Enantioselective synthesis of C3 fluoro-MEP

Article abstract of DOI:10.1039/b613656g

The first enantioselective synthesis of C₃ fluoro-MEP is herein reported. The synthetic pathway developed takes advantage of a selective hydrofluorination of a 2,3-epoxy-1-alcohol to introduce the required tertiary fluoride unit. The Royal Soci

Full text of DOI:10.1039/b613656g

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Enantioselective synthesis of C3 fluoro-MEP
Stephanos Ghilagaber,a William N. Huntera and Rodolfo Marquez*†b
Received 19th September 2006, Accepted 20th October 2006
First published as an Advance Article on the web 10th November 2006
DOI: 10.1039/b613656g
The first enantioselective synthesis of C3 fluoro-MEP is herein reported. The synthetic pathway
developed takes advantage of a selective hydrofluorination of a 2,3-epoxy-1-alcohol to introduce
the required tertiary fluoride unit.
by 2C-methyl-D-erythritol 4-phosphate cytidylyltransferase (MEP
Introduction
cytidylyltransferase or IspD).2
An ATP-dependent 4-(cytidine 5ꢀ-diphospho)-2C-methyl-
erythritol kinase phosphorylates CDP-ME, producing 4-diphos-
phocytidyl-2C-methyl-D-erythritol 2-phosphate (CDP-ME2P).
Next, the CDP-ME2P is converted to 2C-methyl-D-erythritol-2,4-
cyclodiphosphate (MECP) and CMP by MECP synthase (IspF).
The cyclic diphosphate product, MECP, is reduced to 1-hydroxy-
2-methyl-2(E)-butenyl 4-diphosphate by a reductase encoded by
the ispG (formally gcpE) gene, then the ispH (or lytB) gene product
converts the butenyl diphosphate to both isopentenyl diphosphate
(IPP) and dimethylallyl diphosphate (DMAPP) (Fig. 1).
The diseases caused by organisms dependent on the MEP
pathway include tuberculosis, infections of the upper respiratory
tract, a range of sexually transmitted infections, toxoplasmosis,
coccidiosis in poultry, and malaria.3 Furthermore, since the MEP
pathway is not present in animal cells, its selective inhibition could
provide the opportunity to develop selective anti-parasitic and
herbicidal agents.4
Thus, it is not surprising that intermediates of the MEP pathway
and their labelled forms have been considered as a starting
point for the development of biological chemistry tools and
potential therapeutic leads through both synthetic and biological
methods.5,6
However, despite a significant amount of synthetic interest,
the numbers of MEP analogues available are fairly limited.
This is perhaps not surprising considering the densely packed
functionality within a small carbon framework. This is further
Many biological functions including electron transport in respira-
tion and photosynthesis, hormone-based signalling, the regulation
of transcription and post-translational processes that control lipid
biosynthesis, meiosis, apoptosis, protein cleavage and degradation
are dependent on isoprenoids.
Nature utilises two distinct biosynthetic routes for the synthesis
of isoprenoids. Initially, the mevalonate-dependent pathway was
originally considered the sole source of isopentenyl diphosphate
(IPP) and dimethylallyl diphosphate (DMAPP). However, recently
it was determined that in chloroplasts, algae, cyanobacteria,
many species of eubacteria, and apicomplexa, isoprenoids are
synthesised by the 2C-methyl-D-erythritol 4-phosphate (MEP)
pathway, which uses seven enzymes (Fig. 1).1
The MEP pathway starts with the condensation of pyru-
vate and glyceraldehyde 3-phosphate to produce 1-deoxy-D-
xylulose 5-phosphate (DOXP) which is then converted to 2C-
methyl-D-erythritol 4-phosphate (MEP) in reactions catalysed by
DOXP synthase and DOXP reductoisomerase respectively. MEP
reacts with CTP to produce 4-diphosphocytidyl-2C-methyl-D-
erythritol (CDP-ME) and pyrophosphate in a reaction catalysed
aSchool of Life Sciences, University of Dundee, DD1 5EH, UK
bWestCHEM, Department of Chemistry, University of Glasgow, Glasgow,
UK. E-mail: r.marquez@chem.gla.ac.uk; Fax: +44 (0)141 330 4888;
Tel: +44 (0)141 330 8491
† Ian Sword Lecturer of Organic Chemistry.
Fig. 1 The non-mevalonate pathway.
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complicated by the presence of the tertiary C3 hydroxyl-bearing
stereocentre in MEP 1 (Fig. 2).
Fig. 2 MEP 1 and putative MEP analogue 2.
Scheme 3 Reagents and conditions: a) allyl bromide, NaH, TBAI, THF,
0
◦C; b) O3, DMS, CH2Cl2, −78 ◦C; c) Ph3PC(Me)CO2Et, PhH, 80 ◦C;
d) Dibal-H, Et2O, 0 ◦C; e) D-(−)-DIPT, Ti(OiPr)4, tBuOOH, −20 ◦C.
