A convenient chemo-enzymatic synthesis and 18F-labelling of both enantiomers of trans-1-toluenesulfonyloxymethyl-2-fluoromethyl-cyclopropane

Article abstract of DOI:10.1039/b812777h

The present report is concerned with a stereoselective, reliable route to trans-1,2-disubstituted cyclopropanes and in particular to (S,S)-1- tosyloxymethyl-2-fluoromethyl-cyclopropane (1) and (R,R)-1-tosyloxymethyl-2- fluoromethyl-cyclopropane (ent-1) as conformationally restricted, terminally fluorinated C₄-building blocks for medicinal chemistry. The enzymatic kinetic resolution based synthesis of 1 and ent-1 utilises inexpensive, commercially available starting materials. It is based on enantiomeric resolution of rac-cyclopropane carboxylic esters using esterase from Streptomyces diastatochromogenes. Both enantiomers of 1 were prepared selectively in high overall yield over nine steps, starting from ethyl acrylate. The successful radiosynthesis of [¹⁸F]-1 and [¹⁸F]-ent-1 is also reported.

Full text of DOI:10.1039/b812777h

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
A convenient chemo-enzymatic synthesis and 18F-labelling of both enantiomers
of trans-1-toluenesulfonyloxymethyl-2-fluoromethyl-cyclopropane†
Patrick Johannes Riss* and Frank Ro¨sch
Received 24th July 2008, Accepted 19th September 2008
First published as an Advance Article on the web 28th October 2008
DOI: 10.1039/b812777h
The present report is concerned with a stereoselective, reliable route to trans-1,2-disubstituted
cyclopropanes and in particular to (S,S)-1-tosyloxymethyl-2-fluoromethyl-cyclopropane (1) and
(R,R)-1-tosyloxymethyl-2-fluoromethyl-cyclopropane (ent-1) as conformationally restricted, terminally
fluorinated C4-building blocks for medicinal chemistry. The enzymatic kinetic resolution based synthesis
of 1 and ent-1 utilises inexpensive, commercially available starting materials. It is based on enantiomeric
resolution of rac-cyclopropane carboxylic esters using esterase from Streptomyces diastatochromogenes.
Both enantiomers of 1 were prepared selectively in high overall yield over nine steps, starting from ethyl
acrylate. The successful radiosynthesis of [18F]-1 and [18F]-ent-1 is also reported.
Introduction
Fluorine is increasingly included in substitution patterns during
the systematic development of potential pharmaceuticals. The
C–F bond is an isosteric substitution for C–H and an isoelec-
tronic substitution for the hydroxyl group (van der Waals radii:
Scheme 1 (S,S)-(+)-Toluene-4-sulfonic acid 2-fluoromethyl-cyclopropyl-
methyl ester 1 and (R,R)-(-)-toluene-4-sulfonic acid 2-fluoromethyl-cyclo-
propylmethyl ester ent-1.
˚
˚
˚
H: 1.2 A, F: 1.35 A, OH: 1,43 A). Therefore, carbon-bound
fluorine can be introduced as a hydrogen mimic or a hydroxyl
replacement. Its introduction can affect adsorption, distribution
and metabolic properties of a pharmaceutically relevant lead
structure.1 Recent studies have elucidated specific contributions
of fluorine in ligand–protein binding interactions.2 In addition,
fluorine-18 provides unique properties as a radiolabel for positron
emission tomography (PET), a mode of non-invasive imaging and
quantification of biochemical conversions and metabolic rates
in living systems. Among the best suited and most frequently
used PET-radionuclides, fluorine-18 presents outstanding nuclear
and chemical properties.3 For these reasons, fluorinated building
blocks remain of significant interest for the incorporation of
fluorine in defined positions of potential radioligands.
development and optimisation of (stereoselective) cyclopropana-
tion methods, as cyclopropane units can be found in various
natural products and pharmaceuticals.6 Previously published
techniques for the resolution and synthesis of (S,S)- or (R,R)-1,2-
disubstituted cyclopropanes have included: (a) fractional crystalli-
sation of the corresponding trans-1,2-cyclopropane dicarboxylates
followed by reduction, (b) chiral auxiliary-mediated,7 stereose-
lective Simmons–Smith-cyclopropanation of olefins (Charette–
Denmark method),8 (c) the former combined with enzymes,9a
(d) transition metal-complex catalysed carbenoid additions,6d–f ,9b
and (e) multi-step synthesis from enantiomerically enriched start-
ing materials.10 However, yields and enantiomeric excess vary
widely. In addition, the Simmons–Smith-reaction provides only
limited access to cyclopropanes from a,b-unsaturated carbonyl
compounds.6g
Herein we would like to report a convenient route to
2-substituted cyclopropanecarboxylic acid esters as well as
an enzymatic method for the synthesis of diethyl (S,S)-
(+)-cyclopropanedicarboxylate ((+)-4a) and ethyl (R,R)-(-)-
cyclopropanedicarboxylate ((-)-5a) in high enantiomeric excess.
ee-values of 99% for the (S,S)-(+)-enantiomer and 97% for the
corresponding (R,R)-(-)-analogue were achieved, respectively,
after half conversion (E > 200).11 As a complement to the
previously published chemical and enzymatic methods for the
synthesis of 1,2-disubstituted cyclopropanes, the route presented
herein readily affords versatile cyclopropane building blocks 7a
and 7b in very high enantiomeric excess, avoiding sensitive or
expensive reagents. 7a was subsequently employed in the synthesis
of 1 and ent-1. Both labelling synthons [18F]-1 and [18F]-ent-1 were
successfully synthesised from [18F]F- and precursors 11a and ent-
11a in a radiochemical yield of about 50%.
We were interested in (S,S)-1 and (R,R)-ent-1 as C4-synthons
for the introduction of a terminally fluorinated, conformation-
ally restricted cyclopropane ring constraint in suitable (radio-)
pharmaceutical precursors (Scheme 1).4a In addition, trans-1,2-
disubstituted cyclopropanes are versatile (E)-alkene mimics, which
can be employed as isosteric double bond replacements.4 They are
less sensitive to cytochrome p450 affected metabolism in general
and to epoxidation in particular, thus eliminating a potential
source of toxic metabolites.5a,b
The synthesis of 1 and ent-1 required an inexpensive, preparative
scale access to a de-symmetrised cyclopropane precursor in high
enantiomeric excess. Considerable effort has been spent on the
Institute of Nuclear Chemistry, Johannes Gutenberg-University Mainz, Fritz
Strassmann-Weg 2, 55128, Mainz, Germany. E-mail: riss@uni-mainz.de;
Fax: +49 6131 3924692; Tel: +49 6131 3925302
† Electronic supplementary information (ESI) available: Spectra of com-
pounds 1, 8 and 9a. CCDC reference number 691513. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/b812777h
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d were obtained in good enantiomeric excess. The addition of
water miscible solvents, e.g. dioxane, decreased selectivity. In a
multigram scale-up run (15.0 g substrate), ester 4a was isolated in
49% (99% ee) yield, employing an enzyme concentration of 400 mg
l-1. Using diethyl ether for extraction of the non-hydrolysed (S,S)-
ester, the residual enzyme in the buffer solution (containing acid
5a) remained active for further hydrolysis of substrate 4a. The
latter facilitates fast, multi-batch syntheses of optically active ester
(+)-4a without wasting the biocatalyst. In addition, the enzyme
showed sufficient stability in solution at 28 ◦C to employ even
lower concentrations in exchange for prolonged reaction times,
without any significant loss in hydrolytic activity and yield.
