O2F [M - Me] : 219.08214; found: 219.08260.
The NMR data were in a good agreement with those already reported [20].
Note 1. Analogous treatment of 5a/5b (29 mg, 0.12 mmol) in CH
2
Cl
2
with HFP and (S)-2-
with PFP and (S)-2-
(diphenylmethyl)pyrrolidine adducts (0.18 mmol, 18 h, RT) gave a mixture of 13a/13b with
6
3:37 ratio and 92% yield (Determined after product isolation).
Note 2. Analogous treatment of 5a/5b (21 mg, 0.09 mmol) in CH
2
Cl
2
(
5
diphenylmethyl)pyrrolidine adducts (0.135 mmol, 18 h, RT) gave a mixture of 13a/13b with
3:47 ratio and 35% yield (Determined by F NMR analysis, using m-fluorotoluene as an
1
9
internal standard).
4
.2.4. (R)-4-((R,E)-1-fluoro-3-phenylallyl)-2,2-dimethyl-1,3-dioxolane 14a and (R)-4-
(S,E)-1-fluoro-3-phenylallyl)-2,2-dimethyl-1,3-dioxolane 14b
(
DAST
To the solution of DAST (34 μl, 42 mg, 0.26 mmol) in dry CH
solution of alcohols 6a/6b (30 mg, 0.13 mmol) in CH Cl (1 mL) was added dropwise. The
mixture was stirred at -78 °C for 1 h, and then additional 1 h at room temperature. Then, the
reaction mixture was poured into saturated NaHCO containing ice chips and extracted with
CH Cl . The combined organic extracts were washed with water, dried (Na SO ), filtered and
2
Cl (2 mL) at -78 °C the
2
2
2
3
2
2
2
4
evaporated under reduced pressure. The crude product was purified by column
chromatography (5% EtOAc/hexane) to give a mixture of fluorides 14a/14b as colorless oil,
in 62:38 ratio (20 mg, 65% yield).
1
1
4a: H NMR (300 MHz, CDCl3) δ 1.29 (3H, s, C(CH3)2), 1.37 (3H, s, C(CH3)2), 3.92 (1H,
dd, J=8.6 Hz, J=5.5 Hz, CHH), 3.93 (1H, dd, J=8.6 Hz, J=5.6 Hz, CHH), 3.98-4.37 (1H, m,
CH), 4.79-5.03 (1H, m, CHF), 6.18 (1H, ddd, J=16.1 Hz, J=14.2 Hz, J=6.4 Hz, Hv), 6.65
1
9
(
1H, d, J=16.1 Hz, J=3.2 Hz, Hv), 7.04-7.37 (m, 5H, Ph), F NMR (282 MHz, CDCl3)
δ -185.42 (dtd, J=47.8 Hz, J=13.4 Hz, J=3.3 Hz, 1F),

1
1
4b: H NMR (300 MHz, CDCl3) δ 1.30 (3H, s, C(CH3)2), 1.38 (3H, s, C(CH3)2), 3.76 (2H,
dd, J=8.7 Hz, J=6.3 Hz, CHH), 3.98-4.37 (1H, m, CH), 4.79-5.03 (1H, m, CHF), 6.13 (1H,
ddd, J=16.0 Hz, J=11.7 Hz, J=7.9 Hz, Hv), 6.68 (1H, d, J=16.2 Hz, J=4.3 Hz, Hv), 7.04-
1
9
7
.37 (m, 5H, Ph), F NMR (282 MHz, CDCl3) δ -180.93 (dtd, J=47.9 Hz, J=12.8 Hz, J=4.2
Hz, 1F),
HRMS (EI) calcd for C14H17O2F [M]+: 236.12126; found: 236.12228.
Note 1. Analogous treatment of 6a/6b (34 mg, 0.15 mmol) in CH
2
Cl
2
with HFP and (S)-2-
(
6
diphenylmethyl)pyrrolidine adducts (0.22 mmol, 18 h, RT) gave a mixture of 14a/14b with
0:40 ratio and 37% yield (Determined by F NMR analysis, using m-fluorotoluene as an
1
9
internal standard).
Note 2. Analogous treatment of 6a/6b (30 mg, 0.13 mmol) in CH
2
Cl with PFP and (S)-2-
2
(
5
diphenylmethyl)pyrrolidine adducts (0.32 mmol, 18 h, RT) gave a mixture of 14a/14b with
9:41 ratio and 34% yield (Determined by F NMR analysis, using m-fluorotoluene as an
1
9
internal standard).