In the first instance, we have decided to focus on the replacement
of the MEP C3 tertiary hydroxyl unit for a fluorine moiety.7
A readily available fluoro-MEP 3 analogue might be able to
inhibit the cytidyltransferase step (IspD) of the pathway through
competitive inhibition. However, since the C3 fluorine is at a
non-reactive position at this stage, there is the possibility that
it could undergo a conversion with cytidylyltransferase (IspD)
and be incorporated into the pathway to generate fluoro-CDP-
ME 4. Fluoro-CDP-ME would then become an inhibitor of the
kinase step of the pathway (IspE), as phosphorylation would not
be possible, thus preventing the pathway from proceeding any
further. This would open the possibility of selectively probing two
steps of the MEP pathway with a single chemical probe (Scheme 1).
reduction provided us with the desired allylic alcohol precursor
10 in excellent overall yield (Scheme 3).
Finally, an asymmetric epoxidation controlled by a Sharpless
reagent proceeded in excellent yield and high enantioselectivity to
provide us with the key epoxide intermediate 11.8
At this point, we were faced with the most crucial step of the
synthesis in which we would attempt to regio- and stereoselectively
hydrofluorinate the 2,3-epoxy-alcohol ring at the C2 position.
Whilst there have been some reports for enhanced C3 epoxide
openings with fluorine to generate the 3-fluoro-1,2-diols, the
conditions for the generation of the 2-fluoro-1,3-diols have not
been developed to the same extent.9,10 As far as we are aware,
the only work in the area of C2 fluorination was reported by
Mikami, in which mixtures of C2 and C3 fluorination products
were obtained using various mixtures of Lewis acids and fluorine
sources. Furthermore, to the best of our knowledge Mikami’s
study did not extend to the synthesis of tertiary fluorides, which
were required as part of our synthesis.11
Unfortunately, treatment of epoxy-alcohol 11 under Mikami
and Yoneda’s conditions failed to generate any of the desired
tertiary fluoride adduct, causing instead material decomposition.
However, treatment of our epoxy-alcohol intermediate 11 with tri-
ethylamine trihydrofluoride cleanly generated the desired fluoro-
erythrol compound 12 in high yield and with complete regio- and
stereocontrol (Scheme 4).12 To the best of our knowledge, this is
the first time that trisubstituted epoxy-alcohols have been used to
generate the corresponding tertiary 2-fluoro-1,3-diols.
Scheme 1 Potential fluoro-MEP incorporation.
We originally envisioned the highly functionalised fluoro-
MEP unit 3 originating from the suitably protected fluoro-
erythrol unit 5. The erythrol unit 5 could then be anticipated from
the regio- and stereoselective ring opening of epoxide 6 by fluoride
ion (Scheme 2).
Scheme 4 Reagents and conditions: a) TEA–3HF, 100 ◦C; b) 2-
Scheme 2 Retrosynthetic analysis.
methoxypropene, CSA, CH2Cl2, RT.
Protection of the newly generated 1,3-diol afforded the dimethyl
ketal 13, which proved invaluable in corroborating the relative
stereochemistry through 2-dimensional NOE studies (Scheme 4).
Having obtained the differentially protected fluoro-triol 13,
we switched our attention to the selective removal of the PMB
protecting group. Unfortunately, despite a significant amount
of experimentation, the highest yielding deprotection conditions
Results and discussion
Our synthesis began with readily available p-methoxybenzyl
alcohol 8, which was allylated and the resulting allyl ether
ozonolysed to afford the PMB-protected acetaldehyde 9. Wittig
olefination of acetaldehyde 9 then proceeded cleanly to generate
the E conjugated ester as a single diastereomer, which upon
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involving DDQ afforded the desired primary alcohol 14 in 12%
yield (Scheme 5).
Efforts in our group are currently underway to explore the
biological effects of the fluoro-MEP unit on the non-mevalonate
pathway and on co-crystallisation studies. We are also currently
developing the synthesis of other MEP analogues, as well as ex-
ploring the scope and limitations of the epoxide hydrofluorination
reaction for the generation of tertiary 2-fluoro-1,3-diol units.
Experimental
General methods
All reactions were performed in oven-dried glassware under an
inert argon atmosphere. Anhydrous DMF was purchased from
Aldrich Chemical Co. Tetrahydrofuran (THF), diethyl ether, and
dichloromethane (DCM) were distilled before use. Anhydrous
dichloromethane (DCM) was obtained by refluxing over calcium
hydride for one hour, followed by distillation under argon.
Anhydrous THF and diethyl ether were obtained by refluxing
over sodium-benzophenone for one hour, followed by distillation
under argon. All reagents were used as received, unless otherwise
stated. Solvents were evaporated under reduced pressure at 40 ◦C
using a Buchi Rotavapor.
IR spectra were recorded either as thin films on NaCl plates
using a Perkin–Elmer Spectrum BX Fourier Transform spectrom-
eter. Only significant absorptions (mmax) are reported in wavenum-
bers (cm−1), with the following abbreviations used to describe
absorption intensity: w, weak; m, medium; s, strong and br, broad.
1H NMR spectra were recorded at 500 MHz using a Bruker
Avance500 instrument. Chemical shifts (dH) are reported in parts
per million (ppm), and are referenced to the residual solvent peak.
