Multigramme synthesis and asymmetric dihydroxylation of a 4-fluorobut-2E-enoate

Article abstract of DOI:10.3762/bjoc.9.301

Esters of crotonic acid were brominated on a multigramme scale using a free radical procedure. A phase transfer catalysed fluorination transformed these species to the 4-fluorobut-2E-enoates reproducibly and at scale (48-53%, ca. 300 mmol). Asymmetric dihydroxylation reactions were then used to transform the butenoate, ultimately into all four diastereoisomers of a versatile fluorinated C₄ building block at high enantiomeric-enrichment. The (DHQ) ₂AQN and (DHQD)₂AQN ligands described by Sharpless were the most effective. The development and optimisation of a new and facile method for the determination of ee is also described; ¹⁹F{¹H} spectra recorded in d-chloroform/diisopropyl tartrate showed distinct baseline separated signals for different enantiomers.

Full text of DOI:10.3762/bjoc.9.301

Supporting Information
for
Multigramme synthesis and asymmetric dihydroxylation of
a 4-fluorobut-2E-enoate
James A. B. Laurenson1,2, John A. Parkinson1, Jonathan M. Percy*1, Giuseppe
Rinaudo1 and Ricard Roig3,4
Address: 1WestCHEM Department of Pure and Applied Chemistry, University of
Strathclyde, Thomas Graham Building, 295 Cathedral Street, Glasgow G1 1XL,
United Kingdom, 2Carbosynth Ltd., 93 Innovation Drive, Milton Park, Abingdon,
Oxfordshire OX14 4RZ, United Kingdom, 3Department of Chemistry, University of
Leicester, University Road, Leicester LE1 7RH, United Kingdom and 4Lallemand Gb
Ingredients, Dock Road, Felixstowe, Suffolk IP11 3QW, United Kingdom
Email: Jonathan M. Percy - jonathan.percy@strath.ac.uk
* Corresponding author
Experimental procedures and characterization data
S1

General synthetic procedures
13
NMR spectra were recorded on a Bruker AV400 spectrometer (1H 400.03 MHz; C
100.59 MHz; 19F 376.40 MHz) or a Bruker DPX400 spectrometer (1H 400.13 MHz;
13C 100.59 MHz; 19F 376.50 MHz). NMR spectra were recorded using deuterated
solvent as the lock and residual solvent as the internal reference. The multiplicities of
the spectroscopic data are presented in the following manner: app. = apparent, s =
singlet, d = doublet, t = triplet, dd = double doublet, td = triplet doublets, br = broad,
m = multiplet. The appearance of complex signals is indicated by app.
Homocouplings (H–H) are given in Hertz and specified by J; the nuclei involved in
heteronuclear couplings are defined with the observed nucleus given first. Unless
3
stated otherwise, all refer to J couplings. Low resolution ESI analyses were
performed on a Finnigan LC Q Duo mass spectrometer. GC–MS analyses were
performed on a Finnigan Polaris Q spectrometer carried on a 30 m × 0.25 µm PE-5
column running a 40–320 °C ramp over 25 minutes (unless otherwise stated). High
resolution mass spectrometry measurements were carried out at the EPSRC
National Mass Spectrometry Service Centre in Swansea using peak matching to
suitable reference peaks, depending on the technique used. Thin Layer
Chromatography (TLC) was performed on pre-coated aluminium backed silica gel
plates (Merck, silica gel 60 F254). The compounds were visualized using UV light (λ =
254 and 386 nm), potassium permanganate or p-anisaldehyde stains. Flash
chromatography was performed using silica gel (33–70 μm) and a Buchi Sepacore
system. Infra-red (IR) spectra were obtained on a Perkin Elmer Spectrum One FTIR
spectrometer. Melting points were obtained using a Reichert hot stage melting point
apparatus. Optical rotations were performed on a Perkin Elmer Polarimeter 341
using an optical cell (path length 10 cm) maintained at 298 K with a continuous flow
S2

water bath. Solvents were dried (when required) using a PureSolv apparatus
(Innovative Technologies Inc.). All other chemicals and solvents were used as
received from suppliers without any further purification.
CAUTION All the materials made in this study were treated with the utmost
caution; all skin contact and inhalation were avoided with the greatest care. The
presence of the fluorine atom at the chain end may result in the release of
fluoroacetic acid, a fatal poison, upon metabolism. Esters 23 and 24 were viewed
as particularly hazardous because of their volatility; diaphragm pumps used on rotary
evaporators were protected by Dreschel bottles filled with bleach, and rotary pump
exhaust was vented carefully into a fume cupboard. Rotary pump oil was changed
and disposed of upon completion of the work.
Determination of ee by 19F{1H} NMR procedure
The sample to be analysed was dissolved (~2–3 mg/mL) in a mixture of CDCl3 and
diisopropyl L-tartrate (1:1 w/w) and an aliquot (0.75 mL) transferred to an NMR tube.
The spectrometer acquisition parameters were set to:
SW = 40 (sweep width); AQ = 0.8 (acquisition time); O1P = −230 (spectral window
centre); d1 = 5 seconds (relaxation delay). Upon completion of the NMR experiment
the signals for each enantiomer in the resulting spectrum were integrated to
determine the ee of the sample.
Preparation of n-propyl but-2-E-enoate (21)
A solution of crotonic acid (20, 581 mmol, 50 g) in n-propanol (225 mL) containing
concentrated sulfuric acid (6.9 mL) was heated at reflux overnight. The reaction
S3

mixture was then diluted with diethyl ether (100 mL) and washed with aqueous
NaHCO3 (ca. 3 × 75 mL of a saturated aqueous solution) until no more gas was
evolved. The combined aqueous washings were back extracted with diethyl ether (2
× 100 mL) and the combined organic extracts and original layer were dried (MgSO4)
and concentrated in vacuo to afford ester 21 as a colourless oil which was used in
the next step without purification (59.7 g, ca. 80%). The following data were obtained
from a small purified sample (flash chromatography, 10% diethyl ether in hexane): Rf
(12.5% diethyl ether in pet. ether 40–60 °C) 0.66; δH (400 MHz, CDCl3) 6.97 (dq, J =
15.7, 7.0, 1H), 5.84 (dq, J = 15.7, 1.8, 1H), 4.1 (t, J = 7.0, 2H), 1.87 (dd, J = 7.0, 1.8,
3H), 1.72-1.63 (m, 2H), 0.95 (t, J = 7.0, 3H); δC (100 MHz, CDCl3) 166.6, 144.3,
122.7, 65.7, 22.0, 17.8, 10.3; m/z (EI) 129 (15%), 87 (35), 69 (100); HRMS (EI+, [M]+)
calcd. for C7H12O2 128.0831, found 128.0832. The ester was reported previously [S1]
but at a lower level of characterisation.
Preparation of isopropyl but-2-E-enoate (22)
Was prepared from crotonic acid 20 (872 mmol, 75 g), isopropanol (365 mL) and
concentrated sulfuric acid (8.8 mL) according to the previous procedure, work-up
and isolation, to afford ester 22 (86.5 g ca. 77%) as a colourless oil which was used
in the next step without purification. The following data were obtained from a small
purified sample (flash chromatography, 10% diethyl ether in hexane): Rf (20% diethyl
ether in hexane) 0.59; δH (400 MHz, CDCl3) 7.00-6.89 (m, 1H), 5.82 (d, J = 15.7,
1H), 5.10-5.02 (m incl. app. septet, J = 6.3, 1H), 1.86 (d, J = 6.3, 3H), 1.25 (d, J =
6.3, 6H); δC(100 MHz, CDCl3) 166.1, 144.0, 123.3, 67.3, 21.9, 17.8; max(film)/cm-1
3539, 3422, 2981, 2878, 1720, 1660, 1446, 1375, 1293, 1191, 1110, 1002, 834, 690;
S4

