Synthesis of Cryptochiral (R,R)-2,3-Dideuterooxirane as Stereochemical Reference Compound and Chemical Correlation with D-(+)-Glyceraldehyde

Article abstract of DOI:10.1002/ijch.201600111

Chirality plays a pivotal role in chemistry and biology, e.g., structure-specific targeting in drug development or the lock-and-key theory of enzyme interactions. Determining absolute configurations of chiral molecules is essential to understanding such mechanisms and to developing chemical processes involving chiral compounds. In particular, this becomes obvious in the understanding of chemical reaction networks in the context of the origins of life. A stereochemical reference compound that can be correlated with sugars, amino acids, etc. is of great interest. Here, we present the synthesis of enantiopure (R,R)-2,3-dideuterooxirane, of which the absolute configuration has been unambiguously determined by foil-induced Coulomb explosion imaging, and the correlation with the configuration of D-(+)-glyceraldehyde.

Full text of DOI:10.1002/ijch.201600111

Full Paper
DOI: 10.1002/ijch.201600111
Synthesis of Cryptochiral (R,R)-2,3-Dideuterooxirane as
Stereochemical Reference Compound and Chemical
Correlation with D-(+)-Glyceraldehyde
Oliver Trapp*[a, b] and Kerstin Zawatzky[c]
Abstract: Chirality plays a pivotal role in chemistry and biol-
ogy, e.g., structure-specific targeting in drug development or
the lock-and-key theory of enzyme interactions. Determining
absolute configurations of chiral molecules is essential to
understanding such mechanisms and to developing chemi-
cal processes involving chiral compounds. In particular, this
becomes obvious in the understanding of chemical reaction
networks in the context of the origins of life. A stereochemi-
cal reference compound that can be correlated with sugars,
amino acids, etc. is of great interest. Here, we present the
synthesis of enantiopure (R,R)-2,3-dideuterooxirane, of
which the absolute configuration has been unambiguously
determined by foil-induced Coulomb explosion imaging, and
the correlation with the configuration of D-(+)-glyceralde-
hyde.
Keywords: chirality · Coulomb explosion imaging · epoxidation · glyceraldehyde · oxirane
1. Introduction
In 1848, Louis Pasteur[1] made the seminal discovery that
the chiroptical and crystallographic properties of various
tartrates[2] are related to molecular handedness. Vanꢀt
Hoff and Le Bel realized that molecular handedness in
organic compounds can be explained by the tetrahedral
structure of tetrasubsituted sp3-hybridized carbon atoms,
which form stereogenic centers.[3,4] However, the determi-
nation of absolute configurations is a nontrivial problem
and can be a challenging task.[5] The knowledge of the ab-
solute configuration is of great importance, e.g., in the
lock-and-key relationship[6] or structure-specific targeting
in drug development.[7] The configurational standard of
chiral molecules is dextrorotatory D-(+)-glyceraldehyde
D-1[8] (Figure 1).
Emil Fischer introduced the stereochemical descriptors
d and l to assign the rotation of polarized light to optical-
ly active compounds, in particular to sugars and deriva-
tives of sugars,[9–11] which triggered many discussions
about optical activity and absolute configuration at the
beginning of the 20th century.[12]
(+)-Glyceraldehyde as the configurational standard has
the advantage that the relative configuration of amino
acids, sugars, natural products, etc. can be easily correlat-
ed.[13] Single-crystal X-ray diffraction crystallography
(XRD) cannot distinguish between image and mirror
image because the signal intensities only depend on the
lattice planes, but not on the spatial orientation. In 1951,
Bijvoet pioneered anomalous single-crystal XRD to de-
termine the absolute configuration of rubidium sodium
(+)-tartrate dihydrate crystals.[14,15] Here, the anomalous
dispersion effect caused by a heavy atom in a crystal of
an optically active compound is used to determine its ab-
solute configuration. Bijvoet assigned the absolute config-
uration of rubidium sodium (+)-tartrate to be (R,R),
which matched Fischerꢀs assignment of (+)-glyceralde-
hyde D-1, based on a chemical correlation of Wohl and
Momber made in 1917.[10] Anomalous single-crystal
XRD[16–18] is the method of choice to determine absolute
configurations of crystalline chiral compounds.[19,20] In
recent years, vibrational circular dichroism (VCD)[21–23]
and vibrational Raman optical activity (ROA),[24] in com-
bination with quantum-chemical calculations, have
evolved into mature tools to determine absolute configu-
rations.[25–27]
[a] O. Trapp
Ludwig-Maximilians-Universitꢀt Mꢁnchen
Department Chemie
Butenandtstr. 5–13
81377 Mꢁnchen (Germany)
e-mail: oliver.trapp@cup.uni-muenchen.de
[b] O. Trapp
Max-Planck-Institut fꢁr Astronomie
Kçnigstuhl 17
69117 Heidelberg (Germany)
[c] K. Zawatzky
Merck Research Laboratories
Department of Process & Analytical Chemistry
Rahway, New Jersey (USA)
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Recently, novel techniques and approaches to deter-
mine absolute configurations have emerged.[16,25,28–30]
Berger and Schçffler et al.[31] used cold target recoil ion
momentum spectroscopy (COLTRIMS) after laser-in-
duced Coulomb explosion to image both enantiomers of
racemic
mixtures
of
bromochlorofluoromethane
(CHBrClF) and isotopically chiral bromodichlorome-
thane (CHBr37Cl35Cl). The atoms are detected by a posi-
tion- and time-sensitive multichannel plate detector
(MCP), giving the structure of both enantiomers.