The order of citation in parentheses is (1) number of equivalent
nuclei (by integration), (2) multiplicity (s = singlet, d = doublet,
t = triplet, q = quartet, qn = quintet, m = multiplet, br =
broad), (3) coupling constant (J) quoted in Hertz to the nearest
0.5 Hz, and (4) assignment. 13C NMR spectra were recorded at
75.1 or 125.7 MHz using Bruker DPX300 or Bruker Avance500
instruments. 19F NMR spectra were recorded at 376 MHz using
Bruker DPX400 instruments and are referenced to CFCl3. The
19F NMR data was acquired both in coupled and decoupled
mode, with the single decoupled signal being reported. Phosphorus
magnetic resonance spectra (31P) were recorded at 121 MHz using
a Bruker Avance500 instrument. Chemical shifts (dC) are quoted
in parts per million (ppm) and are referenced to the appropriate
solvent peak. The assignment is quoted in parentheses.
Scheme 5 Reagents and conditions: a) 2-methoxypropene, CSA, CH2Cl2,
RT; b) DDQ, CH2Cl2, 0 ◦C to RT; c) Ac2O, Py, RT.
Faced with this disheartening low yield for the PMB removal
step, a different protecting group strategy had to be devised. Thus,
acetylation of the diol intermediate 12 proceeded to generate
the expected bis-acetate 15 in excellent yield. Unfortunately,
PMB removal under the previously developed conditions cleanly
produced the secondary alcohol 16 in good yield, which can be
easily explained through a simple 1,2-acetate migration of the
primary alcohol intermediate (Scheme 5). However, protection of
the diol intermediate 12 as the bis-TBS ether 17 proceeded in
good yield despite the amount of steric hindrance being built into
the system. Gratifyingly, PMB removal under carefully monitored
conditions cleanly provided us with the desired primary alcohol
18 with an improved yield (Scheme 6).13
Scheme 6 Reagents and conditions: a) TBSOTf, 2,6-lutidine, 0 ◦C;
b) SnCl4, PhSH, 0 ◦C; c) (EtO)2P(O)I, Py; d) 90% TFA, 0 ◦C; e) TMSBr,
CH2Cl2, 0 ◦C.
High resolution mass spectra were recorded on a Bruker Mi-
croTOF spectrometer by electrospray ionisation mass spectrome-
ter operating at a resolution of 15 000 full widths at half height.
Flash chromatography was performed using silica gel (Apollo
Scientific Silica Gel 60, 40–63 micron) as the stationary phase. TLC
was performed on aluminium sheets pre-coated with silica (Merck
Silica Gel 60 F254). The plates were visualised by the quenching
of UV fluorescence (kmax 254 nm) and/or by staining with either
anisaldehyde or potassium permanganate followed by heating.
The newly obtained primary alcohol 18 was then treated with
diethyl iodophosphate to sucessfully generate the desired phos-
phate unit 19 in high yield.14 Finally, carefully controlled removal
of both TBS groups generated the diol 20, which upon phosphate
hydrolysis then provided us with the desired enantiomerically pure
fluoro-MEP analogue 3 in excellent yield.
(4-Methoxybenzyloxy)acetaldehyde, 9.
A solution of 4-
methoxybenzyl alcohol 8 (33 g, 0.24 mol) in THF (50 mL) was
added to a suspension of previously washed sodium hydride (60%
oil dispersion, 8.59 g, 0.36 mol) in dry THF (550 mL) at 0 ◦C,
and the mixture was stirred for 30 min. Allyl bromide (60 mL,
0.70 mol) and tetrabutylammonium iodide (4.22 g, 11.42 mmol)
Conclusions
In conclusion, we have now reported the synthesis of the first C3
MEP analogue reported to date, taking advantage of a regio- and
stereoselective C2-epoxide hydrofluorination reaction.
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◦
were then added at 0 C. The reaction was allowed to warm up
dC (75 MHz, CDCl3) 159.6, 139.7, 130.8, 129.8 (2 × CH), 121.6,
114.5 (2 × CH), 72.4, 68.2, 66.6, 55.7 and 14.3 (Found MNa+,
245.1148. C13H18NaO3 requires 245.1256).
to room temperature and was then stirred overnight. The reaction
mixture was then extracted with dichloromethane (500 mL) and
water (300 mL). The organic layer was dried over magnesium
sulfate and the filtrate was evaporated to give 1-allyloxymethyl-
4-methoxybenzene (41 g, 96%); RF [light petroleum–ether (7 : 3)]
[3-(4-Methoxybenzyloxymethyl)-2-methyloxiranyl]methanol, 11.
Diethyl L-tartrate (3.60 mL, 21.1 mmol) and titanium(IV) iso-
propoxide (5.14 mL, 17.4 mmol) were added to a flask charged
=
0.65; mmax (film) 1613 (C C); dH (300 MHz, CDCl3) 7.14 (2 H, d,
˚
J 8.6, 3,5-H; Ar), 6.74 (2 H, d, J 8.6, 2,6-H; Ar), 5.82–5.77 (1 H,
m, CH), 5.20–5.13 (1 H, dd, J 10.5 and 1.5, CHAHB), 5.08–5.04
(1 H, dd, J 10.5 and 1.4, CHAHB), 4.31 (2 H, s, Ar-CH2), 3.86 (2
H, d, J 5.6, OCH2) and 3.64 (3 H, s, OCH3); dC (75 MHz, CDCl3)
159.6, 135.3, 130.9, 129.8, 117.4, 114.3, 72.2, 71.3 and 55.6 (Found
MNa+, 201.0886. C11H14NaO2 requires 201.0994).
