A practical and efficient route for the highly enantioselective synthesis of mexiletine analogues and novel β-thiophenoxy and pyridyl ethers

Article abstract of DOI:10.1021/jo801181d

(Chemical Equation Presented) A practical and efficient procedure for the enantioselective synthesis of mexiletine analogues with use of 10% of spiroborate ester 6 as chirality transfer agent is presented. A variety of mexiletine analogues were prepared in good yield with excellent enantioselectivities (91-97% ee) from readily available starting materials. The developed methodology was also successfully applied for the synthesis of novel β-amino ethers containing thiophenyl and pyridyl fragments.

Full text of DOI:10.1021/jo801181d

A Practical and Efficient Route for the Highly
Enantioselective Synthesis of Mexiletine
Analogues and Novel ꢀ-Thiophenoxy and Pyridyl
Ethers
Kun Huang, Margarita Ortiz-Marciales,*
Viatcheslav Stepanenko, Melvin De Jesu´s, and
Wildeliz Correa
FIGURE 1. Mexiletine and examples of its more potent analogues.
Department of Chemistry, UniVersity of Puerto
Rico-Humacao, CUH Station, Humacao, Puerto Rico 00791
mexiletine in producing a tonic block and 23-fold more potent
in condition of high frequency of stimulation (phasic block).6
Recently, racemate 3 was established as a novel potent blocker
of voltage-gated K+ channels by using structure-based virtual
screening in conjunction with electrophysiological assays in rat
hippocampal neurons.7
margarita.ortiz1@upr.edu
ReceiVed June 3, 2008
The preparation of mexiletine enantiomers has been reported
previously by several groups. Generally, the methods involved
resolution of racemic intermediates,8 enzymatic hydrolysis of
an N-acyl derivative,9 or using a stereospecific, four-step
procedure, in 7.2% overall yield.8b Flippin and co-workers10
reported a convenient procedure for the preparation of stereoi-
somers of mexiletine, but the scope of products was limited by
the availability of chiral substrates and expensive chromium
tricarbonyl complexes of aryl halides: hence, some amines were
provided in the racemate form. Although Franchini’s group6
synthesized the stereoisomers of mexiletine analogues, the use
of 2-phenyloxirane as chiral source restricted the range of
mexiletine analogues. Furthermore, the procedure is also
controlled by the regiospecificity of the ring-opening reaction,11
and the possible racemization of the benzylic carbon by the
substitution of the alkoxy group by the amine.12 Hence, a
practical and efficient route for the synthesis of highly enan-
tiopure mexiletine analogues is highly desirable.
The asymmetric reduction of oxime ethers with borane-based
catalysts offers a facile and direct approach to obtain enan-
tioenriched primary amines; however, more than an stoichio-
metric amount of in situ prepared oxazaborolidine has been
employed to obtain a high degree of enantioselectivity.13a–n Our
recent success in the borane-mediated asymmetric reduction of
O-benzyl oximes, using a truly catalytic amount of the air and
moisture stable spiroborate esters indicated in Figure 2,13o,p
A practical and efficient procedure for the enantioselective
synthesis of mexiletine analogues with use of 10% of
spiroborate ester 6 as chirality transfer agent is presented. A
variety of mexiletine analogues were prepared in good yield
with excellent enantioselectivities (91-97% ee) from readily
available starting materials. The developed methodology was
also successfully applied for the synthesis of novel ꢀ-amino
ethers containing thiophenyl and pyridyl fragments.
Mexiletine (Figure 1) is an effective sodium channel blocker
used as an antiarrhythmic and analgesic oral drug.1,2 Struc-
ture-activity studies in vivo3 and in vitro4 of pharmacologically
active mexiletine indicate that its (-)-(R) enantiomer binds
preferentially to the cardiac sodium channels. In addition, (-)-
(R)-mexiletine is also more active than (+)-(S)-mexiletine on
native skeletal muscular fibers.1b,5 The use of mexiletine as a
racemate in the treatment of neuromuscular disorders is limited
due to its possible side effects.6 The optically active mexiletine
analogue (R)-2 (Figure 1) is 27-fold more potent than (R)-
(6) Franchini, C.; Carocci, A.; Catalano, A. A.; Cavalluzzi, M. M.; Corbo,
F.; Lentini, G.; Scilimati, A.; Scilimati, A.; Tortorella, P.; Camerino, D. C.; Luca,
A. J. Med. Chem. 2003, 46, 5238–5248.
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Grech-Belanger, O. J. Pharm. Pharmacol. 1991, 43, 630–635. (b) Franchini,
C.; Cellucci, C.; Corbo, F.; Lentini, G.; Scilimati, A.; Tortorella, V.; Stasi, F.
Chirality 1994, 6, 590–595.
(1) (a) De Luca, A.; Natuzzi, F.; Desaphy, J.-F.; Loni, G.; Lentini, G.;
Franchini, C.; Tortorella, V.; Conte Camerino, D. Mol. Pharmacol. 2000, 57,
268–277. (b) De Luca, A.; Natuzzi, F.; Duranti, A.; Lentini, G.; Franchini, C.;
Tortorella, V.; Conte Camerino, D. Naunyn-Schmiedeberg’s Arch. Pharmacol.
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6928 J. Org. Chem. 2008, 73, 6928–6931
10.1021/jo801181d CCC: $40.75 2008 American Chemical Society
Published on Web 08/09/2008