HRMS (EI+, [M]+) calcd. for C7H12O2 128.0832, found 128.0830. The data were in
agreement with those reported by Jonczyk et al. [S2].
Preparation of n-propyl 4-bromobut-2-E-enoate (23)
A solution of N-bromosuccinimide (41.7 g, 234 mmol), benzoyl peroxide (283 mg,
1.17 mmol) and ester 21 (30 g, 234 mmol) in chlorobenzene (300 mL) was warmed
slowly to 85 °C over ca. 45 minutes. The reaction mixture was then allowed to stir at
this temperature for 2.5 days. The cooled reaction mixture was then filtered and the
precipitate washed with diethyl ether (200 mL). The combined filtrate and washings
were then washed with NaOH (4 × 200 mL of a 5% aqueous solution) until the
washings were almost colourless, then with brine (200 mL), dried (MgSO4) and
concentrated in vacuo to afford an orange oil. Kugelrohr distillation (80 °C/0.38
mmHg) afforded the bromide 23 as a pale yellow oil (25.97 g, ca. 53% yield) which
was used in the next step without further purification (estimated to be ~90% pure by
1H NMR). The following data were obtained from a small purified sample (flash
chromatography, 10% diethyl ether in hexane): Rf (20% diethyl ether in hexane)
0.59; δH (400 MHz, CDCl3) 7.00 (dt, J = 15.4, J = 7.3, 1H), 6.04 (dt, J = 15.4, J = 1.3,
1H), 4.11 (t, J = 6.8, 2H), 4.01 (dd, J = 7.3, J = 1.3, 2H), 1.75-1.64 (m, 2H), 0.96 (t, J
= 7.3, 3H); δC (100 MHz, CDCl3) 165.4, 141.5, 124.6, 66.2, 29.1, 21.9, 10.3;

max(film)/cm-1 2969, 2879, 1722 (C=O), 1655 (C=C); m/z (EI+) 207 (100%), 147 (50),
68 (30); HRMS (EI+, [M]+) calcd for C7H11BrO2 205.9934, found 205.9931; Anal.
Calcd. for C7H11BrO2: C, 40.60; H, 5.35; Br, 38.59. Found: C, 40.51; H, 5.12; Br,
38.41.
S5

Preparation of isopropyl 4-bromobut-2-E-enoate (24)
Was prepared from a solution of N-bromosuccinimide (60.7 g, 341 mmol), benzoyl
peroxide (362 mg, 1.5 mmol) and ester 22 (39.7 g, 310 mmol) in chlorobenzene (200
mL) and according to the previous procedure, work-up and isolation the bromide 24
was obtained (33.8 g, ca 48%). The following data were obtained from a small
purified sample (Flash chromatography, 0–25% diethyl ether in hexane): Rf (10%
diethyl ether in hexane) 0.28; δH (400 MHz, CDCl3) 7.02-6.94 (m, 1H), 6.06-6.01 (m
incl. app. dt, J = 15.2, J = 1.1, 1H), 5.12-5.04 (sept., J = 6.3, 1H), 4.01 (dd, J = 7.3,
1.1, 2H), 1.27 (d, J = 6.3, 6H); δC (100 MHz, CDCl3) 165.0, 141.3, 125.2, 68.2, 29.2,
21.8; max(film)/cm-1 3419, 2982, 2939, 1718, 1654, 1468, 1313, 1280, 1197, 1108,
976, 909, 823, 722, 584; m/z (EI+) 209 (85), 207 (100), 149 (24), 109 (7), 81 (14), 68
(21); HRMS (EI+, [M]+) calcd. for C7H11BrO2 205.9937, found 205.9936.
Preparation of n-propyl 4-fluorobut-2-E-enoate (25)
Bromoester 23 (22.05 g, 106 mmol) was added to a solution of KF·2H2O (39.9 g,
424 mmol) and Bu4NHSO4 (43.2 g, 127 mmol) in acetonitrile (500 mL) and the
mixture was heated at reflux overnight. The mixture was then diluted with water (400
mL) and extracted with diethyl ether (1 × 400 mL and 2 × 150 mL). The combined
organic extracts were washed with brine (300 mL), dried (MgSO4) and concentrated
in vacuo, then fractionally distilled under reduced pressure (55–70 °C/0.08 mmHg) to
afford fluoride 25 (10.2 g ca. 66%) as a pale yellow oil. The material (estimated to be
~90% pure by 1H NMR) was used in subsequent reactions. The following data were
S6

obtained from a small purified sample (Flash chromatography, 10% Et2O in hexane):
Rf (20% diethyl ether in hexane) 0.55; δH (400 MHz, CDCl3) 6.96 (ddt, 3JH-F = 22.7, J
= 15.9, 3.8, 1H), 6.12 (dq, J = 15.9, 4JH-F = 2.0, 1H), 5.06 (ddd, 2JH-F = 46.2, J = 3.8,
2.0, 2H), 4.12 (t, J = 6.7, 2H), 1.75-1.65 (m, 2H), 0.96 (t, J = 7.3, 3H); δC (100 MHz,
CDCl3) 165.8, 141.3 (d, 2JC-F 16.0), 121.4 (d, 3JC-F 11.4), 81.1 (d, 1JC-F 171.3), 66.2,
2
3
4
21.9, 10.3; δF (376 MHz, CDCl3) -223.3 (tdd, JF-H 46.2, JF-H 22.7, JF-H 2.0);