In contrast to the racemic mixture 4a which remains liquid at
Results and discussion
Our approach is based on the enantiomeric resolution of racemic
mixtures of esters 4a–d (Scheme 2) employing an esterase from
Streptomyces diastatochromogenes (ESD; E.C.3.1.1.1.), which we
have found to show useful selectivity for the hydrolysis of
cyclopropane carboxylic esters in the past.12
◦
r.t., neat (+)-4a crystallised in colourless platelets (mp = 38 C)
displaying an optical purity of 99% ee. Acid (-)-5a was obtained
via lyophilisation of the residual buffer solution, followed by acidic
work-up to give carboxylic acid (-)-5a in 46% yield (97% ee).
The relative configuration of compound 4a was verified using
X-ray crystallography (Fig. 1). The absolute configuration of
(+)-4a and (-)-5a was assigned by comparison of the rotational
directions with literature references. Therefore, a reference sample
of ester (+)-4a and acid (-)-5a was hydrolysed to the diacid and
the optical rotations were measured.27b Compound (+)-4a was
assigned diethyl (+)-(S,S)-trans-cyclopropane-1,2-dicarboxylate,
after the hydrolysed product showed the same angle of rotation as
(+)-(S,S)-trans-cyclopropane-1,2- dicarboxylic acid. The (R,R)-
configuration was analogously assigned to (-)-5a.7,26
Scheme 2 Enantiomeric resolution of substrate esters 4a–d.
The Wadsworth–Emmons cyclopropanation was chosen for
the preparation of racemic mixtures 4a–d (Scheme 3), as it
provides straightforward access to the desired trans-configured
1,2-disubstituted cyclopropanes in good yields at low cost.13,15
Therefore, triethyl phosphonoacetate (TEPA) was converted into
the P-ylide with potassium tert-butoxide and subsequently reacted
with epoxides 3a–d. The substrate epoxides 3a–d were either
prepared from parent olefins in >85% yield or obtained from
commercial suppliers. Starting from olefinic precursors, trans-
cyclopropanes were isolated in 56 to 75% yield employing a
two-step procedure via Mn(II) catalysed epoxidation to afford
compounds 3a–b followed by trans-selective cyclopropanation
under Horner–Wadsworth–Emmons conditions (Scheme 3).13,14
In contrast to most copper/rhodium catalysed or non-catalysed
additions of carbenoids which were examined by us, this route
afforded the desired trans-configured cyclopropanes as single
products. Thereby, the elaborate separation of (Z)- or open
chain by-products was made obsolete.16 During initial screening,
racemates 4a–d were hydrolysed employing ESD in phosphate
buffer at pH 7.0. The pH was maintained via the controlled
addition of 2 M NaOH solution. In the case of substrate 4a,
ESD showed a remarkably high selectivity. Only the (R,R)-
configured enantiomer was recognised by the biocatalyst and both
the remaining diester (+)-4a and the acid (-)-5a were isolated
in high yield (49% and 46%, 99% and 97% ee, respectively).
Unfortunately, only low enantioselectivity was observed after half
conversion in all other cases. Neither esters 4b–d nor acids 5b–
Fig. 1 X-Ray diffraction crystal structure of enantiopure (+)-4a.27,28
A
probability of 50% was chosen for the ellipsoids. One ethyl group (C7 and
C8) is disordered unequally over two sites (C8A and C8B).
Diols 6a and ent-6a were conveniently obtained in 82 to 88%
yield via LiAlH4 (LAH) reduction of 4 and 5 in THF using a mod-
ified procedure involving equimolar aqueous hydrolysis and quick
short-path distillation in a Kugelrohr apparatus (Scheme 4).7,17
The optical rotations of both product diols were in accordance
with the assigned absolute configurations.7
Scheme
3 Epoxidation of terminal olefins using the 1,4,7-trime-
thyl-1,4,7-triazacyclononane (12) (TMTACN) Mn(II) ascorbate system,14
followed by cyclopropane synthesis via Wadsworth–Emmons cyclopropa-
nation on 3a–d.
Scheme 4 Reductions of diester (S,S)-(+)-4a or acid (R,R)-(-)-5a to diol
(+)-6a and (-)-ent-6a.
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Compounds (+)-6a and (-)-ent-6a were desymmetrised using
NaH in DMF followed by addition of benzyl chloride and
catalytic amounts of TBAI (Scheme 5). A two-step procedure
involving diacetylation followed by selective removal of one acetyl
group using porcine pancreatic lipase (PPL) in phosphate buffer–
dioxane at pH 7 resulted in de-symmetrised diols 7b in even
higher yield.11,18,21 In addition, this double-enzymatic approach
avoided preparative column chromatography as the products were
substantially pure after complete hydrolysis to the monoacetate
(Scheme 5).
The radiosynthesis of [18F]-1 and [18F]-ent-1 was performed as
illustrated for [18F]-ent-1 in Scheme 8. 6a and ent-6a were converted
to the labelling precursors 11a26 and ent-11a, respectively, followed
by exposure to pre-dried, cyclotron produced, no carrier added
(n.c.a) [18F]fluoride. The labelling synthons [18F]-1 and [18F]-ent-1,
were obtained in a non-decay-corrected radiochemical yield of
52 8% and 50 3%, respectively, after a reaction time of 3 min
in MeCN at 90 ◦C followed by HPLC-purification and solid
phase extraction. Although the convenient half-life of fluorine-
18 facilitates multi-step procedures and the production of 18F-
fluorinated 1 can be automated, direct nucleophilic labelling of
a suitable precursor is even more efficient in some cases. In
this regard, 7a and 7b can serve as versatile building-blocks for
precursor synthesis.
Scheme 5 De-symmetrisation of diol (-)-6a, via benzylation of the anion
(a) or selective hydrolysis of the diacetate (b).
Product alcohols 7a and ent-7a were preferably fluorinated
via sulfonylation followed by a Finkelstein-analogue nucle-
ophilic exchange using CsF in 2-propanol to obtain fluorides
9a and ent-9a (Scheme 6). CsF displays a remarkable solu-
bility (12.6 mole in 1000 g MeOH), while CsBr is the least
soluble in alcohols among all caesium halogenides. Neverthe-
less, as leaving group, the mesylate gave even better results.19
Fluoro-dehydroxylation employing diethylamino sulfur trifluoride
(DAST) in dichloromethane at -80 ◦C to r.t. was also examined.20
Although freshly obtained DAST produced fluorides 9a and
ent-9a in good yields (>90%), reagent stability issues led to poor
reproducibility of fluorination outcomes after a few weeks.
Scheme 8 Preparation of labelling precursors, exemplified for (-)-11a and
subsequent radio-fluorination.
