Enantiodivergent syntheses of (+)- and (?)-1-(2,6-dimethylphenoxy)propan-2-ol: A way to access (+)- and (?)-mexiletine from D-(+)-mannitol

Article abstract of DOI:10.1016/j.carres.2019.107892

Chiron approach was used to acquire optically pure (R)- and (S)-1-(2,6-dimethylphenoxy)propan-2-ol, immediate precursors of (S)- and (R)-mexiletines, respectively. Two different routes were followed from a D-mannitol-derived optically pure common precursor to get the enantiomeric alcohols separately. Comparison of their specific rotation values with the corresponding literature values as well as exact mirror-image relationship between their CD curves proved their high enantiopurity. These alcohols were then transformed to the corresponding amine-drugs in an efficient one-step process instead of two steps described in the literature.

Full text of DOI:10.1016/j.carres.2019.107892

CarbohydrateResearch487(2020)107892
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Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Enantiodivergent syntheses of (+)- and (−)-1-(2,6-dimethylphenoxy)
propan-2-ol: A way to access (+)- and (−)-mexiletine from D-(+)-mannitol
Avrajit Manna, Sandip Chatterjee, Ipsita Chakraborty, Tanurima Bhaumik∗
Department of Chemistry, Jadavpur University, Jadavpur, Kolkata, 700032, West Bengal, India
A R T I C L E I N F O
A B S T R A C T
Keywords:
Chiron approach was used to acquire optically pure (R)- and (S)-1-(2,6-dimethylphenoxy)propan-2-ol,
immediate precursors of (S)- and (R)-mexiletines, respectively. Two different routes were followed from a
D-mannitol-derived optically pure common precursor to get the enantiomeric alcohols separately. Comparison of
their specific rotation values with the corresponding literature values as well as exact mirror-image relationship
between their CD curves proved their high enantiopurity. These alcohols were then transformed to the corre-
sponding amine-drugs in an efficient one-step process instead of two steps described in the literature.
Chiral pool synthesis
Chiron approach
D-(+)-mannitol
Enantiodivergent synthesis
Amine drugs
Common chiral intermediate
1. Introduction
Williamson's aryl ether formation using 2,6-dimethylphenol or phtha-
limide substitution under Mitsunobu's condition followed by imide
Mexiletine, 1 and ent-1 (Fig. 1), is 1-(2,6-dimethylphenoxy)-2-pro-
panamine. It is a class I–B antiarrhythmic oral drug [1]. This drug can
also be used clinically in many disorders [2] such as myotonic syn-
dromes, sporadic amyotrophic lateral sclerosis, Timothy syndrome.
Mexiletine is clinically useful to relieve neuropathic pain and pre-
scribed for treating patients with painful diabetic neuropathy. The
therapeutic effect of mexiletine can be correlated with the block of
voltage-dependent sodium ion channels present in both cardiac and
skeletal muscle fibers. Though this chiral drug is clinically used as ra-
cemate, mexiletine enantiomers are found to differ in both pharmaco-
dynamics and pharmacokinetics. The (R)-isomer, ent-1 was found to be
more potent in experimental arrhythmias [3], in binding studies on
cardiac sodium channels [4], and in producing a tonic block of the
skeletal muscle channel [5]. On the other hand, the (S)-isomer, 1 is
superior for the treatment of allodynia [6]. Consequently, development
of strategies to access both the enantiomers of mexiletine continues to
be at the forefront of organic synthesis. There are reports of many ap-
proaches to access mexiletine enantiomers. Racemic mexiletines have
been resolved by different methods: (i) classical resolution methods
involving formation of diastereomeric salts with di-p-toluoyltartaric
acid [3], dibenzoyltartaric acid [7]; (ii) derivatization with a chiral
auxiliary tetrahydropyranyl-protected (R)-(−)-mandelic acid [8]; (iii)
chromatographic methods utilizing chiral stationary phase or involving
separation of diastereomeric pair produced via covalent derivatization
and (iv) enzymatic processes [10]. Several synthetic strategies have
been reported also. Key reaction involved in many of these was either
hydrazinolysis. Chiral precursors such as (S)-(+)-3-bromo-2-methyl-1-
propanol (overall yield 7.2%) [7], (S)-(+)- and (R)-(−)-2-amino-1-
propanol (overall yields [11a]11a 28% and 32%, respectively) [11a,c],
(S)-(−)- and (R)-(+)-propylene oxide (overall yields 24% and 34%,
respectively) [11b] and (R)-epichlorohydrin (overall yield 34%) [11d]
were stereospecifically converted to the corresponding enantiomers of
mexiletine. Loughhead and co-workers [11a] reported overall yields
(28% and 32%) with reference to the reaction between chiral 2-amino-
1-propanol and 1,3-dimethyl-2-fluorobenzenetricarbonylchromium
complex. They referred to Mahaffy and Hamilton, who prepared the
chromium complex in 28% yield. Hence, overall yields are expected to
be lower than the reported values [11c]. Carocci and co-workers’ [11c]
methodology involving Mitsunobu reaction for the aryl ether bond
formation provided (S)- and (R)-mexiletines in 36–39% and 44–46%
overall yields, respectively. Asymmetric syntheses of both the en-
antiomers of mexiletine have been achieved by Han and co-workers
[12] by nucleophilic substitution of two epimeric (sulfonyloxymethyl)
aziridines as the key step. The overall yield of (S)-mexiletine referred to
a relatively expensive chiral hydroxymethylaziridine derivative was
60%; whereas that of (R)-mexiletine is expected to be lower as it re-
quired isolation of the appropriate intermediate from an epimeric
mixture. Chirality transfer agents were utilized by few scientists toward
the syntheses of mexiletine and their structural analogs. Huang and co-
workers [13] reported use of chiral spiroborate ester as chiral catalyst,
whereas Ryan and co-workers [1,14] used chiral tert-butanesulfinamide
as chiral auxiliary.
