Scalable, stereoselective syntheses of α,β-difluoro-γ-amino acids

Article abstract of DOI:10.1016/j.tet.2016.04.070

Backbone-fluorinated gamma-amino acids are novel shape-controlled building blocks that have potential utility in a variety of biological contexts. However, their synthesis poses challenges in terms of chemo-, regio- and stereoselectivity, and this has proven to be the major bottleneck in the ongoing development of their various biological applications. To address this problem, several new synthetic strategies were investigated in this work. This has led to the identification of new methods that are superior in terms of yield and stereocontrol.

Full text of DOI:10.1016/j.tet.2016.04.070

Tetrahedron 72 (2016) 3305e3317
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Scalable, stereoselective syntheses of a,b-difluoro-g-amino acids
Alpesh Ramanlal Patel a, Xiang-Guo Hu a, Aggie Lawer a, Md. Iqbal Ahmed a,
Catherine Au a, Rasha Jwad a, Johny Trinh a, Christina Gonzalez a, Elizabeth Hannah a,
,
Mohan M. Bhadbhade b, Luke Hunter a
*
a School of Chemistry, UNSW, Australia
b Mark Wainwright Analytical Centre, UNSW, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Backbone-fluorinated gamma-amino acids are novel shape-controlled building blocks that have potential
utility in a variety of biological contexts. However, their synthesis poses challenges in terms of chemo-,
regio- and stereoselectivity, and this has proven to be the major bottleneck in the ongoing development
of their various biological applications. To address this problem, several new synthetic strategies were
investigated in this work. This has led to the identification of new methods that are superior in terms of
yield and stereocontrol.
Received 20 December 2015
Received in revised form 13 April 2016
Accepted 22 April 2016
Available online 24 April 2016
Keywords:
Ó 2016 Elsevier Ltd. All rights reserved.
Fluorination
Amino acids
Stereoselectivity
1. Introduction
exploited in a variety of applications. For example, 1 and 2 were
shown to have different selectivity patterns in GABA receptor
Selective fluorination is a well recognised tool for modulating
the chemical, physical and biological properties of organic mole-
cules.1e10 One of the impacts of incorporating fluorine is that the
molecular conformation can be affected in predictable ways, for
example, due to the fluorine gauche effect.10 Thus, it is possible to
rationally ‘program’ molecules to adopt desired shapes through
selective fluorination chemistry, allowing the function of the mol-
ecule (e.g., binding to a biological target) to be optimised.11e26
For several years we have been exploring this idea in the context
of amino acids (e.g., 1 and 2, Fig. 1).11,13,27,28 We have examined the
preferred conformations of 1 and 2, revealing that the syn-isomer
(1) adopts an extended zigzag shape, while the anti-isomer (2)
adopts a bent backbone shape.28 In both cases this can be ration-
alised in terms of the gauche effect mentioned above. We have
shown that the conformational differences between 1 and 2 can be
binding assays.11 Alternatively, 1 and 2 can be incorporated within
larger molecular architectures via peptide coupling reactions,
where they can dramatically affect the overall conformations of
linear and even cyclic peptides.13
The ongoing development of such applications relies on an ef-
ficient and scalable method for the synthesis of 1 and 2. Un-
fortunately however, the current synthetic method (Scheme 1)28
suffers from several limitations. First, the dihydroxylation of al-
kene 3 proceeds in variable yield, possibly due to the instability of
this (expensive) starting material. Second, in the synthesis of the
syn-difluoro target (1), the fluorination of 5 is low yielding
(10e21%) because the phenyl ring undergoes competing neigh-
bouring group participation and migration to give an undesired
geminal difluoro side product (7), rendering the purification of 6
cumbersome. Third, in the case of the anti-difluoro target (2), the
fluorohydrin 8 is obtained with modest diastereoselectivity which
again necessitates a laborious purification process. Overall then,
there is a clear need to develop a more reliable and scalable syn-
thesis of 1 and 2. Our efforts to do so are detailed herein.
2. Results and discussion
Fig. 1.
a,b-Difluoro-g-amino acids.
2.1. Alternative starting material
To avoid the instability (and expense) of the starting material
* Corresponding author. E-mail address: l.hunter@unsw.edu.sau (L. Hunter).
cinnamyl bromide (3), the cheap and readily available cinnamyl
http://dx.doi.org/10.1016/j.tet.2016.04.070
0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.

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A.R. Patel et al. / Tetrahedron 72 (2016) 3305e3317
Scheme 1. 28 Previous route to , CH3SO2NH2, t-BuOH, H2O, 0 ꢀC; (b) potassium phthalimide, phthalimide, DMF, 80 ꢀC; (c) SOCl2, pyridine,
a,b-difluoro-g-amino acids. (a) AD-mix-b
CH2Cl2, 0 ꢀC then NaIO4, RuCl3, H2O, CH2Cl2, CH3CN, 0 ꢀC; (d) TBAF, THF, CH3CN, 0 ꢀC then H2SO4, H2O, THF, rt; (e) DeoxoFluorÒ (neat), 70 ꢀC; (f) NaIO4, RuCl3, H2O, CH2Cl2, CH3CN, rt;
(g) H2NNH2$H2O, EtOH, reflux; (h) (CF3SO2)2O, 1,4-diazabicyclo[2.2.2]octane (DABCO), CH2Cl2, e78 ꢀC to rt; (i) Et3N$3HF, 120 ꢀC.
alcohol (10) was utilized instead (Scheme 2). Asymmetric dihy-
droxylation of 10 was straightforward and delivered the triol 11 in
high yield.29 Selective tosylation of the primary alcohol of triol 11
was achieved using 1.3 equiv of p-toluenesulfonyl chloride, fur-
nishing the tosylate 12 in good yield.29 Finally, the Gabriel reaction
of 12 successfully provided the desired phthalimide derivative 4
(Scheme 2), which can be utilized for the synthesis of 1 and 2
according to the methods described above (Scheme 1). Although
the route to 4 from cinnamyl alcohol (10) involved an extra step, the
reproducible yields and the much lower cost of the starting mate-
rial constituted a genuine improvement over the previous route
from cinnamyl bromide (3, Scheme 1).
enantioselectivity.30 The epoxy alcohol 13 was then subjected to
tosylation and a Gabriel reaction to deliver the epoxide 15. Ring-
opening of the epoxide 15 was then attempted using Et3N$3HF,
but unfortunately this gave the fluorohydrin 5 in only 3:2 di-
astereoisomeric ratio as measured by 19F NMR analysis of the crude
reaction mixture. The purification of 5 was laborious and hence this
approach was abandoned. Alternatively, it was previously estab-
lished31 that the precursor epoxide 14 could be ring-opened with
BF3$OEt2 in a highly diastereoselective manner, furnishing the pure
fluorohydrin 16 in reasonable yield. In the current work, fluo-
rohydrin 16 then underwent a Gabriel reaction to deliver com-
pound 8 in 50% yield, thereby intercepting the previous synthesis of
2 via 9 (Scheme 1). Interestingly, it was subsequently discovered
that the yield of 9 could be further increased if the order of the
fluorination and Gabriel reactions was reversed. Fluorination of 16
gave the vicinal difluoride 17 in very good yield (Scheme 3),
alongside a small quantity of a geminal difluoro side product (18;
see ESI). The tosylate 17 was then subjected to a Gabriel reaction to
2.2. Sharpless epoxidation approach
Another route commencing from cinnamyl alcohol (10) was also
investigated (Scheme 3). Asymmetric epoxidation of 10 was carried
out to obtain epoxy alcohol 13 in good yield and with excellent
Scheme 2. Alternative synthesis of diol 4. (a) (DHQD)2PHAL, OsO4, CH3SO2NH2, K3Fe(CN)6, NaHCO3, t-BuOH, H2O, 0 ꢀC; (b) Bu2SnO, TsCl, Et3N, CH2Cl2; (c) potassium phthalimide,
phthalimide, DMF, 80 ꢀC.

A.R. Patel et al. / Tetrahedron 72 (2016) 3305e3317
3307
Scheme 3. Sharpless epoxidation route. (a) D-(ꢁ)-DET, t-BuOOH, Ti(Oi-Pr)4, CH2Cl2, ꢁ20 ꢀC; (b) Et3N, DMAP, TsCl, 0 ꢀC; (c) phthalimide, potassium phtalimide, DMF, 50 ꢀC; (d)
Et3N$3HF, 120 ꢀC; (e) BF3$OEt2, CH2Cl2, ꢁ20 ꢀC; (f) DeoxoFluorÒ (neat), 70 ꢀC; (g) phthalimide, potassium phtalimide, DMF, 90 ꢀC.
efficiently afford compound 9. Overall, this route (Scheme 3) offers
substantial improvements over the literature synthesis of target 2
in terms of yield, diastereoselectivity and ease of purifications.
a mixture of all four products (20e23) in a ratio of 0.24: 0.23: 0.67:
1.00. In an attempt to reduce the amount of product 21 arising
through substitution with retention, the fluorination reaction was
re-attempted using the morpholine-DeoxoFluorÒ adduct (Scheme
4), since this reagent is known to disfavour unimolecular ionisa-
tion processes.33 As expected, the diastereomeric ratio of 20:21
improved from w1:1 to w5:1. Unfortunately however, it proved
extremely difficult to isolate these fluorinated compounds from
the reaction mixture. Hence, this chiral pool approach was
abandoned.
2.3. Chiral pool approach32
The next strategy to be investigated for the synthesis of target 1
was a chiral pool approach (Scheme 4). The commercially available
compound (1S,2S)-2-amino-1-phenylpropane-1,3-diol was identi-
fied as a potential starting point for the synthesis of vicinal
difluoride 20 (Scheme 4) en route to the enantiomer of target 1. The
formation of 20 would require the intermediacy of an aziridinium
species arising through neighbouring group participation of the
appropriately protected amino group. However, this outcome was
not guaranteed because a competing direct substitution of the
primary alcohol could occur to give primary alkyl fluoride products,
and also substitution of the benzylic alcohol could conceivably
proceed via an SN1 mechanism to give a mixture of stereoisomers at
the benzylic position.
Initially the fluorination reaction was attempted with the diallyl
protected substrate 19a (Scheme 4), using DeoxoFluorÒ
(1e3 equiv.) at various temperatures ranging from ꢁ78 ꢀC to 25 ꢀC.
In every case, the crude product mixture contained recovered
starting material along with monofluorinated and difluorinated
products (22, 23); however no vicinal difluorinated products (20,
21) were observed. Next, the benzyl protected substrate 19b was
investigated (Scheme 4). Fluorination with DeoxoFluorÒ delivered
2.4. N-Halosuccinimide approach22
The next approach to be investigated was a racemic synthesis
(Scheme 5). It was recognised that the targets 1 and 2 could still be
valuable for some applications in racemic form: for example, they
could conceivably be incorporated into (diastereoisomeric) pep-
tides and separated thereafter. Several methods are known for the
synthesis of racemic vicinal difluoro motifs.34 For example, olefins
can be converted via halonium intermediates into bromofluoro or
iodofluoro compounds, which can subsequently be converted into
difluoro compounds through nucleophilic substitution.22,35 This
was anticipated to allow a rapid and diastereoselective route to the
targets 1 and 2.
The initial substrates were olefins 24 and 30 (Scheme 5). Re-
action of 24 with N-iodosuccinimide and Olah’s reagent gave three
fluoroiodo products (25e27), which were difficult to separate by

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A.R. Patel et al. / Tetrahedron 72 (2016) 3305e3317
Scheme 4. Chiral pool approach. (a) DeoxoFluorÒ, CH2Cl2, rt; (b) DeoxoFluorÒ, TMS-morpholine, CH2Cl2, rt.
column chromatography. Various reaction solvents were screened
(see Supplementary data), and it was discovered that acetonitrile
gave the best diastereoselectivity with the b-fluoro compound 25
obtained as the major product. The stereochemistry of 25 was
confirmed by X-ray crystallographic analysis (Fig. 2). Subsequently,
various nucleophilic fluorination conditions were screened (in-
cluding AgF, Scheme 5) in an attempt to convert the mixture of
25e27 into vicinal difluoro products. However, only elimination
products (28 and 29) were observed. A similar reaction sequence
was attempted using substrate 30 (Scheme 5). Iodofluorination of
30 delivered all four possible isomers of the product (31e34) as an
inseparable mixture, but once again with quite good selectivity for
the desired anti-isomers (31, 32). However, addition of AgF to the
reaction mixture unfortunately gave a complex mixture of products
(Scheme 5), with 19F NMR analysis of the crude reaction mixture
suggesting that rearrangement products were present (charac-
terised by distinctive triplet signals around ꢁ230 ppm, corre-
sponding to primary alkyl fluorides). The reaction sequences
Scheme 5. Attempted racemic synthesis commencing with substrates 24 or 30. (a) N-Iodosuccinimide, HF$pyridine, MeCN, rt; (b) AgF, MeCN, 80 ꢀC.