Conclusions
In conclusion, both enantiomers of 1 were prepared selectively
in 18.7% and 16.4% overall yield, respectively, over eight to ten
steps, starting from ethyl acrylate. The more versatile intermediates
(S,S)-(+)-7a and (S,S)-(+)-7b were obtained in 20.5% and 22.2%
yield, respectively, over 5 steps. Again, cyclopropanation using
epoxide precursors and TEPA-anion in DME proved to be a useful
route to 2-substituted cyclopropane-1-carboxylic acid esters in
trans-configuration. Although enzymatic resolution of substrates
4b–d failed due to the lack of selectivity in the hydrolytic cleavage of
the ethyl esters, both (+)-4a and (-)-5a were separated and isolated
in high yields and high enantiomeric excess. Furthermore, [18F]-1
and [18F]-ent-1 were successfully synthesised for the first time and
isolated in a non-decay corrected radiochemical yield of 52 8%
and 50 3%.
Scheme 6 Two-step fluorination via mesylation and Finkelstein exchange
Compounds (+)-4a, (-)-5a, along with de-symmetrised diols
7a, ent-7a, 7b and ent-7b provide broad access to enantiomerically
enriched 1,2-disubstituted trans-cyclopropanes. Utilising the route
presented herein, these can be prepared in a synthetically useful
multigram scale, thereby providing the means for the synthesis of
a broad range of 1,2-disubstituted cyclopropane building blocks.
with CsF dissolved in 2-propanol.
Hydrogenolytic cleavage of the fluorides in 2-methoxy-2-
methyl-propane (MTBE) followed by concentration and tosyla-
tion in one pot finally afforded target compounds (S,S)-(+)-1 and
(R,R)-(-)-ent-1 in 87% yield over two steps (Scheme 7).25
Experimental
NMR-spectra were recorded with a Bruker AC 200 FT-NMR-
spectrometer, J values are given in Hertz, chemical shifts are
reported downfield from TMS (d = 0 ppm) referred to the solvent
1
residual signal H NMR (300 MHz, CHCl3 7.224 ppm) and 13C
NMR (100 MHz, CDCl3 77.0 ppm). Field desorption (FD) mass
spectra were recorded on a Finnigan MAT90 FD spectrometer.
HRMS-spectra were measured on a Micromass QTOF Ultima
Scheme 7 Debenzylation of ether (-)-9a and subsequent tosylation to
final product (-)-1.24
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3 spectrometer. IR-spectra were obtained from a Nicolet 6700
FTIR spectrometer. Boiling points are uncorrected. Enantiomeric
excesses of volatile cyclopropanes were determined by gas-
chromatography using hydrogen as carrier gas on a Macherey-
Nagel Lipodex E capillary column. All chemicals were obtained
in commercial quality from Acros Organics, Sigma Aldrich, VWR,
TCI or STREM and used without further purification. Enzymes
697(ArH). dH (300 MHz, CDCl3): 2.20 (dd, J = 2.6 Hz, J = 4.8 Hz,
1 H, O–CH2–), 2.79 (t, J = 4.4 Hz, 1 H, O–CH2–), 3.14–3.21 (m,
1 H,–CH–O), 3.42 (dd, J = 5.9, J = 11.4 Hz, 1 H,–OCH2–), 3.75
(dd, J = 3.0 Hz, J = 11.4 Hz, 1 H, –OCH2–), 4.54 (d, J = 12.1 Hz,
1 H, ArCH2–), 4.60 (d, J = 11.8 Hz, 1 H, ArCH2–), 7.28–7.38 (m,
5 H, ArH). dC (100 MHz, CDCl3): 44.3, 50.9, 70.8, 73.3, 127.8,
128.4, 137.9. m/z (FD) 164.1 (100) [M + H]+ C10H12O2 requires
164.0837.
R
were obtained from Julich Chiral Solutions (Codexisꢀ) (ESD,
recombinant from E. coli) and Sigma-Aldrich (PPL, from hog
pancreas). Optical rotations were determined using a Perkin-
Elmer polarimeter 241 running at 546 and 578 nm (Hg-lamp) at
17 to 25 ◦C and were extrapolated to the sodium D line. [a]D
values are given in 10-1 deg cm2 g-1. TLC was conducted on
self-cut Merck silica gel 60 covered aluminium plates. Detection
and staining was performed either using iodine on silica gel,
potassium permanganate solution, UV fluorescence, vanillin–
sulfuric acid, Seebach-reagent (phosphomolybdic acid, cerium
sulfate, H2SO4) or Dragendorff-reagent (basic bismuth nitrate,
potassium iodide and tartaric acid). Column chromatography was
performed on Acros silica gel 60, 0.063-0.200 mesh, p. a. solvents
for chromatography were washed with aqueous acid and base
and distilled once, prior to use. Anhydrous solvents were used for
reactions.
General procedure for cyclopropane synthesis, compounds 4a–d:
At 0 ◦C, potassium tert-butoxide (11.22 g, 0.1 mol) was dissolved
in 1,2-dimethoxyethane (100 ml) under nitrogen. To this solution,
triethyl phosphonoacetate (29.27 g, 0.13 mol) was added dropwise
over 30 min. After effervescence ceased the slightly turbid solution
was slowly heated to 40 ◦C while epoxide 3a–d (75 mmol) was
added dropwise. The temperature was raised to 60 ◦C until all of
the epoxide had been consumed (monitored by TLC), followed
by reflux for 8 to 12 h to complete the cyclopropane formation.
The reaction was quenched using saturated ammonium chloride
solution (25 ml). In all cases except 3b, prolonged reaction times
lead to product degradation. Ethyl acetate (50 ml) was added and
phases were separated. The aqueous phase was extracted once with
ethyl acetate (50 ml), the combined organic phase was washed with
brine, dried and concentrated in vacuo. The residue was purified
via flash chromatography on silica gel to afford 38 to 90% of 4a–d
as colourless oils.
General procedure for the synthesis of epoxides 3a–b:
To a solution of olefin (1 mol) in MeCN (50 ml) were added
1 ml of an 0.4 M TMTACN stock solution in MeCN, 2 ml
of an 150 mM stock solution of Mn(II)acetate-tetrahydrate in
water and 30 ml of a 80 mM stock solution of sodium ascorbate
in water. The mixture was cooled to 0 ◦C, and approximately
1.8 equiv. of 30% H2O2-solution (stabilised with 1 ppm of Sn) was
added in portions until all olefin had been consumed (monitored
by TLC). The organic phase was separated and the aqueous layer
was extracted with EtOAc (75 ml). The combined organic layers
were dried, concentrated and distilled in vacuo to afford epoxides
3 in >80% yield.
trans-Cyclopropane-1,2-dicarboxylic acid diethyl ester, com-
pound 4a6g,9c,d,16b,16c,26a
. From ethyl 2,3-epoxypropanoate 3a yield
9.63 g (52 mmol, 69%). Found: C, 57.95; H 7.6 C9H14O4
requires C, 58.05; H, 7.6%. nmax/cm-1 (neat): 2993(CH), 1716(CO),
1447(CH2), 1407, 1367(CH3), 1322, 1172(C(O)–O–C), 1033, 743.
dH (300 MHz, CDCl3): 1.22 (t, J = 7 Hz, 3 H, CH3), 1.38 (p,
J = 1.5 Hz, J = 7.4 Hz, 2 H, –CH2–), 2.11 (p, J = 1.5 Hz,
J = 7.4 Hz, 2 H, –CH–), 4.10 (q, J = 7 Hz, 2 H, –OCH2–). dC
(100 MHz, CDCl3): 14.2, 15.2, 22.4, 31.0, 171.7. m/z (FD) 186.1
(100) [M + H] C9H15O4 requires 186.0892.
