Steric considerations on improving the diastereomeric ratio of (+)- and (-)-neomenthyl phenyl sulfoxides using bulky-headed oxidant hexadecyltrimethylammonium periodate and assignment of their configuration

Article abstract of DOI:10.1002/chir.22454

Abstract The bulky-headed oxidant hexadecyltrimethylammonium periodate affords the diastereomeric pairs, (Ss)-(+)/(Rs)-(+) and (Ss)-(-)/(Rs)-(-)-neomenthyl phenyl sulfoxides in stereochemically pure states with improved diastereomeric excess (48% diastere

Full text of DOI:10.1002/chir.22454

CHIRALITY 27:370–374 (2015)
Short Communication
Steric Considerations on Improving the Diastereomeric Ratio of (+)-
and (À)-Neomenthyl Phenyl Sulfoxides Using Bulky-Headed Oxidant
Hexadecyltrimethylammonium Periodate and Assignment of Their
Configuration
1
1
1
2
*
UMESH V. CHAUDHARI, DEEPAK SINGH, PRADEEP T. DEOTA, AND ASHUTOSH V. BEDEKAR
1Applied Chemistry Department, Faculty of Technology & Engineering, The M. S. University of Baroda, Vadodara, Gujarat, India
2Department of Chemistry, Faculty of Science, The M. S. University of Baroda, Vadodara, Gujarat, India
ABSTRACT
The bulky-headed oxidant hexadecyltrimethylammonium periodate affords the
diastereomeric pairs, (Ss)-(+)/(Rs)-(+) and (Ss)-(À)/(Rs)-(À)-neomenthyl phenyl sulfoxides in
stereochemically pure states with improved diastereomeric excess (48% diastereomeric excess
[de]) as compared to its nonbulky counterpart, sodium metaperiodate (28% de) from respective
(+)/(À)-neomenthyl phenyl sulfides. Steric effects involving the head group volume of
hexadecyltrimethylammonium periodate is found to play a role in improving the diastereomeric
ratio of the products. The two diastereomers can be readily separated by column chromatogra-
phy. Absolute configuration at the sulfur center in (+)-neomenthyl phenyl sulfoxide was deter-
mined by single-crystal X-ray crystallography and found to be Ss. Relative configurations of
other sulfoxides were assigned based on the configuration of (+)-neomenthyl phenyl sulfoxide.
Chirality 27:370–374, 2015. © 2015 Wiley Periodicals, Inc.
KEY WORDS: diastereoselective; hexadecyltrimethylammonium periodate; steric hindrance;
neomenthyl phenyl sulfoxides
Optically active sulfoxides are often used as chiral auxiliaries
and ligands for numerous asymmetric transformations.1,2 The
past two decades have seen an extensive use of chiral sulfoxides
in asymmetric synthesis, establishing their role as one of the
most efficient and versatile chiral controllers.3,4 Various
methods have been developed to carry out asymmetric
oxidation of sulfides to optically pure sulfoxides in either
diastereoselective or enantioselective mode.1–4 The diastereo-
selectivity achieved has been generally accounted for by invok-
ing either steric or neighboring group participation.5
Menthol and its derivatives are among those that have
found application as chiral auxiliaries for the preparation of
optically active sulfoxides.6 Chiral (+)-methyl neomenthyl
sulfoxides (2a and 2b) are often intermediates in the synthe-
sis of chiral oxiranes via corresponding sulfoximines in asym-
metric methylene transfer reactions. Oxidation of (1S,2S,5R)-
(+)-methyl neomenthyl sulfide (1) using hydrogen peroxide
furnished the epimeric sulfoxides (2a and 2b) (Scheme 1)
in a ratio of 35:65, with the major isomer (2b) having sulfox-
ide oxygen oriented away from the C-2 isopropyl group.7,8
Similar observations are reported in the literature for
the oxidation of different neomenthyl sulfides. Recently,
Demakova et al. reported the oxidation of (1S,2S,5R)-(+)-
hetaryl neomenthyl sulfides using various reagents to yield
two diastereomeric hetaryl neomenthyl sulfoxides in different
ratios.9
It was envisaged that a better diastereomeric excess of
neomenthyl sulfoxides could be achieved using bulkier oxi-
dants, which would have limited access to the sulfur center from
the more hindered side having isopropyl group. Consequently,
the oxidation would result via the approach of the oxidant from a
less hindered side, giving better stereodifferentiation.