The idea to use the Coulomb explosion of molecules to
expand the structure and to determine the position of the
initial structure by position- and time-sensitive detection
was pioneered by Zeev Vager and coworkers at the Weiz-
mann Institute.[32–36] In this experiment, molecules are
ionized, accelerated by a high-energy accelerator on
a thin diamond foil (Figure 2), where the valence elec-
trons are stripped off (molecular striptease). By repulsion
of the positively charged ions, a magnified structure is ob-
tained. This technique has been applied to determine the
structure of small molecular fragments such as formyl cat-
ions, etc. Emanuel Gil-Av was fascinated by this experi-
ment, and intended to determine absolute configurations
by direct imaging of a small molecule via Coulomb explo-
sion.[37,38]
Very recently, this idea has been realized and foil-in-
duced Coulomb explosion imaging (CEI) was extended
to unambiguously and theoretically independently deter-
mine the absolute configuration of enantiopure (R,R)-2,3-
dideuterooxirane (R,R)-2.[39] In this experiment, (R,R)-
2,3-dideuterooxirane (R,R)-2, derived from D-glyceralde-
hyde (Figure 1), was used. Unfortunately, glyceraldehyde
forms a carbocation by cleavage of the hydroxyl group at
C2 under electron impact ionization. Consequently, the
stereogenic center is lost. The chiral target compound
had to fulfil the following criteria: (i) correlation of its
Figure 1. Configuration of D- and L-glyceraldehyde and derivation
of 2,3-dideuterooxirane by ring closure of the adjacent hydroxyl
groups in glyceraldehyde, substitution of the carbonyl moiety by
hydrogen, and hydrogen by deuterium, and introduction of
a second deuterium atom.
sense
of
chirality
with
D-glyceraldehyde
D-
1 (Figure 1);[40] (ii) high stereointegrity under harsh condi-
tions; (iii) ionizability without fragmentation; (iv) volatili-
ty at room temperature; and (v) low molecular weight to
Figure 2. Experimental setup to determine the absolute configuration of molecules by foil-induced Coulomb explosion imaging (CEI).
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achieve the necessary acceleration and speed (~1% of
the speed of light) for the CEI experiment. The stereo-
chemical information in cryptochiral (R,R)-2 is conserved
by the introduction of deuterium atoms. The oxirane
moiety shows improved stereointegrity, even under ioniz-
ing conditions, and by introduction of a second deuterium
atom, the stereochemical information is doubled due to
the C2-symmetry.
The 3-dimensional images of (R,R)-2,3-dideuterooxir-
ane and (S,S)-2,3-dideuterooxirane molecules were ob-
tained at the CEI setup at the Max-Planck-Institute for
Nuclear Physics in Heidelberg, Germany.
the formed silyl ether. The triphenylsilyl propargyl alco-
hol 3 was trans-deuterated in a Denmark reduction by re-
action with LiAlD4 and quenching with D2O solely yield-
ing the trans deuterated compound (E)-4.[44] As already
mentioned, the pivotal step of the synthesis is the Sharp-
less epoxidation of (E)-4 using a semi-catalytic proto-
col.[39,45] In this protocol, 10 mol% Ti(IV) isopropoxide
and (+)-diisopropyl tartrate were used, which gave 2,3-di-
deutero-((2S,3S)-3-triphenylsilyl)oxiran-2-yl)methanol
(S,S)-5 in excellent yield (94%) and enantiomeric purity
(erꢀ97.5%), determined by enantioselective HPLC anal-
ysis using Chiralpakꢁ AD-H or Chiralpakꢁ IA columns.
The advantage of the semi-catalytic protocol is that de-
composition of the tert-butyl hydroperoxide with iron(II)-
sulfate gives, under these conditions, a rapid phase sepa-
ration and avoids too much decomposition of the sensi-
tive epoxide. Oxidation of (S,S)-5 to 2,3-dideutero-
((2S,3S)-3-(triphenyl-silyl)oxirane)-2-carbaldehyde (S,S)-6
was achieved by a Parikh-Doering oxidation[46–48] using di-
methyl sulfoxide (DMSO) and pyridine sulfur trioxide
complex as oxidant in excellent yield (86.2%) under very
mild reaction conditions.
Here, an improved synthesis of enantiopure (R,R)-2,3-
dideuterooxirane and the correlation with the configura-
tion of D-glyceraldehyde is presented.
2. Results and Discussion
Schwab et al.[41,42] reported a synthesis of (R,R)-2,3-dideu-
terooxirane (R,R)-2 and (S,S)-2,3-dideuterooxirane at
a small scale. However, this protocol involved several
low-yield steps, with an overall yield of about 10%. To
obtain (R,R)-2,3-dideuterooxirane (R,R)-2 as a stereo-
chemical key reference material, we targeted 7 g of
(R,R)-2,3-dideuterooxirane (R,R)-2 to perform the CEI
experiments to obtain a large data set for an unambigu-
ous and statistically sound determination of the absolute
configuration.
The improved synthetic protocol, with the transforma-
tion of the key intermediate 2,3-dideutero-((2S,3S)-3-(tri-
phenylsilyl)oxirane)-2-carbaldehyde (S,S)-6 into the cor-
responding volatile ketal [4,5-2H2]-(4R)-9 for enantiose-
lective GC analysis and chemical correlation, with the
non-deuterated derivative obtained from (+)-glyceralde-
hyde, is depicted in Scheme 1.