Ethyl 2,3-epoxypropanoate, compound 3a:14
trans-2-Benzyloxymethylenecyclopropane-1-carboxylic
acid
ethyl ester, compound 4b15a
.
From 3-benzyloxymethylene-1,2-
From ethyl acrylate (1 mol) 94.3 g (812 mmol, 81%), dis-
epoxypropane 3b, yield: 15.7 g (68 mmol, 90%), chromatographed
on silica gel, Rf = 0.6 (light petroleum–Et2O, 7 : 3). Found:
C, 71.8; H, 7.75 C14H18O3 requires C, 71.8; H, 7.7. nmax/cm-1
(neat): 3028(ArH), 2977(CH), 2859(CH), 1720(CO), 1647, 1496,
1453(CH2), 1367(CH3), 1202(C(O)–O–C), 1177(C(O)–O–C),
1085(OCH2), 735(ArH), 697(ArH). dH (300 MHz, CDCl3):
0.80–0.89 (m, 1 H, –CH2–), 1.22 (p, J = 4.4 Hz, 1 H, –CH2–), 1.23
(t, J = 7 Hz, 3 H, CH3), 1.54 (p, J = 4.4 Hz, 1 H, –CH–C(O)),
1.67–1.78 (m, 1 H, –CH–), 3.38 (dq, J = 10.3 Hz, J = 14.0 Hz,
2 H, –CH2–O), 4.10 (q, J = 7 Hz, 2 H, –OCH2–), 4.50 (s, 2 H,
ArCH2–), 7.31 (m, 5 H, ArH). dC (100 MHz, CDCl3): 12.9, 14.2,
18.6, 21.6, 60.6, 71.6, 72.7, 127.7, 128.4, 138.8, 173.8. m/z (FD)
234.2 (100) [M + H]+ C14H18O3 requires 234.1256.
◦
tilled at 4 mbar, bp = 42–44 C (lit.,22a 60–62 ◦C (17 mm)).
Found: C, 51.78; H, 6.95 C5H8O3 requires C, 51.72; H, 6.94%.
n
max/cm-1 (neat) 2986(CH), 1735(CO), 1468(CH2), 1387(CH3),
1291(C(O)–O–C), 1251(epoxide), 1200(C(O)–O–C), 1029(C(O)–
O–C), 915(epoxide), 819(epoxide), 720(CH2). (lit.,22b 1750) dH
(300 MHz, CDCl3): 1.25 (t, J = 7.0 Hz, 3 H, CH3), 2.90 (dd,
=
J = 4 Hz, J = 6 Hz, 1 H, CH–), 2.93 (dd, J = 2.5 Hz, J = 6 Hz,
=
=
1 H, CH–) 3.39 (dd, J = 2.5 Hz, J = 4 Hz, 1 H, CH2), 4.20 (q,
J = 7.0 Hz, 2 H, –OCH2–), 4.21 (q, J = 7.4 Hz, 1 H, –OCH2–). dC
(100 MHz, CDCl3): 14.07, 46.18, 47.33, 61.75, 169.45. m/z (FD)
117.05 ([M + H]+ C5H8O3 requires 116.0473).
3-Benzyloxymethylene-1,2-epoxypropane, compound 3b:23
trans-2-Allyloxymethylenecyclopropane-1-carboxylic acid ethyl
From allyl benzyl ether (0.1 mol), yield: 13.6 g (83 mmol, 83%).
Found: C, 73.45; H, 7.7 C10H12O2 requires C, 73.15; H, 7.4%.
ester, compound 4c16e
. From allyl-glycidyl ether 3c, yield 9.8 g
(53 mmol, 71%), chromatographed on silica gel, Rf = 0.55 (light
petroleum–Et2O, 3 : 2). Found C, 65.0 H, 8.9. C10H16O3 requires C,
65.2; H, 8.8%; nmax/cm-1 (neat): 2983(CH), 1720(CO), 1448(CH2),
1366(CH3), 1269(C(O)–O–C), 1175(C(O)–O–C), 1085(OCH2),
n
max/cm-1 (neat) 3071(CH), 3057(CH), 3030(ArH), 2859(CH),
1496, 1453(CH2), 1383(CH3), 1252(epoxide), 1200(C(O)–O–
C), 1029(C(O)–O–C), 898(epoxide), 845(epoxide), 736(ArH),
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(1.9 mmol, 38%), [a]2D0 = +4.1; (c 1.00, MeOH). See 4d for spectral
=
=
996(C C), 943(C C). dH (300 MHz, CDCl3): 0.81–0.93 (m, 1 H,
–CH2–), 1.24 (t, J = 7 Hz, 3 H, CH3), 1.26–1.34 (m, 1 H, –CH2–),
1.58 (p, J = 4 Hz, 1 H, –CH–), 1.74–1.84 (m, 1 H, –CH–C(O)),
3.46 (dd, J = 8.5 Hz, J = 9.9 Hz, 1 H, O–CH2–), 3.72 (dd, J =
5.8 Hz, J = 10.3 Hz, 1 H, O–CH2–), 3.92 (dq, J = 1.5 Hz, J =
5.5 Hz, 2 H, –CH2–O), 4.12 (q, J = 7.0 Hz, 2 H, –OCH2–), 5.17
data.
(-)-(R,R)-Cyclopropane-1,2-dicarboxylic acid ethyl ester, com-
pound (-)-5a9b–c
.
From trans-cyclopropane-1,2-dicarboxylic acid
diethyl ester 4a, yield: 363 mg (2.3 mmol, 46%), [a]2D3 = -203.4; (c
1.00, EtOH) (lit.,12b–c [a]D20 = +148.5; (c 6.7, EtOH, ee = 90.4%).
Found C, 53.4; H, 6.4. C7H10O4 requires C, 53.16; H, 6.4%.
=
=
(d, J = 10.3 Hz, 1 H, CH2), 5.26 (d, J = 17.3 Hz, 1 H, CH2),
5.80–5.93 (m, 1 H). dC (100 MHz, CDCl3): 13.1, 14.2, 18.5, 22.0,
71.2, 71.7, 117.2, 134.4, 173.0. m/z (FD) 185.2 (100) [M + H]+
C10H16O3 requires 184.1099.
n
max/cm-1 (neat): 2985(CH), 1692(CO), 1460(CH2), 1379(CH3),
1180(C(O)–O–C). dH (300 MHz, CDCl3): 1.22 (t, J = 7.0 Hz, 3 H,
CH3), 1.38–1.51 (m, 2 H, –CH2–), 2.08–2.22 (m, 2 H, –CH–C(O)),
4.10 (q, J = 7.0 Hz, 2 H, –CH2–), 11.5 (brs, 1H, COOH). dC
(100 MHz, CDCl3): 14.1, 15.8, 22.0, 23.0, 61.3, 171.4, 178.1. m/z
(FD) 159.1 (100) [M + H]+ C7H10O4 requires 158.0579.
trans-2-Chloromethylenecyclopropane-1-carboxylic acid ethyl es-
ter, compound 4d16c,d,f
. From epichlorohydrine 3d, yield 3.72 g
(28.5 mmol, 38%), chromatographed on silica gel, Rf = 0.7 (light
petroleum–Et2O, 4 : 1). As a neat compound, 4d will decompose
albeit slowly at 4 ◦C. Found: C, 51.8; H, 6.85. C7H11ClO2 requires
C, 51.7; H, 6.8; Cl, 21.80%; dH (300 MHz, CDCl3): 0.87–0.98 (m,
1 H), 1.23 (t, J = 7 Hz, 3 H, CH3), 1.29 (p, J = 4.4 Hz, 1 H, –CH2–),
1.62 (p, J = 4.4 Hz, 1 H, –CH–), 1.77–1.87 (m, 1 H, –CH–C(O)),
3.46 (dd, J = 1.1 Hz, J = 7.0 Hz, 2 H, Cl–CH2–), 4.10 (q, J = 7 Hz,
2 H, –OCH2–). dC (100 MHz, CDCl3): 11.4, 14.2, 14.9, 20.5, 46.8,
60.7, 172.9. m/z (FD) 162,1 (100) C7H11ClO2 requires 162.0448.
