A regio- and stereoisomeric study of allylic alcohol fluorination with a range of reagents

Article abstract of DOI:10.1016/j.jfluchem.2009.03.003

A range of dehydroxyfluorination reagents was reacted with separate diastereoisomers of a chiral allylic alcohol to explore both the regio- and stereoselectivity ratios of direct versus allylic fluorination. The allylic alcohol stereoisomers gave the same

Full text of DOI:10.1016/j.jfluchem.2009.03.003

Journal of Fluorine Chemistry 130 (2009) 537–543
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
A regio- and stereoisomeric study of allylic alcohol fluorination
with a range of reagents
*
Stefano Bresciani, Alexandra M.Z. Slawin, David O’Hagan
School of Chemistry and Centre for Biomolecular Sciences, University of St Andrews, North Haugh, St Andrews, Fife, Scotland, KY16 9ST, UK
A R T I C L E I N F O
A B S T R A C T
Article history:
A range of dehydroxyfluorination reagents was reacted with separate diastereoisomers of a chiral allylic
alcohol to explore both the regio- and stereoselectivity ratios of direct versus allylic fluorination. The
allylic alcohol stereoisomers gave the same predominant fluorinated diastereoisomer indicating that the
reaction proceeds with a significant SN1 component via an allylic carbocation intermediate, which is
quenched by fluoride ion, predominantly from the least hindered face. None of the reagents displayed
very high regio- or stereoselectivity, although in all cases the allylic fluorination products predominated.
ß 2009 Elsevier B.V. All rights reserved.
Received 7 December 2008
Received in revised form 10 March 2009
Accepted 11 March 2009
Available online 24 March 2009
Keywords:
Fluorination reagents
DAST
Deoxo-FluorTM
TFEDMA
FLUOLEADTM
Dehydroxyfluorination
1. Introduction
sulfurtrifluoride (DAST), the more user-friendly form of SF4, which
became commercially available in the 1980s [5]. Subsequently
The presence of fluorine in licensed drugs continues to be
significant [1–3] and pharmaceutical products are increasingly
emerging with fluorine both attached to aromatic rings but
increasingly with fluorine at a stereogenic centre [4]. Dehydroxy-
fluorination is an important reaction in this context and it is
particularly attractive if conditions can be found to convert an
enantiomerically pure alcohol in a stereospecific manner to an
enantiomerically pure organo-fluorine product. However often
these reactions proceed via a partial SN1 type reaction course and
they can be subject to some loss in stereointegrity. Dehydroxy-
fluorinations are mediated with a range of reagents, although the
first widely utilised reagent in this context was diethylamine
Deoxo-FluorTM has emerged [6] as a second-generation DAST
reagent which is finding wide utility because it is more heat stable
and less hazardous for large-scale conversions than DAST. Other
reagents such as Ishikawa’s [7] and Yarovenko’s [8] reagents have
been explored in dehydroxyfluorinations, but they have not found
wide utility, and perfluoro-1-butanesulfonyl fluoride (PBSF) has
been reported for this transformation [9]. Most recently, tetra-
fluoroethyldimethylamine (TFEDMA) was introduced as a com-
mercially available reagent and the scope and limitations of this
reagent are still emerging [10]. The novel new fluorinating reagent
with high stability and ease of handling, FLUOLEADTM, is an
alternative to current fluorinating reagents [11].
In a synthetic programme in our laboratory we required to
fluorinate the diastereoisomers of allylic alcohol 1 (a and b) for
conversion to 2 (a and b) as illustrated in Scheme 1. This substrate
has a number of complicating features with respect to the
* Corresponding author. Tel.: +44 1334 467176; fax: +44 1334 463808.
E-mail address: do1@st-and.ac.uk (D. O’Hagan).
0022-1139/$ – see front matter ß 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2009.03.003

538
S. Bresciani et al. / Journal of Fluorine Chemistry 130 (2009) 537–543
Scheme 1. Diastereoisomers 1a and 1b can generate four different isomeric products as a result of dehydroxyfluorination progressing either by direct or allylic fluorination.
dehydroxyfluorination reaction. Firstly fluorination can proceed
either by direct substitution of OH for F to give 2, or by an allylic
substitution reaction [12] to generate product 3. Also for each
reaction course there is two stereochemical outcomes, thus
diastereoisomers 1a and 1b can give rise to a mixture of four
products, 2a/2b, and/or 3a/3b. In this paper we report the
outcomes of the regio- and stereoselectivity of fluorination
reactions of 1a and 1b with DAST, Deoxo-FluorTM, TFEDMA, PBSF
relative stereochemistry of diastereoisomers 5a and 5b required to
be assigned. This was achieved by preparing the dinitrobenzoyl
esters 6 as illustrated in Scheme 3. The esters were crystalline and
the relative stereochemistry of the major isomer 6a derived from
5a was determined by X-ray structure analysis (Scheme 3).