A.R. Patel et al. / Tetrahedron 72 (2016) 3305e3317
3309
Fig. 2. X-ray crystal structures of compounds 25, 36, 37 and 39 (CCDC numbers: 1418490, 1418489, 1418488 and 1418491).
commencing from both 24 and 30 were reattempted using N-bro-
mosuccinimide instead of N-iodosuccinimide; however, only the
starting materials were recovered in both cases.
In order to improve the regioselectivity of the halofluorination
reactions (Scheme 5), a phenyl group was incorporated into a new
substrate (35, Scheme 6). When olefin 35 was treated with N-
proceeded with excellent diastereoselectivity, delivering the de-
sired bromofluoro compound 39 in high yield. However, sub-
sequent attempts to convert 39 into a vicinal difluoro product
resulted in an undesired elimination reaction, giving fluoroalkenes
40 and 41 (Scheme 6). Overall, because of the difficulties in con-
verting the fluorohalo intermediates into difluoro species (Schemes
5 and 6) it was concluded that the racemic approach to vicinal
difluorinated amino acids was not viable.
bromosuccinimide and Olah’s reagent, the expected a-fluorinated
compound 36 was formed as the major product, along with a small
quantity of the diastereomer 37. The bromofluoro intermediates 36
and 37 were separable by column chromatography. However, when
the bromofluorination reaction mixture was treated with AgF
(Scheme 6), the undesired rearrangement product 7 was obtained
in 53% yield. This result was analogous to the rearrangement
The stereochemical assignments of the fluorohalo intermediates
25, 36, 37 and 39 were secured using X-ray crystallographic analysis
(Fig. 2).
2.5. Exploiting the p-nitro group as a tool for selectivity
problem encountered in the first-generation synthesis of
1
(Scheme 1).36 In order to prevent this rearrangement process, a p-
nitro substituent was included in the modified substrate 38
(Scheme 6). The bromofluorination reaction of substrate 38
Although the racemic approach (Scheme 6) was ultimately un-
successful, the high stereoselectivity observed with substrate 38
prompted us to investigate the p-nitro substituent in a new context.
Scheme 6. Attempted racemic synthesis commencing with substrates 35 or 38. (a) N-Bromosuccinimide, HF$pyridine, DCM, rt; (b) AgF.

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A.R. Patel et al. / Tetrahedron 72 (2016) 3305e3317
The design of the new strategy (Scheme 7) was also informed by
our recent work towards -trifluoro-
-amino acids,37 in which
p-nitro group (Scheme 7) delivered significant benefits in the
synthesis of target 1, by greatly improving the chemo- and
diastereoselectivity.
a,
b,
g
d
the p-nitro substituent was again shown to improve the regio- and
stereoselectivity in fluorination reactions. Accordingly, the new
starting material 42 (itself available in two steps from commercial
materials) underwent asymmetric epoxidation followed by tosy-
lation to give compound 44 in good yield (Scheme 7). Compound
44 then underwent a Gabriel reaction to give 45, and subsequent
epoxide ring-opening using Et3N$3HF gave a mixture of fluorohy-
drin 46 and the corresponding diol 47 in 1:1 ratio with 46 in 44%
yield. The enantiopurity of fluorohydrin 46 was confirmed by its
derivatisation into a Mosher ester (see Supplementary data). In an
attempt to improve the moderate yield of 46, the order of the
fluorination and Gabriel reactions was reversed (Scheme 7). How-
ever, this resulted mainly in formation of the undesired primary
alkyl fluorides 52 and 53 rather than the desired tosylate 51, despite
the screening of several fluorinating reagents and mild reaction
conditions (see Supplementary data). Nevertheless, the modest-
yielding synthesis of 46 via 45 was still considered to be practical
and scalable, since the diastereoselectivity was excellent. The flu-
orohydrin 46 was then subjected to deoxyfluorination (Scheme 7).
Gratifyingly, this reaction furnished the desired difluoro compound
48 with excellent diastereoselectivity and with no evidence of
rearrangement. The p-nitrophenyl group was then converted to the
corresponding acetanilide (49), which was obtained in good yield
alongside a small quantity of an unexpected imide product (see
Supplementary data). Finally, oxidation of the aryl moiety of 49
delivered the known carboxylic acid 50. Overall, the inclusion of the
The diol 47, which was produced as a side product in the ring-
opening reaction of epoxide 45 (Scheme 7), was exploited in an
alternative synthesis of the anti-difluoro target 2 (Scheme 8). Diol 47
was converted into the corresponding cyclic sulfate 54,38 then
reacted with TBAF to deliver the fluorohydrin 55 along with a minor
quantity of the ketone 56 which presumably arose through a com-
peting elimination process. Next, deoxyfluorination of 55 proceeded
in moderate yield, and the anti-difluoro compound 57 was sub-
sequently carried through a standard sequence of transformations
to deliver the target 2 (Scheme 8). The absolute stereochemistry of
diol 47 was validated by an X-ray crystal structure of a chlorohydrin
side product (60), which arose during the cyclic sulfate formation/
ring-opening sequence (see Supplementary data). Overall, this
route (Scheme 8) constitutes another viable synthesis of the target
2, while also preventing wastage of the diol 47.
3. Conclusion
Several new synthetic approaches to the backbone-fluorinated
amino acids 1 and 2 were investigated, in order to address the
limitations of the previous syntheses. Target 2 is now available
through a robust, scalable, seven-step sequence (Scheme 3), which
offers dramatic improvements in terms of diastereoselectivity and
consequent ease of purifications. Target 1 remains the greater
synthetic challenge; a new 10-step sequence was developed in this
t
Scheme 7. Exploiting the p-nitro group for improved selectivity. (a) D-(ꢁ)-DET, BuOOH, Ti(OiPr)4, CH2Cl2, ꢁ20 ꢀC; (b) Et3N, DMAP, TsCl, 0 ꢀC; (c) phthalimide, potassium phtha-
limide, DMF, 90 ꢀC; (d) Et3N$3HF, 120 ꢀC; (e) DeoxoFluorÒ (neat), 70 ꢀC; (f) H2, Pd/C, Ac2O, 25 ꢀC; (g) NaOI4, RuCl3, MeCN, DCM, H2O, 25 ꢀC; (h) Et3N$3HF, 100 ꢀC.

A.R. Patel et al. / Tetrahedron 72 (2016) 3305e3317
3311
Scheme 8. Conversion of diol 47 into target 2. (a) SOCl2, pyridine, CH2Cl2, 0 ꢀC; then NaIO4, RuCl3, H2O, CH2Cl2, CH3CN, 0 ꢀC; (b) TBAF, THF, CH3CN, 0 ꢀC then H2SO4, H2O, THF, 25 ꢀC;
(c) DeoxoFluorÒ (neat), 80 ꢀC; (d) H2, Pd/C, Ac2O; (e) NaOI4, RuCl3, MeCN, DCM, H2O.
work (Scheme 7), and although this requires more steps than the
previous synthesis, it does overcome the greatest difficulty which
was to achieve good chemoselectivity and reproducibility in the
second fluorination step. Overall, this work has addressed the
major bottleneck in the ongoing development of biological appli-
cations of 1 and 2, and the synthetic methods developed in this
work may contribute to the wider deployment of selective fluori-
nation chemistry as a tool for optimising the properties of bioactive
molecules more generally.
singlet. Melting points were determined using a Stanford Research
Systems OptiMelt automated melting point apparatus. Optical ro-
tations were measured with a PerkineElmer Model 341 polarim-
eter at 589 nm with a path length of 1 dm; solution concentrations
are reported in grams per 100 mL and specific rotations are re-
ported in units of degrees dmꢁ1 cm3 gꢁ1. Infrared (IR) spectra were
obtained using a Bruker Alpha-E FTIR 41 spectrometer. Mass
spectra were recorded by the Mass Spectrometry Unit at The Uni-
versity of New South Wales, using a Bruker Daltonics fourier
transform ion cyclotron resonance mass spectrometer (high reso-
lution electrospray ionisation) operating in the positive ion mode;
signal intensities are quoted as a percentage of the base peak. Di-
astereoisomeric ratios were determined by NMR. An enantiomeric
or diastereomeric excess quoted as >99% indicates that no amount
of the minor isomer was observed by the respective methods used.
4. Experimental section
4.1. Reagents and instrumentation
All reactions were performed in oven-dried glassware unless
stated otherwise, under a nitrogen atmosphere with magnetic
stirring. All anhydrous solvents were obtained by passage through
columns of activated alumina. Triethylamine was stored over po-
tassium hydroxide pellets. All other commercial reagents and sol-
vents were of synthetic grade and used as received. Reactions were
monitored by thin layer chromatography using Merck aluminium-
backed silica gel 60 F254 (0.2 mm) TLC plates. TLC plates were
visualised under short-wave UV light (254 nm) and then by stain-
ing with ceric ammonium molybdate or potassium permanganate.
Flash chromatography was performed using Davisil 40e63 mesh
silica gel; eluting solvents are stated as volume/volume mixtures.
Nuclear magnetic resonance (NMR) spectra were obtained using
a BBFO PROBE 300, TBI PROBE 400 or CRYO PROBE 600 MHzBruker
Avance III spectrometer, at 300 K; chemical shifts are reported in
parts per million downshift from tetramethylsilane. 1H and 13C
4.1.1. 2-((2R,3R)-2,3-Dihydroxy-3-phenylpropyl)isoindoline-1,3-
dione (4).28 A mixture of tosylate 12 (0.336 g, 1.04 mmol), potas-
sium phthalimide (0.193 g, 1.04 mmol), phthalimide (0.153 g,
1.04 mmol) and DMF (9.0 mL) was stirred at 90 ꢀC overnight. The
mixture was then cooled and concentrated to a volume of w10 mL.
Water (100 mL) was added and the mixture was extracted with
DCM (4ꢂ20 mL). The combined organic layers were dried (Na2SO4)
and concentrated onto silica. The crude product was subjected to
flash chromatography eluting with 8:1/4:1 DCM/EtOAc to yield
the title compound as a white solid (169 mg, 69%); Rf 0.22 (8:1 DCM/
EtOAc); [
a]
þ20 (c 0.05, EtOH) [lit.28 for enantiomer: [
a
]
ꢁ17 (c
D
D
0.69, EtOH)]; 1H NMR (300 MHz, CDCl3)
d 7.85e7.68 (m, 4H,
phthalimide), 7.41e7.28 (m, 5H, Ph), 4.61 (d, J¼5.1 Hz, 1H, PheCH),
4.06 (m, 1H, CHeCH2), 3.94e3.88 (m, 2H, CH2); spectral data in
accordance with literature values.28
NMR spectra were calibrated using the residual chloroform peak (
d
7.26 ppm and 77.16 ppm, respectively) as the internal standard. All
d
4.1.2. (ꢃ)-(R)-2-(3,3-Difluoro-2-phenylpropyl)isoindoline-1,3-dione
(7).28 N-Bromosuccinimide (10.0 mg, 0.052 mmol) was added to
a mixture of 35 (10.0 mg, 0.038 mmol), HF/pyridine (0.04 mL) and
resonances were assigned by inspection of the coupling constants
and chemical shift. The multiplicities of NMR signals are denoted as
follows: s¼singlet, d¼doublet, t¼triplet, m¼multiplet, br s¼broad