A solution of freshly prepared 1-allyloxymethyl-4-methoxy-
benzene (17.43 g, 0.10 mol) in dichloromethane (800 mL), was
treated with ozone at −78 ◦C until the blue colour of ozone
endured. At this point, argon was bubbled through until the blue
colour disappeared. Methyl sulfide (120 mL, 1.63 mol) was then
added to the solution and the resulting mixture stirred until TLC
analysis indicated reaction completion (ca. 3 h). The solvents were
evaporated under vacuum, and the crude residue purified by flash
column chromatography (silica gel, light petroleum–ether (4 : 6))
to generate the desired glycoaldehyde 9 as a clear oil (15.12 g, 86%);
with activated powdered 4 A molecular sieves (3 g) in dry
dichloromethane (180 mL) at −23 ◦C. The mixture was stirred
while tert-butyl hydroperoxide (23.6 mL, 5–6 M in decanes) in dry
dichloromethane (60 mL) was added dropwise, and the resulting
solution was stirred for 30 min at −23 ◦C. A solution of 4-(4-
methoxybenzyloxy)-2-methylbut-2-en-1-ol 10 (10 g, 45.1 mol) in
dry dichloromethane (50 mL) was then added slowly, and the
resulting reaction mixture was stirred for 6 h at −23 ◦C. The
reaction was then quenched with water (98.1 g; 20 times the
weight of the titanium(IV) isopropoxide used) and was stirred for
a further 40 min, while allowing the suspension to warm to room
temperature. To hydrolyse the tartrate, a 30% aqueous solution
of sodium hydroxide saturated with sodium chloride was added
and the biphasic mixture was stirred vigorously for 30 min. The
mixture was filtered through a pad of silica and Celite to break
up the emulsion, and the phases were separated. The aqueous
phase was extracted with dichloromethane (2 × 100 mL), the
combined organic extracts were dried over magnesium sulfate
and the filtrate was evaporated under vacuum. The residue was
purified by flash chromatography on silica gel eluting with light
petroleum–ether (3 : 7) to give [3-(4-methoxybenzyloxymethyl)-2-
methyloxiranyl]methanol 11 (9.72 g, 91%, >90% ee); RF [DCM]
0.13; [a]D −4 (c = 0.1, DCM); mmax (film) 3390 (O–H); dH (300 MHz,
CDCl3) 7.20 (2 H, d, J 8.6, 3,5-H; Ar), 6.81 (2 H, d, J 8.6, 2,6-H;
Ar), 4.51 (1 H, d, J 11.5, CH2) 4.40 (1 H, d, J 11.5, CH2), 3.73 (3
H, s, OCH3), 3.64–3.46 (4 H, m, CH, CH2 and CHAHB), 3.23–3.20
(1 H, dd, J 6.1 and 4.5, CHAHB)), 2.10 (1 H, bs, OH) and 1.19
(3 H, s, CH3); dC (75 MHz, CDCl3) 159.7, 130.2, 130.0 (2 × CH),
114.2 (2 × CH), 73.3, 68.5, 65.5, 60.6, 58.6, 55.7 and 14.7 (Found
MNa+, 261.1097. C13H18NaO4 requires 261.1205).
=
RF [light petroleum–ether (4 : 6)] 0.27; mmax (film) 1732 (C O); dH
(500 MHz, CDCl3) 10.2 (1 H, s, CH), 7.23 (2 H, s, 3,5-H; Ar), 6.79
(2 H, s, 2,6-H; Ar), 4.78 (2 H, s, CH2), 4.23 (2 H, s, CH2) and 3.65
(3 H, s, CH3); dC (125 MHz, CDCl3) 200.7, 163.1, 129.6, 128.8,
114.0, 75.0, 73.4 and 55.6 (Found MNa+, 203.0679. C10H12NaO3
requires 203.0786).
4-(4-Methoxybenzyloxy)-2-methylbut-2-en-1-ol, 10. A solu-
tion of (4-methoxybenzyloxy)acetaldehyde 9 (20 g, 0.11 mol)
in benzene (700 mL) was treated with (carbethoxyethyli-
dene)triphenylphosphorane (58.5 g, 0.16 mol) and was refluxed
overnight. The solvent was evaporated under vacuum, and the
crude residue triturated with diethyl ether. The mixture was then
filtered to remove the solid triphenylphosphine oxide, and the
filtrate was then evaporated under vacuum to give the desired
(2E)-4-(4-methoxybenzyloxy)-2-methylbut-2-enoic acid ethyl es-
2-Fluoro-4-(4-methoxybenzyloxy)-2-methylbutane-1,3-diol, 12.