∗ Corresponding author.,
E-mail addresses: tanurimabhaumik@gmail.com, tanurima.bhaumik@jadavpuruniversity.in (T. Bhaumik).
https://doi.org/10.1016/j.carres.2019.107892
Received 10 August 2019; Received in revised form 30 November 2019; Accepted 10 December 2019
Availableonline16December2019
0008-6215/©2019ElsevierLtd.Allrightsreserved.

A. Manna, et al.
CarbohydrateResearch487(2020)107892
conventional functional group modifications of the two functionally
differentiated masked primary hydroxyl groups in 3 were to be carried
out without disturbing the chiral center to which they were attached.
More obviously we could say that displacement of the two modified
primary hydroxyl groups by nucleophilic hydride and 2,6-dimethyl-
phenol in two possible alternative ways would allow us to access both
the enantiomeric alcohols in optically pure forms. As optical integrity
would be maintained throughout, there would be no ambiguity in the
assignment of absolute configurations to the chiral centers of the final
products as well as of all the synthetic intermediates.
Fig. 1. Enantiomers of mexiletine.
In few synthetic procedures, the two secondary alcohols 2 and ent-2
(Scheme 1) were involved as the immediate precursors of mexiletine
enantiomers. In the year 2000, Carocci and co-workers [11b] stereo-
specifically synthesized these two alcohols from two enantiomeric
chiral precursors (vide supra). They also reported, for the first time,
highly stereoselective conversion of the two secondary alcohols 2 and
ent-2 into mexiletines ent-1 (e.e. 96%) and 1 (e.e. 93%), respectively,
with inversion of configuration. The overall procedure for this alcohol
to amine conversion consisted of two steps, (i) Mitsunobu's Gabriel-type
reaction of the alcohol with phthalimide (yield: 68% from alcohol 2,
84% from alcohol ent-2) and (ii) hydrazinolysis (yield: 66% for amine
ent-1, 70% for amine 1). Later on, Sasikumar and co-workers [15a]15a
(2009) as well as Sadhukhan and co-workers [15b] (2012) modified
slightly the above mentioned two-step procedure to access (R)-mex-
iletine ent-1 from (S)-alcohol 2. They applied hydrolytic kinetic re-
solution strategy to obtain (S)-alcohol 2. Sasikumar and co-workers
[15a] used Jacobsen catalyst, whereas Sadhukhan and co-workers
[15b] employed recyclable macrocyclic CoIII-salen complex. Both the
alcohols, 2 and ent-2, were also synthesized by Bredikhina and co-
workers in 2015 [6]. The key step used by them was the direct re-
solution of rac-3-(2,6-dimethylphenoxy)propane-1,2-diol by entrain-
ment procedure. Recently in 2018, Nagai and co-workers [16] reported
enzymatic asymmetric reduction of a suitable ketone to produce alco-
hols 2 and ent-2.
2. Results and discussion
The synthesis was initiated by a reported [19] conversion of
D-mannitol 4 into 2,3-di-O-cyclohexylidine-(R)-(+)-glyceraldehyde 5,
which was then reduced to the corresponding alcohol 6 by following a
literature procedure [20] (Scheme 2). Tosylation (TsCl/Et3N/DCM)
with slightly modified literature procedure [21] led to the formation of
our desired chiral intermediate in almost quantitative yield. Having
prepared this chiral template 3, we paid our attention to its transfor-
mation to both the secondary alcohols 2 and ent-2 (see Scheme 2).