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A.R. Patel et al. / Tetrahedron 72 (2016) 3305e3317
DCM (0.04 mL), and the resulting mixture was stirred for 3 h at
25 ꢀC. Silver(I) fluoride (6.5 mg, 0.052 mmol) was added, and the
mixture was stirred for 16 h in the dark. Water (1 mL) was added,
and the mixture was partitioned between EtOAc (5 mL) and H2O
(5 mL). The organic layer was washed with saturated aqueous
NaHCO3 (5 mL) and brine (5 mL), dried (MgSO4) and concentrated
in vacuo to afford a mixture of 7, 36 and 37 in 53:27:16 ratio.
chromatography eluting with 3:7 hexane/EtOAc to yield the title
compound as a viscous pale brown oil (3.18 g, 85%); Rf 0.20 (3:7
hexane/EtOAc); [
a
]
D ꢁ26 (c 3.52, CHCl3) [lit.29 for enantiomer: [
a]
D
þ21 (c 3.68, CHCl3)]; 1H NMR (300 MHz, CDCl3)
d 7.28 (m, 5H, ArH),
4.58 (d, J¼7.1 Hz, 1H, PheCH), 4.56 (br s, 1H, OH), 4.49 (br s, 1H,
OH), 3.83e3.73 (m, 2H, 2ꢂCHeOH), 3.41 (m, 2H, CH2); spectral
data in accordance with literature values.29
Data for 7: 19F NMR (282 MHz, CDCl3)
d
ꢁ119.9 (ddd, J¼283.4,
55.7, 13.7 Hz, 1F), ꢁ125.5 (ddd, J¼283.4, 55.7, 16.5 Hz, 1F); 19F{1H}
4 . 1. 6 . ( 2 R , 3 R ) - 2 , 3 - D i h y d r o x y - 3 - p h e n y l p r o p y l - 4 -
methylbenzenesulfonate (12).29 Dibutyltin oxide (0.44 g, 2 mol %)
was added to a solution of triol 11 (15.0 g, 89.2 mmol) in anhydrous
DCM (200 mL) and stirred for 20 min until fully dissolved. DIPEA
(0.318 mL, 1.96 mmol) and p-toluenesulfonyl chloride (18.7 g,
98.1 mmol) were added and the mixture was stirred overnight at
NMR (282 MHz, CDCl3)
d
ꢁ119.9 (d, J¼283.4 Hz, 1F), ꢁ125.5 (d,
J¼283.4 Hz, 1F); spectral data in accordance with literature
values.28
4.1.3. 2-((2S,3S)-3-Fluoro-2-hydroxy-3-phenylpropyl)isoindoline-
1,3-dione (8).28 A mixture of compound 16 (5.70 g, 17.5 mmol),
phthalimide (3.10 g, 20.9 mmol), potassium phthalimide (3.90 g,
20.9 mmol) and DMF (100 mL) was stirred at 90 ꢀC overnight. The
mixture was concentrated, and the residue was partitioned be-
tween water (100 mL) and EtOAc (80 mL). The aqueous layer was
extracted with EtOAc (5ꢂ50 mL) and the combined organic layers
were dried over MgSO4, filtered, and concentrated to give the title
compound as an off-white solid (3.98 g, 76%); 1H NMR (300 MHz,
0
ꢀC then quenched with water. The mixture was extracted with
DCM (3ꢂ100 mL), dried (Na2SO4) and concentrated. The crude
product was purified by flash chromatography eluting with 9:1
DCM/ethyl acetate to yield the title compound as a pale yellow oil
(17.5 g, 61%); Rf 0.35 (9:1 DCM/EtOAc); [
a
]
D ꢁ18 (c 2.3, CHCl3) [lit.29
for enantiomer: [
a
]
D þ15 (c 1.2, CHCl3)]; 1H NMR (300 MHz, CDCl3)
d
7.78 (d, J¼8.3 Hz, 2H, ArH), 7.34e7.27 (m, 7H, ArH), 4.68 (d,
J¼6.1 Hz, 1H, PheCH), 4.10e4.04 (m, 2H, CH2), 3.94e3.88 (m, 1H,
CHeCH2), 2.45 (s, 3H, CH3); spectral data in accordance with liter-
ature values.29
CDCl3)
d 7.83 (m, 2H, tosyl ArH), 7.71 (m, 2H, tosyl ArH), 7.43e7.31
(m, 5H, ArH), 5.47 (dd, J¼46.6, 4.7 Hz, 1H, CHFeCH), 4.34 (m, 1H,
CHeOH), 3.91 (dd, J¼14.1, 8.6 Hz, 1H, CH2eNPht), 3.79 (dd, J¼14.1,
4.1 Hz, 1H, CH2eNPht), 2.63 (d, J¼5.7 Hz, 1H, OH); 19F NMR
4.1.7. ((2S,3S)-3-Phenyloxiran-2-yl)methanol (13).30 Titanium iso-
propoxide (3.81 g, 13.4 mmol), followed by 5.5 M tert-butyl hy-
droperoxide (TBHP) (17.2 mL, 179 mmol), were added to a stirred
(282 MHz, CDCl3)
(282 MHz, CDCl3)
d
ꢁ188.9 (dd, J¼46.6, 18.3 Hz, 1F); 19F{1H} NMR
ꢁ188.9 (s, 1F); spectral data in accordance with
d
literature values.28
solution of molecular sieves and
L-(þ)-DET (4.20 g, 20.1 mmol) in
dichloromethane (770 mL) at ꢁ20 ꢀC. The mixture was allowed to
stir at ꢁ20 ꢀC for 1 h. A solution of compound 10 (12.0 g, 89.4 mmol)
in dichloromethane (17 mL) was then added dropwise over 30 min.
The reaction was allowed to stir overnight and then quenched at
ꢁ20 ꢀC with 10% aqueous NaOH solution saturated with NaCl
(7.2 mL). Diethyl ether (100 mL) was added and the reaction mix-
ture was warmed to 0 ꢀC. The stirring was maintained for 15 min at
0 ꢀC while MgSO4 and Celite were added. The mixture was allowed
to settle and the solution was filtered through a pad of Celite and
washed with diethyl ether. Purification by flash chromatography
(3:2 hexane/EtOAc) provided the title compound as a yellow oil
(10.9 g, 81%); Rf 0.42 (7:3 hexane/EtOAc); 1H NMR (300 MHz, CDCl3)
4.1.4. 2-((2R,3S)-2,3-Difluoro-3-phenylpropyl)isoindoline-1,3-dione
(9).28 A mixture of compounds 17 and 18 (5.0 g, 15.5 mmol),
phthalimide (2.50 g, 17.0 mmol), potassium phthalimide (3.20 g,
17.0 mmol) and DMF (100 mL) was stirred at 90 ꢀC overnight. The
mixture was concentrated, and the residue was partitioned be-
tween water (100 mL) and EtOAc (80 mL). The aqueous layer was
extracted with EtOAc (5ꢂ50 mL) and the combined organic layers
were dried (MgSO4), filtered, and concentrated under reduced
pressure. The residue was purified by flash chromatography eluting
with 9:1 hexane/EtOAc to give the title compound as a white solid
(2.70 g, 65%); [
a
]
D
þ40.8 (c 0.98, CHCl3); mp 110e113 ꢀC; 1H NMR
(300 MHz, CDCl3)
d
7.84 (m, 2H, ArH), 7.72 (m, 2H, ArH), 7.44e7.35
d
7.33e7.28 (m, 5H, ArH), 4.06 (m,1H, CHeHeOH), 3.95 (d, J¼2.2 Hz,
(m, 5H, ArH), 5.72 (ddd, J¼46.4, 12.9, 4.4 Hz, 1H, CHFeCHFeCH2),
5.14 (ddddd, J¼47.6, 16.5, 8.7, 4.4, 3.6 Hz, 1H, CHFeCHFeCH2), 4.20
(dddd, J¼14.5, 12.4, 8.7, 0.7 Hz, 1H, CHFeCH2), 3.92 (dddd, J¼29.5,
1H, PheCHO), 3.80 (dd, J¼12.7, 4.7 Hz, 1H, CHeHeOH), 3.28e3.25
(m, 1H, OCHeCH2), 2.86 (br s, 1H, OH); spectral data in accordance
with literature values.30
14.5, 3.6, 0.7 Hz,1H, CHFeCH2); 19F NMR (282 MHz, CDCl3)
d
ꢁ193.3
(ddd, J¼46.4, 16.5, 16.3 Hz, 1F, CHFeCHFeCH2), e195.2 (ddddd,
4 . 1 . 8 . ( ( 2 S , 3 S ) - 3 - P h e n y l o x i r a n - 2 - y l ) m e t h y l - 4 -
methylbenzenesulfonate (14). To a solution of compound 13 (8.30 g,
55.0 mmol) in DCM (350 mL) was added triethylamine (15.3 mL,
110 mmol), DMAP (0.672 g, 5.5 mmol) and p-toluenesulfonyl
chloride (15.7 g, 83.0 mmol). The mixture was stirred for 3 h and
water was subsequently added. The mixture was extracted with
DCM (2ꢂ150 mL) and the combined organic layers were dried over
MgSO4, filtered and concentrated under reduced pressure. Purifi-
cation by flash column chromatography (9:1/3:2 hexane/EtOAc)
provided the title compound as a colourless solid (11.0 g, 50%); Rf
J¼47.6, 29.5, 16.3, 12.9, 12.4 Hz, 1F, CHFeCHFeCH2); 19F{1H} NMR
(282 MHz, CDCl3)
d
ꢁ193.3 (d, J¼16.3 Hz, 1F, CHFeCHFeCH2),
e195.2 (d, J¼16.3 Hz, 1F, CHFeCHFeCH2); spectral data in accor-
dance with literature values.28
4.1.5. (1R,2R)-1-Phenylpropane-1,2,3-triol (11)29. A mixture of po-
tassium ferricyanide (22.1 g, 67.1 mmol), potassium carbonate
(9.27 g, 67.1 mmol), sodium hydrogen carbonate (5.63 g,
67.1 mmol) and (DHQD)2PHAL (0.17 g, 0.22 mmol) in tert-butanol
(110 mL) and water (110 mL) was stirred at 25 ꢀC for 10 min, then
cooled to 0 ꢀC. Osmium tetroxide (2% solution in water, 1.14 mL,
0.067 mmol) was then added followed by methanesulfonamide
(0.500 g, 5.26 mmol) to form a red solution. The mixture was
stirred at 0 ꢀC for 30 min prior to the addition of compound 10
(3.00 g, 22.4 mmol), and the mixture was then stirred for 48 h at
0 ꢀC. Sodium sulfite (3.00 g) was added, and stirring continued for
1 h before extraction with EtOAc (7ꢂ75 mL) and a wash with brine.
The combined organic layers were dried (NaSO4) and concentrated
onto silica. The crude product was purified using flash
0.62 (7:3 hexane/EtOAc); mp 44e48 ꢀC; [
IR (neat) nmax (cmꢁ1) 2987, 1730, 1594, 1439, 1352, 1271, 1170; 1H
NMR (300 MHz, CDCl3) 7.84 (m, 2H, tosyl ArH), 7.38e7.31 (m, 5H,
a]
D ꢁ41.7 (c 1.27, CHCl3);
d
ArH), 7.17 (m, 2H, tosyl ArH), 4.36 (dd, J¼11.5, 3.6 Hz, 1H,
CHeHeOTs), 4.14 (dd, J¼11.5, 5.7 Hz, 1H, CHeHeOTs), 3.77 (d,
J¼2.0 Hz, 1H, AreCHO), 3.25 (ddd, J¼5.7, 3.6, 2.0 Hz, 1H,
CHOeCH2eOTs), 2.46 (s, 3H, tosyl CH3); 13C{1H} NMR (75 MHz,
CDCl3)
d 145.3 (ArC), 135.6 (ArC), 132.7 (ArC), 130.0 (ArC), 128.7
(ArC), 128.6 (ArC), 128.0 (ArC), 125.8 (ArC), 69.5 (CH2eOTs), 58.6