=
ter (23.6 g, 81%); RF [DCM] 0.33; mmax (film) 1625 (C C) and 1715
Triethylamine trihydrofluoride (35 mL, 220 mmol) and [3-
=
(C O); dH (300 MHz, CDCl3) 7.3 (2 H, d, J 8.4, 3,5-H; Ar), 6.93–
(4-methoxybenzyloxymethyl)-2-methyloxiranyl]methanol
11
6.87 (3 H, m, CH and 2,6-H; Ar), 4.50 (2 H, s, Ar-CH2), 4.26–4.12
(4 H, m, 2 × CH2), 3.83 (3 H, s, OCH3), 1.85 (3 H, s, CH3) and
1.32 (3 H, t, J 7.2, CH3); dC (75 MHz, CDCl3) 167.9, 159.7, 138.4,
130.2, 129.9, 129.8, 114.2, 72.8, 66.9, 61.1, 55.7, 14.6 and 13.2
(Found MNa+, 287.1254. C15H20NaO4 requires 287.1362).
Diisobutylaluminium hydride (155 mL, 1 M in hexane) was
added to a solution of 4-(4-methoxybenzyloxy)-2-methylbut-2-
enoic acid ethyl ester (15.4 g, 58.3 mmol) in dry ether (300 mL)
at 0 ◦C, and the resulting reaction mixture was stirred at 0 ◦C for
1 h. Water (3 mL) was added, and the resulting white precipitate
stirred for 1 h at room temperature. The crude mixture was then
filtered through Celite and the filtrate evaporated under vacuum
to afford 4-(4-methoxybenzyloxy)-2-methylbut-2-en-1-ol 10 as a
(12.72 g, 53.5 mmol) were refluxed at 100 ◦C for 20 h. The
mixture was then cooled down to room temperature, poured
into chloroform (190 mL) and neutralised with sat. sodium
hydrogen carbonate. The organic layer was separated, dried over
magnesium sulfate and the solvent was evaporated under vacuum.
The crude residue was then purified by flash chromatography on
silica gel eluting with 100% diethyl ether to afford the desired
2-fluoro-4-(4-methoxybenzyloxy)-2-methylbutane-1,3-diol 12 as
a yellow oil (10.15 g, 74%); RF [DCM] 0.11; [a]D −14 (c = 0.1,
DCM); mmax (film) 3408 (O–H); dH (300 MHz, CDCl3) 7.28 (2 H,
d, J 8.4, 3,5-H; Ar), 6.91 (2 H, d, J 8.5, 2,6-H; Ar), 4.53 (2 H, s,
CH2), 4.09–4.03 (1 H, m, CH), 3.83 (3 H, s, OCH3), 3.78–3.55
(4 H, m, 2 × CH2), 2.69 (2 H, bs, 2 × OH) and 1.32 (3 H, d, JHF
22.6, CFCH3); dC (75 MHz, CDCl3) 164.1, 130.0, 129.9 (2 × CH),
114.3 (2 × CH), 97.3 (d, JCF 171.2), 73.7, 71.9 (d, JCF 26.8), 70.1,
66.5 (d, JCF 24.1), 55.7 and 17.7 (d, JCF 22.5); dF (376.4 MHz,
CDCl3, CFCl3) −162.8 (Found MNa+, 281.1148. C13H19FNaO4
requires 281.1267).
=
clear oil (12.35 g, 95%); RF [DCM] 0.21; mmax (film) 1612 (C C)
and 3390 (O–H); dH (300 MHz, CDCl3) 7.17 (2 H, d, J 8.7, 3,5-H;
Ar), 6.78 (2 H, d, J 8.7, 2,6-H; Ar), 5.75–5.51 (1 H, m, CH), 4.34
(2 H, s, Ar-CH2), 3.95 (2 H, d, J 7.3, CH2), 3.88 (2 H, s, CH2),
3.70 (3 H, s, OCH3), 2.47 (1 H, s, OH) and 1.55 (3 H, s, CH3);
100 | Org. Biomol. Chem., 2007, 5, 97–102
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1-[2,4-Bis(tert-butyldimethylsilanyloxy)-3-fluoro-3-methylbut-
oxymethyl]-4-methoxybenzene, 17. tert-Butyldimethylsilyl triflu-
oromethanesulfonate (2.7 mL, 11.76 mmol) and 2,6-lutidine
(1.82 mL, 15.6 mmol) were added to a solution of 2-fluoro-4-(4-
methoxybenzyloxy)-2-methylbutane-1,3-diol 12 (1.0 g, 3.87 mmol)
in dry dichloromethane (76 mL) at −78 ◦C. The solution was