max(film)/cm-1 2971, 2882, 1722 (C=O), 1669 (C=C); m/z (EI+) 163 (8%), 147 (80),
87 (100), 59 (19); HRMS (EI+, [M]+) calcd. for C7H11FO2 146.0738, found 146.0736,
(EI+, [M + H]+) calcd. for C7H12FO2 147.0816, found 147.0815.
Preparation of isopropyl 4-fluorobut-2-E-enoate (26)
Was prepared from bromoester 24 (34.5 g, 167 mmol), KF·2H2O (62.1 g, 668 mmol)
and Bu4NHSO4 (67.22 g, 200 mmol) in acetonitrile (650 mL) according to the
previous procedure, work-up and isolation. Fractional distillation under reduced
pressure (55–70 °C/0.08 mmHg) afforded ester 26 as a pale yellow oil (7.34 g, 30%,
1
estimated to be ~95% pure by H NMR) was used in subsequent reactions without
any further purification. The following data were obtained from a small purified
sample (flash chromatography, 10% diethyl ether in hexane): Rf (10% diethyl ether in
hexane) 0.22; δH (400 MHz, CDCl3) 6.99-6.86 (m, 1H), 6.11-6.04 (m incl. app. d, J =
15.7, 1H), 5.11-4.96 (m, 3H), 1.26 (d, J = 6.7, 6H); δC (100 MHz, CDCl3) 165.2, 141.0
2
3
1
(d, JC-F = 17.6), 122.0 (d, JC-F = 11.4), 81.1 (d, JC-F = 172.7), 68.1, 21.8; δF (376
2
3
4
MHz, CDCl3) -230.1 (tdd, JF-H = 46.5, JF-H = 22.4, JF-H = 1.7); max(film)/cm-1 3430,
2983, 2878, 1721, 1667, 1469, 1376, 1305, 1279, 1182, 1108, 999, 912, 836, 680,
587; m/z (EI+) 233 (10%), 147 (100), 87 (80), 59 (10); HRMS (EI+, [M]+) calcd. for
S7

C7H11FO2 146.0738, found 146.0738, (EI+, [M + H]+) calcd. for C7H12FO2 147.0816,
found 147.0815.
Preparation of n-propyl (2S*,3S*)-dihydroxy-4-fluorobutanoate ((±)-28c);
Upjohn dihydroxylation of 25
A solution of NMO (1.4 g, 11.4 mmol) in water (1 mL) was added to a mixture of t-
BuOH and acetone (10 mL of a 1:1 mixture) at 0 °C. Ester 25 (836 mg, 5.7 mmol)
was then added in one portion, the mixture allowed to stir for 15 minutes and then
OsO4 (1.4 mL of a 2.5 wt % solution in t-BuOH) was added dropwise by syringe over
20 minutes. The mixture was allowed to continue stirring and warm slowly to room
temperature overnight. The reaction was quenched by the addition of sodium sulfite
(8 g) and diluted with water (30 mL). The aqueous solution was then extracted with
EtOAc (2 × 30 mL) and the combined organic extracts were dried (MgSO4) and
concentrated in vacuo to afford diol 28c as an orange gum that was used without
purification (855 mg, ca. 83%). The following data were obtained from a small
purified sample (flash chromatography, 1% methanol in 1:1 ethyl acetate/hexane): Rf
(50% ethyl acetate in hexane) 0.47; δH (400 MHz, CDCl3) 4.50 (ddd, 2JH-F = 46.6, J =
9.4, 6.1, 2H), 4.27 (br s, 1H), 4.25-4.13 (m, 3H), 3.33 (br s, 1H), 2.85 (br s, 1H), 1.70
(sextet, J = 7.2, 2H), 0.95 (t, J = 7.2, 3H); δC (100 MHz, CDCl3) 172.8, 83.0 (d, 1JC-F
170.6), 70.5 (d, 2JC-F = 21.0), 70.0 (d, 3JC-F = 5.1), 68.0, 21.8, 10.2; δF (376 MHz,
CDCl3) -225.5 (td, 2JF-H = 46.9, 3JF-H = 13.4); max(film)/cm-1 3454, 2982, 2865, 1756,
1451, 1375, 1287, 1220, 1105, 927; HRMS (ES+, [M + H]+) calcd. for C7H14FO4
=
181.0871, found 181.0871; Anal. Calcd.: C, 46.66; H, 7.27; Found C, 46.34; H, 7.30.
S8

Preparation of n-propyl (2S,3S)-dihydroxy-4-fluorobutanoate (28b); Sharpless
asymmetric dihydroxylations of 25
Sharpless AD with 2 mol % osmium/2 mol % ligand
A solution of K3Fe(CN)6 (2 g, 6.09 mmol), K2CO3 (840 mg, 6.09 mmol), MeSO2NH2
(195 mg, 2.03 mmol), (DHQD)2PHAL, (2 mol %), K2OsO4·2H2O (2 mol %) in a
mixture of t-BuOH and water (14 mL, 1:1 v/v) was cooled to 0 °C in a jacketed flask
(connected to circulating chiller) and allowed to stir for ca. 30 min until a
homogenous solution with a deep orange colour was observed. Fluoroester 25 (300
mg, 2.03 mmol) was then added in one portion and the mixture was allowed to stir at
0 °C for 15 hours (reaction completion was confirmed by micro work-up of an aliquot
and analysis by 19F NMR). The reaction was quenched by the addition of solid
sodium sulfite (2 g) and allowed to warm to room temperature. A colour change from
yellow to grey was observed. Water (30 mL) was then added and the suspension
was extracted with ethyl acetate (3 × 30 mL). The combined organic extracts were
then washed with brine (30 mL), KOH (30 mL of a 1 M solution), dried (MgSO4) and
concentrated in vacuo. Purification by flash chromatography (Buchi Sepacore, 1%
methanol in 1:1 ethyl acetate/hexane) afforded diol 28b as a colourless oil (163 mg,
44%). Data were identical to those described previously for 28c apart from; [α]D -13.2
(c 1.0, CDCl3), 89% ee by 19F{1H} NMR, L-(+)-DIPT/CDCl3.
S9

General procedure for AD-mix β standard conditions
Crude diol 28b was prepared from a solution of fluoroester 25 (1.04 g, 7.1 mmol),
AD-mix β (9.94 g) and methyl sulfonamide (675 mg, 7.1 mmol) in 1:1 t-BuOH/water
(70 mL) according to the procedure and work-up described previously. Purification
by flash chromatography (Buchi Sepacore, 50% diethyl ether in hexane) afforded
diol 28b as a colourless oil (700 mg, 54%, 72% ee by 19F{1H} NMR, L-(+)-
DIPT/CDCl3).
1 mol % osmium/10 mol % ligand
Diol 28b was prepared from a solution of ester 25 (73 mg, 0.5 mmol), AD-mix β (700
mg), methyl sulfonamide (48 mg, 0.5 mmol), (DHQD)2PHAL (9 mol %), K2OsO2(OH)4
(0.6 mol %) and NaHCO3 (1.5 mmol) in t-BuOH/water (5 mL, 1:1 v/v) according to
the procedure and work-up described previously to afford diol 28b (71 mg, ca. 79%,
90% ee by 19F{1H} NMR, L-(+)-DIPT/CDCl3).
General procedure for modified AD-mix β conditions
1 mol % osmium/5 mol % ligand
Crude diol 28b was prepared from a solution of fluoroester 25 (2.19 g, 15 mmol),
AD-mix β (21 g), methyl sulfonamide (1425 mg, 15 mmol), (DHQD)2PHAL (4 mol %),
K2OsO2(OH)4 (0.6 mol %) and NaHCO3 (45 mmol) in 1:1 t-BuOH/water (150 mL)
according to the procedure and work-up described previously to afford diol 28b (1.87
g, 78%, 91% ee by 19F{1H} NMR, L-(+)-DIPT/CDCl3).
S10