EXPERIMENTAL
General Methods
(À)-Menthol (enantiomeric excess [ee]: 99%) and (+)-menthol
(ee: 99%) were purchased from Sigma Aldrich (St. Louis, MO). All sol-
vents were distilled prior to use and stored on oven-dried molecular
sieves (4Å). Thin-layer chromatography (TLC) analyses were done on
glass plates using silica gel G containing 13% calcium sulfate as binder.
The spots were visualized in iodine vapor. Column chromatography was
performed using Acme’s silica gel (60–120 mesh size) and elution was
done using light petroleum (60–80) and ethyl acetate mixtures. Melting
points were recorded in open capillary tubes and are uncorrected. 1H
NMR and 13C NMR spectra were recorded on a Bruker (Billerica, MA)
(400/500) FT-NMR spectrometer (1H NMR 400/500 MHz and 13C
NMR at 100 MHz) using CDCl3 as solvent. The chemical shifts, in parts
per million (ppm), are either relative to tetramethylsilane (TMS) as an in-
ternal standard or the residual peak of the solvent. Multiplicities of sig-
nals are denoted as doublet (d), doublet of quartet (dq), and multiplet (m).
Mass spectra were recorded on a Thermo-Fisher (Waltham, MA) DSQ II
*Correspondence to: P.T. Deota, Applied Chemistry Department, Faculty of
Technology & Engineering, The Maharaja Sayajirao University of Baroda,
Post Box No. 51, Kalabhavan, Vadodara 390 001, Gujarat, India. E-mail:
deotapt@yahoo.com
Received for publication 27 December 2014; Accepted 25 March 2015
DOI: 10.1002/chir.22454
Published online 7 May 2015 in Wiley Online Library
(wileyonlinelibrary.com).
In the above examples, the skeleton of the neomenthyl
group behaves as a chiral auxiliary, with the equatorial isopro-
pyl appendage exerting steric hindrance to the oxidant.
However, the diastereoselectivity for this sulfoxidation is
moderate using achiral oxidants.
© 2015 Wiley Periodicals, Inc.

DIASTEREOMERIC RATIO OF (+)- AND (À)-NEOMENTHYL PHENYL SULFOXIDES
371
(10 ml) at room temperature was added KOH solution
(1.5 g, 27.2 mmol) in dry ethanol (10 ml). The reaction mix-
ture was then heated to 60°C, followed by addition of the ap-
propriate menthyl tosylate (4a or 4b) (8.5 g, 27.2 mmol) in
dry ethanol (30 ml) and was allowed to stir for 12 h. The sol-
vent was evaporated under vacuum and the residue was ex-
tracted with ethyl acetate (4 x 25 ml). The combined
organic extracts were washed with water (30 ml), brine
(20 ml), and dried over anhydrous sodium sulfate. The
solvent was removed under reduced pressure to obtain the
crude product as a pale yellow liquid, which after chro-
matography over a column of silica gel using light petroleum
afforded pure sulfide 5a (2.91 g, 52%); [α]D = + 98.25 (c = 1.00,
Scheme 1. Oxidation of (+)-methyl neomenthyl sulfide (1) using hydro-
gen peroxide-acetic acid.
GCMS instrument. Mass Spectra (HRMS) were recorded on an Agilent (Palo
Alto, CA) Q-Tof B.05.00 (B5042.0) high-resolution MSMS spectrometer
using electrospray ionization mode. For crystals of 6a the intensity data were
collected at 293K on a Nonius Kappa CCD diffractometer system equipped
with graphite-monochromated CuKa radiation (λ = 1.5418Å). The structure
was solved by a direct method (SIR97) and refined by a full-matrix least-
squares procedure based on F2. All nonhydrogen atoms were refined aniso-
tropically; hydrogen atoms were located at the calculated positions and were
refined by using a riding model with isotropic thermal parameters fixed at 1.2
times the Ueq value of the appropriate carrier atom.
CCDC: 1030433 For calculation of head group volume both TBAPI
and CTAPI were built in the Schrodinger suite (New York, NY). Energy
of molecules under study were optimized using Density Functional The-
ory (DFT) within the Schrodinger suite, and such optimized structures
were used to measure the required dimension of the molecules to calcu-
late head volume of the structures under study. DFT is a quantum me-
chanical method mainly used to determine the ground state of systems.