To access (R)-1-(2,6-dimethylphenoxy)propan-2-ol, ent-2, the tosy-
loxy group in the tosylate 3 was substituted by 2,6-dimethylphenol
(K2CO3/DMF) to obtain the ether 7 in 82% yield. Acid induced deke-
talization (TFA/H2O/MeOH) of the compound 7 produced the diol 8
[6] in 80% yield. Deprotection led to regeneration of the primary and
the secondary alcoholic OH groups. As per our synthetic plan, the pri-
mary hydroxyl group was selectively tosylated (TsCl/Et3N/DCM) to
acquire tosylate 9 in moderate yield (70%). It was evident that only a
primary tosylate like 9 could lead us unambiguously to our desired
secondary alcohol ent-2 via substitution of the tosyloxy group by nu-
cleophilic hydride. Treatment of the tosylate 9 with LiAlH4 in THF
produced (R)-1-(2,6-dimethylphenoxy)propan-2-ol, ent-2. Specific ro-
tation value (Table 1) as well as 1H and 13C NMR spectral data [22] of
our synthesized molecule were closely comparable to those reported in
the literature. As expected its 13C NMR spectrum showed no char-
acteristic peak for the tosyloxy group. Moreover, signal for methylene
protons of CH2OTs group at δ 4.21–4.35 (m) in the spectrum of the
tosylate 9 was replaced by a methyl signal at δ 1.27 (d) in ent-2.
To get the optical antipode of (R)-1-(2,6-dimethylphenoxy)propan-
2-ol, ent-2 from the same tosylate intermediate 3 without any loss of
optical integrity, the tosyloxy group in 3 ought to be substituted by
nucleophilic hydride instead of 2,6-dimethylphenol. Toward this end,
acid promoted deprotection of the crucial intermediate 3 (p-TSA/
MeOH) gave the diol 10 [23] in 85% yield. The tosyloxy group was then
displaced by nucleophilic hydride (LiAlH4/THF) to get (S)-propane-1,2-
diol 11 [24]. Selective tosylation (TsCl/Et3N/DCM) of the primary
hydroxyl group in 11 generated the primary tosylate 12 [25]. Similar to
the compound 9, here also selective tosylation of the primary hydroxyl
group was confirmed via its displacement by 2,6-dimethylphenol
(K2CO3/DMF) leading to formation of our expected (S)-1-(2,6-di-
methylphenoxy)propan-2-ol, 2. 1H and 13C NMR spectral data of our
The uses of
antiomeric pairs Do-fmbaionlnoigtioclalalnydacottivheercosmugpaorusnidns tahree wsyenllthdeosceusmoefnteend-
in literature [17]. However, till date, to the best of our knowledge,
there is no report of syntheses of both the enantiomers of mexiletine
from a carbohydrate molecule. The two enantiomers have not also been
synthesized from any common chiral precursor. Since we could re-
cognize latent D-glyceraldehyde carbohydrate symmetry in alcohols 2
and ent-2, we initiated our project in this direction as part of our
continued interest in the chiral pool syntheses of potentially bioactive
natural and unnatural molecules using chiron approach [18].
Herein, we wish to report enantiodivergent syntheses of two sec-
ondary alcohols 2 and ent-2 (Scheme 1), the evident precursors of
mexiletine enantiomers ent-1 and 1, respectively, from a D-mannitol-
derived optically pure known D-glyceraldehyde derivative, the tosylate
3. The chirality of C-2 stereogenic center of the C2-symmetric in-
expensive chiral pool molecule
efficiently translated to the chiraDli-tmyaonfntihtoel o4nlwy ostuelrdeobgeendiicreccetnlytearnodf
the two enantiomeric target alcohol molecules unaffected. Simple
Scheme 1. Retrosynthetic analysis.
2

A. Manna, et al.
CarbohydrateResearch487(2020)107892
Scheme 2. Reagents and conditions: (a) (i) cyclohexanone, HC(OEt)3, BF3·OEt2 (cat.), dry DMSO, rt, 12 h, 65%, (ii) NaIO4, CH3CN–H2O (3:2), 0 °C- rt, 6 h, 95%; (b)
NaBH4, methanol, 0 °C- rt, 3 h, 92%; (c) TsCl, Et3N, dry DCM, 0 °C- rt, 6 h, 97%; (d) 2,6-dimethylphenol, K2CO3 (anhydrous), dry DMF, 60 °C, 12 h, for 3 to 7: 82%,
for 12 to 2: 72%; (e) 80% TFA-H2O, methanol, rt, 24 h, 80%; (f) TsCl, Et3N, dry DCM, 0 °C–5 °C, for 8 to 9: 2 h, 70%, for 11 to 12:1 h, 69%.; (g) LiAlH4, dry THF, 0 °C-
rt, for 9 to ent-2: 3 h, 74%, for 10 to 11: 4 h, 72%; (h) p-TSA (cat.), methanol, rt, 24 h, 85%.
triphenylphosphine (two equivalents) in CCl4-DMF (1:4) solvent (at
90 °C). Their work encouraged us to apply their methodology on our
synthesized alcohols 2 and ent-2 so as to access mexiletines in only one
step instead of two steps as stated in the literature (vide supra). To our
utmost satisfaction, our synthesized (R)-(+)- and (S)-(−)-1-(2,6-di-
methylphenoxy)propan-2-ol, i.e. ent-2 and 2 smoothly produced (S)-
(+)-mexiletine 1 (82% yield) and (R)-(−)-mexiletine ent-1 (79%
Scheme 3. Reagents and conditions: (a) NaN3, PPh3, CCl4-DMF (1:4), 90 °C,
yield), respectively in only one step. The overall yields for the reported
3 h, 82% for ent-2 to 1, 79% for 2 to ent-1.