stirred for 1 h at −78 ◦C and was then quenched with a (1 : 1) mix-
ture of concentrated pH 7 buffer and water at −78 ◦C. The mixture
was then allowed to warm to room temperature over 30 min, the
organic layer was separated and the aqueous layer was extracted
with dichloromethane (3 × 40 mL). The combined organic layers
were then dried over sodium sulfate, and the solvent removed
under vacuum. The crude residue was then purified by flash col-
umn chromatography on silica gel eluting with 10% ether in light
petroleum ether to give 1-[2,4-bis-(tert-butyldimethylsilanyloxy)-
3-fluoro-3-methylbutoxymethyl]-4-methoxybenzene 17 as a clear
oil (1.85 g, 98%); RF [light petroleum–ether (9 : 1)] 0.83; [a]D −4.2
(c = 1, DCM); mmax (film) 2954 (Ar–H); dH (500 MHz, CDCl3) 7.24
(2 H, d, J 8.7, 3,5-H; Ar), 6.85 (2 H, d, J 8.7, 2,6-H; Ar), 4.41
(2 H, s, CH2), 4.07–4.04 (1 H, m, CH), 3.78 (3 H, s, OCH3), 3.68–
3.63 (1 H, m, CHAHB), 3.62–3.60 (2 H, m, CH2), 3.42–3.38 (1 H,
m, CHAHB), 1.19 (3 H, d, JHF 22.0, CFCH3), 0.88 (9 H, s, 3 × CH3),
0.85 (9 H, s, 3 × CH3), 0.07 (3 H, s, CH3), 0.06 (3 H, s, CH3), 0.05
(3 H, s, CH3) and 0.00 (3 H, s, CH3); dC (125 MHz, CDCl3) 159.0,
130.4, 129.2 (2 × CH), 113.7 (2 × CH), 97.3 (d, JCF 172.7), 72.9,
72.7 (d, JCF 27.2), 72.0 (d, JCF 4.5), 65.7 (d, JCF 24.7), 25.7 (3 ×
CH3), 25.6 (3 × CH3), 18.2, 18.1, 17.3 (d, JCF 22.7), −2.9, −4.1,
−5.0 and −5.2; dF (376.4 MHz, CDCl3, CFCl3) −158.96 (Found
MNa+, 509.2880. C25H47FNaO4Si2 requires 509.2889).
bottomed flask containing 2,4-bis(tert-butyldimethylsilanyloxy)-
3-fluoro-3-methylbutan-1-ol 18 (0.28 g, 0.77 mmol) and pyridine
(0.25 mL, 3.09 mmol) in dry DCM (10 mL) at −40 ◦C. The
reaction was allowed to warm up to room temperature and stirred
for 2 h. The mixture was then washed with a solution of 3%
KHSO4 (10 mL), saturated NaHCO3 (10 mL), and brine (10 mL).
The organic layer was then dried over magnesium sulfate and
the solvent was removed under vacuum. The crude residue was
then purified by flash chromatography on silica gel eluting with
diethyl ether–petroleum ether (40–60) (7 : 3) to give the expected
phosphoric acid 2,4-bis(tert-butyldimethylsilanyloxy)-3-fluoro-3-
methylbutyl ester diethyl ester 19 as a yellow oil (0.3 g, 78%); RF
=
[DCM] 0.12; [a]D −7.7 (c = 1, DCM); mmax (film) 1265 (P O); dH
(500 MHz, CDCl3) 4.19–4.16 (1 H, m, CH), 4.09–4.04 (5 H, m,
2 × CH2 and CHAHB), 3.90–3.84 (1 H, m, CHAHB), 3.61–3.54 (2
H, m, CH2), 1.29–1.26 (6 H, m, 2 × CH3), 1.17 (3 H, d, JHF 5.7,
CFCH3), 0.85 (9 H, s, 3 × CH3), 0.82 (9 H, s, 3 × CH3), 0.07 (3
H, s, CH3), 0.04 (3 H, s, CH3), 0.01 (3 H, s, CH3), 0.00 (3 H, s,
CH3); dC (125 MHz, CDCl3) 96.7 (d, JCF 173.3), 72.5 (d, JCF 9.0),
68.8 (d, JCF 11), 65.4 (d, JCF 25.2), 63.8, 63.7, 25.8 (6 × CH3), 18.3,
18.1, 17.3 (d, JCF 22.4), 16.2, 16.1, −4.4, −5.1, −5.3 and −5.5;
dF (376.4 MHz, CDCl3, CFCl3) −162.3; dP (200.2 MHz, CDCl3)
−0.96 (Found MH+, 503.2782. C21H49FO6PSi2 requires 503.2784).