1
CHCl3). H NMR (500 MHz, CDCl3): δ 0.84 (3H, d, J = 6.6
Hz), 0.89-0.93 (7H, m), 1.15-1.30 (3H, m), 1.70-1.80 (3H, m),
1.89 (1H, dq, Jd = 13.5 Hz, Jq = 2.8 Hz), 1.98-2.07 (1H, m),
3.63 (1H, m), 7.10-7.50 (5H, m). 13C NMR (100 MHz, CDCl3):
δ 20.6, 21.2 (2 x C, ÀCH(CH3)2), 22.2 (CH3), 26.2 (CH2), 26.5
(CH), 30.2 (ÀCH(CH3)2), 35.4, 40.5 (2 x C, CH2), 48.5 (CH, to
which isopropyl group is attached), 49.7 (ÀCHSC6H5), 126.1
(CH, aromatic), 128.8 (2 x CH, aromatic), 131.0 (2 x CH, aro-
matic), 136.8 (Cq, aromatic attached to sulfur). MS m/z
249.25 (M+ + 1). (À)-neomenthyl phenyl sulfide (5b) (2.96 g,
53%); [α]D = À97.63 (c = 1.00, CHCl3) as colorless liquid. Rf
0.82 (light petroleum).
Oxidation of sulfides (5a and 5b) using CTAPI. To stirred
solution of sulfides (0.5 g, 2.02 mmol) in aqueous methanol
(8:2) (10 ml) at room temperature was added cetyltri-
methylammonium periodate (CTAPI) (1.3 g, 7.07 mmol) in
portions over a period of 15 min. The mixture was then stirred
for 45 h. The reaction mixture was filtered and the filtrate was
extracted with ethyl acetate (5 × 25 ml), dried over anhydrous
sodium sulfate, and evaporated under reduced pressure to
give a mixture of diastereomeric sulfoxides ((6a and 6a’)
(0.38 g, 72%)) or (6b and 6b’) (0.37 g, 71%)) depending on
the sulfide used. The ratio of (6a and 6a’) was found to be
(À)- and (+)-menthyl-p-toluenesulfonate (4a and 4b). (À)-4a was
prepared according to the published procedure8 as depicted
in Scheme 2 starting from (1R,2S,5R)-(À)-menthol (3a),
yield 93%; mp 92–94°C; [α]D = À69.02 (c = 2.99, CHCl3)
(lit.10 [α]D = À69.5 (c = 2.99, CHCl3)) while (+)-4b from
(1S,2R,5S)-(+)-menthol (3b) following a similar procedure,
yield 92%; mp 90–92°C; [α]D = +68.61 (c = 2.99, CHCl3).
(+) and (À)-neomenthyl phenyl sulfides (5a and 5b). To a stirred
solution of thiophenol (2.5 g, 22.7 mmol) in dry ethanol
Scheme 2. Preparation of (1S,2S,5R)-(+) and (1R,2R,5S)-(À)-neomenthyl phenyl sulfides (5a and 5b).
Chirality DOI 10.1002/chir

372
CHAUDHARI ET AL.
25.71:74.28 and that of (6b and 6b’) to be 26.38:73.62 as de-
aromatic), 131.3 (2 x CH, aromatic), 144.3 (Cq, aromatic at-
tached to sulfoxide). HRMS (ESI) m/z [M+Na]+ calculated
for C16H24OS: 287.1446 found: 287.1440.
1
termined by H NMR of their mixtures. Column chromato-
graphy of the product mixture over silica gel with light
petroleum/ethyl acetate (80:20) afforded major diastereo-
meric sulfoxide 6a’ as a white amorphous solid (0.28 g,
53%); Rf 0.52 (25% EtOAc/ light petroleum); mp = 120°C;
[α]D = + 230.77 (c = 0.7, CHCl3); 1H NMR (400 MHz, CDCl3):
δ 0.77 (3H, d, J = 6.4 Hz), 0.87-1.01 (3H, m), 1.06 (3H, d,
J = 6.4 Hz), 1.09 (3H, d, J = 6.4 Hz), 1.35-1.46 (1H, m),
1.75-1.96 (3H, m), 2.17-2.28 (1H, m), 2-30-2.34 (1H, m), 2.78
(1H, m), 7.48-7.62 (5H, m). 13C NMR (100 MHz, CDCl3): δ
21.4, 21.4 (2 x C, ÀCH(CH3)2), 22.9 (CH3), 26.4 (CH2),
27.8 (CH), 29.6 (ÀCH(CH3)2), 34.3, 35.2 (2 x C, CH2),
48.2 (CH, to which isopropyl group is attached), 62.1
(ÀCHSOC6H5), 124.5 (CH, aromatic), 128.9 (2 x CH,
aromatic), 130.2 (2 x CH, aromatic), 144.2 (Cq, aromatic
attached to sulfoxide). HRMS (ESI) m/z [M+Na]+ calcu-
lated for C16H24OS: 287.1446 found: 287.1449.