Dehydroxyfluorination reactions were then conducted on the
product mixtures 1a/1b, using the five fluorination reagents, and the
resultant ratios of 2a/2b and 3a/3b are summarised in Scheme 4 and
Table 1. All give very modest regio- and stereoselectivity. During the
preparation of fluorosphingosine derivatives, De Jonghe et al.
studied the fluorination of a similar motif [16] using DAST at
ꢀ78 8C, alsowithmodest selectivity. Howeverinour caseonly a very
low conversion was obtained at ꢀ78 8C with DAST, Deoxo-FluorTM
and TFEDMA and conversion was only moderately improved at 0 8C.
Thus for these three reagents warmer reactions temperatures were
necessary. Fluorination with PBSF reagent was found to be very
unreactive, evenafterprolongedheatingandtheuseofalargeexcess
of reagent. Reaction of FLUOLEADTM at 0 8C proved efficient in terms
of conversion, but gave a similar product profile to the other more
established reagents that were investigated.
and FLUOLEADTM
.
2. Results and discussion
Mixtures of diastereoisomers 1a and 1b were prepared but with
different diastereoisomeric biases. The syn addition of lithium
acetylide to aldehyde (R)-4 was conducted under conditions
designed to promote chelation-control [13] as illustrated in
Scheme 2. This generated 5b as the major isomer, but with low
diastereoselectivity (de 9%, determined by chiral GC-FID). A similar
reaction was explored under non-chelation conditions using
titanium tri-isopropoxychloride, to promote anti-selective addi-
tion [14] as illustrated in Scheme 2. This gave 5a in much higher
diastereoisomeric excess (de 62%, determined by chiral GC-FID).
The two product mixtures of 5a/5b were then transformed
separately by propargylic reduction to the corresponding allylic
alcohols 1a/1b using LiAlH4 [15] as illustrated in Scheme 2. These
allylic alcohol reductions gave exclusively the E-olefins. The
It is apparent that regioisomers 3 predominate over regioi-
somers 2 in all of these reactions. In the case of direct fluorination
to give 2, the major isomer is 2a in all cases despite the
stereochemical bias of both starting diastereoisomer mixtures of
1a/1b. Consequently it is concluded that dehydroxyfluorination
proceeds with a significant SN1 type component to the reaction
Scheme 2. Reagents and conditions: (i) benzyl propargyl ether, n-BuLi, THF, ꢀ78 8C, then 4, 4 h, 81%; (ii) LiAlH4, hexanes, reflux, 2 h, 45%; (iii) Benzyl propargyl ether, n-BuLi,
ClTi(Oi-Pr)3, THF, ꢀ78 8C, then 4, 4 h, 82%; (iv) LiAlH4, hexanes, reflux, 2 h, 55%.

S. Bresciani et al. / Journal of Fluorine Chemistry 130 (2009) 537–543
539
Scheme 3. (a) Reagents and conditions: (i) 3,5-dinitrobenzoyl chloride, pyridine, 0 8C then RT, 16 h; (ii) crystallisation in absolute ethanol, 70%. (b) X-ray structure of 6a.
Scheme 4. Fluorination of allylic alcohol 1a/1b gave 2a and the inseparable mixture of isomers 2b/3a/3b.
Scheme 5. Synthesis and X-ray structure of 7a: (i) AD-mix-
b, t-BuOH/H2O, 0 8C then RT, 3 days; (ii) crystallisation from Et2O, 37%.
pathway, with a bias for fluoride attack predominantly to one face
of a reaction intermediate. The configuration of this predominant
isomer was determined after conducting a Sharpless dihydroxyla-
tion [17] reaction on 2a to generate the crystalline derivative 7a for
X-ray structure analysis (Scheme 5). The X-ray structure clearly
shows that there is an anti relationship between the C–F bond and
the vicinal acetonide ether C–O bond in stereoisomer 2a.
To complete the stereochemical analysis of this reaction the
diastereoisomer preference for the allylic substituted products 3a/
3b was explored. TFEDMA reaction on 1a (de 75%) resulted in a
diastereoisomeric ratio of 1:0.7 (determined by 19F NMR) for 3a:3b
with a slight bias in favour of the syn diastereoisomer 3b. The
stereochemistry of 3b was again determined after Sharpless
dihydroxylation of an inseparable mixture of 2b/3a/3b. Silica gel
chromatography purified a 1:0.7 diastereoisomeric mixture of
diols favouring 8b [18]. These stereoisomers were converted
directly to their corresponding cyclic sulfates [19] 9a and 9b
(Scheme 6) and diastereoisomers 9a and 9b were successfully
separated by flash chromatography. The minor isomer 9a was
crystallised and the corresponding X-ray derived structure is
illustrated in Scheme 6. By inference the major isomer formed in
the allylic fluorination reaction of 1a (de 75%) is therefore 3b.
The diastereofacial preference exhibited by reacting these
dehydroxyfluorinating reagents (Table 1) with 1a and 1b is
Table 1
Influence of the dehydroxyfluorinating agent on direct or allylic fluorination of 1a/1b in DCM as a solvent.