TABLE 1. Screening of Different Catalysts for the Reduction of
11a
entry
cat.
temp (°C)
cat. (equiv)
yield (%)
ee (%)a
1
2
3
4
5
6
4
5
6
6
7
8
0
22
0
0
22
22
0.10
0.10
0.10
0.25
0.10
0.10
87
40
84
92
80
76
70(R)
57(R)
97(R)
99(R)
81(S)
82(S)
FIGURE 2. Spiroborate esters derived from nonracemic aminoalcohols
and ethylene glycol.
SCHEME 1. Synthetic Route to 12a
a Determined by chiral HPLC (Chiralcel OD-H column) of acetyl
derivatives.
catalysts 5, 7, and 8 was rather low at 0 °C. The complete
conversion was achieved at room temperature (22 °C) affording
57%, 81%, and 82% ee, respectively, (entries 2, 5, and 6, Table
1). Spiroborate ester 6 provided the best enantioselectivities
(Table 1, entries 3 and 4).
Under the optimized conditions, a variety of O-benzyl oximes
were prepared and reduced in dioxane employing 10% spirobo-
rate ester 6 and 4 equiv of BH3 ·THF at 0 °C. Table 2 illustrates
the results for various O-benzyl oximes that were reduced to
the enantiopure amines in 91-97% ee in good to excellent
isolated yield. Noteworthy, (S)-mexiletine was prepared in 94%
ee and 84% chemical yield (entry 2), illustrating, clearly, the
catalyst ability to differentiate between the methyl and the
alkoxy moiety in the borane reduction. Generally, substituents
on each aryl group influenced slightly the enantioselectivities
(entries 3-11). For example, O-benzyl oximes bearing both
electron-withdrawing and electron-donating aryl groups provided
higher enantioselectivities (entry 3 and 6). The absolute con-
figuration of products was determined by comparing the optical
rotations with the corresponding known compounds.
Our current efforts in the design of novel neuronal nicotinic
acetylcholine receptors (nAChRs) agonists led us to target
enantiopure arylamino ethers as therapeutic agents for the
treatment of CNS and peripheral nervous system disorders.15,16
Within the past ten years, a series of selective agonist of human
neuronal nAChRs, such as Epibatidine (13),17 A-85380 (14),18
ABT-594 (15),19 A-84543 (16),20 and SIB-1553A (17)21 (Figure
prompted us to investigate their application for the enantiose-
lective synthesis of ꢀ-amino ethers of biological interest.
The synthesis of 12a, as outlined in Scheme 1, was selected
as a model protocol. The aryloxy acetophenone 9a was prepared
from the 2-chloro- or 2-bromoacetophenone with different bases
(NaOH, NaH, and K2CO3). After optimization, it was found
that treatment of 2-bromoacetophenone with K2CO3 (1.5 equiv)
and 2,6-dimethylphenol (1.5 equiv) in DMF at room temperature
for 24 h gave the desired ketone in 81% yield. The oxime was
then prepared by addition of NH2OH·HCl and pyridine at 0
°C.14 Since the enantiofacial selectivity in the reduction of CdN
bonds depends not only on the chirality’s transfer agent but also
on the E/Z isomeric purity,13 the main (Z) isomer was easily
obtained by simple recrystallization. The pure (Z)-benzyl oxime
ether 11a was obtained in high yield from (Z)-oxime with use
of NaH and benzyl bromide in DMF at -30 °C.
Initially, we screened the spiroborates presented in Figure 2
for the reduction of O-benzyl oxime 11a. The reactivity of
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J. Org. Chem. Vol. 73, No. 17, 2008 6929

TABLE 2. Asymmetric Reduction of Representative Oxime Benzyl
Ethers with 0.1 equiv of Catalyst 6a,b,c,d
FIGURE 3. Neuronal nicotinic acetylcholine receptors agonist.
TABLE 3. Asymmetric Synthesis of Novel Amines with 0.1 equiv
of Catalyst 6a,b,c
a CHCl3 as solvent. b Determined by chiral HPLC (Chiralcel OD-H
column). c Determined by 31P NMR analysis of the phosphonate
derivative.23
material chemistry,22 especially fluorinated aromatics which are
widely found in many modern drugs.
On the basis of related structural features present in nAChRs
agonists, highly enantiopure benzylic primary amines or flu-
orinated aryl groups with ꢀ-thiophenoxy or pyridyloxy groups
of biological significance were prepared by using the previous
procedure in good yield with excellent enantioselectivity
(94-97% ee), as shown in Table 3.
In summary, the preparation of chiral mexiletine analogues,
in addition to novel ꢀ-thiophenoxy and pyridyl ethers, was
achieved by a facile four-step synthesis in good yield and
a CHCl3 as solvent. b Determined by amine on chiral HPLC (Chiralcel
OD-H column). c Determined by acetyl derivative on Chiralcel OD-H
column. d Determined by GC of acetyl derivative on Chiral column
(CP-Chirasil-DexCB).
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6930 J. Org. Chem. Vol. 73, No. 17, 2008