A.R. Patel et al. / Tetrahedron 72 (2016) 3305e3317
3313
(CHOeCH2eOTs), 58.4 (AreCHO), 21.7 (tosyl CH3); HRMS (ESI, þve)
yl)-2-fluoro-3-iodobutanoate (26); (ꢃ)-methyl-(2S,3S)-4-(1,3-
dioxoisoindolin-2-yl)-3-fluoro-2-iodobutanoate (27). To a mixture
of methyl-(E)-4-(1,3-dioxoisoindolin-2-yl)but-2-enoate (100 mg,
0.41 mmol), HF/pyridine (0.4 mL) and MeCN (0.4 mL) at 25 ꢀC was
added N-iodosuccinimide (13.0 mg, 0.056 mmol), and the resulting
mixture was stirred for 16 h. Water (5 mL) was added, and the
mixture was partitioned between EtOAc (10 mL) and H2O (10 mL).
The organic layer was washed with saturated aqueous NaHCO3
(10 mL) and brine (10 mL), dried (MgSO4) and concentrated in
vacuo. The residue was purified via flash chromatography eluting
with 80:20 hexane/EtOAc to give colourless oil comprising a mix-
ture of 25, 26 and 27 in 78:21:1 ratio, as calculated from 19F NMR
analysis (combined yield 150 mg, 94%). A small quantity of 25 was
subsequently isolated for characterisation purposes.
C
16H16O4SNaþ [MþNa]þ requires m/z 327.0769, found 327.0772.
4.1.9. 2-(((2S,3S)-3-Phenyloxiran-2-yl)methyl)isoindoline-1,3-dione
(15). A mixture of compound 14 (1.50 g, 4.93 mmol), potassium
phthalimide (0.91 g, 4.9 mmol), phthalimide (0.73 g, 4.9 mmol) and
DMF (50 mL) was stirred at 50 ꢀC for 16 h. The solvent was evap-
orated and the residue was purified by column chromatography
(6:1 hexane/EtOAc) to give the title compound as a white solid
(0.86 g, 63%); Rf 0.46 (7:3 hexane/EtOAc); mp 74e80 ꢀC; [
(c 1.2, CHCl3); IR (neat) nmax (cmꢁ1) 2928, 1771, 1706, 1611, 1389,
1172, 1070; 1H NMR (300 MHz, CDCl3)
7.89e7.73 (m, 4H, phtha-
a]
D þ22.9
d
limide), 7.36e7.25 (m, 5H, Ph), 4.16 (dd, J¼14.4, 4.6 Hz, 1H,
CHeHeNPht), 3.88 (d, J¼1.9 Hz, 1H, AreCHO), 3.86 (dd, J¼14.4,
5.7 Hz, 1H, CHeHeNPht), 3.25 (ddd, J¼5.7, 4.6, 1.9 Hz, 1H,
Data for 25: Rf 0.23 (80:20 hexane/EtOAc); IR (neat) nmax (cmꢁ1
2900, 1747, 1740, 1640, 1310, 1280, 1240, 1110, 500; 1H NMR
(400 MHz, CDCl3) 7.88 (m, 2H, ArH), 7.75 (m, 2H, ArH), 5.12 (dddd,
)
CHOeCH2eNPht); 13C{1H} NMR (75 MHz, CDCl3)
d 168.2 (C]O
phthalimide), 134.4 (ArC),134.3 (ArC), 132.4, 128.6 (ArC), 128.5
(ArC), 125.7 (ArC), 123.6 (ArC), 59.0 (PheCHO), 58.1 (CHOeCH2),
39.5 (CH2eNPht); HRMS (ESI, þve) C17H13NO3Naþ [MþNa]þ re-
quires m/z 302.0793, found 302.0798.
d
J¼47.3, 8.8, 8.2, 3.2 Hz, 1H, CHF), 4.50 (dd, J¼7.9, 8.8 Hz, 1H, CHI),
4.35 (ddd, J¼28.0, 14.6, 3.2 Hz, 1H, CH2), 4.14 (ddd, J¼14.8, 14.6,
8.2 Hz, 1H, CH2), 3.79 (s, 3H, CH3); 13C{1H} NMR (100 MHz, CDCl3)
d
168.9 (d, J¼4.4 Hz, CO2Me), 168.0 (C]O phthalimide), 134.4 (ArC),
4.1.10. (2S,3S)-3-Fluoro-2-hydroxy-3-phenylpropyl-4-
132.0 (ArC), 123.7 (ArC), 89.6 (d, J¼183.1 Hz, CHF), 53.5 (CH3), 40.5
methylbenzenesulfonate (16).31 BF3$OEt2 (16.1
mL, 0.13 mmol) was
(d, J¼20.8 Hz, CHI), 17.0 (d, J¼24.1 Hz, CH2); 19F NMR (377 MHz,
added to a stirred 0.25 M solution of compound 14 (119 mg,
0.39 mmol) in dichloromethane at ꢁ20 ꢀC over 5 min. A saturated
aqueous solution of NaHCO3 (5 mL) was then added, and the
mixture was stirred until the two layers became clear. The aqueous
layer was extracted with DCM (3ꢂ10 mL) and the combined organic
layers were dried (MgSO4) and concentrated under reduced pres-
sure. The residue was purified by flash chromatography eluting
with 4:1 hexane/EtOAc to give the title compound as a yellow oil
CDCl3)
d
ꢁ175.1 (dddd, J¼47.3, 28.0, 14.8, 7.9 Hz, 1F, CHFeCH2); 19
F
{1H} NMR (377 MHz, CDCl3)
d
ꢁ175.1 (s, 1F, CHFeCH2); HRMS (ESI,
þve) C13H11FINO4Naþ [MþNa]þ requires m/z 413.9609, found
413.9604.
Data for 26: Rf 0.23 (80:20 hexane/EtOAc); 19F NMR (282 MHz,
CDCl3)
CDCl3)
d
ꢁ186.1 (dd, J¼46.9, 21.6 Hz, 1F); 19F{1H} NMR (282 MHz,
ꢁ186.1 (s, 1F).
d
Data for 27: Rf 0.23 (80:20 hexane/EtOAc); 19F NMR (282 MHz,
(78.3 mg, 63%); [
CDCl3)
a
]
þ0.27 (c 0.19, CHCl3); 1H NMR (300 MHz,
CDCl3)
1F).
d
ꢁ202.7 (m, 1F); 19F{1H} NMR (282 MHz, CDCl3)
ꢁ202.7 (s,
d
D
d
7.78 (m, 2H, ArH), 7.37e7.26 (m, 7H, ArH), 5.54 (dd, J¼46.5,
5.3 Hz, 1H, CHFeCH), 4.16e4.05 (m, 2H, CHHeOTs and CHeOH),
3.95e3.88 (m, 1H, CHHeOTs), 2.65 (br s, 1H, OH), 2.46 (s, 3H, tosyl
4.1.13. (ꢃ)-2-((2S,3R)-2-Bromo-3-fluoro-3-phenylpropyl)isoindo-
line-1,3-dione (36); (ꢃ)-2-((2S,3S)-2-bromo-3-fluoro-3-
CH3); 19F NMR (282 MHz, CDCl3)
19F{1H} NMR (282 MHz, CDCl3)
d
ꢁ192.2 (dd, J¼46.5, 19.1 Hz, 1F);
d
ꢁ192.2 (s, 1F); spectral data in
phenylpropyl)isoindoline-1,3-dione
(37). N-Bromosuccinimide
accordance with literature values.31
(0.300 g, 1.547 mmol) was added to a mixture of 35 (0.300 g,
1.139 mmol), HF/pyridine (1.14 mL) and DCM (1.14 mL) at 25 ꢀC. The
mixture was stirred for 16 h. Water (10 mL) was added, and the
mixture was partitioned between EtOAc (15 mL) and H2O (5 mL).
The organic layer was washed with saturated aqueous NaHCO3
(15 mL) and brine (15 mL), dried (MgSO4) and concentrated in
vacuo. The residue was purified by flash chromatography eluting
with 85:15 hexane/EtOAc to give compound 36 as a colourless oil
(0.371 g, 90%) and compound 37 as a colourless oil (20.6 mg, 5%).
4 . 1 . 11 . ( 2 R , 3 S ) - 2 , 3 - D i fl u o r o - 3 - p h e n y l p r o p y l - 4 -
methylbenzenesulfonate (17); (R)-3,3-difluoro-2-phenylpropyl-4-
methylbenzenesulfonate (18). DeoxoFluorÒ (15.0 mL, 81.0 mmol)
was added to compound 16 (6.90 g, 21.3 mmol) in a plastic reaction
vessel. The mixture was stirred at 70 ꢀC for 16 h. The mixture was
cooled, diluted with DCM (25 mL), and saturated ice-cooled aque-
ous NaHCO3 (20 mL) was added dropwise. After the bubbling
ceased, the organic layer was separated, dried over MgSO4, filtered,
and concentrated under reduced pressure. The residue was purified
by flash chromatography (85:15 hexane/EtOAc) to give a 6:1 mix-
ture of compound 17 and the rearrangement product 18 (combined
yield 5.07 g, 73%) (see ESI).
Data for 36: Rf 0.29 (85:15 hexane/EtOAc); IR (neat) nmax (cmꢁ1
2930, 1717, 1752, 1631, 1350, 1289, 1227, 1118, 510; 1H NMR
(300 MHz, CDCl3) 7.84 (m, 2H, phthalimide), 7.72 (m, 2H, phtha-
)
d
limide), 7.44e7.28 (m, 5H, Ph), 5.72 (dd, J¼46.1, 6.2 Hz, 1H, CHF),
4.85 (dddd, J¼15.3, 8.9, 6.2, 5.5 Hz, 1H, CHBr), 4.24 (dd, J¼14.4,
8.9 Hz, 1H, CH2), 4.17 (dd, J¼14.4, 5.5 Hz, 1H, CH2); 13C{1H} NMR
Data for 17: Rf 0.47 (7:3 hexane/EtOAc); 1H NMR (300 MHz,
CDCl3)
d
7.78e7.76 (m, 2H, tosyl ArH), 7.42e7.26 (m, 7H, tosyl ArH
(75 MHz, CDCl3)
d
167.9 (C]O phthalimide), 136.3 (d, J¼20.2 Hz, Ph
and Ph), 5.59 (ddd, J¼45.8, 10.9, 5.3 Hz, 1H, CHFeCHFeCH2), 4.85
(ddddd, J¼46.8, 16.6, 8.8, 5.3, 3.6 Hz, 1H, CHFeCHFeCH2), 4.34 (m,
1H, CH2eOTs), 4.26 (m, 1H, CH2eOTs), 2.47 (s, 3H, CH3); 19F NMR
quaternary C), 134.3 (phthalimide), 131.9 (phthalimide), 129.3 (d,
J¼1.9 Hz, Ph meC), 128.7 (Ph peC), 126.3 (d, J¼7.1 Hz, Ph oeC), 123.6
(phthalimide), 94.9 (d, J¼178.4 Hz, CHF), 50.4 (d, J¼25.4 Hz, CHBr),
(282 MHz, CDCl3)
d
ꢁ192.1 (ddd, J¼46.4, 16.6, 16.6 Hz, 1F), e195.9
40.6 (d, J¼5.2 Hz, CH2); 19F NMR (282 MHz, CDCl3)
d
ꢁ176.4 (dd,
(m, 1F); 19F{1H} NMR (282 MHz, CDCl3)
d
ꢁ192.1 (d, J¼16.6 Hz, 1F),
J¼46.3, 15.4 Hz, 1F, PheCHF); 19F{1H} NMR (282 MHz, CDCl3)
e195.9 (d, J¼16.6 Hz, 1F).
d
ꢁ176.4 (s, 1F, PheCHF); HRMS (ESI, þve) C17H13FBrNO2Naþ
Data for 18: Rf 0.47 (7:3 hexane/EtOAc); 19F NMR (282 MHz,
[MþNa]þ requires m/z 384.0006, found 384.0001.
CDCl3)
d
ꢁ121.5 (ddd, J¼283.3, 56.6,16.9 Hz, 1F), e123.6 (d, J¼283.3,
Data for 37: Rf 0.23 (85:15 hexane/EtOAc); IR (neat) nmax (cmꢁ1
)
56.6, 16.9 Hz, 1F); 19F{1H} NMR (282 MHz, CDCl3)
de121.5 (d,
2939, 1726, 1759, 1622, 1363, 1281, 1241, 1118, 515; 1H NMR
J¼283.3 Hz, 1F), e123.6 (d, J¼283.3 Hz, 1F).
(300 MHz, CDCl3) d 7.85 (m, 2H, phthalimide), 7.73 (m, 2H, phtha-
limide), 7.41e7.27 (m, 5H, Ph), 5.59 (dd, J¼45.9, 4.9 Hz, 1H, CHF),
4.1.12. (ꢃ)-Methyl-(2S,3R)-4-(1,3-dioxoisoindolin-2-yl)-3-fluoro-2-
iodobutanoate (25); (ꢃ)-methyl-(2R,3S)-4-(1,3-dioxoisoindolin-2-
4.79 (m, 1H, CHBr), 4.22 (dd, J¼14.3, 9.1 Hz, 1H, CH2), 4.01 (dd,
J¼14.3, 5.6 Hz, 1H, CH2); 13C NMR (75 MHz, CDCl3)
d 167.9 (C]O