1 mol % osmium/5 mol % (DHQD)2AQN ligand
Crude diol 28b was prepared from a solution of fluoroester 25 (3 g, 20.3 mmol),
K3Fe(CN)6 (20 g, 60.9 mmol), K2CO3 (8.4 g, 60.9 mmol), MeSO2NH2 (1.95 g, 20.3
mmol), (DHQD)2AQN, (5 mol %, 870 mg), K2OsO4·2H2O (2 mol %, 74 mg) in a
mixture of t-BuOH and water (140 mL, 1:1 v/v) according to the procedure and work-
up described previously to afford diol 28b (2.63 g, 72%, 97% ee by 19F{1H} NMR, L-
(+)-DIPT/CDCl3).
Preparation of n-propyl (2R,3R)-dihydroxy-4-fluorobutanoate (28a)
General procedure for AD-mix α standard conditions
Crude diol 28a was prepared from a solution of fluoroester 25 (1.04 g, 7.1 mmol),
AD-mix α (9.94 g) and methyl sulfonamide (675 mg, 7.1 mmol) in 1:1 t-BuOH/water
(70 mL) according to the procedure and work-up described previously. Purification
by flash chromatography (Buchi Sepacore, 50% diethyl ether in hexane) afforded the
desired product 28a as a colourless oil (712 mg, 56%, 66% ee by 19F{1H} NMR, L-
(+)-DIPT/CDCl3).
Sharpless AD with 2 mol % osmium/2 mol % ligand
Crude diol 28a was prepared from a solution of fluoroester 25 (302 mg, 2.07 mmol),
K3Fe(CN)6 (2.04 g, 6.21 mmol), K2CO3 (858 mg, 6.21 mmol), MeSO2NH2 (198 mg,
2.07 mmol), (DHQ)2PHAL, (2 mol %), K2OsO4.2H2O (2 mol %) in t-BuOH/water (14
mL, 1:1 v/v) according to the procedure and work-up described previously.
Purification by flash chromatography (Buchi Sepacore, 2% methanol in 1:1 ethyl
acetate/hexane) afforded diol 28a as a colourless oil (163 mg, 45%). Data were
S11

identical to those described previously for 28c apart from; [α]D +12.8 (c 1.0, CDCl3),
80% ee by 19F{1H} NMR, L-(+)-DIPT/CDCl3.
General procedure for modified AD-mix α conditions:
1 mol % osmium/10 mol % ligand
Crude diol 28a was prepared from a solution of fluoroester 25 (73 mg, 0.5 mmol),
AD-mix α (700 mg), methyl sulfonamide (48 mg, 0.5 mmol), (DHQ)2PHAL (9 mol %),
K2OsO2(OH)4 (0.6 mol %) and NaHCO3 (1.5 mmol) in t-BuOH/water (5 mL, 1:1 v/v)
according to the procedure and work-up described previously to afford diol 28a (54
mg, ca. 60%, 82% ee by 19F{1H} NMR, L-(+)-DIPT/CDCl3).
General procedure for modified AD-mix α conditions:
1 mol % osmium/5 mol % ligand
Crude diol 28a was prepared from a solution of fluoroester 25 (1.6g, 10.8 mmol), AD-
mix α (15.1 g), methyl sulfonamide (1027 mg, 10.8 mmol), (DHQ)2PHAL (4 mol %),
K2OsO2(OH)4 (0.6 mol %) and NaHCO3 (32.4 mmol) in a mixture of t-BuOH/water
(110 mL, 1:1 v/v) according to the procedure and work-up described previously to
afford diol 28a (1.56 g ca. 80%, 83% ee by 19F{1H} NMR, L-(+)-DIPT/CDCl3).
1 mol % osmium/5 mol % (DHQ)2AQN ligand
Crude diol 28a was prepared from a solution of fluoroester 25 (1.5 g, 10.2 mmol),
K3Fe(CN)6 (10 g, 30.6 mmol), K2CO3 (4.2 g, 30.6 mmol), MeSO2NH2 (975 mg, 10.2
mmol), (DHQ)2AQN, (5 mol %, 435 mg), K2OsO4·2H2O (2 mol %, 37 mg) in a mixture
of t-BuOH and water (70 mL, 1:1 v/v) according to the procedure and work-up
S12

described previously to afford diol 28a (640 mg, 59%, 95% ee by 19F{1H} NMR, L-(+)-
DIPT/CDCl3).
Preparation of n-propyl (2S*,3S*)-dibenzyloxy-4-fluorobutanoate ((±)-29c)
Benzoic anhydride (1.13 g, 5 mmol), DMAP (49 mg, 0.4 mmol) and
poly(vinylpyridine) (2.5 g, 2.5 mmol) were added to a solution of diol 28c (360 mg, 2
mmol) in DCM (20 mL) at room temperature. The mixture was then shaken at room
temperature overnight. Analysis of the crude mixture by 19F NMR showed the
reaction had not gone to completion. Benzoic anhydride (0.57 g, 2.5 mmol) was
added and the mixture was shaken at room temperature for a further 4 hours.
19
Analysis of an aliquot by F NMR confirmed full conversion of the starting material
had taken place. The mixture was diluted with diethyl ether (10 mL), filtered, and the
precipitate washed with Et2O (10 mL). The filtrate was then washed with NaHCO3 (3
× 15 mL of a saturated aqueous solution), brine (15 mL), dried (MgSO4) and
concentrated in vacuo to afford a brown oil (700 mg, ca. 90% purity). Purification by
Flash chromatography (Buchi Sepacore, 10% diethyl ether in hexane) afforded
dibenzoate 29c as a colourless syrup (622 mg, 80%): Rf (10% diethyl ether in
hexane) 0.29; δH (400 MHz, CDCl3) 8.11 (m incl. app. d, J = 17.7, 2H), 8.09 (m incl.
app. d, J = 17.7, 2H), 7.64-7.56 (m, 2H), 7.50-7.42 (m, 4H), 5.96-5.86 (dq, J = 13.7,
J = 3.7, 1H), 5.70 (d, J = 3.7, 1H), 4.78 (dqd, 2JH-F = 46.5, J = 9.7, J = 5.6, 2H) , 4.14
(t, J = 6.7, 2H), 1.66-1.56 (m, 2H), 0.87 (t, J = 7.8, 3H); δC (100 MHz, CDCl3) 166.8,
1
165.4, 165.2, 133.7, 133.6, 130.0, 129.9, 128.6, 128.5, 80.2 (d, JC-F = 174.2), 70.6
3
2
(d, JC-F = 4.4), 70.3 (d, JC-F = 23.4), 67.7, 21.8, 10.2; δF (376 MHz, CDCl3) -230.3
S13