RESULTS AND DISCUSSION
We recently reported selective oxidation of structurally
different sulfides to corresponding sulfoxides using
hexadecyltrimethylammonium periodate (cetyltrimethylam-
monium periodate, CTAPI),11 which has a bulky head group.
Such unwieldiness is lacking in conventional oxidants like hy-
drogen peroxide, sodium metaperiodate, m-chloroperbenzoic
acid, etc.
In order to examine our hypothesis (vide supra) we quickly
prepared (1S,2S,5R)-(+)-neomenthyl phenyl sulfide (5a) in
two steps from (À)-menthol (3a) via (À)-menthyl tosylate
(4a).12 Nucleophilic attack of thiophenol on 4a in ethanolic
potassium hydroxide at 78°C for 10 h resulted in 5a
(Scheme 2).
(1S,2S,5R)-(+)-Neomenthyl phenyl sulfide (5a) was ini-
tially subjected to oxidation using sodium metaperiodate, by
the procedure of Leonard and Johnson,13 which furnished
an epimeric pair of sulfoxides (6a and 6a’) in 35.98:64.01
(63%) (Scheme 3).
Oxidation of 5a using CTAPI in water–methanol (8:2) at
25°C for 45 h following our reported procedure11 resulted in
the formation of diastereomeric sulfoxides (6a and 6a’) in
25.71:74.28 (72% ) (Scheme 3). The observed improvement
in the diastereomeric ratio in oxidation using CTAPI might
be attributed to the steric hindrance between its bulky head
group and the equatorial isopropyl group in 5a. No oxidation
Further elution of the column with light petroleum / ethyl
acetate (70:30) gave the minor diastereomeric sulfoxide 6a
as a colorless crystal (0.09 g, 17%); Rf 0.39 (25% EtOAc/ light
1
petroleum); mp = 80°C; [α]D = + 114.02 (c = 0.7, CHCl3); H
NMR (400 MHz, CDCl3): δ 0.70 (3H, d, J = 6.2 Hz), 0.98
(3H, d, J = 6.4 Hz), 1.0-1.08 (1H, m), 1.13 (3H, d, J = 6.4 Hz),
1.25-1.46 (3H, m), 1.63-1.72 (1H, m), 1.76-1.87 (1H, m), 1.89-
1.95 (1H, m), 2.00-2.03 (1H, m), 2.25-2.34 (1H, m), 3.37 (1H,
m), 7.50-7.55 (3H, m) 7.71-7.75 (2H, m). 13C NMR (100
MHz, CDCl3): δ 22.0, 22.2 (2 x C, ÀCH(CH3)2), 22.3 (CH3),
26.0 (CH2), 27.9 (CH), 29.5 (ÀCH(CH3)2), 35.7, 37.7 (2 x C,
CH2), 50.4 (CH, to which isopropyl group is attached), 65.7
(ÀCHSOC6H5), 125.7 (CH, aromatic), 129.1 (2 x CH,
Scheme 3. Oxidation of 5a and 5b using NaIO4, cetyltrimethylammonium periodate (CTAPI) and n-tetrabutylammonium periodate (TBAPI).
Chirality DOI 10.1002/chir

DIASTEREOMERIC RATIO OF (+)- AND (À)-NEOMENTHYL PHENYL SULFOXIDES
373
was observed at lower temperature (0-5°C) even after 10 h
when explored for further improvement in the diastereomeric
ratio.
CTAPI is relatively smaller, and hence the oxidation occurs
with better diastereoselectivity. Energy minimized structures
of 5a, 6a, 6a’, CTAPI, and TBAPI are shown in Figure 1.