3314
A.R. Patel et al. / Tetrahedron 72 (2016) 3305e3317
phthalimide), 136.4 (d, J¼20.3 Hz, Ph quaternary C), 134.4 (phtha-
limide), 131.8 (phthalimide), 129.3 (d, J¼1.3 Hz, Ph meC), 128.7 (Ph
peC), 126.1 (d, J¼7.1 Hz, Ph oeC), 123.7 (phthalimide), 92.9 (d,
J¼182.1 Hz, CHF), 52.3 (d, J¼23.7 Hz, CHBr), 41.6 (d, J¼3.8 Hz, CH2);
residue which was recrystallised from hexane/EtOAc to give the title
compound as yellow needles (3.12 g, 96%); mp 114e115 ꢀC; [
a]
D
ꢁ6.49 (c 0.133, MeCN); 1H NMR (400 MHz, CDCl3)
d 8.21 (d,
J¼8.8 Hz, 2H, ArH), 7.45 (d, J¼8.8 Hz, 2H, ArH), 4.08 (dd, J¼12.9,
2.3 Hz,1H, CH2OH), 4.05 (d, J¼2.1 Hz,1H, AreCHO), 3.86 (dd, J¼12.9,
3.3 Hz, 1H, CH2OH), 3.19 (dt, J¼3.3, 2.2 Hz, 1H, CHOeCH2), 1.82 (br s,
1H, CH2OH); spectral data in accordance with literature values.39
19F NMR (282 MHz, CDCl3)
d
ꢁ178.6 (dd, J¼45.9, 20.3 Hz, 1F,
PheCHF); 19F{1H} NMR (282 MHz, CDCl3)
d
ꢁ178.6 (s, 1F, PheCHF);
HRMS (ESI, þve)
C
17H13FBrNO2Naþ [MþNa]þ requires m/z
384.0006, found 384.0003.
4.1.17. ((2R,3R)-3-(4-Nitrophenyl)oxiran-2-yl)methyl-4-
methylbenzenesulfonate (44). Triethylamine (1.6 mL, 12 mmol) and
DMAP (74.5 mg, 0.61 mmol) were added to a solution of compound
43 (1.20 g, 6.10 mmol) in DCM (30 mL) at 0 ꢀC. p-Toluenesulfonyl
chloride (1.70 g, 9.15 mmol) was then added in portions and the
mixture was stirred for 1 h. The reaction mixture was partitioned
between water (50 mL) and EtOAc (50 mL). The organic layer was
washed with water (25 mL) and brine (25 mL), and dried over
MgSO4. The volatiles were removed under reduced pressure and
the residue was purified by flash chromatography eluting with
85:15/60:40 hexane/EtOAc to afford the title compound as
4.1.14. (ꢃ)-2-((2S,3R)-2-Bromo-3-fluoro-3-(4-nitrophenyl)propyl)
isoindoline-1,3-dione
(39). N-Bromosuccinimide
(8.6
mg,
0.044 mmol) was added to a mixture of 38 (10.0 mg, 0.032 mmol),
HF/pyridine (0.04 mL) and DCM (0.04 mL), and the resulting mix-
ture was stirred at 25 ꢀC for 16 h. Water (1 mL) was added, and the
mixture was partitioned between EtOAc (5 mL) and H2O (5 mL). The
organic layer was washed with saturated aqueous NaHCO3 (5 mL)
and brine (5 mL), dried (MgSO4) and concentrated in vacuo. The
residue was purified by flash chromatography eluting with 80:20
hexane/EtOAc to give the title compound as a colourless oil (12.7 mg,
96%); Rf 0.39 (80:20 hexane/EtOAc); IR (neat) nmax (cmꢁ1) 2939,
1711, 1759, 1639, 1367, 1256, 1223, 1154, 525; 1H NMR (600 MHz,
a brown solid (1.4 g, 67%); Rf 0.4 (70:30 hexane/EtOAc); [
(c 0.071, MeCN); mp 105e106 ꢀC; IR (neat) nmax (cmꢁ1) 1512, 1344,
963, 835; 1H NMR (300 MHz, CDCl3)
a
]
D ꢁ12.3
CDCl3)
d
8.21 (br d, J¼8.9 Hz, 2H, O2NC6H4), 7.84 (dd, J¼5.6, 3.0 Hz,
d
8.21 (d, J¼8.8 Hz, 2H,
2H, phthalimide), 7.73 (dd, J¼5.6, 3.0 Hz, 2H, phthalimide), 7.61 (br
d, J¼8.9 Hz, 2H, O2NC6H4), 5.80 (dd, J¼46.0, 6.2 Hz, 1H, CHF), 4.81
(m,1H, CHBr), 4.21 (br d, J¼7.3 Hz, 2H, CH2); 13C{1H} NMR (150 MHz,
C6H4NO2), 7.82 (d, J¼8.3 Hz, 2H, C6H4NO2), 7.42e7.35 (m, 4H,
C6H4CH3), 4.32 (dd, J¼11.7, 3.9 Hz, 1H, CH2), 4.22 (dd, J¼11.7, 5.4 Hz,
1H, CH2), 3.91 (d, J¼1.9, 1H, O2NC6H4eCHO), 3.23 (ddd, J¼5.4, 3.9,
1.9 Hz, 1H, CHOeCH2), 2.46 (s, 3H, C6H4CH3); 13C{1H} NMR
CDCl3)
d 167.8 (C]O phthalimide), 148.4 (O2NeC), 142.9 (d,
J¼20.0 Hz, ArCeCHF), 134.5 (phthalimide), 131.7 (phthalimide),
127.4 (d, J¼8 Hz, O2NePh oeC), 123.9 (Ph meC), 123.8 (phthali-
mide), 93.6 (d, J¼183.6 Hz, CHF), 49.1 (d, J¼25.1 Hz, CHBr), 40.5 (d,
(300 MHz, CDCl3) d 148.3 (CeNO2), 145.5 (CeS), 143.2 (CeCHO),
132.7 (CeCH3), 130.2 (ArC), 128.2 (ArC), 126.6 (ArC), 124.0 (ArC),
68.6 (CH2), 59.3 (CHOeCH2), 55.6 (O2NC6H4eCHO), 21.8 (CH3);
HRMS (ESI, þve) C16H15NO6Naþ [MþNa]þ requires m/z 372.0512,
found 372.0511.
J¼5.1 Hz, CH2); 19F NMR (282 MHz, CDCl3)
d
ꢁ178.2 (dd, J¼46.0,
15.5 Hz, 1F); 19F{1H} NMR (282 MHz, CDCl3)
d
ꢁ178.2 (s, 1F); HRMS
(ESI, þve) C17H12FBrN2O4Naþ [MþNa]þ requires m/z 428.9857,
found 428.9852.
4.1.18. 2-(((2R,3R)-3-(4-Nitrophenyl)oxiran-2-yl)methyl)isoindoline-
1,3-dione (45). A solution of tosylate 44 (8.64 g, 24.7 mmol) and
potassium phthalimide (5.50 g, 4.02 mmol) in DMF (100 mL) was
stirred overnight at 55 ꢀC. The mixture was cooled and concen-
trated to dryness. The residue was dissolved in ethyl acetate
(400 mL) and the solution was washed with water (3ꢂ400 mL) and
brine (1ꢂ200 mL). The organic layer was dried (MgSO4) and con-
centrated under reduced pressure to yield the title compound as
4.1.15. (E)-2-(3-Fluoro-3-(4-nitrophenyl)allyl)isoindoline-1,3-dione
(40); (Z)-2-(3-fluoro-3-(4-nitrophenyl)allyl)isoindoline-1,3-dione
(41). N-Bromosuccinimide (8.6 mg, 0.044 mmol) was added to
a mixture of 38 (10.0 mg, 0.032 mmol), HF/pyridine (0.04 mL) and
DMF (0.04 mL), and the resulting mixture was stirred for 3 h at
25 ꢀC. Silver(I) fluoride (5.6 mg, 0.044 mmol) was added, and the
mixture was stirred for 16 h at 80 ꢀC in the dark. Water (1 mL) was
added, and the mixture was partitioned between EtOAc (5 mL) and
H2O (5 mL). The organic layer was washed with saturated aqueous
NaHCO3 (5 mL) and brine (5 mL), dried (MgSO4) and concentrated
in vacuo to afford a mixture of 40, 41 and 38 in 18:1:1 ratio.
a yellow solid (7.75 g, 97%); Rf 0.3 (70:30 hexane/EtOAc); [
(c 0.039, MeCN); mp 176e178 ꢀC; IR (neat) nmax (cmꢁ1) 1699, 1509,
1338, 936; 1H NMR (300 MHz, CDCl3)
a]
D þ25.9
d
8.18 (d, J¼8.8 Hz, 2H,
C6H4NO2), 7.89 (m, 2H, phthalimide), 7.75 (m, 2H, phthalimide),
7.43 (d, J¼8.8 Hz, 2H, C6H4NO2), 4.21 (dd, J¼14.5, 4.3 Hz, 1H, CH2),
3.99 (d, J¼1.9 Hz, 1H, O2NC6H4eCHO), 3.86 (dd, J¼14.5, 5.9 Hz, 1H,
CH2), 3.21 (ddd, J¼5.9, 4.3, 1.9 Hz, 1H, CHOeCH2); 13C{1H} NMR
Data for 40: 19F NMR (282 MHz, CDCl3)
1F); 19F{1H} NMR (282 MHz, CDCl3)
ꢁ96.3 (s, 1F).
Data for 41: 19F NMR (282 MHz, CDCl3)
ꢁ115.8 (d, J¼35.2 Hz,
1F); 19F{1H} NMR (282 MHz, CDCl3)
ꢁ115.8 (s, 1F).
d
ꢁ96.3 (d, J¼19.9 Hz,
d
d
(75 MHz, CDCl3) d 168.1 (C]O), 147.9 (O2NeC), 144.0 (CeCHO),
d
134.5 (ArC), 132.0 (ArC), 126.5 (ArC), 123.9 (ArC), 123.8 (ArC), 59.6
(CHOeCH2), 57.2 (O2NC6H4eCHO), 39.2 (CH2); HRMS (ESI, þve)
4.1.16. ((2R,3R)-3-(4-Nitrophenyl)oxiran-2-yl)methanol (43).39 An
oven dried 500 mL three neck round bottom flask was charged with
C
17H12N2O5Naþ [MþNa]þ requires m/z 347.0638, found 347.0633.
ꢀ
3 A activated molecular sieves (1.0 g) and dry DCM (100 mL). The
4.1.19. 2-((2R,3S)-3-Fluoro-2-hydroxy-3-(4-nitrophenyl)propyl)iso-
indoline-1,3-dione (46); 2-((2R,3S)-2,3-dihydroxy-3-(4-nitrophenyl)
propyl)isoindoline-1,3-dione (47). In an oven dried pressure flask,
a mixture of compound 45 (54.9 mg, 0.17 mmol) and Et3N$3HF
(1.0 mL) was stirred overnight at 120 ꢀC. The mixture was diluted
with DCM (50 mL) and washed with saturated aqueous NaHCO3
(3ꢂ30 mL). The organic layer was dried over MgSO4 and purified by
column chromatography eluting with 80:20 hexane/EtOAc to afford
compound 46 as an off-white powder (25.5 mg, 44%) and com-
pound 47 as a yellow powder (26.4 mg, 45%).
mixture was cooled to ꢁ20 ꢀC and then (ꢁ)-DET (258 mg,
1.25 mmol), Ti(O-i-Pr)4 (236 mg, 0.83 mmol) and 5.5 M TBHP
(6.1 mL, 33 mmol) were added. After 30 min, a solution of com-
pound 42 (2.99 g, 16.7 mmol) in dry DCM (50 mL) was added slowly
via cannula and the mixture was stirred for 2 h at ꢁ20 ꢀC. The
mixture was quenched at ꢁ20 ꢀC by the addition of a 10% aqueous
NaOH solution saturated with NaCl (1.5 mL). Diethyl ether (10% v/v)
was added, and the mixture was warmed to 10 ꢀC. The mixture was
then stirred for an additional 10 min at 10 ꢀC and then MgSO4 (1.5 g)
and Celite (200 mg) were added, and stirred for another 15 min.The
mixture was allowed to settle, and the clear solution was filtered
through a pad of Celite and washed with diethyl ether (40 mL). The
volatiles were removed under reduced pressure to afford a crude
Data for 46: Rf 0.5 (95:5 DCM/EtOAc); [
MeCN); mp 225e226 ꢀC; IR (neat) nmax (cmꢁ1) 3334, 1694, 1515,
1341,1001; 1H NMR (600 MHz, CDCl3)
8.26 (d, J¼8.3 Hz, 2H,
C6H4NO2), 7.86 (dd, J¼5.4, 3.1 Hz, 2H, phthalimide), 7.75 (dd, J¼5.5,
a]
þ1.17 (c 0.223,
D
d