added dropwise during 1 h with a syringe pump. The resulting
mixture was stirred at 0 °C until the conversion was complete in
about 48 h. The reaction was quenched with 6 N HCl and basified
with 6 N NaOH. The reaction mixture was extracted with ether
and the combined organic phases were washed with brine, dried
over anhydrous MgSO4, and concentrated under reduced pressure.
The residue was purified by flash column chromatography and
purified by silica gel/hexane:ethyl acetate (2:1) column chroma-
excellent enantioselectivities. The highly enantioselective reduc-
tion of benzyloxime R-ethers, efficiently catalyzed by 10% of
the novel spiroborate ester 6, is applicable for a wide range of
other bioactive compounds. Considering the convenience and
efficiency of this route, this methodology should open new
avenues for further research.
20
Experimental Section
tography as a colorless oil: yield 84% (101 mg); 97% ee; [R]D
-28.5 (c 1.2, CHCl3) [lit6 -14 (c 2, MeOH)], % ee not given; 1H
NMR (400 MHz, CDCl3) δ 1.99 (s, 2H), 2.33 (s, 6H), 3.93 (m,
2H), 4.51 (m, 1H), 6.99 (m, 1H), 7.07 (m, 2H), 7.35-7.44 (m,
3H), 7.52 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 16.4, 56.4, 77.8,
124.0, 126.0, 127.6, 128.5, 128.9, 130.9, 142.3, 155.5; GC-MS m/z
241.1 (M+). The Enantiomeric excess was determined by HPLC
for the acetyl derivative with use of a Chiralcel OD-H column (9:1
hexane:2-propanol), 0.8 mL/min, 254 nm, minor enantiomer tR )
11.3 min, major enantiomer tR ) 16.2 min.
General Procedure for the Preparation of Ketones: 2-(2,
6-Dimethylphenoxy)-1-phenylethanone3 (9a). To a 100 mL
round-bottomed flask charged with a magnetic stirrer, 2-bromoac-
etophenone (1.99 g, 10 mmol), 2,6-dimethylphenol (15 mmol), and
K2CO3 (15 mmol) was added 20 mL of DMF and the resulting
mixture was stirred for 24 h at room temperature. The reaction
was quenched with 50 mL of H2O and the aqueous phase was
extracted with diethyl ether (3 × 40 mL). The combined organic
phases were washed with 2 N NaOH (2 × 20 mL) to remove the
excess of phenol, dried over MgSO4, and concentrated under
reduced pressure. The residue was purified by flash column
chromatography on silica gel/hexane:ethyl acetate (5:1), as a yellow
Acknowledgment. Financial support by the National Insti-
tutes of Health through their MBRS (GM 08216) and INBRE
(NC P20 RR-016470) grants is greatly appreciated. We express
our special gratitude to the NSF-MRI (01-07) and NIH-MBRS
programs to have made possible the acquisition of a 400 MHz
NMR spectrometer.
6
1
solid: mp 57-59 °C (lit. mp 60-61 °C); yield 81% (1.94 g); H
NMR (400 MHz, CDCl3) δ 2.23 (s, 6H), 5.02 (s, 2H), 6.89 (m,
1H), 6.97 (m, 2H), 7.41 (m, 2H), 7.52 (m, 1H), 7.90 (m, 2H); 13
C
NMR (100 MHz, CDCl3) δ 16.3, 74.5, 124.5, 127.9, 128.8, 129.0,
130.8, 133.7, 134.7, 155.7, 194.1; GC-MS m/z 240.2 (M+).
General Procedure for the Asymmetric Reduction of O-
Benzyl Oximes: (R)-2-(2,6-Dimethylphenoxy)-1-phenylethylamine
(12a). To a 50 mL reaction tube with catalyst 6 (33 mg, 0.1 mmol)
under N2 was added 10 mL of anhydrous dioxane and 4 mL of
BH3 ·THF (1 M in THF) in one portion. After the mixture was
stirred for 1 h at room temperature, the clear solution was cooled
at 0 °C and the benzyl oxime (1 mmol) in 5 mL of dioxane was
Supporting Information Available: Experimental proce-
dures, analytical data, and all spectra for 9a-p, 10a-p, 11a-p,
12a-p,and derivatives and enantiomeric determination for
12a-p. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO801181D
J. Org. Chem. Vol. 73, No. 17, 2008 6931