two-step procedures were 59% [11b] for (S)-mexiletine and 45% [11b],
68% [15b], 71% [15a] for (R)-mexiletine. We performed the reactions
synthesized molecule showed absence of tosyloxy group and appear-
ance of signals for 2,6-dimethylphenoxy group. Specific rotation value
of the molecule synthesized by us in this way was closely comparable to
those reported in the literature (Table 1). 1H and 13C NMR data were
also similar [22].
under the same conditions as reported by Vidya Sagar Reddy and co-
workers. However, both our reactions took only 3 h to complete,
whereas, as per the literature, primary alcohols require 4 h–6 h and
secondary alcohols require 8 h–10 h. To the best of our knowledge, this
is the first time when any single step conversion of alcohols to mex-
iletines has been achieved. HRMS and NMR spectral data of the two
pure amines supported this transformation. For instance, upfield shifts
of the methine proton (from δ 4.22–4.23 to δ 3.34 for amine 1, from δ
4.22 to δ 3.37 for amine ent-1) and methine carbon (from δ 67.1 to δ
47.3 for amine 1, from δ 67.3 to δ 47.3 for amine ent-1) were observed
as predicted because of replacement of the OH group attached to the
methine carbon by a NH2 group. Both the 1H and 13C NMR spectra are
almost identical and they are closely similar to those reported in the
literature [22].
Since, we utilized ‘chiron approach’ from D-(+)-mannitol to access
both the enantiomers 2 and ent-2, they were enantiomerically pure. It
was evident from the almost equal and opposite specific rotation values
of these two enantiomers (Table 1), which were synthesized following
two different routes from a D-mannitol-derived chiral template 3.
Additionally, CD spectrum of individual enantiomer synthesized by us
was acquired with its methanolic solution of concentration 500 μg/mL.
The CD curve (Fig. 2a) of the (S)-isomer 2 displayed negative Cotton
effect whereas that of the (R)-isomer ent-2 showed positive Cotton
effect (in the wavelength region of 234.5 nm–229 nm). The spectra of
the enantiomers exhibited exact mirror image relationship further
corroborating their enantiopurity. As expected, their NMR spectra were
identical [22].
Specific rotation values of the two amines (Table 1) synthesized by
us were found to be almost equal; however their signs of rotation were
opposite. This demonstrated enantiomeric relationships between them.
These values were also very closely similar to the corresponding specific
rotation values reported in the literature (Table 1). This is suggestive of
inversion of configuration with almost similar type of high stereo-
selectivity at the stereogenic center as in the two-step transformation by
Carocci and co-workers. Here again, CD spectra of our synthesized
enantiomeric amines were recorded with their methanolic solutions of
same concentration as for the precursor alcohols (500 μg/mL). Similar
to the (S)-alcohol 2, the CD curve (Fig. 2b) of the (S)-isomer 1 displayed
negative Cotton effect; whereas that of the (R)-isomer ent-1 exhibited
Now, these two secondary alcohols 2 and ent-2 had already been
transformed into mexiletines, ent-1 and 1, respectively (vide supra).
Hence, we have achieved for the first time an enantiodivergent formal
synthesis of mexiletine enantiomers from a D-(+)-mannitol-derived
scaffold.
In the year 2000, Vidya Sagar Reddy and co-workers [26], reported
a convenient and efficient one-pot transformation of primary and sec-
ondary alcohols to the corresponding amines using sodium azide and
Table 1
Comparison of specific rotation data of alcohols and mexiletines.
Research work
(R)-Mexiletine
(S)-Mexiletine
(R)-Alcohol
(S)-Alcohol
25
25
25
25
25
25
Our work
[α]D − 2.86 (c 4.61, CHCl3)
[α]D +2.64 (c 4.82, CHCl3)
[α]D +1.21 (c 4.8, CHCl3)
[α]D − 1.06 (c 5.02, CHCl3)
Sasikumar et al. [15a]
Carocci et al. [11b]
[α]D − 2.4 (c 5, CHCl3)
[α]D − 1.3 (c 5, CHCl3)
20
20
20
20
[α]D − 2.7 (c 4.7, CHCl3)
[α]D +2.5 (c 4.9, CHCl3)
[α]D +0.9 (c 5.5, CHCl3)
[α]D − 1.1 (c 5, CHCl3)
3

A. Manna, et al.
CarbohydrateResearch487(2020)107892
Fig. 2. CD spectra of synthesized molecules 2, ent-2, 1 and ent-1.
positive Cotton effect as in the case of (R)-alcohol ent-2 (but in the
wavelength region of 253.5 nm–247.5 nm). The CD spectra of the
amines 1 and ent-1, synthesized by us, showed exact mirror image re-
lationship affirming again their enantiomeric relationship.