A.R. Patel et al. / Tetrahedron 72 (2016) 3305e3317
3315
3.0 Hz, 2H, phthalimide), 7.61 (d, J¼8.9 Hz, 2H, C6H4NO2), 5.54 (dd,
J¼46.6, 6.1 Hz, 1H, CHF), 4.23 (m, 1H, CHFeCHOH), 3.99e3.96 (m,
2H, CHOHeCH2), 3.08 (d, J¼6.6 Hz, 1H, CHOH); 13C{1H} NMR
3.9 Hz, 1H, CH2), 2.21 (s, 3H, COCH3); 13C{1H} NMR (150 MHz,
CD3CN) 168.9 (C]O phthalimide), 168.9 (COCH3), 141.2 (d,
d
J¼2.0 Hz, ArC), 135.4 (ArC), 135.4 (ArC), 133.0 (ArC), 128.3 (ArC),
124.1 (ArC), 124.1 (ArC), 92.5 (dd, J¼177.0, 19.0 Hz, CHF), 91.7 (dd,
J¼183.4, 21.4 Hz, CHF), 38.9 (dd, J¼24.6, 6.3 Hz, CH2), 18.6 (COCH3);
(150 MHz, CDCl3)
d 169.0 (C]O), 148.3 (O2NeC), 143.3 (d,
J¼20.0 Hz, ArCeCHF), 134.6 (ArC), 134.6 (ArC), 131.9 (ArC), 127.2 (d,
J¼8.3 Hz, m-NO2C6H4), 123.8 (d, J¼11.5 Hz, o-NO2C6H4), 93.2 (d,
J¼179.1 Hz, CHF), 72.5 (d, J¼25.2 Hz, CHOH), 40.3 (d, J¼5.0 Hz, CH2);
19F NMR (376 MHz, CD3CN)
d
ꢁ192.5 (br s,1F, AreCHF), ꢁ201.7 (br s,
1F, CHFeCH2); 19F{1H} NMR (376 MHz, CD3CN)
d
ꢁ192.5 (br s, 1F,
19F NMR (282 MHz, CDCl3)
NMR (282 MHz, CDCl3)
C
d
ꢁ191.9 (dd, J¼46.4,13.8 Hz,1F); 19F{1H}
AreCHF), ꢁ201.7 (br s, 1F, CHFeCH2); HRMS (ESI, þve)
d
ꢁ191.9 (s, 1F); HRMS (ESI, þve)
C
19H17F2N2Oþ3 [MþH]þ requires m/z 359.1202, found 359.1181.
17H13FN2O5Naþ [MþNa]þ requires m/z 367.0701, found 367.0696.
Data for 47: Rf 0.1 (95:5 DCM/EtOAc); [
a]
D ꢁ3.1 (c 0.285, MeCN);
4.1.22. (2S,3S)-4-(1,3-Dioxoisoindolin-2-yl)-2,3-difluorobutanoic
acid (50).28 To a stirred mixture of compound 49 (10.8 mg,
mp 92e93 ꢀC; IR (neat) nmax (cmꢁ1) 3470, 1770, 1703, 1518, 1397; 1H
NMR (600 MHz, CD3Cl3)
d
8.20 (d, J¼8.9 Hz, 2H, O2NC6H4), 7.86 (dd,
30.1
was added NaIO4 (184 mg, 0.86 mmol) followed by RuCl3 (8 mg,
30 mol), and the resulting mixture was stirred for 5 d. The mixture
mmol), acetonitrile (0.9 mL), DCM (0.9 mL) and H2O (1.1 mL)
J¼5.5, 3.1 Hz, 2H, phthalimide), 7.56 (dd, J¼5.4, 3.0 Hz, 2H, phtha-
limide), 7.61 (d, J¼8.7 Hz, 2H, O2NC6H4), 4.74 (dd, J¼6.2, 4.5 Hz, 1H,
O2NC6H4CHOH), 4.09 (ddd, J¼9.3, 5.5, 3.5 Hz, 1H, CHOHCH2), 4.01
(dd, J¼14.8, 5.7 Hz, 1H, CH2), 3.91 (dd, J¼14.8, 3.4 Hz, 1H, CH2), 3.51
(d, J¼4.3 Hz,1H, ArCHOH), 2.81 (d, J¼4.8 Hz,1H, CHOHCH2); 13C{1H}
m
was filtered through Celite and washed with EtOAc. The filtrate was
concentrated under reduced pressure, and the residue was purified
by flash chromatography eluting with 97:3 DCM/EtOAc followed by
100:10:0.5 DCM/MeOH/CH3COOH to afford the title compound as
a white solid (3.8 mg, 74%), plus recovered starting material
(2.7 mg, 25%).
NMR (150 MHz, CD3Cl3)
d 169.5 (C]O), 147.7 (O2NeC), 147.6
(ArCeCHOH), 134.6 (ArC), 131.8 (ArC), 127.5 (ArC), 123.8 (ArC), 123.7
(ArC), 74.2 (CHOHeCH2), 73.9 (ArCeCHOH), 40.0 (CH2); HRMS (ESI,
þve)
C
17H14N2O6Naþ [MþNa]þ requires m/z 365.0744, found
Data for 50: Rf 0.1 (5:95:0.1 EtOAc/DCM/CH3COOH); 1H NMR
365.0727.
(400 MHz, CD3CN) d 7.84e7.80 (m, 4H, phthalimide), 5.29e5.10 (m,
2H, CHFeCHF), 4.10e4.01 (m, 2H, CH2); 19F NMR (376 MHz, CD3CN)
4.1.20. 2-((2S,3S)-2,3-Difluoro-3-(4-nitrophenyl)propyl)isoindoline-
1,3-dione (48). A mixture of fluorohydrin 46 (0.75 g, 2.2 mmol) and
DeoxoFluorÒ (4.1 mL, 22 mmol) was heated at 70 ꢀC for 16 h. The
mixture was cooled to 0 ꢀC and diluted with DCM (10 mL) before
washing with saturated aqueous NaHCO3 (10 mL). The organic
layer was dried (MgSO4) and concentrated under reduced pres-
sure. The residue was purified by flash chromatography eluting
with 30:70 DCM/hexane to afford the title compound as a yellow
solid (277 mg, 37%), plus recovered starting material (289 mg,
38%).
d
ꢁ202.2 (m, 1F, PheCHF), ꢁ210.5 (m, 1F, CHFeCH2); 19F{1H} NMR
(376 MHz, CD3CN)
d
ꢁ202.2 (br s, 1F, PheCHF), ꢁ210.5 (br s, 1F,
CHFeCHF); spectral data in accordance with literature values.28
4.1.23. (2S,3R)-3-Fluoro-2-hydroxy-3-(4-nitrophenyl)propyl-4-
methylbenzenesulfonate (51); (2R,3S)-2-(fluoromethyl)-3-(4-
nitrophenyl)oxirane (52); (1R,2S)-1,3-difluoro-1-(4-nitrophenyl)
propan-2-ol (53). In an oven dried pressure flask, a mixture of
epoxide 44 (60.0 mg, 0.17 mmol) and Et3N$3HF (2.8 mL) was stirred