Fluorinating agent
Temp. (time)
Major allylic alcohol
Ratioa, 2a/2b/3a/3b
Yield (%)b
substrate, de (%)
(2a)
(2b,3a,3b)
TFEDMA
RT (1 h)
1a, 75%
2.0/1.0/2.9/4.2
1.5/1.0/2.2/2.7
1.2/1.0/1.7/3.7
2.5/1.0/3.7/3.9
1.5/1.0/2.1/2.2
1.5/1.0/2.6/2.7
1.9/1.0/2.6/2.8
11
11
9
44
45
48
46
44
44
NDc
DAST
RT (4.5 h)
55 8C (3.5 h)
RT (1 h)
1a, 75%
Deoxo-FluorTM
TFEDMA
1a, 75%
1b, 17%
1b, 17%
1b, 17%
1a/1b dr 1:1
13
12
10
NDc
DAST
RT (4.5 h)
55 8C (3.5 h)
0 8C (40 min)c
Deoxo-FluorTM
FLUOLEADTM
Ratio in the crude mixture determined by 19F NMR spectroscopy.
Determined after two rounds of chromatography.
Not determined. Product ratios determined by 19F NMR only, although the conversion was high.
a
b
c

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S. Bresciani et al. / Journal of Fluorine Chemistry 130 (2009) 537–543
Scheme 6. Reagents and conditions: (i) AD-mix-
b, t-BuOH/H2O, 0 8C then RT, 3 days, 60%; (ii) NaIO4, RuCl3, MeCN, H2O, 0 8C, 30 min, then SOCl2, pyridine, DCM, 0 8C, 2.5 h,
61%. X-ray structure establishes the absolute configuration of 9a and by inference both 3a and 3b.
Fig. 1. Fluorination of 1a/1b generates a carbocation intermediate (shown for TFEDMA) which is stabilised both by the allylic double bond and the adjacent ether oxygen,
which shields one face of the carbocation from fluoride ion attack.
consistent with a significant SN1 component to the reaction
mechanism. Presumably a combination of steric and electronic
effects associated with the acetonide and its proximate ether
oxygen influences facial attack to an intermediate carbocation as
illustrated in Fig. 1.
Allylic fluorination also showed a significant, but much reduced
facial bias consistent with this mechanistic model. In conclusion
we have explored a dehydroxyfluorination reaction on substrate
1a/1b which is prone to both direct and allylic substitution. The
particular case studied explored several fluorinating reagents. The
stereochemical preference of both direct substitution by fluoride
and allylic fluorination was explored by recourse to solving X-ray
structures of appropriate product derivatives.
Reaction temperatures below 0 8C were maintained using a bath-
cooling apparatus LP Technology RP-100-CD. Thin layer chroma-
tography (TLC) was performed using Macherey-Nagel Polygram Sil
G/UV254 plastic plates; visualisation was achieved by inspection
under UV light (255 nm) or by the staining with a solution of basic
potassium permanganate or phosphomolybdic acid. Column
chromatography was performed using silica gel 60 (40–63
mm)
from Apollo Scientific Ltd. Low-resolution and high-resolution
mass spectra were recorded using a Micromass GCT (time-of-
flight), high performance, orthogonal acceleration spectrometer
coupled to an Agilent Technologies 6890N GC system. Electrospray
mass spectrometry (ESMS) was performed on a high performance
orthogonal acceleration TOF mass spectrometer, coupled to a
Waters 2975 HPLC. Only major peaks are reported and intensities
are quoted as percentages of the base peak. NMR spectra were
recorded on either a Bruker AV-300 or a Bruker AV-400 spectro-
meters. Samples were prepared in CDCl3. For 1H and 13C NMR
calibration was carried out on the residual solvent signal at 7.26
(1H) and 77.16 (13C). For 19F NMR, CFCl3 as an external reference
was used. Optical rotations were measured using a Perkin-Elmer
3. Experimental
3.1. General experimental procedures
All reagents were obtained from commercial sources and were
used without further purification. Dry tetrahydrofuran, dichlor-
omethane and hexane were obtained from the Solvent Purification
System MB SPS-800. All moisture sensitive reactions were carried
out under a positive pressure of N2 using oven-dried glassware.
Model 341 polarimeter [a]D values are determined at 589 nm and
25 8C and reported in 10ꢀ1 ꢁ cm2 gꢀ1. The measurement of
diastereomeric excess was conducted by Chiral Gas Chromato-

S. Bresciani et al. / Journal of Fluorine Chemistry 130 (2009) 537–543
541
graphy (FID) and 1H NMR spectroscopy. Chiral GC column: Chiral
BetadexTM, Supelco, Beta Dex 225, fused silica capillary column,
Data for major diastereoisomer (5a): 1H NMR (400 MHz, CDCl3)
7.38–7.26 (m, 5H), 4.58 (s, 2H), 4.52 (dt, J = 4.4, 1.7 Hz, 1H), 4.28–
d
(60 ꢁ 0.25 ꢁ 0.25
m
m film thickness).