(-)-(R,R)-2-Benzyloxymethylenecyclopropane-1-carboxylic acid,
compound (-)-5b. From ethyl trans-2-benzyloxymethylene-
cyclopropane-1-carboxylate 4b yield: 459 mg (2.25 mmol, 45%),
[a]D23 = -14.6; (c 1.00, EtOH) (lit.,15a [a]2D2 = -152 (c 0.51, CHCl3) ee
>95%). Found C, 69; H, 7.0. C12H14O3 requires C, 69.9; H, 6.8%.
n
max/cm-1 (neat) 3028(Ar–H), 2858(CH), 1690(CO), 1454(CH2),
1075(OCH2), 735(Ar–H), 696(Ar–H). dH (300 MHz, CDCl3): 0.9–
0.96 (m, 1 H, –CH–), 1.26 (p, J = 4.4 Hz, 1 H, –CH2–), 1.56 (p,
J = 4.4 Hz, 1 H, –CH2–), 1.75–1.82 (m, 1 H, –CH–C(O)), 3.34 (dd,
J = 6.6 Hz, J = 10.3 Hz, 1H), 3.46 (dd, J = 5.9 Hz, J = 10,3 Hz,
1 H), 4.51 (s, 2 H), 7.25–7.38 (m, 5 H, ArH), 11.2 (brs, 1H, COOH).
dC (100 MHz, CDCl3): 13.7, 18.4, 22.5, 71.2, 72.6, 127.7, 128.4,
138.0, 180.2. m/z (FD) 206.2 (100) C12H14O3 requires 206.0943.
General procedure for enzymatic hydrolysis employing ESD,
compounds (S,S)-4 and (R,R)-5:
Racemic esters 4a–d (5 mmol) were suspended in phosphate buffer
(5 ml) at pH 7.0. The temperature was adjusted to 28 ◦C and the
reaction was initiated via the addition of 5 mg of ESD. pH was kept
at 7.0 via the automated, controlled addition of 2 M NaOH. After
1.25 ml (2.5 mmol) of NaOH had been added (14–28 h depending
on substrate and the ratio of enzyme to substrate), the reaction
buffer was extracted with diethyl ether (2 ¥ 10 ml) followed by
CH2Cl2 (2 ¥ 10 ml). The organic phases were combined, dried over
Na2SO4 and concentrated in vacuo, to afford 4a–d as colourless
oils. The remaining phosphate buffer was lyophilised overnight
and 5a–d were isolated from the residue via acidic work-up. An
aliquot of both ester and acid fraction was dissolved in alcohol
(1 ml) and the optical rotary power was measured as an indicator
for enantioselectivity of the reaction.
(-)-(R,R)-2-Allyloxymethylenecyclopropane-1-carboxylic acid,
compound (-)-5c. From trans-2-allyloxymethylenecyclopropane-
1-carboxylic acid ethyl ester 4c, yield: 343 mg (2.2 mmol, 44%),
[a]2D3 = -0.7; (c 3.33, EtOH). Found C, 61.8; H, 7.9. C8H12O3
requires C, 61.5; H, 7.7%. nmax/cm-1 (neat) 2930(CH), 1675(CO),
=
1464(CH2), 1087(O–CH2), 1007, 928(C C). dH (300 MHz,
CDCl3): 0.87–0.97 (m, 1 H, –CH–), 1.24 (p, J = 4.4 Hz, 1 H,
–CH2–), 1.55 (p, J = 4.4 Hz, 1 H, –CH2–), 1.69–1.81 (m, 1 H,
–CH–C(O)), 3.31 (dd, J = 6.6 Hz, J = 10.7 Hz, 1 H), 3.41 (dd,
J = 6.3 Hz, J = 10.7 Hz, 1H), 3.94 (d, J = 5.9 Hz, 2 H), 5.13 (d,
J = 10.3 Hz, 1 H), 5.24 (d, J = 17.3 Hz, J = 1.1 Hz, 1 H), 5.79–5.95
(m, 1 H), 11.28 (brs, 1 H, COOH). dC (100 MHz, CDCl3): 13.6,
18.4, 22.5, 71.2, 71.6, 117.2, 134.5, 180.1. m/z (FD) 156.1 (100)
C8H12O3 requires 156.0786.
(+)-(S,S)-Cyclopropane-1,2-dicarboxylic acid diethyl ester, com-
pound (+)-4a. From trans-cyclopropane-1,2-dicarboxylic acid
diethyl ester 4a, yield: 0.456 g (2.45 mmol, 49%), [a]2D0 = +168.8;
(c 1.15, EtOH) (lit.,12b–c [a]2D2 = +150.6; (c 6.8, EtOH; ee = 100%).
See 4a for spectral data.
(-)-(R,R)-2-Chloromethylenecyclopropane-1-carboxylic
acid,
compound (-)-5d16g
.
From trans-2-chloromethylenecyclopro-
pane-1-carboxylic acid ethyl ester 4d, yield: 246 mg (2.4 mmol,
48%), [a]2D3 = -3.8; (c 1.00, EtOH). nmax/cm-1 (neat) 3001(CH),
2945(CH), 2870(CH), 1675(CO), 1464(CH2), 1190(C(O)–O–C),
928, 705, 659. dH (300 MHz, CDCl3): 1.00–1.07 (m, 1 H, –CH–),
1.37 (p, J = 4.4 Hz, 1 H, –CH2–), 1.65 (p, J = 4.4 Hz, 1 H,
–CH2–), 1.85–1.92 (m, 1 H, –CH–C(O)), 3.43 (dd, J = 7.0 Hz,
J = 11.0 Hz, 1H), 3.51 (dd, J = 6.6 Hz, J = 11.4 Hz, 1H), 11.39
(brs, 1 H, COOH). dC (100 MHz, CDCl3): 15.7, 20.3, 24.5, 46.4,
179.5 m/z (FD) 134,1 (100) C5H7ClO2 requires 134.0135.
(+)-(S,S)-2-Benzyloxymethylenecyclopropane-1-carboxylic acid
ethyl ester, compound (+)-4b. From trans-2-benzyloxymethylene-
cyclopropane-1-carboxylic acid ethyl ester 4b, yield: 510 mg
(2.2 mmol, 44%), [a]D20 = +9.8; (c 1, MeOH). (lit.,15a [a]2D2 (R,R) =
-77 (c 0.44, CHCl3) ee >95%). See 4b for spectral data.