The key step of the synthesis (Scheme 1a) is the enan-
tioselective epoxidation of (E)-4 by a modified semi-cata-
lytic Sharpless procedure[39,43] using titanium(IV) tetraiso-
propoxide, (+)-diisopropyl tartrate and tert-butyl hydro-
peroxide. The advantage is that the configuration of the
epoxide formed by the Sharpless asymmetric epoxidation
is very well predictable, because the conversion is con-
trolled by the configuration of the tartrate in the active
complex. Therefore, under the reaction conditions de-
scribed here, (S,S)-5 is formed with an enantiopurity of
er=97.5%. The advantage of the triphenylsilyl group
over the trimethylsilyl group as protecting group is that
the enantiopurity can be improved by recrystallization of
(S,S)-5, which is, for the corresponding trimethylsilyl, not
possible.
The decarbonylation[49] step was the most critical step
of the synthesis, because this required 167g Wilkinson cat-
alyst in stoichiometric amounts. Decarbonylation of (S,S)-
6 by stoichiometric reaction with the Wilkinson catalyst
RhCl(PPh3)3 gave 2,3-dideutero-(2S,3R)-2-(triphenylsilyl)-
oxirane (2S,3R)-7 in 86.6% yield under retention of the
configuration at C2. (R,R)-2 was then released as a gas
by removal of the triphenylsilyl group under retention of
the configuration at C2 by treating with tetraethylammo-
nium fluoride in DMSO in 90.7% yield (7.6 g). This cor-
responds to an overall yield of 39%.
XRD structures of compounds 3, (E)-4, (S,S)-5, and
(S,S)-6 are depicted in Figure 3.
For the chemical correlation of key intermediate (S,S)-
6 and (+)-glyceraldehyde (+)-1, a strategy was developed
to convert both compounds into the same derivative,
which can be analyzed by enantioselective chromatogra-
phy. Interestingly, it turned out that this was more chal-
lenging than expected, because there are no suitable pro-
tocols for the separation of racemic glyceraldehyde avail-
able. We decided to transform (S,S)-6 and (+)-glyceralde-
hyde (+)-1 into the same volatile derivative suitable to be
analyzed by enantioselective GC. We first transformed
racemic glyceraldehyde rac-1 and (+)-glyceraldehyde
(+)-1 by ketalization using 2,2-dimethoxypropane, cata-
lyzed by p-toluenesulfonic acid into the corresponding
ketals 9, respectively (Scheme 1c).
There are excellent reports about the regioselective
transformation of epoxy aldehydes into their correspond-
ing ketals under retention of the configuration at C2, and
inversion of the configuration at C3 by acetone under cat-
alysis of TiCl4 as the Lewis acid.[40,50] We converted (S,S)-
6 into (2S,3R)-2,3-dideutero-3-(triphenylsilyl)-2,3-O-iso-
propylidene-glyceraldehyde [4,5–2H2]-(4S,5S)-8, which
The improved protocol starts with the synthesis of tri-
phenylsilyl propargyl alcohol 3 by introducing the triphe-
nylsilyl protecting group using ethyl magnesium bromide
to deprotonate propargyl alcohol, followed by reaction
with triphenylsilyl chloride and successive deprotection of
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Scheme 1. a) Synthesis of (R,R)-2,3-dideuterooxirane (R,R)-2 via the key intermediate 2,3-dideutero-((2S,3S)-3-(triphenylsilyl)oxirane)-2-car-
baldehyde (S,S)-6. b) Ketalization of 2,3-dideutero-((2S,3S)-3-(triphenylsilyl)oxirane)-2-carbaldehyde (S,S)-6 giving volatile ketal [4,5-2H2]-
(4R)-9 for GC analysis. c) Transformation of D-glyceraldehyde 1 into the ketal (4R)-9 for chemical correlation.
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about 30%. The electron impact mass spectra show that
a methyl group of the ketals is abstracted, resulting in
a base peak of [MÀ15]+ at m/z 117 for the dideuterated
ketal [4,5-2H2]-(4R)-9 and m/z 116 for the monodeuterat-
ed ketal. Isotopic labeling allows the distinguishing of the
reaction product formed by regioselectively ring-opened
oxirane, and ring opening under keto-enol tautomeriza-
tion of the adjacent carbaldehyde group (m/z 116), which
is accompanied by proton-deuteron exchange at C2.
The chromatograms show that the ketal derived from
(+)-glyceraldehyde is coeluted with isotopically labeled
[4,5-2H2]-(4R)-9 obtained from (S,S)-6, which is stereo-
chemically connected with (R,R)-2.
3. Conclusion
We have presented an improved synthetic protocol to
synthesize (R,R)-2,3-dideuterooxirane (R,R)-2, of which
absolute configuration was determined by Coulomb ex-
plosion imaging. The absolute configuration was chemi-
cally correlated with (+)-glyceraldehyde D-1, via the key
intermediate 2,3-dideutero-((2S,3S)-3-(triphenyl-silyl)oxir-
ane)-2-carbaldehyde (S,S)-6.
Figure 3. XRD structures of compounds 3, (E)-4, (S,S)-5, and (S,S)-
6.
was consecutively desilylated using tetrabutylammonium
fluoride (TBAF), giving (2R,3S)-2,3-dideutero-2,3-O-iso-
propylideneglyceraldehyde [4,5-2H2]-(4R)-9 (Scheme 1b).
Stereochemical correlation was achieved by enantiose-
lective GC-MS measurements of these ketals (Figure 4).
The separation of the ketal enantiomers is achieved with
an excellent separation factor a of 1.15. The measured
enantiomeric ratio of [4,5-2H2]-(4R)-9 was lower than ex-
pected. Interpretation of the electron impact mass spectra
of the peaks of the enantiomers of [4,5-2H2]-(4R)-9
proved that a proton-deuteron exchange occurred to
The assignment of the absolute configuration of (R,R)-
2,3-dideuterooxirane (R,R)-2 by Coulomb explosion
imaging and its correlation with D-(+)-glyceraldehyde in-
dependently proves the correctness of Fischerꢀs assump-
tion, and proves the reliability of former methods of as-
signing absolute configurations.