References
[
1] a) K. Uneyama, Organofluorine Chemistry, Blackwell Publishing Ltd., Oxford (2006), b)
D. O’Hagan, Chem. Soc. Rev. 37 (2008) 308-319.
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[
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1.
[
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(2009) 6950–6952.
[
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15] M. Bilska-Markowska, M. Rapp, T. Siodła, A. Katrusiak, M. Hoffmann, H. Koroniak,
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(
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[
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[
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Figure
1.
Allylic
fluorides
derived
from
di-O-isopropylidenehexofuranose
and O-isopropylidenepentofuranose [16].
Figure 2. NMR coupling constant values supporting absolute configuration at carbon atom directly
attached to the fluorine atom.

Scheme 1. Deoxyfluorination reaction.
Scheme 2. Reagents and conditions (i) CH CHMgBr, THF, RT; (ii) PhMgBr, THF, RT; (iii)
2
o
PhCCH, n-BuLi, THF, -78 C.
o
Scheme 3. Reagents and conditions (i) LiAlH
4
, Et O, 0 C, 3.5 h.
2
Scheme 4. Diastereoselectivity of Grignard reaction.
Scheme 5. Formation of fluorinating reagents.

Scheme 6. Reagents and conditions of deoxofluorination reaction (i) adduct of PFP and (S)-2-
diphenyl-methyl)pyrrolidine 8, CH Cl , RT; (ii) adducts of HFP and (S)-2-(diphenylmethyl)-
pyrrolidine 9a/9b, CH Cl , RT; (iii) DAST, -78 °C (2 h), RT (1 h)
(
2
2
2
2
Scheme 7. Stabilization of allylic carbocation intermediate by adjacent bottom-face ether oxygen
causing regio- and stereocontrol of fluorination leading to 10a/10b or 11.

Scheme 8. The mechanism of dehydroxyfluorination with the mixture of 9a/9b (in the 1/32
ratio) as fluorinating reagent.
Scheme 9. Reaction of cinnamyl alcohol with DAST [22].

Table 1. Preparation of alcohols via Grignard reactions.
Ratioa
47:53
44:56
40:60
44:56
Yield [%]
b
Alcohols
3
4
5
6
a/3b
a/4b
a/5b
a/6b
53
50
54
82
1
a
Determined by H NMR spectroscopy for isolated mixtures of alcohols.
Determined after product isolation.
b

Table 2. Preparation of fluorides by using different deoxyfluorination reagents.
Fluorinating
reagent
Alcohols
(ratio)
Fluorides
(ratio)
Yield
[%]
a
c
b,d
8
a/9b
DAST
1:2:9.5
1:2:10
1:2:9.5
28/60
33/62
27/52
c
b,d
b,d
9
47:53
44:56
c
a
8
a/9b
DAST
44:56
34:66
41:59
39
53
a
9
b
60
8
a/9b
DAST
53:47
63:37
76:24
35a
b
9
40:60
92
b
99
a
8
a/9b
DAST
59:41
60:40
62:38
34
37
65
a
9
44:56
b
a
Determined by 19F NMR spectroscopy using m-fluorotoluene as an internal standard (δ=-114.1 (m, 1F)) before column
chromatography.
b
Determined after product isolation.
Related to the mixture of compouds 10a/10b/11.
Related to the mixture of compouds 10a/10b and compound 11: (10a/10b)/11.
c
d