for 16 h at 100 ꢀC. The reaction mixture was cooled to room tem-
perature, diluted with DCM (50 mL) and quenched with saturated
aqueous NaHCO3 at 0 ꢀC. The organic layer was washed with water
(3ꢂ30 mL), dried over Na2SO4 and concentrated in vacuo. The
residue was purified by flash chromatography eluting with 80:20
hexane/EtOAc to afford compound 51 as a white solid (2.0 mg, 3%),
plus compound 52 as a white solid (3.5 mg, 5%), plus compound 53
as a white solid (5.4 mg, 15%).
Data for 48: Rf 0.2 (70:30 hexane/EtOAc); [
MeCN); mp 202e203 ꢀC; IR (neat) nmax (cmꢁ1) 1706, 1513, 1004; 1H
NMR (400 MHz, CD3CN)
a]
ꢁ9.6 (c 0.094,
D
d
8.25 (d, J¼8.4 Hz, 2H, C6H4NO2), 7.86 (m,
2H, phthalimide), 7.80 (m, 2H, phthalimide), 7.68 (d, J¼8.7 Hz, 2H,
C6H4NO2), 5.90 (ddd, J¼45.4, 23.7, 2.8 Hz, 1H, C6H4eCHF), 5.09
(ddddd, J¼46.6, 23.7, 8.0, 4.5, 2.8 Hz, 1H, CHFeCHFeCH2), 4.13 (ddd,
J¼14.4, 13.1, 8.0, 0.6 Hz, 1H, CH2), 3.96 (ddd, J¼26.5, 14.4, 4.5 Hz, 1H,
CH2); 13C{1H} NMR (150 MHz, CD3CN)
d
168.9 (C]O), 149.3
Data for 51: Rf 0.33 (EtOAc/hexane 80:20); IR (solution in DCM)
(O2NeC), 143.3 (dd, J¼21.0, 4.0 Hz, ArCeCHF), 135.4 (ArC), 133.0
(ArC), 128.4 (d, J¼8.1 Hz, oeNO2C6H4), 124.6 (ArC), 124.1 (ArC), 91.8
(dd, J¼179.4, 18.7 Hz, AreCHF), 91.4 (dd, J¼183.3, 20.6 Hz,
CHFeCH2), 38.7 (dd, J¼25.7, 6.9 Hz, CH2); 19F NMR (376 MHz,
nmax (cmꢁ1) 3520, 2954, 1600, 1523, 1348, 1175, 1096, 990, 815; 1
H
NMR (600 MHz, CD3CN)
d
8.19 (d, J¼8.5 Hz, 2H, C6H4NO2), 7.77 (d,
J¼8.1 Hz, 2H, C6H4CH3), 7.54 (d, J¼8.5 Hz, 2H, C6H4NO2), 7.43 (d,
J¼8.1 Hz, 2H, C6H4CH3), 5.48 (dd, J¼46.0, 5.8 Hz, 1H, CHF), 4.09 (m,
2H, CHOHeCH2), 4.06 (m, 1H, CHOHeCH2), 3.73 (d, J¼5.8 Hz, 1H,
CHOH), 2.45 (s, 3H, C6H4CH3); 13C{1H} NMR (150 MHz, CDCl3)
CD3CN)
d
ꢁ199.0 (dddd, J¼45.4, 23.7, 10.0, 0.6 Hz, 1F, PheCHF),
ꢁ203.4 (ddddd, J¼46.6, 26.5, 23.7, 13.1, 10.0 Hz, 1F, CHFeCH2); 19F
{1H} NMR (376 MHz, CD3CN)
d
ꢁ199.0 (d, J¼10.0 Hz, 1F, PheCHF),
d
149.2 (O2NeC), 146.7 (CeS), 144.6 (d, J¼19.3 Hz, ArCeCHF), 133.3
ꢁ203.4 (dd, J¼10.0 Hz, 1F, CHFeCHF); HRMS (ESI, þve)
(ArCeCH3), 131.1 (oeCH3C6H4), 128.9 (meCH3C6H4), 128.8 (d,
J¼7.4 Hz, meNO2C6H4), 124.3 (oeNO2C6H4), 92.7 (d, J¼175.3 Hz,
CHF), 71.5 (dd, J¼26.7 Hz, CHOH), 71.1 (d, J¼4.2 Hz, CHOeCH2eOTs),
C
17H12F2N2O4Naþ [MþNa]þ requires m/z 369.0657, found 369.0673.
4.1.21. N-(4-((1S,2S)-3-(1,3-Dioxoisoindolin-2-yl)-1,2-
difluoropropyl)phenyl)acetamide (49). To a solution of compound
48 (326 mg, 0.94 mmol) in freshly distilled acetic anhydride (15 mL)
was added Pd/C (5%, 250 mg), and the mixture was stirred under
a H2 balloon for 5 h. The mixture was filtered through a small pad of
Celite, washed with methanol and concentrated under reduced
pressure. The residue was purified by column chromatography
eluting with 97:3/80:20 DCM/EtOAc to afford the title compound
21.8 (CH3); 19F NMR (564 MHz, CDCl3)
d
ꢁ188.8 (dd, J¼46.0, 11.0 Hz,
1F, PheCHF), 19F{1H} NMR (282 MHz, CDCl3)
d
ꢁ188.8 (s, 1F,
PheCHF); HRMS (ESI, þve) C16H16FNO6SNaþ [MþNaþ] requires m/z
392.0575, found 392.0570.
Data for 52: Rf 0.40 (80:20 EtOAc/hexane); IR (solution in DCM)
nmax (cmꢁ1) 3495, 3114, 2963, 1741, 1603, 1518, 1459, 1350, 1250,
1109, 984, 858, 763; 1H NMR (300 MHz, CDCl3)
d
8.23 (d, J¼8.7 Hz,
2H, C6H4NO2), 7.47 (d, J¼8.7 Hz, 2H, C6H4NO2), 4.75 (ddd, J¼47.6,
11.0, 2.6 Hz, 1H, CHH), 4.57 (ddd, J¼47.6, 11.0, 4.7 Hz, 1H, CHH), 3.99
(br s, 1H, O2NC6H4eCHO), 3.30 (dddd, J¼14.1, 4.7, 2.6, 2.1 Hz, 1H,
as a white solid (218 mg, 65%); Rf 0.43 (5:95 EtOAc/DCM); [
(c 0.118, MeCN); mp 138e140 ꢀC; IR (neat) nmax (cmꢁ1) 1796, 1715,
1388; 1H NMR (400 MHz, CD3CN)
7.84e7.77 (m, 4H, C6H4NO2),
a
]
D ꢁ7.15
d
CHOeCH2); 13C{1H} NMR (75 MHz, CDCl3)
d 148.2 (CeNO2), 143.7
7.54e7.49 (m, 4H, phthalimide), 5.74 (ddd, J¼45.7, 21.6, 3.9 Hz, 1H,
AreCHF), 5.06 (ddddd, J¼47.4, 21.6, 8.3, 3.9, 3.9 Hz, 1H, CHFeCH2),
4.07 (ddd, J¼14.4, 13.5, 8.3 Hz, 1H, CH2), 3.82 (ddd, J¼27.4, 14.4,
(CeCHO), 126.6 (ArC), 124.1 (ArC), 81.6 (d, J¼173.1 Hz, CH2eF), 60.4
(d, J¼23.3 Hz, CHOeCH2), 54.5 (d, J¼8.3 Hz, O2NC6H4eCHO); 19F
NMR (282 MHz, CDCl3)
d
ꢁ229.5 (dt, J¼47.3, 14.3 Hz, 1F); 19F{1H}