4.-Experimental
4.1 Materials and Methods
All reagents and solvents were obtained from Sigma-Al-
drich, Taufkirchen, Germany, and were used without fur-
ther purification, unless otherwise noted. THF was freshly
distilled from sodium under an argon atmosphere. Deu-
terated solvents were purchased from Euriso-Top. NMR
spectra were recorded on Bruker Avance 600, Bruker
Avance 500, Bruker Avance 300, and Bruker ARX-250
spectrometers at RT. Chemical shifts (in ppm) were refer-
enced to residual solvent protons. MS spectra were re-
corded on a Finnigan MAT TSQ 700 or a JEOL JMS-700
spectrometer. IR spectra were recorded on a Thermo
Nicolet 6700 ATR-FT-IR instrument. Intensity data for
crystal structure analysis were measured on a Bruker
APEX diffractometer.
Figure 4. GC-MS traces to assign the elution order of the enantio-
mers of the ketals 9 obtained from a) racemic D,L-glyceraldehyde;
b) (+)-glyceraldehyde (+)-1; and c) 2,3-dideutero-((2S,3S)-3-(triphe-
nylsilyl)oxirane)-2-carbaldehyde (S,S)-6 (SIM trace at m/z 117 ([[4,5-
2H2]-(4R)-9 ÀCH3]+)). Separation conditions: 25 m Chirasil-b-Dex
(0.25 mm i.d., 250 nm film thickness), isothermal at 808C, 80 kPa
He as carrier gas.
4.2 (Enantioselective) GC-MS Analysis
Gas chromatographic separations were performed on
a Thermo Trace PolarisQ GC-MS or Thermo Trace ISQ
GC-MS equipped with an autosampler/split injector
(2508C), a flame-ionization detector (2508C) and a quad-
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rupole ion-trap MS (Thermo, San Jose, California,
U.S.A.). Electron impact mass spectra (EI-MS, ion source
temperature 2008C, electron energy 70 eV) were record-
ed on a Thermo Trace PolarisQ GC-MS or Thermo Trace
ISQ GC-MS, chemical ionization mass spectra (CI-MS,
ion source temperature 2008C, electron energy 70 eV,
methane (3.0 mLminÀ1) as reagent gas). For standard
analysis, a 25 m HP-5MS column was used. For enantiose-
lective separations, a fused silica column coated with
Chirasil-b-Dex[51,52] (25 mꢂ0.25 mm i.d., 0.5 mm film
thickness) was employed. Helium was used as the inert
carrier gas.
The ether extracts were washed with brine and saturated
NaHCO3-solution. After concentration giving a white
solid, the crude product was purified by flash chromatog-
raphy using ethyl acetate/n-hexane (20 :80, v/v) affording
triphenylsilyl propargyl alcohol in 56.2% yield as color-
less needles (68.3 g, 0.22 mol). TLC (ethyl acetate/n-
hexane (10 :90, v/v)): Triphenylsilyl propargyl alcohol
Rf =0.12, triphenylsilanol Rf =0.36, triphenylsilyl proparg-
yl triphenylsilyl ether Rf =0.62. 1H NMR (300 MHz,
CDCl3): d=1.65 (t, J=6 Hz, 1H), 4.32 (d, J=6 Hz, 2H),
7.27 (m, 9H), 7.57 (m, 6H). 13C NMR (75 MHz, CDCl3):
d=51.92, 85.94, 108.38, 128.03, 130.06, 133.07, 135.55.
ATR-IR: u=3262, 3062, 2178, 1482, 1427, 1356, 1304,
1262, 1231, 1182, 1112, 1112, 1035, 997, 987, 854, 740, 697.
HR-MS (FAB+): m/z=315.1196, calcd. for C21H19OSi
[M+H]+: 315.1199.
4.3 Enantioselective HPLC Analysis
HPLC measurements were performed on an Agilent
Technologies 1200 HPLC-MS (Agilent Technologies, Palo
Alto, California, USA), equipped with a binary solvent
pump, an autosampler, membrane solvent degasser, DAD
detector and a quadrupole mass spectrometer Agilent
6120, equipped with an APCI source. All operations were
controlled by the Agilent ChemStation software (Agilent
Technologies, Palo Alto, California, USA). Enantioselec-
tive separations were performed on a Chiralpakꢁ AD-H
or Chiralpakꢁ IA columns (250 mm, i.d. 4.6 mm, particle
size 5 mm), which were bought from Chiral Technologies,
Illkirch, France. The solvents used (n-hexane and 2-prop-
anol) were obtained from Sigma-Aldrich (HPLC-grade
quality).
2,3-Dideutero-(E)-(3-triphenylsilyl)-2-propenol (E)-4.