An oxidant can approach the sulfur center in 5a via two
pathways. Equatorial isopropyl group in 5a poses more
steric hindrance to the incoming bulky headed oxidant, thus
making path-I less favored as compared to path-II. Therefore,
in oxidation using CTAPI, sulfoxide 6a is obtained as a minor
diastereomer, while 6a’ as major one. No reaction was
observed in the case of TBAPI as oxidant, as the counterion
IOÀ4 responsible for oxidation is unable to access the sulfur
center from either path due to long n-butyl chains, as shown
in Figure 1.
It was thought that oxidants bulkier than CTAPI might fur-
ther improve a de ratio in favor of 6a’ due to high steric
consideration. With this contention, 5a was subjected to oxi-
dation following the procedure of Santaniello et al.14 using
tetrabutylammonium periodate (TBAPI, head group volume
66.97 Å3) which has a bulkier head group than CTAPI
(head group volume 9.02 Å3). However, in contrast to
our anticipation it was found that the reaction did not
proceed at all even after 12 h under reflux. This could be
due to the excessively large head volume of TBAPI, which
perhaps completely blocks the oxidant from approaching
the sulfur center. The head group volume in the case of
A similar study was also performed on (1R,2R,5S)-(À)-
neomenthyl phenyl sulfide (5b), an enantiomer of 5a
Fig. 1. Energy minimized structures of 5a, 6a, 6a’, CTAPI and TBAPI.
Fig. 2. ORTEP diagram of 6a.
Chirality DOI 10.1002/chir

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CHAUDHARI ET AL.
(Scheme 3) obtained from (1S,2R,5S)-(+)-menthol (3b)
(Scheme 2) to examine the replicability. The results obtained
are in good agreement with those of oxidation of 5a using
three oxidants differing in their size.
ACKNOWLEDGEMENTS
We thank the Head, Chemistry Department, Faculty of
Science, Dr. Ashok Vishwakarma, Mr. Sanjay Verma and Mr.
Hemant Mande, The M.S. University of Baroda, for their help
in single crystal X-ray analysis. We also thank Prof. M. R. Yadav
and Mr. Ashish Kanhed, Pharmacy Department, The M.S. Uni-
versity of Baroda, for their help in head volume of oxidants.
The diastereomeric sulfoxides (6a/a’ and 6b/b’) obtained
from 5a and 5b exhibited considerable mobilities during
TLC analysis and hence their separation was easily achieved
by silica gel column chromatography. Compounds 6a and
6b are crystalline in nature, while 6a’ and 6b’ are amor-
1
SUPPORTING INFORMATION
phous. All the structures were confirmed by H as well as
13C NMR spectra and HRMS analysis. The absolute configu-
ration at sulfur in sulfoxide 6a was determined using single
crystal X-ray crystallography and was found to be Ss
(Figure 2). Accordingly, the epimeric sulfoxide 6a’ was con-
sidered Rs configuration at sulfur and sulfoxides 6b and 6b’
being enantiomers of 6a and 6a’ were assigned Rs and Ss,
respectively.
Additional supporting information may be found in the
online version of this article at the publisher’s web-site.
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1
An examination of the H NMR spectra of the sulfoxides
6a and 6a’ showed that the proton H-1 and three protons
of methyl group attached to C-5 of 6a appear at δ 3.37
and 0.70 ppm, while signals from these protons in 6a’
are observed at δ 2.78 and 0.77 ppm, respectively. This
difference in chemical shift allows for determination of
the diastereomeric purity of the compounds by simple
integration of the respective proton signals in the 1H
NMR spectrum. The oxidation products of 5a and 5b
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In summary, two new sulfoxides, 6a, 6a’, and their enantio-
mers, 6b, 6b’, have been prepared and their configurations de-
termined. The present work shows the effect of bulky headed
oxidant in improvement of diastereomeric ratio of (+)- and
(À)-neomenthyl phenyl sulfoxides (6a/6a’and 6b/6b’)
considering steric aspects. An overall increase of about 20% in
de was achieved using CTAPI for oxidation of (1S,2S,5R)-(+)-
and (1R,2R,5S)-(À)-neomenthyl phenyl sulfides 5a and 5b. A
study to explore the effect of the head volume of less bulkier
quaternary ammonium oxidants than TBAPI on the diaste-
reoselectivity of neomenthyl sulfoxides is currently under
way. Further, the protocol presented here can in principle
be used for other oxidations intended for achieving
diastereodifferentiation.
Chirality DOI 10.1002/chir