3316
A.R. Patel et al. / Tetrahedron 72 (2016) 3305e3317
NMR (282 MHz, CDCl3)
d
ꢁ229.5 (s, 1F); HRMS (ESI, þve)
Data for 56: Rf 0.44 (4:1 hexane/EtOAc); mp 166e168 ꢀC; IR
(neat) nmax (cmꢁ1) 2942, 1767, 1702, 1517, 1344, 988, 853, 761; 1H
C9H8FNO3Naþ [MþNaþ] requires m/z 220.0380, found 220.0381.
Data for 53: Rf 0.43 (80:20 EtOAc/hexane); IR (solution in DCM)
nmax (cmꢁ1) 3361, 2958, 1605, 1519, 1344, 1290, 1203, 1106, 1011,
NMR (300 MHz, CDCl3)
(m, 4H, Ph), 4.19e4.14 (m, 2H, COCH2), 3.50e3.45 (m, 2H, CH2); 13
{1H} NMR (75 MHz, CDCl3)
196.1 (PheC]O), 168.5 (NeC]O),
d 8.09e7.87 (m, 4H, phthalimide), 7.86e7.72
C
734; 1H NMR (300 MHz, CDCl3)
d
8.28 (d, J¼8.9 Hz, 2H, C6H4NO2),
d
7.59 (d, J¼8.9 Hz, 2H, C6H4NO2), 5.55 (dd, J¼45.8, 6.9 Hz, 1H, CHF),
4.70 (dddd, J¼25.0, 14.9, 5.0, 2.1 Hz, 1H, CHH), 4.54 (dddd, J¼24.8,
14.9, 5.0, 2.1 Hz, 1H, CHH), 4.13 (m, 1H, CHOHeCH2), 2.26 (d,
150.9 (CeNO2), 141.0 (PhCeCO), 134.5 (ArC), 134.5 (ArC), 129.4
(ArC), 124.3 (ArC), 123.7 (ArC), 37.7 (COeCH2), 33.6 (CH2ePht);
HRMS (ESI, þve) C17H12N2O5Naþ [MþNaþ] requires m/z 347.0638,
found 347.0635.
J¼6.1 Hz, 1H, CHOH); 13C{1H} NMR (75 MHz, CDCl3)
d 148.4
(O2NeC), 143.3 (d, J¼19.2 Hz, ArCeCHF), 127.4 (d, J¼7.5 Hz,
meNO2C6H4), 123.9 (d, J¼8.9 Hz, oeNO2C6H4), 91.3 (dd, J¼177.5,
6.6 Hz, CHF), 82.9 (dd, J¼170.1, 4.5 Hz, CH2), 72.3 (dd, J¼26.8,
4.1.26. 2-((2S,3R)-2,3-Difluoro-3-(4-nitrophenyl)propyl)isoindoline-
1,3-dione (57); (Z)-2-(3-fluoro-3-(4-nitrophenyl)allyl)isoindoline-
1,3-dione (41). Neat DeoxoFluorÒ (0.107 mL, 0.581 mmol) was
added to fluorohydrin 55 (20 mg, 0.058 mmol) and the mixture was
stirred at 80 ꢀC in a sealed plastic reaction vessel overnight. The
mixture was cooled to 0 ꢀC, diluted with DCM (3.5 mL) and
quenched with saturated aqueous NaHCO3 (5 mL). The aqueous
layer was extracted with DCM (2ꢂ10 mL). The combined organic
layers were dried (MgSO4) and concentrated, and the residue was
subjected to flash chromatography eluting with 4:1 hexane/EtOAc
to yield compound 57 as a yellow oil (9.0 mg, 45%) plus compound
41 as a white solid (3.8 mg, 20%).
19.3 Hz, CHOH); 19F NMR (282 MHz, CDCl3)
d
ꢁ189.7 (dd, J¼46.0,
9.9 Hz, 1F, CHF), ꢁ236.2 (dt, J¼46.7, 19.9 Hz, 1F, CH2F); 19F{1H} NMR
(282 MHz, CDCl3)
d
ꢁ189.7 (s, 1F, CHF), ꢁ236.2 (s, 1F, CH2F); HRMS
(ESI, þve) C9H9F2NO3Naþ [MþNaþ] requires m/z 240.0443, found
240.0439.
4.1.24. 2-(((4R,5S)-5-(4-Nitrophenyl)-2,2-dioxido-1,3,2-
dioxathiolan-4-yl)methyl) isoindoline-1,3-dione (54). Diol 47
(500 mg,1.46 mmol) was dissolved in DCM (15 mL) and the solution
was cooled to 0 ꢀC. Pyridine (0.35 mL, 4.4 mmol) and thionyl
chloride (0.21 mL, 2.9 mmol) were then added dropwise, and the
resulting mixture stirred for 30 min. Saturated aqueous CuSO4
(20 mL) was added and stirring continued for a further 15 min prior
to extraction with DCM (3ꢂ15 mL). The combined organic layers
were dried and concentrated under reduced pressure to yield a pale
yellow film. The residue was redissolved in acetonitrile (10 mL) and
DCM (10 mL) and cooled to 4 ꢀC to produce a deep red solution. A
Data for 57: Rf 0.21 (4:1 hexane/EtOAc); [
CH3CN); IR (neat) nmax (cmꢁ1) 1774, 1715, 1524, 1391, 1347; 1H NMR
(300 MHz, CDCl3) 8.27e8.24 (m, 2H, Ph), 7.86e7.72 (m, 4H,
phthalimide), 7.64e7.61 (m, 2H, Ph), 5.71 (ddd, J¼45.9, 12.6, 4.6 Hz,
1H, eCHF),
eCHF), 5.12 (ddddd, J¼47.0, 15.3, 8.0, 4.6, 4.4 Hz, 1H,
4.15 (dddd, J¼14.6, 13.0, 8.0, 1.0 Hz, 1H, CHH), 3.93 (dddd, J¼25.9,
14.6, 4.4, 0.8 Hz, 1H, CHH); 13C{1H} NMR (75 MHz, CDCl3)
167.9
a
]
D
þ0.26 (c 0.16,
d
a
b
d
solution of RuCl3 (5 mg, 20
m
mol) dissolved in water (10 mL) was
(NeC]O), 148.5 (CeNO2), 141.4 (dd, J¼20.0, 4.0 Hz, PhCeCF), 134.5
(ArC), 131.8 (ArC), 127.2 (d, J¼8.0 Hz, ArC), 124.0 (ArC), 123.7 (ArC),
91.2 (dd, J¼181.7, 24.0 Hz, PheCF), 89.7 (dd, J¼183.1, 26.4 Hz,
CFeCH2), 38.0 (dd, J¼25.1, 6.0 Hz, CH2); 19F NMR (282 MHz, CDCl3)
added, followed by sodium metaperiodate (624 mg, 2.92 mmol).
The mixture was stirred for 5 min at 0 ꢀC before addition of diethyl
ether (80 mL) and washing with water (80 mL), saturated NaHCO3
(2ꢂ80 mL) and brine (2ꢂ80 mL). The organic layer was dried
(NaSO4) and concentrated to yield the title compound as a white
foam (446 mg, 76%), which was carried onto the next step without
purification or characterization.
d
ꢁ194.1 (ddd, J¼45.9, 16.2, 16.2 Hz, 1F), e195.3 (m, 1F); 19F{1H}
NMR (282 MHZ, CDCl3)
d
ꢁ194.1 (d, J¼16.2 Hz, 1F), e195.3 (d,
J¼16.2 Hz,1F); HRMS (ESI, þve) C17H12F2N2Oþ4 [MþHþ] requires m/z
347.0838, found 347.0836.
Data for 41: Rf 0.31 (4:1 hexane/EtOAc); mp 98e100 ꢀC; IR (neat)
4.1.25. 2-((2R,3R)-3-Fluoro-2-hydroxy-3-(4-nitrophenyl)propyl)iso-
indoline-1,3-dione (55); 2-(3-(4-Nitrophenyl)-3-oxopropyl)isoindo-
line-1,3-dione (56). A mixture of compound 54 (446 mg,
1.06 mmol), TBAF (1 M solution in THF, 2.59 mL, 2.59 mmol) and
anhydrous acetonitrile (23 mL) was stirred at 0 ꢀC for 1 h. The
mixture was concentrated to yield a brown oil. This residue was
redissolved in a mixture of concentrated sulfuric acid (0.44 mL),
nmax (cmꢁ1) 1708, 1511, 1397, 1325; 1H NMR (300 MHz, CDCl3)
d
8.36e8.18 (m, 2H, Ph), 7.92e7.71 (m, 4H, phthalimide), 7.71e7.58
(m, 2H, Ph), 5.79 (ddd, J¼35.2, 7.3, 7.1 Hz, 1H, CFCH), 4.62 (dd, J¼7.1,
1.8 Hz, 2H, CH2); 13C{1H} NMR (75 MHz, CDCl3)
168.1 (C]O), 148.5
d
(CeNO2), 137.8 (ArC), 134.5 (ArC), 132.4 (ArC), 125.6 (ArC), 124.3
(ArC), 123.9 (ArC), 104.5 (d, J¼15.1 Hz, CF]C), 32.5 (d, J¼7.5 Hz,
CH2); 19F NMR (282 MHz, CDCl3)
d
ꢁ115.8 (d, J¼35.2 Hz,1F); 19F{1H}
water (80
mL) and THF (80 mL) and the resultant solution was
NMR (282 MHZ, CDCl3)
d
115.8 (s, 1F); HRMS (ESI, þve)
stirred at room temperature overnight. The reaction was quenched
with brine (50 mL) and water (50 mL), and then extracted with
DCM (100 mL, 50 mL). The combined organic layers were dried
(MgSO4) and concentrated onto silica. The crude product was
subjected to flash chromatography eluting with 4:1 hexane/EtOAc
to give compound 55 as a white solid (167 mg, 41%), compound 56
as a white solid (66 mg, 16%) and a mixture of compounds 60a and
60b as transparent needles (9.8 mg, 3%).
C
17H11FN2O4Naþ [MþNaþ] requires m/z 349.0595, found 349.0597.
4.1.27. N-(4-((1R,2S)-3-(1,3-Dioxoisoindolin-2-yl)-1,2-
difluoropropyl)phenyl) acetamide (58). Palladium on charcoal (10%,
w10 mg) was added to a solution of compound 57 (14.2 mg,
0.041 mmol) in freshly distilled acetic anhydride (4 mL). The mix-
ture was stirred at room temperature under a balloon of H2 gas for
6 h. The reaction mixture was filtered through a pad of Celite (EtOAc
wash) and concentrated under reduced pressure. The residue was
subjected to flash chromatography eluting with 95:5 DCM/EtOAc to
yield the title compound as an off white solid (5.1 mg, 35%); Rf 0.20
Data for 55: Rf 0.31 (4:1 hexane/EtOAc); [
CH3CN); mp 158e160 ꢀC; IR (neat) nmax (cmꢁ1) 3471, 1767, 1699,
1519, 1342, 794; 1H NMR (300 MHz, CDCl3)
8.30e8.20 (m, 2H, Ph),
a
]
ꢁ11 (c 0.14,
D
d
7.90e7.70 (m, 4H, phthalimide), 7.60e7.50 (m, 2H, Ph), 5.63 (dd,
J¼46.2, 3.4 Hz, 1H, CHF), 4.35e4.21 (m, 1H, CHOH), 3.97e3.95 (m,
(95:5 DCM/EtOAc); 1H NMR (600 MHz, CDCl3)
d 7.90e7.55 (m, 4H,
phthalimide), 7.54e7.53 (m, 4H, Ph), 5.58 (ddd, J¼45.9, 12.2, 4.6 Hz,
1H, PheCHF), 5.11 (ddddd, J¼47.8, 13.8, 8.0, 4.6, 3.7 Hz, 1H,
CHFeCH2), 4.20 (dddd, J¼14.8, 13.0, 8.0, 1.5 Hz, 1H, CHH), 3.92
(dddd, J¼28.7, 14.8, 3.7, 0.8 Hz,1H, CHH), 2.25 (s, CH3); 13C{1H} NMR
2H, CH2); 13C{1H} NMR (150 MHz, CDCl3)
d 168.0 (C]O), 147.6
(CeNO2), 143.7 (d, J¼20.8 Hz, PhCeCF), 133.8 (ArC), 131.7 (ArC),
126.9 (d, J¼8.0 Hz, ArC),123.1 (ArC),122.9 (ArC), 92.7 (d, J¼179.5 Hz,
CeF), 70.5 (d, J¼21.2 Hz, CeOH), 40.2 (d, J¼5.0 Hz, CH2); 19F NMR
(150 MHz, CDCl3)
d 168.0 (C]O), 140.1 (CeNHCOCH3), 134.4 (ArC),
(282 MHz, CDCl3)
(282 MHz, CDCl3)
d
d
ꢁ196.1 (dd, J¼45.7, 20.6 Hz, 1F); 19F{1H} NMR
ꢁ196.1 (s, 1F); HRMS (ESI, þve) C17H14FN2O5þ
134.2 (ArC), 132.3 (ArC), 131.9 (ArC), 123.7 (ArC), 123.5 (ArC), 91.7
(dd, J¼179.2, 21.8 Hz, PheCF), 90.1 (dd, J¼182.3, 27.3 Hz, CFeCH2),
37.9e37.6 (m, 1C, CH2), 21.7 (CH3); 19F NMR (376 MHz, CDCl3)
[MþHþ] requires m/z 345.0881, found 345.0833.

A.R. Patel et al. / Tetrahedron 72 (2016) 3305e3317
3317
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d
C
ꢁ191.2 (m, 1F), ꢁ195.6 (m, 1F); 19F{1H} NMR (376 MHz, CDCl3)
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The authors are grateful to the Australian Research Council
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Supplementary data
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Reproductions of the NMR spectra of all new compounds, and
further details of selected fluorination reaction trials, are provided
as Supplementary data. This material is available free of charge via
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