Lithium aluminum deuteride (>99.0 atom% deuterium,
9.0 g, 215.3 mmol) was suspended in anhydrous THF
(700 ml). Triphenylsilyl propargyl alcohol (67.7 g,
215.3 mmol), dissolved in 200 ml anhydrous THF, was
slowly added under stirring at room temperature. After 2
days, deuterium oxide (99.9 atom% deuterium, 15.6 ml,
861.2 mmol) was slowly added at 08C. Then 500 ml dieth-
yl ether, saturated ammonium chloride solution, and 50 g
(+)-tartaric acid were added to dissolve the aluminum
precipitate and to achieve a phase separation. The aque-
ous phase was extracted with diethyl ether. The ether ex-
tracts were washed with brine and water and dried over
MgSO4. After concentration, the white solid was crystal-
lized from n-hexane/ethyl acetate, affording the product
4.4 Syntheses
1
as colorless needles in 99.6% yield (68.3 g, 214.5 mol). H
Triphenylsilyl propargyl alcohol 3. In a three-necked
flask, equipped with a mechanical stirrer and a reflux
condenser, magnesium turns (20.7 g, 0.85 mol) were
placed and covered with a layer of anhydrous THF. Ethyl
bromide (92.6 g, 0.85 mol, 65.8 ml) dissolved in 450 ml an-
hydrous THF was slowly added via a dropping funnel
under an argon atmosphere and slight reflux. After com-
plete addition, this solution was refluxed for 1 h. 23.8 g
Propargyl alcohol, dissolved in 200 ml anhydrous THF,
was slowly added. Then tripenylchlorosilane (250 g,
0.85 mol), dissolved in a mixture of 450 ml anhydrous
THF and 150 ml triethylamine (freshly distilled from
CaH2), was slowly added under vigorous stirring. The
mixture solidified during the reaction. This mixture was
stirred for another 12 h. Then THF was removed from
the mixture by a rotary evaporator; water, diethyl ether,
and diluted HCl were added to dissolve the residue. The
organic layer was separated, and the residue extracted
three times with diethyl ether. The organic extract was
washed with saturated NaHCO3-solution and water. After
removal of diethyl ether, the residue was dissolved in
100 ml THF and stirred with 200 ml 1N H2SO4 solution
for 5 h at 708C. Saturated ammonium chloride solution
was added and the solution extracted with diethyl ether.
NMR (300 MHz, CDCl3): d=1.46 (t, J=6 Hz, 1H), 4.19
(d, J=6 Hz, 2H), 7.30 (m, 9H), 7.45 (m, 6H). 13C NMR
(75 MHz, CDCl3): d=65.7, 122.7 (t, 13 Hz), 128.4, 130.1,
134.8, 136.4, 150.7 (t, 14 Hz). ATR-IR: u=3260, 3064,
1588, 1426. HR-MS (FAB+): m/z=319.1439, calcd. for
C21H19D2OSi [M+H]+: 319.1482.
2,3-Dideutero-((2S,3S)-3-triphenylsilyl)oxiran-2-yl)me-
thanol (2S,3S)-5. The key step of the synthesis was the
enantioselective epoxidation of 4 by a modified Sharpless
procedure[45] employing semi-catalytic amounts of the ti-
tanium(IV) isopropoxide and (+)-diisopropyl tartrate. In
a dry round-bottom flask, equipped with a dropping
funnel, 24 g molecular sieve 4ꢃ and 200 ml anhydrous di-
chloromethane were cooled to À208C under an argon at-
mosphere.
Then
(+)-diisopropyl
tartrate
(5.1 g,
21.6 mmol, 4.5 ml) were dissolved, and titanium(IV) iso-
propoxide (5.5 g, 19.5 mmol, 5.7 ml) was slowly added
using
a syringe. 2,3-Dideutero-(E)-(3-triphenylsilyl)-2-
propenol (68.9 g, 216.4 mmol), dissolved in 100 ml anhy-
drous dichloromethane, was then added. The temperature
was carefully controlled and kept at À208C. Anhydrous
tert-butyl hydroperoxide solution in toluene (3.6 mol/l,
443.5 mmol, 122.2 ml) was slowly added. After 5 h of con-
tinuous stirring, the flask was stored for another 12 h in
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a refrigerator at À208C. The reaction mixture was then
quenched by adding a mixture of iron(II)-sulfate heptahy-
drate (90.2 g, 324.5 mmol) and (+) tartaric acid (3.2 g,
21.6 mmol) dissolved in ice water (180 ml) and 200 ml di-
ethyl ether. After 1 h of vigorous stirring, this was filtrat-
ed through Celite and the organic phase was separated.
The aqueous phase was extracted with diethyl ether. The
combined organic phases were washed with brine. After
concentration, giving a white solid, the crude product was
purified by flash chromatography using ethyl acetate/n-
hexane (20 :80, v/v), affording (2S,3S)-5 in 94% yield
(68.0 g, 203.3 mmol) as colorless crystals and an enantio-
meric purity (er), determined by enantioselective HPLC,
of 97.5% after recrystallization from n-hexane/ethyl ace-
moved in vacuo and the product was isolated by flash
chromatography using ethyl acetate/n-hexane (10 :90, v/v)
to give (2S,3R)-7 in 86.6% yield (47.6 g, 153.4 mmol).
The reaction product was directly used to prepare (R,R)-
2,3-dideuterooxirane by desilylation of the triphenylsilyl
1
group. H NMR (300 MHz, CDCl3): d=2.59 (s, 1H), 7.45
(m, 6H), 7.65 (m, 9H).
(R,R)-2,3-Dideuterooxirane (R,R)-2. (2S,3R)-7 was re-
acted with tetraetlylammonium fluoride dihydrate (31.9 g,
172.0 mmol) in DMSO (155 ml) in a three-necked flask,
equipped with a condenser, a gas inlet, and a cooling trap
at the end of the condenser. The reaction was performed
under a gentle stream of Ar through the reaction mixture
in 98.6% yield (7.1 g). 1H-NMR (500.13 MHz, CDCl3,
À108C): d=2.70–2.71 (m, 2H, 1-H/2-H). 13C-NMR
(125.77 MHz, CDCl3, À108C): d=40.7 (t, J=23.9 Hz).
GC-MS (CI): m/z=47.01 [M+1]+.
