Stereoselective synthesis and X-ray structure determination of labeled [1, 2, 3-13C3]-1-(Phenylsulfinyl)-3-benzyloxyacetone

Article abstract of DOI:10.1007/s10870-007-9226-5

[1,2,3-¹³C₃]-1-(Phenylsulfinyl)-3-benzyloxyacetone, C₁₆H₁₆O₃S, (3) has been synthesized and its crystal structure has been determined by a single-crystal X-ray diffraction analysis. The X-ray diffract

Full text of DOI:10.1007/s10870-007-9226-5

J Chem Crystallogr (2007) 37:663–667
DOI 10.1007/s10870-007-9226-5
ORIGINAL PAPER
Stereoselective Synthesis and X-Ray Structure Determination
of Labeled [1, 2, 3- C ]-1-(Phenylsulfinyl)-3-Benzyloxyacetone
1
3
3
Ernest M. Asani Æ Victor N. Khrustalev Æ Rachel M. Williamson Æ
Rodolfo A. Martinez Æ Clifford J. Unkefer Æ Tatiana V. Timofeeva
Received: 17 November 2006 / Accepted: 27 June 2007 / Published online: 3 August 2007
ꢀ
Springer Science+Business Media, LLC 2007
1
3
13
Keywords [1,2,3- C ]-1-(Phenylsulfinyl)-
Abstract [1,2,3- C ]-1-(Phenylsulfinyl)-3-benzyloxyac-
3
3
etone, C H O S, (3) has been synthesized and its crystal
1
3-benzyloxyacetone Á Chiral sulfur Á Synthesis Á
6 16 3
structure has been determined by a single-crystal X-ray
diffraction analysis. The X-ray diffraction study revealed
that compound 3 crystallizes in the monoclinic crystal
system in the acentric space group Pc, with cell constants
at T = 100 K: a = 16.073(5), b = 5.5079(16), c = 7.949(2)
Molecular and crystal structures
Introduction
ꢁ
3
13
[1,2,3- C ]-1-(phenylsulfinyl)-3-benzyloxyacetone,
˚
˚
A, b = 100.221(4) , V = 692.6(3) A , Z = 2, d
= 1.383
calc
3
3
g/cm . Compound 3 contains the chiral tetravalent three-
coordinated sulfur atom, which has a distorted tetrahedral
configuration with a lone electron pair occupying one of
the tetrahedron vertices. In the crystal, the molecules are
packed in stacks along the b axis; the stacks consist of the
molecules of the same chirality. Furthermore, the stacks of
the molecules of the opposite chirality alternate along the c
axis. The molecules in neighboring stacks are arranged by
head-to-tail orientations. There are no short intermolecular
contacts in the crystal of 3.
C H O S, (3) is a very reactive species towards electro-
1
6 16 3
philes and bases. Compound 3 can be readily converted to
the b-hydroxyl sulfoxides [1] and has been used to syn-
1
3
thesize chiral [2- C]-glycerol [2]. It was then used in
feeding experiments to show labeling of the C-2 of the
1
glycolate units from [2- C]-glycerol in soraphen A [3] and
3
1
3
leucomycin [4] and C-1 from [1(3)- C] glycerol in con-
canamycin [5]. Furthermore, b-keto sulfoxides can be
alkylated at the a-carbon atom leading to a variety of other
chain extension [6].
Furthermore, it should be noted that these chiral sulf-
oxides are useful auxiliaries in asymmetrical synthesis [7].
They are of potential interest in the fields of biology and
material sciences and they have been used, for instance, in
the synthesis of chiral liquid crystals with ferroelectric
properties [8].
E. M. Asani Á V. N. Khrustalev Á R. A. Martinez (&) Á
T. V. Timofeeva (&)
Department on Natural Sciences, New Mexico Highlands
University, Las Vegas, NM 87701, USA
e-mail: rudy@nmhu.edu
Experimental
T. V. Timofeeva
e-mail: tvtimofeeva@nmhu.edu
Materials and General Methods
V. N. Khrustalev
Institute of Organoelement Compounds, Russian Academy of
Sciences, Moscow 119991, Russia
All chemicals were purchased from Sigma-Aldrich and
Fisher scientific chemical company. These reagents and
chemicals were used without further purification. Dichlo-
romethane was used as the main solvent for all extractions.
R. M. Williamson Á C. J. Unkefer
Bioscience Division, Los Alamos National Laboratory, National
Stable Isotope Resource, Los Alamos, NM 87701, USA
1
13
All H NMR and proton decoupled C NMR spectra were
123