3.86 (m, 5H), 2.56 (brs, OH), 1.47 (s, 3H), 1.38 (s, 3H); 13C NMR
(125 MHz, CDCl3)
d 137.4 (C) 128.6 (CH), 128.2 (CH), 128.0 (CH),
3.2. (R)-2,2-Dimethyl-1,3-dioxolane-4-carbaldehyde (4)
110.3 (C), 83.9 (C), 82.4 (C), 77.9 (CH), 71.8 (CH), 65.4 (CH2), 62.7
(CH), 57.4 (CH2), 26.5 (CH3), 25.2 (CH3); MS (ESI, +ve) m/z 299.11
[M–Na]+ (55), 259 [M–H–H2O]+ (100); HRMS (ES+) C16H20O4Na+
requires m/z 299.1260, found 299.1259.
Saturated aqueous NaHCO3 (2 cm3) was added to a stirred
solution
of
1,2:5,6-di-O-isopropylidene-
D-mannitol
(3.3 g,
13 mmol) in CH2Cl2 (30 cm3) while maintaining the temperature
below 25 8C. Sodium metaperiodate (5.3 g, 25 mmol) was then
added over a 20 min period with vigorous stirring and the reaction
was allowed to proceed for 4 h while the temperature was
maintained below 30 8C. The solution was then decanted from the
solid and the remaining solid was stirred with additional CH2Cl2
(10 cm3) for 5 min and it was again decanted from the solid. The
CH2Cl2 solutions were combined and concentrated in vacuo and
then distilled under reduced pressure (67–72 8C, 30 mmHg) giving
4 as a colourless oil (1.46 g, 67%).
3.5. (S)-4-(Benzyloxy)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-
ynyl 3,5-dinitrobenzoate (6a)
3,5-Dinitrobenzoyl chloride (0.482 g, 2.0 mmol) was added to
a solution of 5a (0.515 g, 1.8 mmol, de 62%) in dry pyridine
(29 cm3) at 0 8C. After stirring for 16 h at ambient temperature the
reaction mixture was poured into ice water and extracted into
Et2O (3ꢁ 70 cm3). The product was purified over silica gel (9:1
hex:EtOAc ! 5:1) to give 6a which was recrystallised from
absolute ethanol (0.593 g, 70%).
[a
]
D + 76.28 (c 1.3, benzene), lit. [20] [
a]D + 73.18 (c 1.3,
benzene); 1H NMR (300 MHz, CDCl3)
d
9.63 (d, J = 1.9 Hz, 1H),
mp 86–88 8C (from EtOH), [
plate)/cmꢀ1 2923, 1764, 1629, 1545, 1459, 1345, 1273, 1153, 1074,
721; 1H NMR (400 MHz, CDCl3)
9.25 (t, 1H, J = 2.1 Hz), 9.21 (d, 2H,
a]D + 38.88 (c 0.5, CHCl3); nmax (KBr
4.31 (ddd, J = 7.3 Hz, 4.8 Hz, 1.9 Hz, 1H), 4.10 (dd, J = 8.8, 7.3 Hz,
1H), 4.02 (dd, J = 8.8, 4.8 Hz, 1H), 1.41 (s, 3H), 1.34 (s, 3H); 13C NMR
d
(75 MHz, CDCl3)
d
201.8 (CHO), 111.2 (C), 79.8 (CH), 65.5 (CH2),
J = 2.1 Hz), 7.39–7.27 (m, 5H), 5.88–5.83 (m, 1H), 4.58 (s, 2H), 4.55–
26.2 (CH3), 25.1 (CH3); MS (CI+) m/z 131.07 [M–Na]+ (100); HRMS
(CI+) C6H10O3H+ requires m/z 131.0708, found 131.0704.
4.46 (m, 1H), 4.27–4.15 (m, 4H), 1.38 (s, 3H), 1.39 (s, 3H); 13C NMR
(125 MHz, CDCl3)
d 161.6 (C), 148.9 (C), 137.2 (C), 133.4 (C), 129.8
(CH), 128.7 (CH), 128.2 (CH), 122.9 (CH), 111.0 (C), 84.9 (C), 79.6
(C), 76.3 (CH), 72.1 (CH2), 66.6 (CH), 65.6 (CH2), 57.3 (CH2), 26.5
(CH3), 25.0 (CH3); MS (ESI, +ve) m/z 493.06 [M–Na]+ (100); HRMS
(ESI, +ve) C23H22N2O9Na+ requires m/z 493.1223, found 493.1218.
3.3. (R)-4-(Benzyloxy)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-
yn-1-ol (5b)
n-BuLi (1.6 M in n-hexane, 9.63 cm3, 15.4 mmol) was added to a
stirred solution of benzyl propargyl ether (2.27 cm3, 15.4 mmol) in
dry THF (19 cm3) at ꢀ78 8C. After stirring at ꢀ78 8C for 1.5 h, a
solution of 4 (1.0 g, 7.7 mmol) in THF (8 cm3) was added dropwise
to the mixture and the reaction stirred for 4 h at ꢀ78 8C. The
reaction mixture was then poured into saturated aqueous NH4Cl
(50 cm3) at ꢀ78 8C. Water (70 cm3) was added and the reaction
mixture was extracted with Et2O (3ꢁ 110 cm3). The Et2O extract
was successively washed with water and brine, then dried (MgSO4)
and concentrated in vacuo. The crude product was purified over
silica (9:1 hex:EtOAc ! 3:1) to give the desired alcohol 5b (1.723 g,
81%, de 9% determined by chiral GC-FID) as a clear oil.