1
tate. H NMR (300 MHz, CDCl3): d=1.77 (t, J=6 Hz,
1H), 3.68 (dd, J1 =12.6 Hz, J2 =8.6 Hz, 1H), 3.99 (dd, J1 =
12.6 Hz, J2 =5.8 Hz, 1H), 7.39 (m, 9H), 7.57 (m, 6H). 13C
NMR (75 MHz, CDCl3): d=45.7 (t, 24 Hz), 55.9 (t,
26 Hz), 62.8, 128.3, 129.8, 132.1, 136.1. ATR-IR: u=3401,
3066, 1586, 1484, 1426, 1111. HR-MS (FAB+): m/z=
317.1327, calcd. for C21H17D2OSi [MÀOH]+: 317.1330.
2,3-Dideutero-((2S,3S)-3-(triphenylsilyl)oxirane)-2-car-
baldehyde (2S,3S)-6. (2S,3S)-5 (65.0 g, 194.3 mmol) was
dissolved in anhydrous DCM (630 ml) in a 5000 ml
round-bottom flask and cooled to 08C. Then triethyla-
mine (281.7 ml, 2021.1 mmol) and anhydrous DMSO
(276.1 ml, 3887.0 mmol) were added. Under vigorous stir-
ring, and cooling at 08C, pyridine sulfur trioxide complex
(185.7 g, 1167.0 mmol) was added in small portions every
10 min. After completion of the addition, the reaction
mixture was stirred at 08C for 3 h. Then n-pentane
(1400 ml) and diethyl ether (1400 ml) were added. The or-
ganic phase was then isolated and washed with saturated
NaHCO3 and brine. The organic phase was then dried
over MgSO4 and concentrated. Non-converted (S,S)-5
was removed by crystallization after the addition of n-
hexane and ethyl acetate. The supernatant liquid was pu-
rified by flash chromatography using ethyl acetate/n-
hexane (20 :80, v/v), affording (S,S)-6 in 86% yield
(64.6 g, 194.3 mmol) as colorless crystals. 1H NMR
(300 MHz, CDCl3): d=7.43 (m, 9H), 7.57 (m, 6H), 8.97
(s, 1H). 13C NMR (75 MHz, CDCl3): d=46.1 (t, 18 Hz),
56.3 (t, 21 Hz), 128.3, 130.6, 130.7, 136.0, 198.5. ATR-IR:
[4,5-2H2]-(4S,5S)-2,2-dimethyl-5-(triphenylsilyl)-1,3-di-
oxolane-4-carbaldehyde [4,5-2H2]-(4S,5S)-8. (2S,3S)-6
(1.00 g, 3.01 mmol) was dissolved in dichloromethane
(30 mL) and 3 ꢃ molecular sieves (3 g) and acetone (442
mL, 6.02 mmol, 2 eq.) were added.[27,50] The mixture was
stirred at room temperature for 30 min, then cooled to
À788C and tin tetrachloride (105 mL, 0.90 mmol, 0.30 eq.)
was added dropwise. After another 30 min of stirring, the
reaction flask was stored in a freezer at À408C for 7 days.
The resulting orange mixture was quenched by the addi-
tion of 10 mL of an ice-cold 10% aqueous potassium hy-
droxide solution and stirred for 5 min. The phases were
separated and the aqueous phase extracted with dichloro-
methane (3ꢂ20 ml). After drying (MgSO4) the combined
organic extracts were concentrated in vacuo. Flash chro-
matography (SiO2, n-pentane/diethylether 10 :1, Rf =0.28)
afforded [4,5-2H2]-(4S,5S)-2,2-dimethyl-5-(triphenylsilyl)-
1,3-dioxolane-4-carbaldehyde (881 mg, 75%) as a viscous
1
oil. H-NMR (600 MHz, CDCl3): d=1.37 (s, 3 H), 1.53 (s,
3 H), 7.28–7.32 (m, 6 H), 7.34–7.38 (m, 3 H), 7.52 (d, J=
6.88 Hz, 6 H) 9.03 (s, 1 H). 13C NMR (151 MHz, CDCl3):
d=24.7, 27.4, 69.5 (t, J=20.1 Hz), 82.8 (t, J=23.6 Hz),
111.4, 128.1, 130.2, 132.1, 136.0, 200.0.
[4,5-2H2]-(4R)-2,2-dimethyl-1,3-dioxolane-4-carbalde-
hyde [4,5-2H2]-(4R)-9. [4,5-2H2]-(4S,5S)-8 (10.0 mg,
26.0 mmol) was dissolved in THF (50 mL) and TBAF
(1 M, 52 mL, 52.0 mmol) was added. The mixture was
stirred for 16 h at room temperature and analyzed by
GC-MS.
u=3066, 2810, 1722, 1685, 1427, 1112. HR-MS (EI+): m/
+
C
z=332.1176, calcd. for C21H16D2O2Si [M] : 332.1201, m/
z=259.0954, calcd. for C18H15Si [SiPh3]+: 259.0943, m/z=
255.0805, calcd. for C15H11D2O2Si [MÀSiPh3]+: 255.0810.
2,3-Dideutero-(2S,3R)-2-(triphenylsilyl)oxirane
GC-MS (EI+): m/z 133.17 [M+H]+ (2.9), 117.20
[MÀCH3]+ (80), 103.16 [MÀCHO]+ (100).
(2S,3R)-7.