Phosphoric acid diethyl ester 3-fluoro-2,4-dihydroxy-3-methyl-
butyl ester, 20. A solution of phosphoric acid 2,4-bis(tert-
butyldimethylsilanyloxy)-3-fluoro-3-methylbutyl ester diethyl es-
ter 19 (0.27 g, 0.54 mmol) in dichloromethane (4 mL) was
treated with 90% TFA (2.5 mL) at room temperature, and the
resulting mixture stirred for 30 min. The volatile solvents were
then evaporated and the crude residue was co-evaporated with
toluene and finally purified by flash chromatography on silica gel
eluting with 10% methanol in DCM to give phosphoric acid diethyl
ester 3-fluoro-2,4-dihydroxy-3-methylbutyl ester 20 as a clear oil
(0.11 g, 75%); RF [DCM–MeOH (9 : 1)] 0.63; [a]D −5.4 (c = 1,
2,4-Bis(tert-butyldimethylsilanyloxy)-3-fluoro-3-methylbutan-1-
◦
ol, 18. A −78 C solution of 1-[2,4-bis(tert-butyldimethylsilan-
yloxy)-3-fluoro-3-methylbutoxymethyl]-4-methoxybenzene
17
(1.37 g, 2.82 mmol) and thiophenol (0.36 mL, 3.51 mmol) in
dry dichloromethane (18 mL) was treated with tin(IV) chloride
(2.91 mL, 1 M solution in dichloromethane). The reaction mixture
was stirred at −78 ◦C for 20 min and was then quenched with
saturated sodium hydrogen carbonate (15 mL). The aqueous layer
was extracted with DCM (2 × 30 mL), the combined organic
layers were dried over sodium sulfate, and the solvent removed
under vacuum. The crude residue was purified by flash column
chromatography on silica gel eluting with DCM to give the desired
2,4-bis(tert-butyldimethylsilanyloxy)-3-fluoro-3-methylbutan-1-
ol 18 as a clear oil (0.86 g, 83%); RF [light petroleum–ether (9 : 1)];
[a]D −2.4 (c = 1, DCM); mmax (film) 3300 (O–H); dH (500 MHz,
CDCl3) 3.92–3.88 (1 H, m, CH), 3.67–3.53 (4 H, m, 2 × CH2),
2.22 (1 H, bs, OH), 1.21 (3 H, d, JHF 22.3, CFCH3), 0.84 (9 H, s,
3 × CH3), 0.83 (9 H, s, 3 × CH3), 0.06 (3 H, s, CH3), 0.05 (3 H, s,
CH3), 0.01 (3 H, s, CH3) and 0.00 (3 H, s, CH3); dC (125 MHz,
CDCl3) 97.8 (d, JCF 171.5), 73.8 (d, JCF 26.2), 65.3 (d, JCF 26.2),
63.1 (d, JCF 5.5), 25.9 (6 × CH3), 18.3, 18.2, 17.9 (d, JCF 22.9),
−4.6, −4.9, −5.4 and −5.6; dF (376.4 MHz, CDCl3, CFCl3)
−160.0 (Found MH+, 367.2494. C17H40FO3Si2 requires 367.2495).
=
DCM); mmax (film) 3412 (O–H) and 1266 (P O); dH (500 MHz,
CDCl3) 4.24–4.19 (1 H, m, CH), 4.13–4.01 (6 H, m, 3 × CH2),
3.76–3.57 (2 H, m, CH2), 1.29 (6 H, t, J 7.1, 2 × CH3) and 1.20 (3
H, d, JHF 22.3, CFCH3); dC (75 MHz, CDCl3) 96.1 (d, JCF 170.7),
70.9 (d, JCF 29.1), 68.7 (d, JCF 5.9), 66.3 (d, JCF 23.1), 64.4, 64.3,
16.6 (d, JCF 22.6), 16.1 and 16.0; dF (376.4 MHz, CDCl3, CFCl3)
−163.4; dP (200.2 MHz, CDCl3) −0.10 (Found MH+, 275.1063.
C9H21FO6P requires 275.1054).
Phosphoric acid 3-fluoro-2,4-dihydroxy-3-methylbutyl ester, 3.
Trimethylsilyl bromide (0.69 mL, 5.31 mmol) was added to a
solution of phosphoric acid diethyl ester 3-fluoro-2,4-dihydroxy-
3-methylbutyl ester 20 (0.22 g, 0.80 mmol) in dichloromethane
(3 mL), and the resulting mixture stirred at room temperature for
24 h. The volatile solvents were then evaporated and a 1 : 1 solution
of ethanol and water (4 mL) was added to the residue. After 30 min,
the solvents were evaporated under vacuum, and this procedure
was repeated three times. Finally, the crude residue was purified
by flash chromatography on silica gel C18-reversed phase eluting
with 10% methanol in DCM to generate the phosphoric acid 3-
fluoro-2,4-dihydroxy-3-methylbutyl ester 3 as a clear oil (94 mg,
54%); RF [DCM–MeOH (3 : 7)] 0.39; [a]D −7 (c = 0.1, DCM); mmax
(film) 3300 (O–H); dH (300 MHz, DMSO) 7.90–5.77 (4 H, bs, 4 ×
OH), 4.01–3.91 (1 H, m, CH), 3.92–3.71 (2 H, m, CH2), 3.52–2.28
(2 H, m, CH2) and 1.14 (3 H, d, J 22.7, CH3); dC (75 MHz, DMSO)
Phosphoric acid 2,4-bis(tert-butyldimethylsilanyloxy)-3-fluoro-
3-methylbutyl ester diethyl ester, 19. Iodine (0.20 g, 0.79 mmol)
was added to a solution of triethyl phosphite (0.15 mL, 0.88 mmol)
in dry DCM (2 mL) at 0 ◦C, and the solution was stirred for
20 min at 0 ◦C and then for 1 h at room temperature. The freshly
made phosphorylation agent was then added slowly to a round-
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99.6 (d, JCF 171.2), 70.7 (d, JCF 25.8), 66.6, 64.4 (d, JCF 23.1)
and 17.2 (d, JCF 23.1); dF (376.4 MHz, CDCl3, CFCl3) −160.9;
dP (200.2 MHz, CDCl3) 0.91 (Found MH− 217.0272. C5H11FO6P
requires 217.0277).
Rohdich, Eur. J. Org. Chem., 2001, 3221; (d) M. Fellermeier, M. M.