2
3
(td, JF-H = 47.0, JF-H = 12.6); max(film)/cm-1 3070, 2970, 2674, 1971, 1915, 1729,
1602, 1452, 1289, 1104, 1026, 935, 804, 712; HRMS (ES+, [M + NH4]+) calcd. for
C21H21FO6NH4 406.1660, found 406.1663, (ES+, [2M + NH4]+) calcd. for
C42H42F2O12NH4 794.2983, found 794.2990.
Preparation of n-propyl (2S,3S)-dibenzyloxy-4-fluorobutanoate (29b)
Was prepared from benzoic anhydride (127 mg, 0.56 mmol), DMAP (7 mg, 0.056
mmol) poly(vinylpyridine) (280 mg, 0.28 mmol), and diol 28b (50 mg, 0.28 mmol) in
DCM (3 mL) according to the procedure, work-up and purification described
previously to afford dibenzoate 29b as a colourless oil (88 mg, 81%). Data were
identical to those for 29c apart from; [α]D +47.6 (c 0.55, CHCl3); HPLC (Chiralcel OD-
H column, hexane/iPrOH 98/2, 1 mL min-1, 280 nm): tR (major) 18.1 min, 91% ee.
Preparation of n-propyl (2R,3R)-dibenzyloxy-4-fluorobutanoate (29a)
Was prepared from benzoic anhydride (127 mg, 0.56 mmol), DMAP (7 mg, 0.056
mmol), poly(vinylpyridine) (280 mg, 0.28 mmol), diol 28a (50 mg, 0.28 mmol) in DCM
(3 mL) according to the procedure, work-up and purification described previously to
afford dibenzoate 29a as a colourless oil (86 mg, 79%). Data were identical to those
for 29c apart from; [α]D -50.4 (c 0.5, CHCl3); HPLC (Chiralcel OD-H column,
hexane/iPrOH 98/2, 1 mL min-1, 280 nm): tR (major) 11.7 min, 83% ee.
S14

Preparation of (4S*,5S*)-5-(fluoromethyl)-[1,3,2]-dioxathiolane-4-(n-
propyloxycarbonyl)-2,2-dioxide ((±)-32c); direct sequence from 25
A solution of NMO (384 mg, 3.3 mmol) in water (0.5 mL) was added to a 1:1 mixture
of t-BuOH/acetone (4 mL) at 0 °C. Ester 25 (239 mg, 1.64 mmol) was then added
and the mixture was allowed to stir for 15 minutes, and then OsO4 (330 µL of a 2.5
wt % solution in t-BuOH) was added dropwise by syringe over 20 minutes. The
mixture was allowed to continue stirring and slowly warmed to room temperature
19
overnight. The progress of this reaction was monitored by the F NMR spectra. The
reaction was quenched by the addition of sodium sulfite (1.7 g), stirred for 30
minutes and eluted through a pad of Celite with EtOAc/MeOH (30 mL a 1:1 mixture).
The filtrate was then concentrated in vacuo to afford the diol 28c (δF 19F{1H} -223.3).
Crude diol 28c was taken up in dry DCM (6 mL), cooled to 0 °C and treated with
pyridine (370 μL, 4.6 mmol) and SOCl2 (170 μL, 3.3 mmol). After stirring for 15
minutes, the reaction was quenched with water (10 mL) and extracted with DCM (3 ×
10 mL). The combined organic extracts were then washed with brine (10 mL), dried
(MgSO4) and concentrated in vacuo to afford crude (±)-31c as a mixture of
diastereoisomers (δF 19F{1H} -225.8 and -234.0).
Crude cyclic sulfite (±)-31c was taken up in a mixture of acetonitile (8 mL) and water
(1.5 mL), cooled to 0 °C and solid NaIO4 (491 mg, 2.3 mmol) followed by RuCl3
(catalytic, ~ 1 drop from a capillary) were added. After stirring for 10 minutes, the
reaction mixture was diluted with Et2O (10 mL) and filtered through a pad of Celite.
The organic filtrate was then washed with water (10 mL), NaHCO3 (10 mL of a
S15

saturated aqueous solution), brine (10 mL), dried (MgSO4) and concentrated in
vacuo to afford cyclic sulfate (±)-32c (δF 19F{1H} -223.4). Purification by flash
chromatography (Buchi Sepacore, 30% ethyl acetate in hexane) afforded (±)-32c as
a colourless oil (117 mg, 29% from 25): Rf (30% ethyl acetate in hexane) 0.42; δH
3
(400 MHz, CDCl3) 5.21 (d, J = 7.3, 1H), 5.14 (dddd JH-F = 21.7, J = 7.3, = 3.3, 2.2,
1H), 4.9–4.66 (m, 2H) 4.25-4.21 (m, 2H), 1.78-1.73 (m, 2H), 0.98 (t, J = 7.4, 3H); δC
(100 MHz, CDCl3) 164.7, 79.2 (d, 1JC-F = 181.3), 74.7 (d, 3JC-F = 6.8), 80.5 (d, 2JC-F
=
2
2
19.9), 69.1, 21.7, 10.1; δF (376 MHz, CDCl3) -223.4 (ddd, JF-H = 47.3, JF-H = 45.9,
3JF-H = 21.7); max(film)/cm-1 3670, 3527, 2975, 2885, 1771, 1745; HRMS (EI, [M +
H]+) calcd. for C7H12FO6S 243.0333, found 243.0341; Anal. Calcd. for C7H11FO6S: C,
34.71; H, 4.58; S, 13.24. Found: C, 35.05; H, 4.69; S, 13.25.
Preparation of (4S,5S)-5-(fluoromethyl)-[1,3,2]-dioxathiolane-4-(n-
propyloxycarbonyl)-2,2-dioxide ((+)-32b) from 28b
Was prepared from diol 28b (792 mg, 4.4 mmol), dry DCM (20 mL), pyridine (1.36
μL, 17.6 mmol), SOCl2 (615 μL, 8.8 mmol) then NaIO4 (1.3 g, 6.2 mmol), RuCl3
(catalytic ~2–3 drops from a capillary), acetonitrile (25 mL) and water (5 mL)
according to the procedure, work-up and purification described previously to afford
cyclic sulfate (+)-32b (340 mg, 29% yield). Data were identical to those described
previously for (±)-32c apart from; [α]D +23.4 (c 1.0, CDCl3); HPLC (Chiralcel OD-H
column, hexane/iPrOH 85/15, 1 mL min-1, 280 nm): tR (major) 14.5 min, 92% ee.
S16