2,3-Dideutero-((2S,3S)-3-(triphenylsilyl)oxir-
rac-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde
rac-9.
ane)-2-carbaldehyde (60 g, 180.4 mmol) was dissolved in
700 ml anhydrous acetonitrile in a round-bottom flask
equipped with a reflux condenser under an argon atmos-
phere. Then the Wilkinson catalyst (tris-(triphenylphos-
D/L-Glyceraldehyde (50.0 mg, 0.55 mmol) was suspended
in acetone (2 mL) and p-toluene sulfonic acid monohy-
drate (0.30 mg, 1.60 mmol, 0.20 mol%) was added. The
mixture was cooled to 08C and dimethoxypropane
(63.0 mg, 0.61 mmol, 1.09 eq.) was added. After 16 h stir-
ring at room temperature, a clear solution had formed,
which was analyzed by GC-MS. GC-MS (EI+): m/z=
phine)-rhodium(I)-chloride[26]
RhCl(PPh3)3
(167 g,
180.4 mmol) was added and the mixture was heated
under reflux (808C) for 4 h. Then the solvent was re-
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131.20 [M+H]+ (0.1), 115.15 [MÀCH3]+ (100), 101.16
[18] a) R. W. W. Hooft, L. H. Straver, A. L. Spek, J. Appl. Crys-
tallogr. 2008, 41, 96–103; b) H. D. Flack, M. Sadki, A. L.
Thompson, D. J. Watkin, Acta Crystallogr. Sect. A: Found.
Crystallogr. 2011, A67, 21–34; c) S. Parsons, P. Pattison,
H. D. Flack, Acta Crystallogr. Sect. A: Found. Crystallogr.
2012, A68, 736–749.
[19] J. D. Dunitz, X-ray analysis and the structure of organic mol-
ecules, Cornell University Press, New York, 1979.
[20] N. Harada, Chirality 2008, 20, 691–723.
[21] P. J. Stephens, J. Phys. Chem. 1985, 89, 748–752.
[22] T. B. Freedman, X. Cao, R. K. Dukor, L. A. Nafie, Chirality
2003, 15, 743–758.
[23] P. J. Stephens, F. J. Devlin, J.-J. Pan, Chirality 2008, 20, 643–
663.
[MÀCHO]+ (93).
(4R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde (4R)-
9. (+)-Glyceraldehyde (10.0 mg, 0.11 mmol) was suspend-
ed in acetone (1 mL) and p-toluene sulfonic acid mono-
hydrate (0.06 mg, 0.33 mmol, 0.20 mol%) was added. The
mixture was cooled to 08C and dimethoxypropane
(14.8 mL, 0.12 mmol, 1.09 eq.) was added. After 16 h stir-
ring at room temperature a clear solution had formed,
which was analyzed by GC-MS. GC-MS (EI+): m/z=
131.19 [M+H]+ (0.2), 115.11 [MÀCH3]+ (100), 101.17
[MÀCHO]+ (95).
[24] L. D. Barron, M. P. Bogaard, A. D. Buckingham, J. Am.
Chem. Soc. 1973, 95, 603–605.
[25] L. D. Barron, A. D. Buckingham, Chem. Phys. Lett. 2010,
492, 199–213.
Acknowledgements
This work was supported by the ERC under Grant
Agreements No. StG 258740 and the Max-Planck Society.
We thank Dr. Frank Rominger (Organisch-Chemisches
Institut, Ruprecht-Karls-University Heidelberg) for XRD
measurements. XRD structures of compounds 3, (E)-4,
(S,S)-5, and (S,S)-6 are available from the Cambridge
Crystallographic Data Centre under reference numbers
CCDC 964292, CCDC 964293, CCDC 964294, and
CCDC 964295, respectively.
[26] J. Haesler, I. Schindelholz, E. Riguet, C. G. Bochet, W. Hug,
Nature 2007, 446, 526–529.
[27] P. L. Polavarapu, Chirality 2012, 24, 909–920.
[28] D. Patterson, M. Schnell, J. M. Doyle, Nature 2013, 497,
475–478.
[29] J. Ding, D. G. Hall, Angew. Chem. 2013, 125, 8227–8231;
Angew. Chem. Int. Ed. 2013, 52, 8069–8073.
[30] M. Mꢄller, C. M. Orben, N. Schꢄtzenmeister, M. Schmidt,
A. Leonov, U. M. Reinscheid, B. Dittrich, C. Griesinger,
Angew. Chem. 2013, 125, 6163–6165; Angew. Chem. Int.
Ed. 2013, 52, 6047–6049.
[31] M. Pitzer, M. Kunitski, A. S. Johnson, T. Jahnke, H. Sann, F.
Sturm, L. P. H. Schmidt, H. Schmidt-Bçcking, R. Dçrner, J.
Stohner, J. Kiedrowski, M. Reggelin, S. Marquardt, A.
Schießer, R. Berger, M. S. Schçffler, Science 2013, 341,
1096–1100.
[32] a) A. Faibis, G. Goldring, Z. Vager, Phys. Rev. Lett. 1977,
39, 695–698; b) I. Plesser, Z. Vager, R. Naaman, Phys. Rev.
Lett. 1986, 56, 1559–1562.
References
[1] L. Pasteur, Acad. Sci. Paris C. R. 1848, 26, 535–538.
[2] H. D. Flack, Acta Crystallogr. Sect. A: Found. Crystallogr.
2009, 65, 371–389.
[3] J. H. Van’t Hoff, Arch. Neerl. Sci. Exactes Nat. 1874, 9, 445–
454.
[4] A. M. Rouhi, Chem. Eng. News 1999, 77, 28–32.
[5] S. Allenmark, J. Gawronski, Chirality 2008, 20, 606–608.
[6] E. Fischer, Ber. Dtsch. Chem. Ges. 1894, 27, 2985–2993.
[7] H. Caner, E. Groner, L. Levy, I. Agranat, Drug Discovery
Today 2004, 9, 105–110.
[33] G. Both, E. P. Kanter, Z. Vager, B. J. Zabransky, D. Zajf-
man, Rev. Sci. Instrum. 1987, 58, 424–427.
[34] Z. Vager, N. Naaman, E. P. Kanter, Science 1989, 244, 426–
431.