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J Chem Crystallogr (2007) 37:663–667
recorded on a Bruker AC-300 broadband high field NMR
X-ray Crystal Structure Determination of 3
spectrometer. A 5% solution of pure sample in CDCl with
3
0
.03% tetramethylsilane (TMS) was used for the analysis.
Data were collected on a Bruker three-circle diffractometer
equipped with a SMART APEX-II CCD area detector with
˚
graphite-monochromated MoKa radiation (k = 0.71073 A,
u and x scan mode) and corrected for Lorentz and polari-
zation effects and for absorption [9]. For details, see
Table 1. The structure was solved by direct methods and
Synthesis of Compound 2
1
3
A solution of C-thioanisole (20.0 g, 161.29 mmol) in
dichloromethane (200 mL) was added to silicic acid slurry
2
refined by full-matrix least-squares refinement on F with
anisotropic displacement parameters for all non-hydrogen
atoms. The hydrogen atoms were generated geometrically
and included in the refinement with fixed positional and
thermal parameters. The absolute structure of 3 was
objectively determined by the refinement of the Flack
parameter, which was 0.02(5). All calculations were carried
out using the SHELXTL (PC Version 6.12) program [10].
(
10.9 g silica in 32.7 mL of deionized water). This mixture
was stirred for 10 min after that sulfuryl chloride (19.59 g,
45.16 mmol, 0.9 equiv.) was added at room temperature.
1
Initial NMR after about 10 min of reaction time showed
the complete formation of methyl phenyl sulfoxide. The
mixture was quenched with a saturated sodium bicarbonate
until fizzing stopped. This entire mixture was poured into a
separatory funnel containing dichloromethane (75 mL) and
DI water (100 mL). The organic layer was separated,
washed thoroughly with deionized water (3 · 100 mL).
The combined organic layers were dried over anhydrous
sodium sulfate, filtered and all volatile components were
removed under reduced pressure to afford 20.4 g of a white
Table 1 Crystallographic data for 3
Compound
3
Empirical formula
Fw
C
16 16 3
H O S
crystalline solid which was used in the next reaction
1
without purification. H NMR (300 MHz in CDCl with
288.35
100
3
Temperature (K)
Cryst size (mm)
Cryst syst
0
.03% TMS), d: 7.67, 7.66, 7.64, 7.53 7.51 (m, 5H), 2.95
s), 2.49 (s) (d, J = 138.99). C NMR (300 MHz in
0.50 · 0.40 · 0.30
Monoclinic
Pc
1
3
(
CDCl ), d: 145.88, 131.15, 129.48, 123.60, 44.11.
3
Space group
˚
a (A)
16.073(5)
5.5079(16)
7.949(2)
˚
b (A)
˚
c (A)
Synthesis of Compound 3
a (deg)
b (deg)
c (deg)
90
1
1- C]-Methyl phenyl sulfoxide (6 g, 42.55 mmol) and
3
[
100.221(4)
90
dry THF (60 mL) were placed in an oven dried 100 mL
round bottom flask equipped with a magnetic stir bar,
rubber septum, and a nitrogen inlet. The mixture was flu-
shed under a constant flow of nitrogen and set to À78 ꢁC
using a dry ice and 100% ethanol bath. Lithium diisopro-
pylamide (42.55 mL, 63.88 mmol) was added slowly for a
period of 5 min and after about 45 min of stirring [1,
3
˚
V (A )
692.6(3)
Z
2
À3
dc (g cm
F (000)
)
1.383
304
À1
l (mm
)
0.238
h range (deg)
2.58–27.09
À20 ꢀ h ꢀ 20
À7 ꢀ k ꢀ 7
À10 ꢀ l ꢀ 10
5857
1
3
2
- C ]-ethyl-1-benzyloxy glycolate (6.89 g, 42.55 mmol)
2
Index range
was added slowly to the reaction mixture. The reaction was
then allowed to warm up to room temperature. After about
3
h of stirring, the reaction mixture was poured into a se-
No. of rflns collected
No. of unique rflns
paratory funnel containing dichloromethane (150 mL) and
deionized water (100 mL). The aqueous layer was then
extracted and poured into another separatory funnel con-
taining dichloromethane (75 mL). This mixture was then
acidified to a pH of 2 and the organic layer was separated,
dried over sodium sulfate, filtered and concentrated in
2850 [Rint = 0.0221]
2787
No. of rflns with I > 2r(I)
R1; wR2 (I > 2r(I))
R1; wR2 (all data)
0.0323; 0.0735
0.0332; 0.0741
2850/2/181
1.001
Data/restraints/parameters
2
GOF on F
vacuo to afford 9.5 g (86%) of a light yellow crystalline
1
material. H NMR (300 MHz in CDCl with 0.03% TMS),
À3
)
˚
Largest diff peak/hole (eA
0.251/À0.184
0.932; 0.890
3
Abs cor Tmax;
T
min
d: 7.5170, (5 H, m).
1
23