(+)-(S,S)-2-Allyloxymethylenecyclopropane-1-carboxylic acid
ethyl ester, compound (+)-4c. From trans-2-allyloxymethylene-
cyclopropane-1-carboxylic acid ethyl ester 4c, yield: 414 mg
(2.25 mmol, 45%), [a]2D0 = +1.7; (c 1.00, MeOH). See 4c for spectral
data.
Preparative scale procedure for the enzymatic resolution of
compound 4a:
(+)-(S,S)-2-Chloromethylenecyclopropane-1-carboxylic
acid
ethyl ester, compound (+)-4d. From trans-2-chloromethylene-
cyclopropane-1-carboxylic acid ethyl ester 4d, crude yield: 249 mg
In a setup for reactions at controlled pH, 4a (15.1 g, 80 mmol)
was suspended in phosphate buffer (50 ml) at pH 7.1. After
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[a]D21 = +17.7; (c 2.15, CHCl3) (lit.,8c [a]D23 = 13.8 (c 2.25, CHCl3
ee = 94%), [a]2D3 = 23.0; (c 1.23, EtOH), [a]2D0 = -21.7; (c 1.31,
EtOH). Found: C, 75.35; H, 8.45. C12H16O2 requires C, 75.0;
H, 8.4%. nmax/cm-1 (neat) 3379(OH), 3032(Ar–H), 2859(CH),
1453(CH2), 1363(CH3), 1070(OCH2), 1049, 734(Ar–H), 696(Ar–
H). dH (300 MHz, CDCl3): 0.38–0.47 (m, 2 H, –CH2–), 0.91–1.03
(m, 2 H, –CH–), 3.15–3.32 (m, 2 H, –CH2–O), 3.39–3.51 (m, 2 H,
O–CH2–), 4.5 (s, 2 H, ArCH2–O), 7.22–7.37 (m, 5 H, ArH). dC
(100 MHz, CDCl3): 8.0, 16.8, 19.8, 66.3, 72.6, 73.5, 127.6, 127.7,
128.4, 138.3. m/z (FD) 192.2 (100) C12H16O2 requires 192.1150.
the addition of 20 mg of ESD the reaction was initiated. The
progress of hydrolysis was monitored via NaOH consumption of
the pH-stat setup. After 18 to 24 hours of continuous stirring at
28 ◦C the NaOH consumption ended. The reaction was terminated
R
and filtered through a pad of celiteꢀ. The non hydrolysed (S,S)-
ester was extracted with diethyl ether (2 ¥ 50 ml) and methylene
chloride (2 ¥ 50 ml). After subsequent combination, drying and
concentration of the organic phases, (S,S)-4 was obtained in 49%
yield of (+)-4a as colourless crystals displaying an optical purity
99% ee (Fig.1, crystal structure). [a]2D4 = 168.8 (c 1.15, EtOH).
The remaining reaction mixture was lyophilised to leave a
residue that was re-dissolved in a small amount of ice-cooled
HCl (10 ml) with cooling. Subsequent exhaustive extraction with
portions of diethyl ether (30 ml) at pH 1.8 afforded acid 5a in 46%
yield and 97% ee.27
Desymmetrisation of diols 6 to compounds 7b and ent-7b:24,26a,29,30
Diol 6 (1.53 g, 15 mmol) was dissolved in methylene chloride
(30 ml), cooled to 0 ◦C and acetic anhydride (5 ml) was added. The
reaction was initiated via the addition of one drop of 97% H2SO4.
After stirring at RT for 14 h the reaction mixture was extracted
with water (15 ml), dried and concentrated in vacuo. The residue
was purified via bulb-to-bulb distillation in a Kugelrohr apparatus
(R,R)-Diol and (S,S)-diol, compound 6 and ent-6:7,10,17,26
A solution of 4a or 5a (5.58 g, 30 mmol) in dry THF (10 ml)
was added dropwise to a stirred solution of LiAlH4 powder (95%)
1.0 equiv. (1.2 g, 30 mmol) and 1.25 equiv. (1.5 g, 37.5 mmol),
respectively, in THF (90 ml) at 0 ◦C. The reaction mixture was
heated to reflux for 4 h. After 4 h, a solution of 4.1 (2.22 ml,
123 mmol) and 5.1 equiv. (2.76 ml, 153 mmol) of water in THF
(8 ml) was added dropwise with stirring under reflux, to obtain
a fine suspension of LiOH and Al(OH)3 in THF. The reaction
mixture was filtered through a pad of celite, and the filter cake
was washed twice with warm THF (15 ml) and once with dry
acetone (15 ml). The filtrate was dried and concentrated in vacuo.
Purification via bulb-to-bulb distillation i◦n a Kugelrohr apparatus
(1 mbar bp = 141 ◦C) (lit.,7 bp = 96–98 C 2 mm) gave products
(R,R)-6 and (S,S)-6 in 88% (2.69 g, 26.4 mmol) and 82% (2.51 g,
24.6 mmol) yield, respectively, as colourless, viscous oil (bp 141 ◦C
at 0.79 mbar). [a]2D1 = -22.6; (c 1.31, EtOH) (lit.,7 [a]2D0 = -26.5¢
(neat) ee >99%). [a]2D4 = +24.5; (c 0.81, EtOH). Found: C, 58.7; H,
9.8. C5H10O2 requires C, 58.8; H, 9.9%. nmax/cm-1 (neat) 3353(OH),
2870(CH), 1430(CH2), 1266, 1056(OCH2). dH (300 MHz, CDCl3):
0.42 (t, J = 6.6 Hz, 2 H, –CH2–), 0.95–1.06 (m, 2 H, –CH–), 3.05
(dd, J = 2.9 Hz, J = 11.4 Hz, 2 H, –CH2–), 3.80 (dd, J = 7.0 Hz,
J = 11.4, 2 H, –CH2–), 4.09 (brs, 2H, OH). dC (100 MHz, CDCl3):
7.07, 19.80, 65.87. m/z (ESI) C5H10O2 requires 102.0681.
to obtain a colourless liquid. [a]2D1 = +17.5; (c 1.00, EtOH), [a]2D5
=
-17.3; (c 1.00, EtOH) (lit.,29 [a]2D3 = -14.1; (c 2.1, EtOH). Found: C,
58.1 H, 7.3 C9H14O4 requires C, 58.05; H, 7.58%; nmax/cm-1 (neat)
2915(CH), 1732(CO), 1449(CH2), 1366(CH3), 1225(C(O)–O–C),
1072(OCH2), 1029. dH (300 MHz, CDCl3): 0.56 (t, J = 6.8 Hz,
2 H, –CH2–), 1.03–1.15 (m, 2 H, –CH–), 2.02 (s, 6 H, CH3), 3.89
(d, J = 7.0 Hz, 4 H, –CH2–O).23 m/z (FD) 186.1 (100) C9H14O4
requires 186.0892.
The product was added to a suspension of 1 g PPL in 20 ml
of 0.1 M phosphate buffer at pH 7.1. The pH was maintained
stable during the hydrolytic de-symmetrisation via the addition of
1.3 M NaOH when necessary. After 19 h, the reaction mixture
R
was filtered through a pad of celiteꢀ. The filter cake was washed
with Et2O (2 ¥ 10 ml) and the organic layer was separated.
