A Practical and Efficient Route for the Highly Enantioselective Synthesis of Mexiletine Analogues and Novel β-Thiophenoxy and Pyridyl Ethers

Abstract

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.Mexiletine (Figure 1) is an effective sodium channel blocker used as an antiarrhythmic and analgesic oral drug. 1,2 Structure-activity studies in vivo 3 and in vitro 4 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)-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. 7The 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-workers 10 reported a convenient procedure for the preparation of stereoisomers 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 group 6 synthesized the stereoisomers of mexiletine analogues, the use of 2-phenyloxirane as chiral source restricted margarita.ortiz1@upr.edu. Supporting Information Available: Experimental procedures, 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. 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 enantiopure mexiletine analogues is highly desirable. NIH Public AccessThe asymmetric reduction of oxime ethers with borane-based catalysts offers a facile and direct approach to obtain enantioenriched primary amines; however, more than an stoichiometric amount of in situ prepared ox...

Addition of HO‐Acids to N,N‐Bis(oxy)enamines: Mechanism, Scope and Application to the Synthesis of Pharmaceuticals

“…1 H NMR (300 MHz, [D]chloroform): δ = 9.02 (s, 1 H, OH), 7.05 (d, J = 7.3 Hz, 2 H, 3‐H), 6.97 (m, 1 H, 4‐H), 4.35 (s, 2 H, CH 2 O), 2.33 (s, 6 H, 2 CH 3 ), 2.17 (s, 3 H, CH 3 ) ppm. The NMR spectra are in accordance with literature data . C 11 H 15 NO 2 (193.25): calcd.…”

Chiral Epoxides via Borane Reduction of 2-Haloketones Catalyzed by Spiroborate Ester: Application to the Synthesis of Optically Pure 1,2-Hydroxy Ethers and 1,2-Azido Alcohols

“…Regioselective ring opening of oxiranes with nucleophiles is an important route to obtain a broad range of nonracemic 1,2-substituted alcohols as intermediates for the synthesis of key pharmaceutical compounds, as well as chiral catalysts 3,17–19. Optically active β-hydroxy ethers are valuable synthetic intermediates in a wide variety of potentially bioactive compounds 2g,17a.…”

Liquid Chromatographic Resolution of Mexiletine and Its Analogs on Crown Ether‐Based Chiral Stationary Phases

“…The two enantiomers of mexiletine and its analogs have been known to show different activity for blocking sodium currents of skeletal muscle fibers as mentioned above and the difference in their activity was found to be dependent on the structures . Especially, mexiletine analogs containing a substituted phenyl group instead of a methyl group at the chiral center and/or a substituted phenoxy group instead of 2,6‐dimethylphenoxy group were found to show different activity in their two enantiomers . In this instance, in order to see the structural characteristics for the resolution of mexiletine and its analogs on CSP 1 , CSP 2 and CSP 3 , various mexiletine analogs were prepared according to the procedure shown in Scheme .…”

“…Between the two enantiomers of mexiletine, (−)‐( R )‐enantiomer was reported to posses greater antiarrhythmic properties than the opposite enantiomer . In addition, the two enantiomers of mexiletine analogs were reported to show different activity in producing a tonic block or as blockers of voltage‐gated Na + channels and, consequently, the enantioselective synthesis of mexiletine analogs has attracted much attention . In this instance, the exact determination of the enantiomeric composition or enantiomeric purity of mexiletine and its analogs are quite important.…”

“…For the determination of the enantiomeric composition or purity of mexiletine and its analogs, the liquid chromatographic method utilizing chiral stationary phases (CSPs) has been applied. For example, Chiralcel OD, OD‐R, and OD‐H (cellulose tris‐3,5‐dimethylphenylcarbamate) columns from Daicel Chemical Industries (Tokyo, Japan) were successfully used for the liquid chromatographic determination of the enantiomeric composition or purity of mexiletine and its analogs . Chiralcel OD‐H and OJ‐H (cellulose tris‐4‐methyl‐benzoate) columns were also used for the resolution of N ‐acyl derivatives of mexiletine …”