Preparation of (4R,5R)-5-(fluoromethyl)-[1,3,2]-dioxathiolane-4-(n-
propyloxycarbonyl)-2,2-dioxide ((−)-32a) from 28a
Was prepared from diol 28a (792 mg, 4.4 mmol), dry DCM (20 mL), pyridine (1.36
μL, 17.6 mmol), SOCl2 (615 μL, 8.8 mmol) then NaIO4 (1.3 g, 6.2 mmol), RuCl3
(catalytic ~2–3 drops from a capillary), acetonitrile (25 mL) and water (5 mL)
according to the procedure, work-up and purification described previously to afford
cyclic sulfate (−)-32a (553 mg, 38% yield). Data were identical to those described
previously for (±)-32c apart from; [α]D -20.5 (c 1.0, CDCl3); HPLC (Chiralcel OD-H
column, hexane/iPrOH 85/15, 1 mL min-1, 280 nm): tR (major) 13.2 min, 80% ee.
Preparation of n-propyl (2R)-benzyloxy-4-fluoro-(3S)-hydroxybutanoate (33b)
Crude cyclic sulfate (+)-32b was prepared from enriched diol 28b (90 mg, 0.5 mmol),
dry DCM (1.5 mL), pyridine (180 μL, 2.3 mmol), SOCl2 (75 μL, 1 mmol), NaIO4 (149
mg, 0.75 mmol), RuCl3 (catalytic ~1 drop from a capillary), acetonitrile (3 mL) and
water (1 mL) and according to the procedure and work-up described previously.
Ammonium benzoate (119 mg, 1 mmol) was added to a solution of (+)-32b in
acetone (2 mL) and the mixture was allowed to stir at room temperature overnight.
After confirmation that the reaction was complete by 19F NMR, the reaction was
concentrated in vacuo and taken up in Et2O (2.5 mL). A solution of sulfuric acid (2.5
mL of a 20% v/v aqueous solution) was then added dropwise and the resulting
S17

mixture was allowed to stir at room temperature overnight. After the consumption of
the starting material had been confirmed by 19F NMR, the mixture was partitioned
between ether (10 mL) and water (10 mL). The aqueous layer was separated,
neutralised with solid NaHCO3 and extracted with ether (2 × 5 mL). The combined
organic extracts were then washed with brine (10 mL), dried (MgSO4) and
concentrated under reduced pressure to yield the crude material as an off white
semi-solid (222 mg). Purification by Flash chromatography (Buchi Sepacore, 10%
diethyl ether in hexane then 0–8% methanol in dichloromethane) afforded
monobenzoate 33b as a colourless oil (85 mg, 60% yield): Rf (10% methanol in
dichloromethane) 0.39; [α]D +2.9 (c 1.25, CDCl3); δH (400 MHz, CDCl3) 8.12-8.06 (m,
2
2H), 7.64-7.59 (m, 1H), 7.50-7.45 (m, 2H), 5.40 (d, J = 5.6, 1H), 4.64 (ddd, JH-F
=
2
47.0, J = 4.5, J = 1.5, 1H), 4.63 (ddd, JH-F = 47.0, J = 5.0, J = 2.0, 1H), 4.50-4.42
(dq, J = 18.7, J = 4.8, 1H), 4.19 (t, J = 6.6, 2H), 1.73-1.64 (m incl. J = 6.6, J = 7.6,
2H), 0.93 (t, J = 7.6, 3H); δC (100 MHz, CDCl3) 168.1, 165.5, 133.7, 130.2, 129.9,
128.8, 128.6, 128.4, 82.9 (1JC-F = 171.3), 72.6 (3JC-F = 5.9), 70.1 (2JC-F = 20.5), 67.6,
21.8, 10.2; δF (376 MHz, CDCl3) -232.0 (td, 2JF-H = 47.0, 3JF-H = 18.4); max(film)/cm-1
3482 (br), 2964, 1973, 1725, 1604, 1451, 1263, 1107, 709; HRMS (ES+, [M + H]+)
calcd. for C14H17FO5NH4 302.1398, found 302.1403, (ES+, [2M + NH4]+) calcd. for
C28H34F2O10NH4 591.2012, found 591.2013.
S18

Preparation of n-propyl (2R,3S)-dibenzoyloxy-4-fluorobutanoate (34b); direct
sequence from 28b
Cyclic sulfate (+)-32b was prepared from diol 28b (245 mg, 1.36 mmol), dry DCM (4
mL), pyridine (487 μL, 6.1 mmol), SOCl2 (204 μL, 2.7 mmol) then NaIO4 (435 mg, 2.8
mmol), RuCl3 (catalytic couple of drops from a capillary) acetonitrile (9 mL) and water
(3 mL) according to the procedure and work-up procedures described previously.
The crude product was taken up in acetone (2 mL) and ammonium benzoate (323
mg, 2.7 mmol) was added. The mixture was allowed to stir at room temperature
overnight. After confirmation that the reaction was complete by 19F NMR, the
reaction was concentrated in vacuo and taken up in Et2O (2.5 mL). A solution of
sulfuric acid (2.5 mL, of a 20% v/v aqueous solution) was then added dropwise and
the resulting mixture allowed to stir at room temperature overnight. After
consumption of the starting material had been confirmed by 19F NMR, the mixture
was diluted with ether (10 mL) and water (10 mL). The aqueous layer was
separated, neutralized with solid NaHCO3 and extracted with ether (2 × 5 mL). The
combined organic extracts were then washed with brine (10 mL), dried (MgSO4) and
concentrated under reduced pressure to yield the crude monobenzoate 33b.
Product 33b was taken up in DCM (14 mL), treated with benzoic anhydride (370 mg,
1.63 mmol), DMAP (33 mg, 20 mol %) and PVP (1.4 g) and shaken overnight at
room temperature. Analysis of an aliquot by 19F NMR confirmed that the reaction had
gone to completion. The mixture was diluted with Et2O (25 mL), filtered, and the
precipitate washed with Et2O (20 mL). The filtrate and washings were combined and
washed with NaHCO3 (3 × 20 mL of a saturated aqueous solution), brine (20 mL),
S19

dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography
(Buchi Sepacore, 10% diethyl ether in hexane) afforded dibenzoate 34b as a
colourless oil (170 mg, 32% from 28b over 3 steps). Rf (10% diethyl ether in pet.
ether 40–60 °C) 0.21; [α]D -4.5 (c 1.1, CDCl3), δH (400 MHz, CDCl3) 8.10-8.03 (m,
4H), 7.64-7.52 (m, 2H), 7.50-7.43 (m, 4H), 5.92-5.88 (m, 1H), 5.69 (dd, J = 4.6, J =
1.1, 1H), 4.94-4.80 (m incl. app. d, 2JH-F = 46.7, 1H), 4.24-4.14 (m, 2H), 1.71-1.62 (m,
2H), 0.92 (t, J = 7.3, 3H); δC (100 MHz, CDCl3) 167.9, 165.3, 165.25, 133.7, 133.6,
130.0, 129.9, 129.1, 128.8, 128.6, 128.4, 80.5 (1JC-F = 175.6), 70.8 (3JC-F = 5.8), 70.9
2
3
(2JC-F = 22.0), 67.7, 21.8, 10.2; δF (376 MHz, CDCl3) -231.0 (td, JF-H = 46.7, JF-H
=
16.7); max(film)/cm-1 3056, 2948, 1733, 1602, 1454, 1263, 1099, 712; HRMS (ES+,
[M + NH4]+) calcd. for C21H21FO6NH4 406.1667, found 406.1660; HPLC (Chiralcel
OD-H column, hexane/iPrOH 98/2, 1mL min-1, 280 nm): tR (major) 11.2 min, 95% ee.
Preparation of n-propyl (2S,3R)-dibenzoyloxy-4-fluorobutanoate (34a)
Dibenzoate 34a was prepared from diol 28a (86 mg, 0.48 mmol), dry DCM (1.4 mL),
pyridine (175 μL, 2.2 mmol), SOCl2 (75 μL, 1 mmol) then NaIO4 (155 mg, 1 mmol)
catalytic RuCl3 (couple of drops from a capillary ~5–10 mg), acetonitrile (3 mL),
water (1 mL) then ammonium benzoate (119 mg, 1 mmol), benzoic anhydride (136
mg, 0.6 mmol), DMAP (12 mg, 20 mol %), PVP (0.5 g) and DCM (5 mL) according to
the procedure described previously to afford dibenzoate 34a (65 mg, 34% over 3
steps). Data were identical to those described previously for 34b apart from; [α]D
+4.4 (c 1.3, CDCl3); HPLC (Chiralcel OD-H column, hexane/iPrOH 98/2, 1 mL min-1,
280 nm): tR (major) 12.7 min, 78% ee.
S20