Additionally, the methodology is flexible. Preparation of several
mexiletine analogs, for evaluation of potential biological activities,
appears feasible by using various differently substituted phenols as
nucleophiles. Even nucleophilic hydride may be replaced by a nucleo-
philic alkyl group to access various analogs differing in alkyl chain
lengths. The extension of the routes reported here to the preparation of
above mentioned analogs will be pursued in our laboratory.
Our route which started from very inexpensive D-mannitol did give
(S)- and (R)-mexiletine in 15% and 13% overall yields, respectively.
However, (S)- and (R)-mexiletine were obtained in 28% and 24%
overall yields, respectively, relative to the known D-mannitol-derived
advanced precursor 3 from which two routes toward enantiomeric
target molecules were diverted. The overall yields of the reported
synthetic procedures, which involved chiral enantiopure molecules as
the source of chirality, have already been mentioned (vide supra).
However, those processes never involved any carbohydrate molecule as
chiral source. Even none of those synthetic pathways did produce both
the enantiomeric amines from the same chiral molecule.
4. Experimental
4.1. General considerations
1H NMR spectra were recorded in a Bruker 500/300 (500/300 MHz
respectively) spectrometer. Chemical shifts were expressed in parts per
million (ppm, δ) with chloroform as an internal standard. The coupling
constants are expressed in Hz. Signal description:
s = singlet,
d = doublet, m = multiplet, dd = doublet of doublet, br s = broad
singlet. Proton decoupled 13C NMR spectra were recorded in a Bruker
500/300 (125/75 MHz respectively). Chemical shifts were expressed in
parts per million (ppm, δ) and were referred to chloroform as an in-
ternal standard. High-resolution mass spectra (HRMS) were recorded
on a TOF spectrometer using electrospray (ESI) method. Optical rota-
tions were measured with an ANTON PAR digital polarimeter. Circular
dichroism of the enantiomers has been carried out in JASCO J815
spectropolarimeter affixed to a thermal programmer model PFD 425 L/
15. Routine monitoring of reactions was carried out using TLC plates
Merck Silica Gel 60 and visualization with iodine and vanillin in
ethanol as development reagent. All the solvents were purified and
dried by standard procedure prior to use. Column chromatographic
purification of compounds was done with silica gel 60–120. All of the
moisture sensitive reactions were performed using thoroughly washed,
oven dried glassware and under argon gas atmosphere.
3. Conclusions
In conclusion, chiron approach has been utilized for the syntheses of
both the enantiomers of 1-(2,6-dimethylphenoxy)propan-2-ol sepa-
rately in optically pure forms from an advanced optically pure pre-
cursor 3 having one stereogenic center. The common intermediate was
synthesized from D-mannitol in four steps with an overall yield of 55%.
The two routes towards two enantiomeric alcohols from the inter-
mediate 3 were different; each consisted of four more steps. Reactions
used were conventional and simple. All of them were moderate to high
yielding. Starting from this D-mannitol scaffold, the overall yields for
(R)- and (S)-alcohol were 34% and 30%, respectively. Chirality of
D-mannitol was efficiently translated to the chirality of the product
molecules, leading to unequivocal assignment of their absolute con-
figurations. To the best of our knowledge, ours is the first synthesis of
1-(2,6-dimethylphenoxy)propan-2-ol enantiomers, which are the im-
mediate precursor of mexiletines, from a carbohydrate molecule. Apart
from that, first time a one-step protocol was applied successfully on the
1-(2,6-dimethylphenoxy)propan-2-ols for their efficient conversions to
the corresponding amine drugs. All the literature procedures available
till date regarding this transformation involved two-step protocols.
Moreover, synthesis of both the enantiomers of 1-(2,6-dimethylphe-
noxy)propan-2-ol and subsequently mexiletine enantiomers from 2,3-
di-O-cyclohexylidine-(R)-(+)-glyceraldehyde 5, which was con-
veniently derived from D-mannitol 4 in two steps, is significant as the
corresponding enantiomer (S)-(−)-glyceraldehyde is not readily avail-
able.
