A practical and convenient method for the efficient and regio- and stereoselective ring-opening of enantiopure monosubstituted epoxides by sodium azide under hydrolytic conditions is reported. The ring–opening of enantiopure styryl and pyridyl (S)-epoxides by N3− in hot water takes place preferentially at the internal position with complete inversion of configuration to produce (R)-2-azido ethanols with up to 99% enantio- and regioselectivity, while the (S)-adamantyl oxirane provides mainly the (S)-1-adamantyl-2-azido ethanol in excellent yield. In general, 1,2-amino ethanols were obtained in high yield and excellent enantiopurity by the reduction of the chiral 1,2-azido ethanols with PPh3 in water/THF, and then converted into the Boc or acetamide derivatives.

The effectiveness of several spiroborate ester catalysts was investigated in the asymmetric borane reduction of 2-, 3-, 4-acetylpyridines under different reaction conditions. Highly enantiomerically enriched 1-(2-, 3- and 4-pyridyl)ethanols and 1-(heterocyclic)ethanols were obtained using 1 to 10% catalytic loads of the spiroborate 5 derived from diphenylprolinol and ethylene glycol.

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...

The enantioselective borane reduction of O-benzyloxime ethers to primary amines was studied under catalytic conditions using the spiroborate esters 5-10 derived from non-racemic 1,2-amino alcohols and ethylene glycol. Effective catalytic conditions were achieved using only 10% of catalyst 5 derived from diphenylvalinol in dioxane at 0 °C resulting in complete conversion to the corresponding primary amine in up to 99% ee. The asymmetric reduction of oxime ethers with non-racemic chiral reducing agents represents an important synthetic route to enantiopure primary amines. 1-5 Over the past two decades, oxazaborolidines have been developed as chirality transfer reagents for the reduction of the carbonyl and imine functionality. 2 The borane-mediated catalytic reduction of ketones using 1,3,2-oxazaborolidines has been extensively investigated. 2b These efforts have led to the synthesis of highly enantiopure alcohols using less than 10 mol % of catalyst. Applying this process to the reduction of the C=N provides direct access to non-racemic primary amines which are widely used as key intermediaries in the synthesis of pharmaceuticals, chiral auxiliaries and catalysts. 1-4 For the borane-mediated reduction of oxime ethers, a stoichiometric amount of the oxazaborolidine is usually required to obtain high enantioselectivities. 3,4 Fontaine et al. 3k even employed 2.5 equiv of the diphenylvalinol-derived B-H oxazaborolidine to achieve complete reduction with high selectivity. Itsuno and coworkers 3b reported the first catalytic borane-based reduction of acetophenone O-benzyl oxime. With 10 mol% of the (S)-diphenylvalinol oxazaborolidine, generated in situ, 52% ee was observed in the product (S)-1-phenylethanamine. This selectivity is much lower than the 93% ee obtained for this substrate employing 1 equiv of the catalyst. In addition to their high cost air-and moisture sensitivity, B-H oxazaborolidines often contain impurities which diminish their effectiveness. 2c-e This has led to the development of alternative catalytic systems for the reduction of oximes, but with only modest success. 5 In the present study, a truly catalytic and highly enantioselective process for the borane-mediated asymmetric reduction of oxime ethers is reported for the first time. Recently, we prepared stable enantiopure spiroborate esters5-10 derived from 1,2-amino alcohols, as new catalysts for the asymmetric reduction of ketones (Fig. 1). 6 These spiroborates proved to be highly reactive and enantioselective catalysts for this process. Coupled with their operational convenience, we felt that they may provide effective catalysts for reduction of oxime ethers thereby providing a new, highly useful entry to non-racemic amines (Scheme 1). 7 Initially, we examined the reduction of (E)-benzyl oxime ether 1a (R = Bn) in toluene employing 50 mol % of spiroborate ester 5 and 2 equiv of BH 3 ·DMS at 50 °C for 12 h followed by 3 h at 110 °C. The amine product 2a was isolated as its carbamate 4 in 75% yield and 93% ee. Seeking milder conditions, we disco...

An asymmetric synthesis for the preparation of nonracemic amines bearing heterocyclic and heteroaromatic rings is described. A variety of important enantiopure thionyl and arylalkyl primary amines were afforded by the borane-mediated enantioselective reduction of O-benzyl ketoximes using 10% of catalyst 10 derived from ( S)-diphenylvalinol and ethylene glycol with excellent enantioselectivity, in up to 99% ee. The optimal condition for the first asymmetric reduction of 3- and 4-pyridyl-derived O-benzyl ketoxime ethers was achieved using 30% of catalytic loading in dioxane at 10 degrees C. ( S)- N-ethylnornicotine ( 3) was also successfully synthesized from the TIPS-protected ( S)-2-amino-2-pyridylethanol in 97% ee.