J Chem Crystallogr (2007) 37:663–667
665
CCDC-627282 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free
of charge via www.ccdc.cam.ac.uk/conts/retrieving.html
(
or from the Cambridge Crystallographic Data Centre, 12,
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223
36033).
3
Fig. 1 Molecular structure of 3. The non-H atoms are shown with the
thermal ellipsoids drawn at the 50% probability level. H atoms are
drawn as circles of arbitrary small radius for clarity
Results and Discussion
1
3
C-methylphenyl sulfide 1 (scheme 1) was oxidized using
sulfuryl chloride and silicic acid in dichloromethane, to
First, compound 3 contains the tetravalent three-coor-
dinated sulfur atom, which has a distorted tetrahedral
configuration with a lone electron pair occupying one of
the tetrahedron vertices. The stereochemically active lone
pair pushes back the O1, C1 and C7 atoms bonded to the
sulfur atom. The resulting distortions towards a trigonal
1
3
give C-methylphenyl sulfoxide 2 [11, 12] in high yield.
The latter was then treated with LDA in a THF solution at
1
3
À78 ꢁC followed by the addition of [1,2- C ]-ethyl-1-
2
1
benzyloxy glycolate to give [1,2,3- C ]-1-(phenylsulfi-
3
3
nyl)-3-benzyloxyacetone, (3) with an 86% overall yield.
The chiral sulfoxide group in compounds 2 and 3 allows
for the stereoselective synthesis of a variety of other chain
extensions. In fact this has been the bases through which
ꢁ
pyramid are evident in the O1–S1–C1 (106.03(9) ), O1–
ꢁ
ꢁ
S1–C7 (106.01(9) ) and C1–S1–C7 (99.15(9) ) bond angles
ꢁ
as compared to the ideal value of 109.5 . The significant
1
3
chiral [2- C]-glycerol was synthesized as it was described
1
in [2]. This chirality makes the H spectrum of 3 remark-
decrease of the C1–S1–C7 bond angle in comparison with
C1–S1–O1 and C7–S1–O1 is related to additional steric
repulsion between the C1 and C7 carbon atoms and the
lone pairs of the O1 oxygen atom. Thus, the sulfur atom in
3 is asymmetric. This chiral center promotes the specific
crystal packing arrangement of the molecules 3 (see
below).
able in the sense that the two methylene hydrogen atoms
close to this chiral centre are different chemically, and this
1
effect can clearly be seen on the H spectrum of this
compound.
The overall scheme leading to the synthesis of com-
pound 3 is presented below:
Second, compound 3 comprises the long chain con-
taining the saturated –CH -methylene carbon atoms, with
Compound 3 was characterized by X-ray crystallogra-
phy. Single crystals suitable for an X-ray diffraction
analysis were obtained by slow evaporation from ethanol
solution over a period of 5 days. The molecular structure of
2
the terminal phenyl substituents. This construction gives
rise to a high flexibility of the molecule 3 and allows it to
adopt various conformations. The high flexibility is also
responsible for the unusual crystal symmetry of 3.
3
along with the atom numbering scheme is shown in
Fig. 1, bond lengths and angles are listed in Table 2.
The X-ray diffraction study revealed that compound 3
crystallizes in the monoclinic crystal system in the acentric
space group Pc. Such very rare (probability of
In the molecule of 3, the C7–C8( = O2)–C9–O3–C10–
C11 fragment is almost planar (the average deviation of the
˚
atoms from the mean-square plane is equal to 0.066 A).
The C7–S1 = O1 sulfinyl sequence is practically perpen-
ꢁ
*0.4 % [13]) crystal symmetry of 3 is related to two
reasons.
dicular to this plane (the dihedral angle is 84.1 ). The
ꢁ
terminal phenyl rings are oriented at angle of 58.3 to each
.
.
Scheme. 1
O
S
1
3
S
CH3
1) wet silica, CH Cl2
13
2
CH3
2
) sulfuryl chloride
(1)
(2
.
.
..
O
O
O
S
13
13
CH3 1) LDA, THF, -78°C
S
C
O
13
13
C
H
C
H
2
2
2) C11H14O3
(2)
(3)
123