4.1.1. (R)-1,4-dioxaspiro[4.5]decan-2-ylmethyl 4-methylbenzenesulfonate
(3)
To a magnetically stirred ice-cold solution of alcohol 6 (5.0 g,
29.03 mmol) in dry dichoromethane (100 mL) was added triethylamine
(8.07 mL, 58.10 mmol). After 15 min of stirring, tosyl chloride (8.3 g,
43.58 mmol) was added to it. The reaction mixture was stirred vigor-
ously at room temperature for 6 h, till the disappearance of starting
material (checked by performing TLC). The reaction was quenched with
water and extracted with dichoromethane (3 × 15 mL). The combined
organic layer was washed with water, brine and dried over anhydrous
4

A. Manna, et al.
CarbohydrateResearch487(2020)107892
sodium sulfate. The solvent was removed under reduced pressure fol-
lowed by purification procedure by column chromatography (silica gel,
ethyl acetate-hexane 1:9) to produce tosylate 3 [21] as a colourless
129.9 (2 × CH), 130.6 (2 × C), 132.6 (C), 145.2 (C), 154.4 (C); HRMS
(ESI) calcd. for C18H22O5SNa [M+Na]+, 373.1086; found, 373.1083.
viscous liquid (9.2 g, 97%): Rf
=
0.62 (1:9 EtOAc
–
hexane);
4.1.5. (R)-1-(2,6-dimethylphenoxy)propan-2-ol (ent-2)
[α]D − 1.56 (c 1.10, CHCl3); υmax/cm−1 (KBr) 1420.3, 1172.2,
1102.4; δH see Supplementary Data 1; δC see Supplementary Data 1;
HRMS (ESI) calcd. for C16H22O5SNa [M+Na]+, 349.1086; found,
349.1089.
To a cooled suspension of lithium aluminium hydride (0.27 g,
7.15 mmol) in dry THF (15 mL) at 0 °C was added dry THF (20 mL)
solution of tosyl compound 9 (1.0 g, 2.85 mmol) dropwise. The re-
sulting reaction mixture was then allowed to attain room temperature
and stirred for 3 h. The reaction mixture was quenched with saturated
aqueous solution of ammonium chloride at 0 °C and the resulting
mixture was filtered and extracted with ethyl acetate (3 × 15 mL). The
combined organic layer was washed with water, brine, dried over an-
hydrous sodium sulfate and evaporated under reduced pressure. The
crude product thus obtained was purified by column chromatography
(silica gel, ethyl acetate-hexane 2:3) to get ent-2 as a viscous liquid
25
4.1.2. (S)-2-((2,6-dimethylphenoxy)methyl)-1,4-dioxaspiro[4.5]decane
(7)
To a stirred solution of 2,6-dimethylphenol (3.4 g, 27.6 mmol) in
dry DMF (50 mL) anhydrous K2CO3 (3.8 g, 27.6 mmol) was added. After
continuous stirring for 1 h tosyl compound 3 (6.0 g, 18.38 mmol) was
added to it. The reaction mixture was warmed at 60 °C and stirred for
12 h. After completion of reaction it was quenched with water (30 mL).
It was extracted with diethyl ether (3 × 30 mL). The combined organic
phase was washed with 2(N) NaOH (2 × 10 mL) to remove excess
phenol. It was dried over anhydrous sodium sulfate and concentrated
under reduced pressure and purified by column chromatography (silica
gel, ethyl acetate-hexane 3:17) to obtain the desired product 7 as a
25
(0.38 g, 74%): Rf = 0.54 (1:4 EtOAc – hexane); [α]D +1.21 (c 4.8,
CHCl3); υmax/cm−1 (KBr) 3213.2, 1476.5, 1206.8; δH see
Supplementary Data 1: Table 1; δC see Supplementary Data 1: Table 2;
HRMS (ESI) calcd. for
203.1053.
C
11H16O2Na [M+Na]+
, 203.1048; found,
25
viscous liquid (4.2 g, 82%): Rf = 0.56 (1:9 EtOAc – hexane); [α]D
4.1.6. (S)-1-(2,6-dimethylphenoxy)propan-2-amine (1)
+1.90 (c 0.42, CHCl3); υmax/cm−1 (KBr) 1476.2, 1104.5; δH (CDCl3,
300 MHz) 1.42 (2H, br s, CH2), 1.60 (4H, s, CH2), 1.64 (4H, br s, CH2),
2.29 (6H, s, CH3), 3.78–3.84 (2H, m, OCH2), 3.97 (1H, dd, J 8.1, 6.2 Hz,
OCH2), 4.19 (1H, dd, J 8.0, 6.7 Hz, OCH2), 4.47–4.51 (1H, m, OCH),
6.92–7.01 (3H, m, ArH); δC (CDCl3, 75 MHz) 16.2 (2 × CH3), 23.9
(CH2), 24.0 (CH2), 25.2 (CH2), 34.9 (CH2), 36.5 (CH2), 66.4 (OCH2),
72.8 (OCH2), 74.2 (OCH), 110.1 (C), 124.0 (CH), 128.9 (2 × CH),
Alcohol ent-2 (0.11 g, 0.61 mmol), sodium azide (0.05 g,
0.77 mmol) and triphenylphosphine (0.32 g, 1.22 mmol) in CCl4-DMF
(1:4, 10 mL) were warmed at 90 °C with vigorous stirring. After 3 h
when the reaction was completed (checked by TLC) it was brought to
room temperature. Finally it was quenched with water (4 mL) and
stirred for 30 min. It was then diluted with ether (30 mL) and washed
rapidly with water again. The ether fraction was cooled to 0 °C and
triturated by glass rod to crystallize out triphenylphosphine oxide. The
ether layer was filtered off and dried over sodium sulfate. The solvent
was evaporated under reduced pressure and the residue was purified by
column chromatography (silica gel, ethyl acetate-hexane 9:11) to ob-
tain amine 1 as a viscous liquid (0.09 g, 82%): Rf = 0.52 (1:4 EtOAc –
130.8 (2 × C) 155.1 (C); HRMS (ESI) calcd. for C17H24O3Na [M+Na]+
299.1623; found, 299.1634.