3.6. (R, E)-4-(Benzyloxy)-1-((R)-2,2-dimethyl-1, 3-dioxolan-4-yl)
but-2-en-1-ol (1b)
A solution of 5b (1.62 g, 5.86 mmol, de 9%) in n-hexane
(6.5 cm3) was added to a suspension of LiAlH4 (0.3 g, 7.62 mmol)
in n-hexane (13 cm3) at 0 8C. The reaction mixture was heated
under reflux for 2 h and was then quenched by dropwise addition
of water (10 cm3). The mixture was filtered and the resultant
precipitate was washed with Et2O (3ꢁ 75 cm3). The combined
organics were dried (MgSO4) and the product purified over silica
gel (9:1 hex:EtOAc ! 3:1) to give alcohol 1b (0.734 g, 45%, de 17%
determined by chiral GC-FID) as a clear oil.
Data for major diastereoisomer (5b): 1H NMR (400 MHz, CDCl3)
d
7.38–7.26 (m, 5H), 4.58 (s, 2H), 4.37 (dt, J = 8.8, 1.7 Hz, 1H), 4.28–
3.86 (m, 5H), 2.70 (brs, OH), 1.46 (s, 3H), 1.38 (s, 3H); 13C NMR
(125 MHz, CDCl3) 137.3 (C) 128.6 (CH), 128.2 (CH), 128.0 (CH),
Data for major diastereoisomer (1b): 1H NMR (400 MHz, CDCl3)
d
7.38–7.26 (m, 5H), 5.98–5.89 (m, 1H), 5.78–5.67 (m, 1H), 4.51 (s,
d
2H), 4.33–4.27 (m, 1H), 4.13–4.07 (m, 1H), 4.05–4.02 (m, 2H),
3.99–3.87 (m, 2H), 2.25 (brs, OH), 1.45 (s, 3H), 1.36 (s, 3H); 13C
110.6 (C), 83.9 (C), 82.3 (C), 78.7 (CH), 71.8 (CH), 66.2 (CH2), 64.3
(CH), 57.4 (CH2), 26.9 (CH3), 25.3 (CH3); MS (ESI, +ve) m/z 299.11
[M–Na]+ (55), 259 [M–H–H2O]+ (100); HRMS (ES+) C16H20O4Na+
requires m/z 299.1260, found 299.1259.
NMR (125 MHz, CDCl3)
d 138.2 (C), 130.5 (CH), 130.4 (CH), 128.5
(CH), 127.8 (CH), 127.8 (CH), 110.0 (C), 78.8 (CH), 73.4 (CH), 72.4
(CH2), 69.9 (CH2), 66.0 (CH2), 26.9 (CH3), 25.4 (CH3); MS (ESI, +ve)
m/z 301.08 [M–Na]+ (100); HRMS (ES+) C16H22O4Na+ requires m/z
301.1416, found 301.1421.
3.4. (S)-4-(Benzyloxy)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-
yn-1-ol (5a)
3.7. (S,E)-4-(Benzyloxy)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)but-
n-BuLi (1.6 M in n-hexane, 13.88 cm3, 22.2 mmol) was added
dropwise to a solution of benzyl propargyl ether (3.27 cm3,
22.2 mmol) in THF (21.0 cm3) at ꢀ78 8C. After 30 min, Ti(Oi-Pr)3Cl
(1 M in n-hexane, 41.0 cm3, 22.2 mmol) was added and the flask
warmed to ꢀ60 8C. To maintain solubility, additional THF (41 cm3)
was added and the solution was stirred for 90 min prior to re-
cooling to ꢀ78 8C. Compound 4 (1.44 g, 11.1 mmol) was then
added in one portion and the mixture stirred for 4 h prior to
quenching with saturated NH4Cl (70 cm3) at ꢀ78 8C. Water
(100 cm3) was added and the reaction mixture was extracted
with Et2O (3ꢁ 150 cm3). The product was purified over silica gel
(9:1 hex:EtOAc ! 3:1) to give the desired alcohol 5a (2.52 g, 82%,
de 9% determined by chiral GC-FID) as a clear oil.
2-en-1-ol (1a)
A solution of 5a (2.431 g, 8.79 mmol, de 62%) in n-hexane
(10 cm3) was added to a suspension of LiAlH4 (0.450 g, 11.9 mmol)
in n-hexane (20 cm3) at 0 8C. The reaction mixture was heated
under reflux for 2 h and was quenched by dropwise addition of
water (15 cm3). The mixture was filtered and the precipitate
washed with Et2O (3ꢁ 100 cm3). The combined organics were
dried (MgSO4) and evaporated and the product purified over silica
gel (9:1 hex:EtOAc ! 3:1) to give alcohol 1a (1.346 g, 55%, de 75%,
determined by chiral GC-FID) as a clear oil.