Raschke, S. Sagner, J. Wungsintaweekul, C. Schuhr, S. Hecht, K. Kis,
T. Radykewicz, P. Adam, F. Rohdich, W. Eisenreich, A. Bacher, D.
Arigini, H. Meinhart and M. H. Zenk, Eur. J. Biochem., 2001, 268,
6302; (e) M. Takagi, T. Kuzuyama, K. Kaneda, H. Watanabe, T. Dairi
and H. Seto, Tetrahedron Lett., 2000, 41, 3395; (f) F. Rohdich, C. A.
Schuhr, S. Hecht, S. Herz, J. Wungsintaweekul, W. Eisenreich, M. Zenk
and A. Bacher, J. Am. Chem. Soc., 2000, 122, 9571; (g) M. Fellermeier,
K. Kis, S. Sagner, U. Maier, A. Bacher and M. H. Zenk, Tetrahedron
Lett., 1999, 40, 2743; (h) D. Ostrovskii, E. Khatatyan, I. Malarova,
I. Shipanova, L. Sibel’dina, A. Shashkov and G. Tansirev, Biofactors,
1992, 3, 261.
6 (a) M. Urbansky, C. E. Davis, J. D. Surjan and R. M. Coates, Org.
Lett., 2004, 6, 135; (b) J. L. Giner and W. V. Ferris, Org. Lett., 2002,
4, 1225; (c) A. T. Koppisch and C. D. Poulter, J. Org. Chem., 2002, 67,
5416; (d) A. Fontana, J. Org. Chem., 2001, 66, 2506; (e) A. T. Koppish,
B. S. J. Blagg and C. D. Poulter, Org. Lett., 2000, 2, 215; (f) K. Kis, J.
Wungsintaweekul, W. Eisenreich, M. H. Zenk and A. Bacher, J. Org.
Chem., 2000, 65, 587; (g) J. F. Hoeffler, C. Pale-Grosdemange and M.
Rohmer, Tetrahedron, 2000, 56, 1485.
7 (a) C. G. Wermuth, ‘Molecular Variations Based on Isosteric Replace-
ments’, in The Practice of Medicinal Chemistry, ed. C. G. Wermuth,
Academic Press, London, 1996, pp. 45–67; (b) B. E. Nordin and P.
Schimmel, J. Biol. Chem., 2002, 277, 20510.
8 M. Hashimoto, M. Matsumoto and S. Terashima, Tetrahedron, 2003,
59, 3019.
9 S. Hara, T. Hoshio, M. Kameoka, M. Sawaguchi, T. Fukuhara and N.
Yoneda, Tetrahedron, 1999, 55, 4947.
10 For an excellent review on the synthesis of b-fluoro alcohols, please see:
G. Haufe, Sci. Synth., 2005, 34, 345.
Acknowledgements
We would like to thank Scottish Enterprise for supporting this
work. We would also like to thank Dr David Adam (GU) for
technical assistance and useful discussions. R.M. would like to
thank Dr Ian Sword and the University of Glasgow for financial
support.
References
1 D. A. Bochar, J. A. Friesen, C. V. Stauffacher and V. W. Rodwell,
Comprehensive Natural Products Chemistry. Isoprenoids, Including
Carotenoids and Steroids, ed. D. E. Cane, Elsevier, Amsterdam, 1999,
vol. 2, pp. 15–44.
2 (a) M. Rohmer, Comprehensive Natural Products Chemistry. Iso-
prenoids, Including Carotenoids and Steroids, ed. D. E. Cane, Elsevier,
Amsterdam, 1999, vol. 2, pp. 45–67; (b) M. Rohmer, Nat. Prod. Rep.,
1999, 16, 565.
3 H. Jomar, J. Wisner, S. Sanderbrand, B. Altineicek, C. Weidemeyer,
M. Hintz, I. Turbachova, M. Eberl, J. Zeidler, H. K. Lichtenthaler, D.
Soldati and E. Beck, Science, 1999, 285, 1573.
4 S. Takahashi, T. Kuzuyama, H. Watanabe and H. Seto, Proc. Natl.
Acad. Sci. U. S. A., 1998, 95, 9879.
5 (a) S. Heccht, J. Wungsintaweekul, F. Rohdich, K. Kis, T. Radykewicz,
C. A. Schuhr, W. Eisenreich, G. Richter and A. Bacher, J. Org.
Chem., 2001, 66, 7770; (b) T. Kuzuyama, S. Takahashi, H. Watanabe
and H. Seto, Tetrahedron Lett., 1998, 39, 4509; (c) C. A. Schuhr, S.
Hecht, K. Kis, W. Eisenreich, J. Wungsintaweekul, A. Bacher and F.
11 K. Mikami, S. Ohba and H. Ohmura, J. Organomet. Chem., 2002, 662,
77.
12 L. Arouna, A. Hedhli and A. Baklouti, Synthesis, 1999, 85.
13 W. Yu, M. Su, X. Gao, Z. Yang and Z. Jin, Tetrahedron Lett., 2000, 41,
4015.
14 Y. Imada, M. Nishida, K. Kutsuwa, S. I. Murahashi and T. Naota, Org.
Lett., 2005, 7, 5837.
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