The remaining buffer solution was extracted with diethyl ether
(20 ml), followed by dichloromethane (20 ml) and again diethyl
ether (20 ml). Subsequent combination, drying and concentration
of the organic layers afforded 7b (1.99 g, 13.8 mmol, 92%) as
colourless liquid. [a]2D5 = +21.9; (c 1.00, EtOH) (lit.,30 [a]D25
=
+7.8; (c 0.35, CH2Cl2, ee ~ 20%). Found: C, 58.5; H, 8.3. C7H12O3
requires C, 58.3; H, 8.4%. nmax/cm-1 (neat) 3004, 2948(CH),
2876(CH), 1717(CO), 1424(CH2), 1369(CH3), 1232(C(O)–O–C),
1067(OCH2), dH (300 MHz, CDCl3): 0.51 (t, J = 7.0 Hz, 2 H,
–CH2–), 0.96–1.11 (m, 2 H, –CH–), 2.03 (s, 3 H, CH3), 3.40 (dd,
J = 6.5 Hz, J = 11.4 Hz, 1 H, –CH2–OAc), 3.89 (dd, J = 6.5 Hz,
J = 11.4 Hz, 1 H, –CH2–OAc), 3.89 (d, J = 6.5, 2 H, O–CH2–).
dC (100 MHz, CDCl3): 8.4, 15.6, 19.8, 21.0, 65.9, 67.8, 171.3. m/z
(FD) 144.1 (100) C7H12O3 requires 144.0786.
Desymmetrisation of diols 6 to 7a
benzyloxmethylene-cyclopropylmethanol:8c,d,10b
Diol 6 (2.04 g, 20 mmol) was added dropwise to a stirred
suspension of 0.75 equiv. NaH 60% dispersion in mineral oil
(600 mg, 15 mmol) in dry DMF (25 ml) under N2 and heated
to 60 ◦C. After cooling to 0 ◦C, 0.75 equiv. benzyl chloride (1.89 g,
15 mmol) and 0.1 mol% of TBAI were added all at once. Stirring
was continued for 45 min during which the reaction mixture was
allowed to warm to RT. Saturated ammonium chloride solution
(5 ml) was added and the resultant mixture was concentrated
in vacuo to leave a residue that was taken up in water (20 ml)
and extracted with dichloromethane (3 ¥ 25 ml). The organic layer
was separated, dried and concentrated in vacuo. The residual oil
was purified via column chromatography on silica gel, to afford
compounds 7a and ent-7a as colourless viscous liquids in 85%
(3.45 g, 12.8 mmol) yield. Rf = 0.7 (EtOAc–light petroleum, 3 : 7)
2-Methylsulfonyloxymethylene cyclopropylmethyl benzyl ether,
compounds 8a and ent-8a:
Alcohols 7a and ent-7a (1.92 g, 10 mmol) were added to 1 equiv.
◦
of triethylamine dissolved in CH2Cl2 (10 ml) and stirred at 0 C
for 30 min. Subsequently, methanesulfonyl chloride was added
dropwise to this mixture. The reaction was quenched via the
addition of cold water (15 ml) with stirring and the mixture
was diluted with CH2Cl2 (10 ml). The organic phase was washed
with 5% sodium carbonate solution (10 ml), dried over anhydrous
sodium sulfate and concentrated in vacuo to afford 8a and ent-8a
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in 90% (2.4 g, 9 mmol) to 97% (2.62 g, 9.7 mmol) yield. [a]D24
=
It was found that the presence of water during the reaction led
to the formation of sulfurous acid dialkyl esters as significant by-
products. See above for spectral data.
+19.1; (c 1.08, EtOH). Found: C, 57.5; H, 7.1, S, 11.5. C13H18O4S
requires C, 57.8; H, 6.7; S, 11.86%. nmax/cm-1 (neat) 3023(Ar–
H), 2937(CH), 2860(CH), 1454(CH2), 1347(CH3), 1168(–SO2–),
1075(OCH2), 738(Ar–H), 698(Ar–H). dH (300 MHz, CDCl3): 0.6–
0.67 (m, 2 H, –CH2–), 1.11–1.24 (m, 2 H, –CH–), 2.99 (s, 3 H,
CH3), 3.30 (dd, J = 6.3 Hz, J = 9,9 Hz, 1 H, O–CH2–), 3.42 (dd,
J = 5.9 Hz, J = 10.3 Hz, 1 H, O–CH2–), 4.1 (d, J = 6.6 Hz, 2 H,
–CH2–O), 4.49 (s, 2 H, ArCH2–O), 7.25–7.37 (m, 5 H, ArH). dC
(100 MHz, CDCl3): 9.0, 16.0, 17.7, 38.1, 66.3, 72.5, 74.0, 127.7,
128.4, 138.2. m/z (FD) 270,2 (100) C13H18O4S requires 270.0926.
2-Tosyloxymethylene cyclopropylmethyl fluoride, compounds 1 and
ent-1:
Pd (5 mol%) on activated carbon was suspended in MTBE (20 ml),
containing 9a or ent-9a (388 mg, 2 mmol) and 2% (v/v) of glacial
acetic acid. Hydrogen was passed through this suspension until all
9 had been consumed. The reaction mixture was filtered through
R
a pad of celiteꢀ to remove the catalyst, and concentrated to
approximately 1 M alcohol per litre. 1.3 equivalents of NEt3 were
added and the reaction mixture was cooled to 0 ◦C. After the
mixture was stirred for 15 min at 0 ◦C, 1.25 equiv p-toluenesulfonyl
chloride (476 mg, 2 mmol) was added in portions. The reaction
was quenched after four to eight hours via the addition of cold,
saturated ammonium chloride solution (15 ml) with stirring.
The organic layer was diluted with dichloromethane (15 ml)
and the organic phase was washed with 5% sodium carbonate
solution (10 ml) followed by water (10 ml). Subsequent drying over
anhydrous sodium sulfate and concentration in vacuo afforded an
oily residue that was purified via flash column chromatography
(AcOEt–light petroleum, 1 : 4) to obtain (S,S)-(+)-1 and ent-
1 as colourless crystals in 87% (450 mg, 1.74 mmol) yield.
[a]2D1 = -18.9; (c 1.00, EtOH), [a]2D5 = +20.4; (c 2.10, EtOH).
Found: C, 55.7; H, 5.9. C12H15FO3S requires C, 55.8; H, 5.85%.