Preparation of n-propyl (2R,3S)-dihydroxy-4-fluorobutanoate (35b)
Cyclic sulfate 32b was prepared from diol 28b (432 mg, 2.4 mmol), dry DCM (7.5
mL), pyridine (895 μL, 11.1 mmol), SOCl2 (357 μL, 4.8 mmol), NaIO4 (770 mg, 3.6
mmol) and catalytic RuCl3 (couple of drops from a capillary ~5–15 mg) according to
the procedure and work-up procedures described previously. Crude 32b was taken
up in DMF (10 mL) and sodium nitrite (828 mg, 12 mmol) was added in one portion
at room temperature, and the mixture was allowed to stir overnight. After
confirmation of consumption of the starting materials by 19F NMR, the reaction was
diluted with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The
combined organic extracts were then dried (Na2SO4) and concentrated under
reduced pressure. The resulting yellow oil was then taken up in diethyl ether (4 mL)
and sulfuric acid added dropwise (4 mL of a 20% v/v aqueous solution). The reaction
mixture was diluted with diethyl ether (10 mL) and washed with NaHCO3 (10 mL of a
saturated solution) then brine (10 mL). The organic layer was then isolated, dried
(MgSO4) and concentrated under reduced pressure. Purification by flash
chromatography (Buchi Sepacore, 0–50% diethyl ether in pet. ether 40–60 °C)
afforded 35b as a colourless oil (52 mg, 12% from 28b): Rf (100% diethyl ether in
pet. ether 40–60 °C) 0.49; δH (400 MHz, CDCl3) 4.64-4.45 (m incl. app. dd, J = 47.0,
J = 5.1, 2H), 4.32 (d, J = 4.0, 1H), 4.22-4.18 (m incl. app. t, J = 6.6, 2H), 4.18-4.12
(m, 1H), 3.32 (br s, 1H), 2.85 (br s, 1H), 1.76-1.67 (m, 2H), 0.97 (t, J = 7.3, 3H); δC
(100 MHz, CDCl3) 172.2, 82.7 (d, 1JC-F = 169.8), 71.7 (d, 2JC-F = 20.5), 69.9 (d, 3JC-F
2
3
= 5.9), 68.0, 21.8, 10.2; δF (376 MHz, CDCl3) -230.2 (td, JF-H = 47.0, JF-H = 16.1);
S21


max(film)/cm-1 3478, 2974, 2556, 1748, 1652, 1296, 1057, 850; HRMS (FAB,
[M+NH4]+) calcd. for C7H17O4NF 198.1136, found 198.1134; 19F{1H} (376 MHz, 1:1
diisopropyl L-tartrate:CDCl3) 94% ee; [α]D +33.4 (c 1.04, CDCl3).
Preparation of (2S,3R)-propyl 4-fluoro-2,3-dihydroxybutanoate (35a)
Diol 35a was prepared from diol 28a (432 mg, 2.4 mmol), dry DCM (7.5 mL), pyridine
(895 μL, 11.1 mmol), SOCl2 (357 μL, 4.8 mmol), NaIO4 (770 mg, 3.6 mmol), catalytic
RuCl3 (couple of drops from a capillary ~5–15mg) then sodium nitrite (828 mg, 12
mmol) and DMF (10 mL) and according to the procedure described previously to
afford anti-diol 35a as a colourless oil (41 mg, 9% from 28a). The data were identical
to those obtained for 35b apart from; F 19F {1H} (376 MHz, 1:1 diisopropyl L-
tartrate:CDCl3) 95% ee; [α]D -34.0 (c 0.99, CDCl3).
Preparation of n-propyl (2R,3R)-O-cyclohexylidene-4-fluorobutanoate (36a)
Diol 28a (314 mg, 1.7 mmol) was taken up in a mixture of cyclohexanone (200 mg,
2.0 mmol) and trimethyl orthoformate (216 mg, 2.0 mmol) in ethyl acetate (5 mL) and
stirred for 15 minutes at room temperature. The yellow solution was then treated with
boron trifluoride diethyl etherate (260 µL, 2.04 mmol). A colour change to dark
orange was observed and the mixture was stirred at room temperature for 48 hours.
S22

The mixture was then diluted with ethyl acetate (30 mL) and the organic phase was
washed with NaHCO3 (30 mL of a saturated aqueous solution), brine (30 mL), dried
(MgSO4) and concentrated in vacuo to afford an orange oil. Purification by flash
chromatography (Buchi Sepacore, 10% diethyl ether in hexane) afforded 36a as a
colourless oil (96 mg, 21%): Rf (10% diethyl ether in hexane) 0.37; [α]D +26.8 (c 1.2,
CDCl3); δH (400 MHz, CDCl3) 4.76-4.32 (m, 4H), 4.21-4.10 (m, 2H), 1.75-1.55 (br m,
10H), 1.45-1.37 (br m, 2H), 0.96 (t, J = 7.1, 3H); δC (100 MHz, CDCl3) 170.7, 112.8,
1
2
3
82.1 (d, JC-F = 175.6), 77.3 (d, JC-F = 20.5) 74.1 (d, JC-F = 7.3), 67.2, 36.2, 35.0,
25.0, 23.8, 23.6, 21.9, 10.3; δF (376 MHz, CDCl3) -230.45 (td, 2JF-H = 47.0, J = 21.2);

max(film)/cm-1 2944, 1760, 1728, 1449, 1362, 1288, 1240, 1159, 1066, 1021, 908,
842, 829, 792, 652; m/z (EI+) 261 (7), 231 (43), 217 (100), 175 (24); HRMS (ES+, [M
+ H]+) calcd. for C13H22FO4 261.1497, found 261.1497.
n-Propyl (2S,3S)-O-cyclohexylidene-4-fluorobutanoate (36b)
Was prepared from diol 28b (1.09 g, 6.1 mmol), cyclohexanone (598 mg, 6.1 mmol),
boron trifluoride diethyl etherate (927 μL, 7.3 mmol) and ethyl acetate (5 mL) and
according to the procedure, work-up and purification described previously to afford
acetal 36b was afforded (393 mg, 19%). The data were identical to those obtained
for 36a apart from; [α]D -30.0 (c 0.8, CDCl3).
S23