,
4.1.3. (R)-3-(2,6-dimethylphenoxy)propane-1,2-diol (8)
To
a magnetically stirred solution of compound 7 (3.0 g,
hexane); [α]D +2.64 (c 4.82, CHCl3); υmax/cm−1 (KBr) 3120.1,
25
10.85 mmol) in methanol (50 mL) catalytic amount (10 drops) of 80%
trifluoro acetic acid-water was added. After stirring at room tempera-
ture for 24 h, the reaction mixture was quenched with two sodium
beads. It was filtered and extracted with ethyl acetate (3 × 15 mL). The
organic layer was washed with brine and dried over anhydrous sodium
sulfate. The solvent was evaporated under reduced pressure and the
residue was purified by column chromatography (silica gel, ethyl
acetate-hexane 3:2) to acquire the target molecule 8 [6] as a colourless
2981.9, 1587.4, 1476.5, 1206.8; δH see Supplementary Data 1: Table 3;
δC see Supplementary Data 1: Table 4; HRMS (ESI) calcd. for
C
11H17NONa [M+Na]+, 202.1208; found, 202.1205.
4.1.7. (R)-2,3-dihydroxypropyl 4-methylbenzenesulfonate (10)
To a magnetically stirred solution of the tosyl compound 3 (3.5 g,
10.72 mmol) in methanol (50 mL) was added p-toluenesulfonic acid
(0.41 g, 2.38 mmol) at once. After stirring the reaction mixture for
24 h at room temperature it was quenched with solid K2CO3. It was
filtered and extracted with ethyl acetate (3 × 20 mL). The organic layer
was washed with brine and dried over anhydrous sodium sulfate. The
solvent was evaporated under reduced pressure and the residue was
purified by column chromatography (silica gel, ethyl acetate-hexane
4:1) to secure the desired compound 10 [23] as a colourless viscous
liquid (2.24 g, 85%): Rf = 0.45 (3:2 EtOAc – hexane); [α]D25 +1.92 (c
1.47, CHCl3); υmax/cm−1 (KBr) 3248.3, 1355.0, 1114.1; δH see Sup-
plementary Data 1; δC see Supplementary Data 1; HRMS (ESI) calcd.
for C10H14O5SNa [M+Na]+, 269.0460; found, 269.0460.
25
viscous liquid (1.7 g, 80%): Rf = 0.38 (3:7 EtOAc – hexane); [α]D
+10.23 (c 0.86, CHCl3); υmax/cm−1 (KBr) 3250.5, 1474.5, 1114.1; δH
see Supplementary Data 1; δC see Supplementary Data 1; HRMS
(ESI) calcd. for C11H16O3Na [M+Na]+, 219.0997; found, 219.0988.
4.1.4. (S)-3-(2,6-dimethylphenoxy)-2-hydroxypropyl 4-methylbenzenesulfonate
(9)
To a magnetically stirred ice-cold solution of the diol 8 (0.8 g,
4.08 mmol) in dry dichloromethane (40 mL) were added triethylamine
(0.68 mL, 4.9 mmol) and tosyl chloride (0.78 g, 4.08 mmol) portion
wise. Stirring was continued at 0 °C–5 °C for about 2 h till the reaction
did not proceed further (checked by performing TLC). Then the reaction
mixture was extracted with dichloromethane (3 × 10 mL) and washed
with brine followed by drying over anhydrous sodium sulfate. It was
then concentrated under reduced pressure and purified by column
chromatography (silica gel, ethyl acetate-hexane 1:1) to acquire the
desired viscous liquid 9 (1.0 g, 70%): Rf = 0.43 (1:4 EtOAc – hexane);
4.1.8. (S)-propane-1,2-diol (11)
To an ice cold suspension of lithium aluminium hydride (0.62 g,
16.33 mmol) in dry THF (50 mL) was added dry THF (70 mL) solution
of tosyl compound 10 (1.62 g, 6.58 mmol) dropwise at 0 °C. The re-
sulting reaction mixture was then allowed to attain room temperature
and stirred for 4 h. After completion of the reaction (checked by TLC) it
was quenched with saturated aqueous solution of ammonium chloride
at 0 °C and the resulting mixture was filtered off and extracted with
ethyl acetate (3 x 25 mL). The combined organic layer was washed
simultaneously with water, brine and dried over anhydrous sodium
sulfate. After evaporating the solvent under reduced pressure the ob-
tained crude product was purified by column chromatography (silica
25
[α]D +5.00 (c 0.24, CHCl3); υmax/cm−1 (KBr) 3230.1, 1401.9,
1179.1, 1104.4; δH (CDCl3, 300 MHz) 2.13 (3H, s, CH3), 2.22 (3H, s,
CH3), 2.46 (3H, s, CH3), 2.64 (1H, br s, OH), 3.85 (2H, dd, J 16.5,
4.6 Hz, OCH2), 4.21–4.35 (3H, m, OCH, OCH2), 6.93–7.01 (3H, m,
ArH), 7.31–7.38 (2H, m, ArH), 7.72–7.84 (2H, m, ArH); δC (CDCl3,
75 MHz) 16.0 (CH3), 16.2 (CH3), 21.7 (CH3), 67.0 (OCH2), 68.8
(OCH2), 70.2 (OCH), 124.5 (CH), 128.0 (2 × CH), 129.0 (2 × CH),
5