2-Fluoromethylene cyclopropylmethyl benzyl ether, compounds 9a
and ent-9a, two-step procedure:
A solution of mesylate 8a or ent-8a (901 mg, 3.3 mmol) was added
dropwise to a stirred solution of dry CsF (750 mg, 5 mmol)
R
in 2-propanol (4.5 ml) at reflux in a Supelco reactivialꢀ with
stirring. After 90 minutes a colourless caesium methane sulfonate
precipitate was observed and all of 8 had been consumed. The
slightly-brown reaction mixture was filtered and the filter cake
was washed with Et2O (2 ¥ 5 ml). The organic phases were
combined, concentrated in vacuo and chromatographed on silica
gel to obtain 9a and ent-9a (560 mg, 2.9 mmol, 88%) as a
colourless oil. [a]2D4 = -29.3; (c 1.00 in EtOH); [a]2D1 = +29.9; (c
1.00, EtOH), Rf = 0.6 (hexanes–Et2O, 9 : 1). Found: C, 74.2;
H, 8.0. C12H15FO requires C, 74.2; H, 7.8%. nmax/cm-1 (neat)
3065(CH), 3010(ArH) 2922(CH), 2861(CH), 1453(CH2), 1123(C–
F), 1091(OCH2), 735(Ar–H), 697(Ar–H), 613(C–F). dH (300 MHz,
CDCl3): 0.54–0.64 (m, 2 H, –CH2–), 1.06–1.18 (m, 2 H, –CH–),
3.25–3.46 (m, 2 H, O–CH2–), 4.17 (ddd, J = 7 Hz, J = 12.5 Hz,
JH–F = 48.6 Hz, 1 H, –CH2–F), 4.52 (s, 2 H, ArCH2–O), 7.25–7.36
(m, 5 H, ArH). dC (100 MHz, CDCl3): 8.2 (d, JC–F = 6.8 Hz), 16.6
n
max/cm-1 (neat) 3025(ArH), 2959(CH), 2915(CH), 2870(CH),
1597, 1495, 1465(CH2), 1380(CH3), 1352(–SO2–), 1307(CH2),
1247(CH3), 1188(–C–F), 1170(–SO2–), 1096, 932(Ar–H), 776(Ar–
H), 571(–C–F), 663, 553. dH (300 MHz, CDCl3): 0.55–0.68 (m,
2 H, –CH2–), 1.06–1.19 (m, 2 H, –CH–), 2.42 (s, 3 H, CH3), 3.91
(d, J = 7.0 Hz, 2 H, –CH2–OTs), 4.20 (dd, J = 6.6 Hz, JH-F
=
(d, JC–F = 6.8 Hz), 16.8 (d, JC–F = 22 Hz), 72.5, 72.8, 86.9 (d, JC–F
=
48.8 Hz, 1 H, –CH2–F), 7.32 (d, J = 7.7 Hz, 2 H, ArH), 7.76
161.2 Hz), 127.7, 128.4, 138.4. dF (376 MHz, CDCl3) -209.6 (t,
J = 48.7 Hz) m/z (FD) 194.2 (100) C12H15FO requires 194.1107.
(d, J = 8.1 Hz, 2 H, ArH). dC (100 MHz, CDCl3): 8.5 (d, JC-F =
6.8 Hz), 15.6 (d, JC-F = 6.8 Hz), 17.4 (d, JC-F = 24.9 Hz), 21.6,
73.5, 85.7 (d, JC-F = 167.3 Hz), 127.8, 129.9, 133.2, 144.8. dF
(376 MHz, CDCl3): -211.92 (1 F, t, JH-F = 48.79 Hz). m/z (FD)
258.1 C12H15FO3S requires 258.0726. HRMS (ESI) 281.0634 (100)
([M + Na] C12H15FNaO3S requires 281.0624).
2-Fluoromethylene cyclopropylmethyl benzyl ether, compounds 9a
and ent-9a, one-step procedure:
In an oven dried flask diethylamino sulfur trifluoride (DAST)
(421 mg, 2.3 mmol) was added to dry dichloromethane (5 ml)
via a septum inlet under dry argon. The flask was cooled to
-80 ◦C and dry 7a and ent-7a (385 mg, 2 mmol) dissolved in
dry dichloromethane (5 ml) was added drop wise via a syringe.
After several minutes of stirring, the flask was warmed to -43 ◦C
(MeCN–dry ice) and the reaction mixture was stirred for 1 h after
2-[18F]Fluoromethylene cyclopropylmethyl tosylate, compounds
[18F]-1 and [18F]-ent-1:
[18F]fluoride was produced by proton bombardment of an iso-
topically enriched [18O]H2O-target, using the 18O[p,n]18F nuclear
reaction. The [18F]HF containing [18O]H2O was passed through a
Waters Accell plus light QMA strong anion exchanger cartridge,
preconditioned with 1 M K2CO3-solution (10 ml) followed by
water (20 ml). The trapped [18F]fluoride was eluted with a solution
◦
which the flask was warmed to 0 C. Stirring was continued for
an additional hour at 0 ◦C and then for 1 h at room temperature.
The flask was cooled back to 0 ◦C prior to the careful, dropwise
addition of 5% sodium carbonate solution (intense foaming),
followed by pentane (5 ml). At this point the organic phase was
separated, quickly dried and passed through a short silica column
to remove the polar DAST-products. The addition of chloroform
(15 ml) instead of hexane followed by further extraction of the
organic phase using sodium carbonate solution (2 ¥ 10 ml), drying
and evaporation of the organic phase gave comparable results. The
product was purified via flash column chromatography to obtain
products 9a and ent-9a in up to 92% (360 mg, 18.5 mmol) yield.
R
of cryptand Kryptofixꢀ K222 (15 mg, 0.04 mmol) and K2CO3
(2 mg,◦0.015 mmol) in MeCN (1 ml). The MeCN was evaporated
at 88 C under a stream of nitrogen (300 ml min-1) in vacuo
(102 mbar) to remove the remaining water. Additional MeCN
was added (2 ¥ 1 ml) and evaporated. The dried [18F]fluoride
complex was redissolved in 1 ml of MeCN containing precursor
11a (4.5 mg, 11 mmol) or ent-11a, respectively, and heated to 90 ◦C
for three minutes. The reaction was quenched via the addition
of HPLC-eluent (MeCN–H2O, 1 : 1; 1 ml) and the reaction
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mixture was purified by semipreparative HPLC (10 ¥ 250 mm
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R
VWR Lichrosorbꢀ RP-18 5 m). The product fraction was collected
after a retention time of 12–15 min. The collected HPLC-solvent
was diluted with water (4 : 1) and the obtained solution was passed
through a VWR EN cartridge. The resin was washed once with
water (3 ml) and dried in a gentle stream of nitrogen (200 ml min-1).
[18F]-1 and [18F]-ent-1 were isolated in a radiochemical purity of
>98% and a non decay corrected radiochemical yield of 52 8%
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Acknowledgements
13 W. S. Whadsworth and W. D. Emmons, J. Am. Chem. Soc., 1961, 79,
The authors are grateful to Prof. Dr G. E. Jeromin for his kind
donation of authentic (-)-(R,R)-cyclopropane-1,2-dicarboxylic
acid as a reference, to Prof. Dr U. Nubbemeyer and to Jacob
Hooker, PhD for proofreading the manuscript together with help-
ful discussions. The authors would like to thank Dr D. Schollmeyer
for the X-ray-diffraction measurement. This study was financially
supported by the DFG grant Ro985/21.
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25 Please note that fluoroalcohols 10 may be strong skin irritants.
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27 (a) An ether solution of acid 5a was dried over sodium sulfate and
exposed to excess diazomethane in ether in a standard 2 ml screw-
cap vial for 20 minutes. The obtained solution can be used for GC-
determination of ee-values; (b) S. R. Landor, P. D. Landor and M.
Kall◦i, J. Chem. Soc., Perkin Trans. 1, 1983, 12, 2921(mp acid = 172–
174 C; (R,R): [a]2D0 = - 218 (c 1, EtOH); (lit.,7 [a]2D0 = -238.8 (c 2.036,
H2O). (S,S) [a]2D0 = +232.4 (c 1, EtOH) (lit.,26d [a]2D0 = +228 (c 1.75,
EtOH).
28 Deposited at the Cambridge Structural Database: CCDC 691513.
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4574 | Org. Biomol. Chem., 2008, 6, 4567–4574
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©