[35] D. Zajfman, Z. Vager, R. Naaman, F. E. Mitchell, E. P.
Kanter, T. Graber, A. Belkacem, J. Chem. Phys. 1991, 94,
6377–6387.
[36] R. Wester, F. Albrecht, M. Grieser, L. Knoll, R. Repnow, D.
Schwalm, A. Wolf, A. Baer, J. Levin, Z. Vager, D. Zajfman,
Nucl. Instrum. Methods Phys. Res. Sect. A 1998, 413, 379–
396.
[8] P. Brewster, E. D. Hughes, C. K. Ingold, P. A. D. S. Rao,
Nature 1950, 166, 178–179.
[9] E. Fischer, Chem. Ber. 1890, 23, 370–394.
[10] E. Fischer, Chem. Ber. 1907, 40, 102–106.
[11] A. Wohl, F. Momber, Ber. Dtsch. Chem. Ges. 1917, 50, 455–
462.
[37] V. Schurig, in From metal organic chemistry to chromatogra-
phy and stereochemistry (Ed.: H. J. Issaq), Marcel Dekker,
New York, 2001, pp. 327–347.
[38] E. Heilbronner, J. D. Dunitz, Reflections on Symmetry in
Chemistry…and Elsewhere, Verlag Helvetica Chimica Acta
and VCH, Basel and Weinheim, 1993, p. 67.
[12] M. A. Rosanoff, J. Am. Chem. Soc. 1906, 28, 114–121.
[13] W. Klyne, J. Buckingham, Atlas of Stereochemistry: Absolute
Configurations of Organic Molecules, Vols. 1 and 2, 2nd Edi-
tion, Chapman and Hall, London, 1978.
[14] J. M. Bijvoet, A. F. Peerdeman, A. J. van Bommel, Nature
1951, 168, 271–272.
[39] P. Herwig, K. Zawatzky, M. Grieser, O. Heber, B. Jordon-
Thaden, C. Krantz, O. Novotny, R. Repnow, V. Schurig, D.
Schwalm, Z. Vager, A. Wolf, O. Trapp, H. Kreckel, Science
2013, 342, 1084–1086.
[40] K. Zawatzky, P. Herwig, M. Grieser, O. Heber, B. Jordon-
Thaden, C. Krantz, O. Novotny, R. Repnow, V. Schurig, D.
Schwalm, Z. Vager, A. Wolf, H. Kreckel, O. Trapp, Chem.
Eur. J. 2014, 20, 5555–5558.
[15] J. M. Bijvoet, Endeavour 1955, 14, 71–77.
[16] a) H. D. Flack, G. Bernardinelli, D. A. Clemente, A.
Linden, A. L. Spek, Acta Crystallogr. Sect. B: Struct. Sci.
2006, 62, 695–701; b) H. D. Flack, G. Bernardinelli, Chirali-
ty 2008, 20, 681–690.
[17] a) Y. Inokuma, S. Yoshioka, J. Ariyoshi, T. Arai, Y. Hitora,
K. Takada, S. Matsunaga, Rissanen, M. Fujita, Nature 2013,
495, 461–467; Corrigendum: b) Y. Inokuma, S. Yoshioka, J.
Ariyoshi, T. Arai, Y. Hitora, K. Takada, S. Matsunaga,
Rissanen, M. Fujita, Nature 2013, 501, 262.
[41] J. M. Schwab, C.-K. Ho, J. Chem. Soc. Chem. Commun.
1986, 872–873.
Isr. J. Chem. 0000, 00, 1 – 10
ꢂ 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.ijc.wiley-vch.de
&8
&
ÞÞ
These are not the final page numbers!

Full Paper
[42] J. M. Schwab, T. Ray, C.-K. Ho, J. Am. Chem. Soc. 1989,
111, 1057–1063.
[48] H. Urabe, T. Matsuka, F. Sato, Tetrahedron Lett. 1992, 33,
4179–4182.
[43] Y. Gao, R. M. Hanson, J. M. Klunder, S. Y. Ko, H. Masa-
mune, K. B. Sharpless, J. Am. Chem. Soc. 1987, 109, 5165–
5180.
[44] S. E. Denmark, T. K. Jones, J. Org. Chem. 1982, 47, 4595–
4597.
[49] K. Ohno, J. Tsuji, J. Am. Chem. Soc. 1968, 90, 99–107.
[50] R. Stꢄrmer, Liebigs Ann. Chem. 1991, 311–313.
[51] V. Schurig, D. Schmalzing, M. Schleimer, Angew. Chem. Int.
Ed. 1991, 30, 987–989.
[52] H. Cousin, O. Trapp, V. Peulon-Agasse, X. Pannecoucke, L.
Banspach, G. Trapp, Z. Jiang, J. C. Combret, V. Schurig,
Eur. J. Org. Chem. 2003, 3273–3287.
[45] T. Katsuki, K. B. Sharpless, J. Am. Chem. Soc. 1980, 102,
5974–5976.
[46] J. R. Parikh, W. von E. Doering, J. Am. Chem. Soc. 1967,
89, 5505–5507.
[47] K. C. Nicolaou, M. E. Duggan, C.-K. Hwang, J. Am. Chem.
Soc. 1989, 111, 6676–6682.
Received: September 4, 2016
Published online: && &&, 0000
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FULL PAPERS
O. Trapp,* K. Zawatzky
&& – &&
Synthesis of Cryptochiral (R,R)-2,3-
Dideuterooxirane as Stereochemical
Reference Compound and Chemical
Correlation with D-
(+)-Glyceraldehyde
Isr. J. Chem. 0000, 00, 1 – 10
ꢂ 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.ijc.wiley-vch.de
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These are not the final page numbers!