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J Chem Crystallogr (2007) 37:663–667
˚
Table 2 Bond lengths [A] and
angles [ꢁ] for 3
S(1)–O(1)
1.5009(15)
C(5)–C(6)
1.388(3)
1.523(3)
S(1)–C(1)
1.796(2)
1.825(2)
C(7)–C(8)
S(1)–C(7)
C(8)–C(9)
1.508(3)
1.509(3)
1.391(3)
1.402(3)
1.381(3)
1.399(3)
1.387(3)
1.399(3)
O(2)–C(8)
1.211(3)
C(10)–C(11)
C(11)–C(16)
C(11)–C(12)
C(12)–C(13)
C(13)–C(14)
C(14)–C(15)
C(15)–C(16)
O(3)–C(9)
1.405(2)
O(3)–C(10)
1.439(2)
C(1)–C(6)
1.393(3)
C(1)–C(2)
1.393(3)
C(2)–C(3)
1.387(3)
C(3)–C(4)
1.391(3)
C(4)–C(5)
1.391(3)
O(1)–S(1)–C(1)
O(1)–S(1)–C(7)
C(1)–S(1)–C(7)
C(9)-O(3)–C(10)
C(6)–C(1)–C(2)
C(6)–C(1)–S(1)
C(2)–C(1)–S(1)
C(3)–C(2)–C(1)
C(2)–C(3)–C(4)
C(5)–C(4)–C(3)
C(6)–C(5)–C(4)
C(5)–C(6)–C(1)
C(8)–C(7)–S(1)
106.03(9)
106.01(9)
99.15(9)
O(2)–C(8)–C(9)
124.02(19)
120.88(19)
114.97(16)
110.95(16)
108.93(16)
119.02(19)
121.21(18)
119.70(18)
120.55(19)
120.23(19)
119.72(19)
119.94(19)
120.53(19)
O(2)–C(8)–C(7)
C(9)–C(8)–C(7)
110.61(15)
120.91(19)
119.82(16)
118.94(15)
119.40(18)
120.09(19)
120.15(19)
120.29(18)
119.14(19)
105.65(13)
O(3)–C(9)–C(8)
O(3)–C(10)–C(11)
C(16)–C(11)–C(12)
C(16)–C(11)–C(10)
C(12)–C(11)–C(10)
C(13)–C(12)–C(11)
C(12)–C(13)–C(14)
C(15)–C(14)–C(13)
C(14)–C(15)–C(16)
C(11)–C(16)–C(15)
other. Moreover, the interplane angle between the C1/C6
phenyl plane and the plane of the C7–S1 = O1 sulfinyl
the stacks of the molecules of the opposite chirality alter-
nate along the c axis (Fig. 2). The molecules in
neighboring stacks are arranged by head-to-tail orienta-
tions. There are no short intermolecular contacts in the
crystal of 3.
ꢁ
fragment is 105.2 , and the interplane angle between the
C11/C16 phenyl plane and the plane of C7–C8( = O2)–
ꢁ
C9–O3–C10–C11 fragment is 109.5 .
In the crystal of 3 the molecules are packed in stacks
along the b axis. It is important to note that the stacks
consist of the molecules of the same chirality. Furthermore,
As it is well-known, the both factors bringing to the rare
crystal symmetry of compound 3 can also give rise to
different polymorphs (for the related derivatives, see [14,
Fig. 2 The crystal packing of 3
viewed down the
crystallographic b axis
1
23

J Chem Crystallogr (2007) 37:663–667
667
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Acknowledgments Authors are grateful to the National Science
Foundation for support via New Mexico EPSCoR program and NSF/
DMR grant for acquisition of single-crystal X-ray diffractometer.
VNK, RAM and TVT are grateful for National Institute of Health for
support via NMHU RIMI program.
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