Data for major diastereoisomer (1a): 1H NMR (400 MHz, CDCl3)
d
7.38–7.26 (m, 5H), 5.98–5.89 (m, 1H), 5.78–5.67 (m, 1H), 4.51 (s,

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S. Bresciani et al. / Journal of Fluorine Chemistry 130 (2009) 537–543
2H), 4.33–4.27 (m, 1H), 4.13–4.07 (m, 1H), 4.05–4.02 (m, 2H),
3.99–3.87 (m, 2H), 2.25 (brs, OH), 1.44 (s, 3H), 1.36 (s, 3H); 13C
Data for 2a: [
a
]D–7.68 (c 1.0, CHCl3), nmax (KBr plate)/cmꢀ1
7.37–7.27 (m,
1215, 1115, 1071, 972; 1H NMR (CDCl3, 300 MHz),
d
NMR (125 MHz, CDCl3)
d
138.2 (C), 130.4 (CH), 129.4 (CH), 128.5
5H), 6.00 (m, 1H), 5.84 (m, 1H), 4.87 (dm, J = 47.9 Hz, 1H), 4.54 (s,
(CH), 127.9 (CH), 127.8 (CH), 109.5 (C), 78.2 (CH), 71.3 (CH), 72.4
(CH2), 70.1 (CH2), 64.9 (CH2), 26.5 (CH3), 25.2 (CH3); MS (ESI, +ve)
m/z 301.08 [M–Na]+ (100); HRMS (ES+) C16H22O4Na+ requires m/z
301.1416, found 301.1421.
2H), 4.15 (m, 1H), 4.10–4.04 (m, 3H), 3.98 (m, 1H), 1.43 (s, 3H), 1.36
(s, 3H); 13C NMR (CDCl3, 75.5 MHz)
d 132.1 (d, J = 11.6 Hz, CH),
138.3 (C), 128.8 (CH), 128.1 (CH), 127.0 (d, J = 18.6 Hz, CH), 120.0
(CH), 109.9 (C), 91.9 (d. J = 173.0 Hz, CH), 76.9 (d, J = 27.7 Hz, CH),
72.8 (CH2), 69.9 (CH2), 65.8 (d. J = 4.2 Hz, CH2), 26.8 (CH3), 25.6
3.8. (R)-4-((S,E)-4-(Benzyloxy)-1-fluorobut-2-enyl)-2,2-dimethyl-
1,3-dioxolane (2a), (R)-4-((R,E)-4-(benzyloxy)-1-fluorobut-2-enyl)-
2,2-dimethyl-1,3-dioxolane (2b), (S)-4-((R,E)-4-(benzyloxy)-3-
fluorobut-1-enyl)-2,2-dimethyl-1,3-dioxolane (3a) and (S)-4-((S,E)-
4-(benzyloxy)-3-fluorobut-1-enyl)-2,2-dimethyl-1,3-dioxolane (3b)
(CH3); 19F NMR (282 MHz, CDCl3)
19F {1H dec} NMR (282 MHz, CDCl3)
d
ꢀ187.95 (dm, J = 47.9 Hz, 1F);
d
ꢀ187.95 (s, 1F); MS (ESI, +ve)
m/z 303.07 [M–Na]+ (100); HRMS (ESI, +ve) C16H21FO3Na+ requires
m/z 303.1372, found 303.1378.
Data for inseparable mixture of isomers 2b/3a/3b: nmax (KBr
plate)/cmꢀ1 1215, 1115, 1071, 972; 19F NMR (282 MHz, CDCl3)
d
3.8.1. General procedure for the reaction of allylic alcohol 1a/1b
mixtures with TFEDMA
ꢀ183.48 (dm, 48.3 Hz, 1F), ꢀ183.87 (m, 1F), ꢀ184.63 (m, 1F); 19F
{1H dec} NMR (282 MHz, CDCl3)
d
ꢀ183.48 (s, 1F), ꢀ183.87 (s, 1F),
A solution of allylic alcohol 1a/1b (5.0 mmol, 10 cm3) in CH2Cl2
was added to a solution of TFEDMA (5.5 mmol, 10 cm3) in CH2Cl2 at
0 8C in a polythene vessel. After addition the reaction mixture was
brought to ambient temperature and stirred for 1 h and the
progress of the reaction was monitored by TLC. The reaction was
worked up by adding saturated NaHCO3 solution and the product
was extracted into CH2Cl2 (3ꢁ 150 cm3). Purification by chroma-
tography (6:1 hex:EtOAc ! 3:1) gave 2a and an inseparable
mixture of isomers 2b/3a/3b. Stereoisomer ratios and yields are
given in Table 1.
ꢀ184.63 (s, 1F); MS (ESI, +ve) m/z 303.04 [M–Na]+ (100); HRMS
(ESI, +ve) C16H21FO3Na+ requires m/z 303.1372, found 303.1375.