Preparation of (2R,3R)-O-cyclohexylidene-4-fluorobutan-1-ol (37a)
A solution of acetal 36a (1.02 g, 3.9 mmol) in dry DCM (40 mL) was cooled to −78 °C
under an atmosphere of nitrogen. DIBAL-H (9.75 mmol, 8.9 mL of a 1.1 M solution in
cyclohexane) was then added dropwise over 20 minutes and the reaction was
allowed to warm slowly to room temperature overnight under a nitrogen atmosphere.
The mixture was diluted with EtOAc (60 mL) and brine (60 mL) forming a viscous
emulsion which was filtered through a pad of wet Celite. The organic layer in the
filtrate was isolated and the aqueous layer was extracted with EtOAc (2 × 50 mL).
The combined organic extracts and the original layer were then dried (MgSO4) and
concentrated in vacuo to afford a yellow oil. Purification by flash chromatography
(Buchi Sepacore, 0–40% ethyl acetate in hexane) afforded alcohol 37a as a pale
yellow oil (300 mg, 38% yield): Rf (50% ethyl acetate in hexane) 0.65; []D -3.2 (c
0.9, CDCl3), δH (400 MHz, CDCl3) 4.65-4.43 (ddd, 2JH-F = 47.5, J = 4.1, J = 3.5, 2H),
4.20-4.10 (m, 1H), 4.08-4.04 (m, 1H), 3.90-3.83 (m incl. app. d, J = 12.1, 1H), 3.70-
3.63 (m, 1H), 1.96-1.89 (m, 1H), 1.69-1.56 (envelope, 8H), 1.45-1.37 (m, 2H); δC
(100 MHz, CDCl3) 110.5, 82.4 (d, 1JC-F = 172.7), 77.8 (d, 3JC-F = 5.9), 75.2 (d, 2JC-F
=
=
2
20.5), 61.9, 36.7, 36.3, 25.0, 23.85, 23.75; δF (376 MHz, CDCl3) -230.8 (td, JF-H
47.0, 3JF-H = 20.7); max(film)/cm-1 3446br, 2938, 2863, 1450, 1366, 1282, 1117, 940,
845; m/z (EI+) 205 (84), 175 (44), 161 (100), 99 (18), 81 (22), 69 (24), 55 (56);
HRMS (ES+, [M + H]+) calcd. for C10H18FO3 205.1234, found 205.1233.
S24

Preparation of (2S,3S)-O-cyclohexylidene-4-fluorobutan-1-ol (37b); direct
preparation from 25
Crude diol 28b was prepared from a solution of fluoroester 25 (2.19 g, 15 mmol),
AD-mix β (21 g), methyl sulfonamide (1.425 g, 15 mmol), (DHQD)2PHAL (4 mol %),
K2OsO2(OH)4 (0.6 mol %) and NaHCO3 (45 mmol) in 1:1 t-BuOH/water (150 mL)
according to the procedure and work-up described previously to afford crude diol
28b (2.43 g, ~89%).
Acetal 36b was prepared from crude diol 28b (2.43 g, 13.5 mmol), cyclohexanone
(1.6 g, 16.2 mmol), boron trifluoride diethyl etherate (2.3 mL, 16.2 mmol) and ethyl
acetate (10 mL) according to the procedure described previously, to afford crude
acetal 36b was afforded (2.1 g, ~59%).
A solution of the crude ester 36b (2.1 g, 8.1 mmol) in dry DCM (140 mL) was cooled
to −78 °C under an atmosphere of nitrogen. DIBAL-H (20.3 mmol, 18.4 mL of a 1.1
M solution in cyclohexane) was then added dropwise over 20 minutes and the
reaction was allowed to warm slowly to room temperature overnight under a nitrogen
atmosphere. The mixture was diluted with EtOAc (100 mL) and brine (100 mL)
forming a viscous emulsion which was filtered through a pad of wet Celite. The
organic layer in the filtrate was isolated and the aqueous layer was extracted with
EtOAc (2 × 100 mL). The combined organic extracts and the original layer were then
dried (MgSO4) and concentrated in vacuo to afford a yellow oil. Purification by flash
chromatography (Buchi Sepacore, 0–40% ethyl acetate in hexane) afforded alcohol
S25

37b as a pale yellow oil (758 mg, 25% over 3 steps); The data were identical to
those obtained for 37a apart from; [α]D +2.9 (c 0.9, CDCl3).
Preparation of ethyl (4R,5R)-O-cyclohexylidene-6-fluoro-hex-2-enoate (39a)
Alcohol 37a and (carbethoxymethylene)triphenylphosphorane (780 mg, 2.24 mmol)
were taken up in a mixture of DCM (4.2 mL) and DMSO (0.7 mL) at room
temperature and allowed to stir at room temperature for 5 minutes. Solid Dess–
Martin periodinane (93 mg, 1.23 mmol) was added causing an instant colour change
to yellow. The reaction was stirred for 30 minutes then diluted with Et2O (50 mL) and
the organic phase washed with NaHCO3 (3 × 50 mL of a saturated aqueous
solution), dried (MgSO4) and concentrated in vacuo to a viscous orange gum.
Purification by flash chromatography (Buchi Sepacore, 0–50% ethyl acetate in
hexane) afforded alkenoate 39a as a 4:1 mixture of E and Z diastereoisomers (114
mg, 74%). Re-purification by flash chromatography (Buchi Sepacore, 0-50% ethyl
acetate in hexane) afforded E-39a as a clear oil (57 mg, 37%): Rf (50% diethyl ether
in hexane) 0.56; [α]D +6.5 (c 1.2, CDCl3), δH (400 MHz, CDCl3) 6.91 (dd, J = 15.7, J =
5.6, 1H), 6.17 (dd, J =15.7, J = 1.5, 1H), 4.68-4.43 (m, 3H), 4.22 (q, J = 7.3, 2H),
4.01-3.97 (m, 1H), 1.70-1.58 (envelope, 8H), 1.57-1.45 (m, 2H), 1.30 (t, J = 7.1, 3H);
δC (100 MHz, CDCl3) 165.8, 143.4, 123.2, 111.4, 81.3 (d, 1JC-F = 174.2), 78.7 (d, 2JC-F
3
= 20.5), 75.6 (d, JC-F = 7.3), 60.7, 36.3, 36.2, 25.0, 23.8, 23.75, 14.2; δF (376 MHz,
2
3
CDCl3) -231.0 (td, JF-H = 47.0, JF-H = 20.7); max(film)/cm-1 3425, 2939, 2863, 1723,
1664, 1450, 1368, 1303, 1278, 1178, 1130, 1034, 976, 908, 847; m/z (EI+) 273 (26),
S26

243 (26), 229 (56), 199 (10), 175 (11), 129 (20), 81 (22); HRMS (EI+, [M]+) calcd. for
C14H21FO4 272.1418, found 272.1419; 82% ee by 19F{1H} NMR, L-(+)-DIPT/CDCl3,
followed by a mixed fraction (E- and Z-diastereoismers, 57 mg, 37%).
References
S1. Kumar, B.; Verma, R. K., Synth. Commun., 1984, 14, 1359.
S2. Fedorynski, M.; Ziolkowska, W.; Jonczyk, A., J. Org. Chem., 1993, 58, 6120.
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