A. Manna, et al.
CarbohydrateResearch487(2020)107892
gel, ethyl acetate-hexane 9:1) to get the product 11 [24] as a viscous
liquid (0.36 g, 72%): Rf = 0.31 (3:2 EtOAc – hexane); [α]D25 +4.25 (c
0.40, CHCl3); υmax/cm−1 (KBr) 3408.3, 1114.1; δH see Supplementary
Data 1; δC see Supplementary Data 1; HRMS (ESI) calcd. for
C3H8O2Na [M+Na]+, 99.0422; found, 99.0424.
4.1.13. CD spectroscopy of mexiletines 1 and ent-1 (Fig. 2b)
CD spectrum of methanolic solution (500 μg/mL) of individual en-
antiomer
was
recorded.
In
the
wavelength
region
of
253.5 nm–247.5 nm, the CD curve of the (S)-isomer 1 displayed ne-
gative Cotton effect, whereas that of the (R)-isomer ent-1 exhibited
positive Cotton effect. The CD spectra of the enantiomeric amines 1 and
ent-1, synthesized by us, showed exact mirror image relationship.
4.1.9. (S)-2-hydroxypropyl 4-methylbenzenesulfonate (12)
To a magnetically stirred ice-cold solution of the diol 11 (0.11 g,
1.45 mmol) in dry dichloromethane (20 mL) were added triethylamine
(0.20 mL, 1.43 mmol) and tosyl chloride (0.28 g, 1.45 mmol) portion
wise. Stirring was continued at 0 °C–5 °C for about 1 h till the reaction
did not proceed further (checked by performing TLC). Then the reaction
mixture was extracted with dichloromethane (3 × 10 mL) and washed
with brine followed by drying over anhydrous sodium sulfate. It was
then concentrated under reduced pressure and purified by column
chromatography (silica gel, ethyl acetate-hexane 11:9) to acquire the
desired product 12 [25] as a viscous liquid (0.23 g, 69%): Rf = 0.42
(2:3 EtOAc – hexane); [α]D25 +12.57 (c 0.42, CHCl3); υmax/cm−1 (KBr)
3176.9, 1401.9, 1104.5, 611.9; δH see Supplementary Data 1; δC see
Supplementary Data 1; HRMS (ESI) calcd. for C10H14O4SNa [M
+Na]+ 253.0510; found, 253.0516.
Declaration of competing interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influ-
ence the work reported in this paper.
Acknowledgements
Financial support from FIST-DST, India and CAS-UGC, India to the
Department of Chemistry, Jadavpur University, India are acknowl-
edged. A.M., S.C. and I.C. wish to thank UGC, New Delhi for their
Senior Research Fellowships. Thanks are due to Dr. R. K. Goswami,
School of Chemical Sciences, I.A.C.S., Kolkata, India for making avail-
able the polarimeter instrument.
4.1.10. (S)-1-(2,6-dimethylphenoxy)propan-2-ol (2)
Appendix A. Supplementary data
To a stirred solution of 2,6-dimethyl phenol (0.08 g, 0.65 mmol) in
dry DMF (10 mL), anhydrous K2CO3 (0.09 g, 0.65 mmol) was added.
After continuous stirring for 1 h tosyl compound 12 (0.1 g, 0.44 mmol)
was added to it. The reaction mixture was warmed at 60 °C and stirred
for 12 h. After completion of reaction the solvent was evaporated under
reduced pressure. It was extracted with diethyl ether (3 × 10 mL). The
combined organic phase was washed with 2(N) NaOH (2 × 5 mL) to
remove excess phenol. It was dried over anhydrous sodium sulfate and
concentrated under reduced pressure and purified by column chroma-
tography (silica gel, ethyl acetate-hexane 2:3) to obtain the desired
alcohol 2 as a viscous liquid (0.056 g, 72%): Rf = 0.54 (1:4 EtOAc –
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.carres.2019.107892.
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7