3.9. (1S,2S,3R)-4-(Benzyloxy)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-
yl)-1-fluorobutane-2,3-diol (7a)
Methanesulfonamide (0.041 g, 0.43 mmol) was added to a
solution of AD-mix-
b
(0.602 g) in tert-butyl-alcohol (2.3 cm3) and
water (2.3 cm3). A solution of 2a (0.120 g, 0.43 mmol) in tert-butyl-
alcohol (2.3 cm3) was then added and the resulting mixture was
stirred at 0 8C for 1 h and then at ambient temperature for 3 days.
Solid Na2SO3 (0.662 g)wasaddedand the mixturestirredfor 30 min.
The product was then extracted into Et2O (3ꢁ 20 cm3) and the
combined organic layers were washed with 2 M KOH (20 cm3) and
concentrated. The product was purified over silica gel (9:1
hex:EtOAc ! 4:1) and 7a was recrystallised from Et2O (0.05 g, 37%).
3.8.2. General procedure for the reaction of allylic alcohol 1a/1b
mixtures with Deoxo-FluorTM
A solution of Deoxo-FluorTM (7.5 mmol, 50%) in THF was added
to a solution of 1a/1b (5.0 mmol) in CH2Cl2 (20 cm3) at 0 8C. After
addition the reaction mixture was heated to 55 8C for 3.5 h and the
progress of the reaction was monitored by TLC. The reaction
mixture was allowed to cool to ambient temperature and was then
worked up by adding saturated aqueous NaHCO3 solution. The
product was extracted into CH2Cl2 (3ꢁ 150 cm3) and was purified
by silica gel chromatography eluting with a hexane/ethyl acetate
gradient (10:1 hex:EtOAc ! 3:1). This gave 2a and an inseparable
mixture of isomers 2b/3a/3b. Stereoisomer ratios and yields are
given in Table 1.
mp 94–96 8C (from Et2O); [
plate)/cmꢀ1 3456, 2727, 1700, 1265, 1225, 1161, 1138, 1115, 1054,
725; 1H NMR (400 MHz, CDCl3)
7.40–7.27 (m, 5H), 4.58 (s, 2H),
a] +1.98 (c 0.6, CHCl3), nmax (KBr
D
d
4.57–4.44 (dm, J = 46.0 Hz, 1H), 4.44–4.37 (m, 1H), 4.14 (ddd,
J = 8.7, 6.5, 6.2 Hz, 1H), 4.06 (ddd, J = 8.7, 5.5, 5.3 Hz, 1H), 4.03–3.95
(m, 1H), 3.90 (dddd, J = 11.2, 6.1, 4.7, 1.7 Hz, 1H), 3.65 (d, J = 5.3 Hz,
1H), 3.08 (d, J = 4.7 Hz, 1H), 2.88 (d, J = 5.9 Hz, 1H), 1.44 (s, 3H), 1.37
(s, 3H); 13C NMR (125 MHz, CDCl3)
d 137.7 (C), 128.7 (CH), 128.1
(CH), 128.0 (CH), 110.2 (C), 91.2 (d, J = 176.8, CH), 74.3 (d, J = 27.3,
CH), 73.8 (CH2), 72.2 (CH2), 71.6 (d, J = 23.3, CH), 68.4 (d, J = 5.4 Hz,
CH), 65.9 (d. J = 4.7 Hz, CH2), 26.5 (CH3), 25.3 (CH3); 19F NMR
3.8.3. General procedure for the reaction of allylic alcohol 1a/1b
mixtures with DASTTM
DASTTM (neat, 7.5 mmol) was added to a solution of 1a/1b
(5.0 mmol) in dry CH2Cl2 (20 cm3) at 0 8C. After addition the
reaction mixture was brought to ambient temperature and stirred
for 4.5 h and the progress of the reaction was monitored by TLC.
The reaction was worked up by adding saturated aqueous NaHCO3
solution and the product was extracted into CH2Cl2 (3ꢁ 150 cm3)
and purified by silica gel chromatography (hexane/ethyl acetate
gradient (6:1 hex:EtOAc ! 3:1). This gave 2a and an inseparable
mixture of isomers 2b/3a/3b. Stereoisomer ratios and yields are
given in Table 1.
(470 MHz, CDCl3)
d
ꢀ198.37 (ddd, J = 46.0, 13.0, 11.2 Hz, 1F); 19F
{1H dec} NMR (470 MHz, CDCl3)
d
ꢀ198.37 (s, 1F); MS (ESI, +ve) m/z
337.19 [M–Na]+ (100); HRMS (ESI, +ve) C16H23FO5Na+ requires m/z
337.1427, found 337.1431.
3.10. (1S,2S,3R)-4-(Benzyloxy)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-
yl)-3-fluorobutane-1,2-diol (8b)
The mixture of isomers 2b/3a/3b (0.468 g, 1.7 mmol) was
treated as described in Section 3.9 and the product was extracted
into CH2Cl2 (3ꢁ 70 cm3) and purified over silica gel eluting with
hexane/ethyl acetate (9:1 hex:EtOAc ! 3:1) to give the desired
diols 8a/8b as a 1:0.7 diastereomeric mixture (0.321 g, 60%)
favouring 8b.
