(R)-1-(1-Naphthyl)ethyl Isocyanate

(R)-(-)

[42340-98-7]  · C13H11NO  · (R)-1-(1-Naphthyl)ethyl Isocyanate  · (MW 197.25) (S)-(+)

[73671-79-1]

(enantiomeric resolving agent for alcohols,1,2 thiols,1,3 sulfonamides,4 and amines5 (forms diastereomers separable by chromatography or crystallization); used in creating enantiomeric stationary phases for liquid chromatography;6,7 reagent in the synthesis of chiral nonracemic allenes8)

Alternate Names: NEI; (R)-1-isocyano-1-naphthylethane.

Physical Data: bp 106-108 °C; fp 93 °C; d 1.13 g cm-3; optical rotation [a]20D = -47° (c 3.5, toluene), [a]24.1D = -50.5° (c 27.9, benzene).

Solubility: freely sol benzene, toluene, and a variety of dry organic solvents; reacts with water.

Form Supplied in: colorless liquid; available commercially >99% pure.

Preparative Methods: from (R)-(+)-1-(1-Naphthyl)ethylamine by reaction with Phosgene or by a method using Trichlorosilane.1

Handling, Storage, and Precautions: stable when stored between 0 and 4 °C; reacts with water; highly toxic; should be handled with proper skin and eye protection in a well-ventilated fume hood.

Resolution of Alcohols.

The reagent (R)-(-)-1-(1-naphthyl)ethyl isocyanate, (R)-NEI, as well as its enantiomer, (S)-NEI, forms diastereomeric carbamates with racemic secondary alcohols (eq 1);1,2 the reaction may be facilitated by base or Lewis acid catalysts.4 The diastereomers can usually be separated by liquid chromatography on silica or alumina, providing a convenient means for analysis or preparative purification of the enantiomers: the resolved alcohols are recovered in high yield under mild, or nonracemizing, conditions by treatment with trichlorosilane/triethanolamine (TEA) (eq 1).9

This general strategy has found wide application in synthesis. Enantiomerically pure cyano alcohols obtained in this way are starting materials in the synthesis of uni- and multicyclic lactones.10-13 High purity enantiomeric epoxides can be prepared by resolution of the appropriate alcohol precursor followed by ring closure.14 Propargylic alcohol enantiomers resolved by this technique are intermediates in the synthesis of the four stereoisomers of 1,2,3-decanetriol,15 and of the sesquiterpene fungal metabolite (+)-sterpurene.16,17 The purification of stereoisomers of secondary alkan- and alkenols by this method is an essential step in the synthesis of biologically active enantiomers of 8-methyl-2-decanol propanoate,18 and of the germination inhibitor (-)-gloeosporone.19 The general method given in eq 1 is used to isolate enantiomerically pure intermediates in the synthesis of the fungal metabolites ascofuranone and ascofuranol,20 of the fungitoxic hydroquinone zonarol,21 and of naturally occurring C-nucleosides and their analogs.22 A hindered endo alcohol is also resolved after derivatization with (R)-NEI.23 In the synthesis of vitamin D3 metabolites, an enynyl alcohol intermediate is resolved with the help of both (R)- and (S)-NEI using crystallization rather than chromatography to separate the diastereomers.24

Indirect analysis of the enantiomeric ratio of an alcohol can be accomplished via separation and quantitation of the diastereomers of eq 1 by high-performance liquid chromatography (HPLC), gas-liquid chromatography (GLC), or supercritical fluid chromatography (SFC). For example, diastereomeric diacylglycerol 1-(1-naphthyl)ethyl carbamates are separated by HPLC on a silica gel column,25 as are the diastereomeric derivatives of the tertiary monoterpene alcohol linalool,26 diastereomers of (unsymmetrically substituted) 1,3-dialkylglycerol ethers are separable by GLC,27 and secondary alcohol enantiomers are derivatized with (R)-NEI and separated by SFC using several different stationary phases.28 The use of a bonded amine HPLC column is reported for the analysis of enantiomers of several 2,3-epoxy-1-propanols following derivatization with (R)- and (S)-NEI.29 Enantiomeric purity of a thiol, a derivative of the enkephalinase inhibitor thiorphan, is also determined after derivatization with (R)-NEI.3

Resolution of Amines.

Amines react with (R)- or (S)-NEI to form the corresponding urea diastereomers which can be separated in a manner analogous to the alcohols in eq 1. Secondary amines thus resolved can be recovered from the diastereomers by hydrolysis, as in the synthesis of chiral nonracemic lactams,5 or by decomposition in refluxing alcohols, as demonstrated by the resolution of several amine drugs.30

Analysis of the enantiomeric ratios of several b-blocking drugs (1-aryloxy-3-isopropylamino-2-propanol derivatives) is carried out by HPLC with UV or fluorescence detection after derivatization with (R)-NEI or (R)-(+)-1-(1-phenyl)ethyl isocyanate (in a reversed-phase system),31,32 or (S)-NEI (on silica gel);33 only the amine function of the drugs reacts with the NEI; the hydroxy group does not.31 Similar schemes for HPLC determination of enantiomeric purity of tetrahydrofolate derivatives34 and of fluoxetine35 are also reported.

In analysis, the original compound need not be recovered after separation, and therefore primary amines such as amino acids can be derivatized and analyzed in the same manner.36 (S)-NEI is employed as a derivatizing reagent in an Edman-like sequencing scheme to assess the extent of racemization of amino acid residues in synthetic peptides.37

Enantiomeric Stationary Phases.

Chiral nonracemic chromatographic stationary phases prepared from b-cyclodextrin, derivatized with (R)- and (S)-NEI, and covalently bonded to a silica support are useful for the direct separation of enantiomers of a wide variety of compounds in both normal-phase and reversed-phase HPLC.6,7,38

Determination of Absolute Configuration of Enantiomeric Compounds.

Empirical rules for the elution order in normal-phase chromatography of diastereomeric carbamates are used to assign absolute configurations of chiral nonracemic compounds resolved by the general method of eq 1.2 Owing to the inflexibility of the carbamate linkage, the relative positions of the most hydrophobic (or repulsive) group on the original compound and the naphthyl group of NEI are fixed in either a syn or an anti configuration in the two diastereomers. The syn conformer is likely to elute last, as its less repulsive moieties are more directly available for interaction with the silica surface.2 The rules fail occasionally.39 1H NMR39,40 and single crystal X-ray diffraction41,42 of purified diastereomers are also used in determining absolute conformation.

Synthesis of Chiral Nonracemic Allenes.

Enantiomerically enriched chiral allenes can be prepared by derivatization of a racemic propargyl alcohol with (R)-NEI, followed by chromatographic separation of the resulting diastereomers and reaction of the purified diastereomers with lithium dialkylcuprates at -78 °C, as shown in eq 2.8,43

Alternative Reagents.

1-(1-Phenyl)ethyl isocyanate (PEI) is a cheaper alternative to NEI; however, diastereomers formed from NEI are usually easier to separate by liquid chromatography.2,5,9 Other alternatives are also used, e.g. in determining the enantiomeric purity of 3-aminoquinuclidine, PEI, NEI, 2,3,4,6-tetraacetyl-b-D-glucopyranosyl isothiocyanate, and (R,R)- and (S,S)-O,O-dibenzoyltartaric acid anhydride are all employed successfully.44 Mandelic Acid and Mosher's reagent, a-methoxytrifluoromethylphenylacetyl chloride, may not be quite as effective as NEI when resolutions are carried out by liquid chromatography.2


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Firoz D. Antia

The R. W. Johnson Pharmaceutical Research Institute, Spring House, PA, USA



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