3.8.4. General procedure for the reaction of allylic alcohol 1a/1b
mixtures with FLUOLEADTM
To a solution of FLUOLEADTM (1.2 mmol in 2.2 cm3 of dry
CH2Cl2) in a polyethylene vessel at 0 8C was added a solution of
allylic alcohol 1a/1b (1.1 mmol in 2.2 cm3 of dry CH2Cl2). After
addition the reaction mixture was stirred at 0 8C for 40 min. The
progress of the reaction was monitored by TLC. The reaction
mixture was worked up by slowly adding saturated aqueous
NaHCO3 solution and the crude product was extracted into CH2Cl2
(3ꢁ 20 cm3). Evaporation of solvents in vacuo gave a product that
was analysed directly by 19F NMR spectroscopy. Stereoisomer
ratios are given in Table 1.
3.11. (1R,2R,3S)-4-(Benzyloxy)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-
yl)-3-fluorobutane [1,3,2] dioxolane 2,2-dioxide (9b) and (1R,2R,3S)-
4-(benzyloxy)-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-
fluorobutane-[1,3,2] dioxolane 2,2-dioxide (9a)
SOCl2 (0.125 cm3, 1.7 mmol) was added to a solution of 8b
(0.447 g, 1.4 mmol, dr 1:0.7) in CH2Cl2 (65 cm3) and pyridine
(0.17 cm3, 2.1 mmol) and the mixture was stirred at 0 8C for

S. Bresciani et al. / Journal of Fluorine Chemistry 130 (2009) 537–543
543
30 min. Saturated CuSO4 (aq) (35 cm3) was then added and the
product extracted into CH2Cl2 (3ꢁ 70 cm3). The organics were
dried (MgSO4) and concentrated and then dissolved in CH3CN
(50 cm3). The solution was cooled to 0 8C and then NaIO4 (0.764 g,
3.5 mmol), RuCl3ꢂ3H2O (1 mol.%) and H2O (35 cm3) were added
and the heterogeneous mixture was stirred vigorously at 0 8C for
3 h. Et2O (140 cm3) was then added and the organic layer was
washed with 5% aqueous NaHCO3 (50 cm3) and dried (MgSO4). The
product was purified over silica gel (9:1 hex:EtOAc ! 4:1) to give
9b (0.322 g, 61%) as an oil and 9a as a white crystalline solid
(0.141 g, 27%).
d
ꢀ198.42 (dddd, J = 46.0, 27.0, 18.0, 11.0 Hz, 1F); 19F {1H dec} NMR
(470 MHz, CDCl3)
Na]+ (100); HRMS (ESI, +ve) C16H21O7FSNa+ requires m/z 399.0888,
found 399.0890.
d
ꢀ198.42 (s, 1F); MS (ESI, +ve) m/z 399.11 [M–
Acknowledgements
We thank Dr V. Petrov of the Dupont Company (Wilmington,
USA) for providing the TFEDMA reagent and Dr T. Umemota and T.
Toyokura, IM&T Research (Denver, CO, USA) for providing a sample
of FLUOLEADTM
.
Data for 9a: mp 38–40 8C (from Et2O); [
CHCl3),
max (KBr plate)/cmꢀ1 3090, 3066, 3033, 2990, 1881, 1812,
1734, 1606, 1396, 1261, 1213, 1061, 986, 953, 833; 1H NMR
(400 MHz, CDCl3) 7.42–7.27 (m, 5H), 5.07–4.76 (m, 3H), 4.62 (d,
a
]
+30.5 (c 0.63,
D
n
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(CH), 128.4 (CH), 128.1 (CH), 111.3 (C), 88.1 (d, J = 184.3, CH), 82.7
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ꢀ206.85
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1061, 986, 953, 833; 1H NMR (400 MHz, CDCl3)
7.42–7.28 (m,
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+23.1 (c 1.9, CHCl3), nmax (KBr plate)/cmꢀ1
D
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d
5H), 5.16 (ddd, J = 11.0, 6.2, 4.0 Hz, 1H), 4.94 (ddt, J = 46.0 Hz,
6.2 Hz, 5.3, 4.1 Hz), 4.83–4.76 (m, 1H), 4.63 (d, J = 11.9 Hz, 1H), 4.57
(d, J = 11.9, 1H), 4.43 (ddd, J = 9.5, 6.2, 3.4 Hz, 1H), 4.18 (dd, J = 9.5,
6.2 Hz, 1H), 4.03 (dd, J = 9.5, 3.4 Hz, 1H), 3.84 (ddd, J = 18.0, 11.5,
4.1, 1H), 3.79 (ddd, J = 27.0, 11.5, 4.1, 1H), 1.42 (s, 3H), 1.35 (s, 3H);
13C NMR (125 MHz, CDCl3)
127.9 (CH), 111.2 (C), 89.0 (d, J = 179.6, CH), 81.1 (d, J = 4.1, CH),
80.2 (d, J = 29.0, CH), 74.0 (CH2), 73.8 (CH), 67.1 (d, J = 22.6 Hz,
CH2), 66.4 (CH2), 26.7 (CH3), 24.9 (CH3); 19F NMR (470 MHz, CDCl3)
ˇ
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