Grignard optically active, reduction

As with the reduction of aldehydes and ketones (16-23), the addition of organometallic compounds to these substrates can be carried out enantioselectively and diastereoselectively. Chiral secondary alcohols have been obtained with high ee values by addition to aromatic aldehydes of Grignard and organolithium compounds in the presence of optically active amino alcohols as ligands. ... 

To assess the stereospecificity of the Grignard and organolithium reactions with menthyl phosphinates, the diastereomeric purity of starting menthyl esters was estimated by pmr spectroscopy (see Sect. 2.2) and, in most cases, highest reported rotations were used to estimate the. enantiomeric purity of the derived optically active phosphine oxides The method of preference for determining the enantiomeric purity of a phosphine oxide, even in those cases in which a value for the rotation of optically pure material is reported, involves stereospecific reduction of the phosphine oxide with hexa-chlorodisilane (see Sect. 2.4) to the corresponding phosphine, followed by quatemization with 2-phenyl-2-methoxy-ethyl bromide and pmr analysis of the diastereomeric phosphonium bromides (Eq. (1)) > This method for determining optical purity, shown ) to be applicable... 

Tertiary phosphines, in the absence of special effects 2 ), have relatively high barriers 8) ca. 30-35 kcal/mol) to pyramidal inversion, and may therefore be prepared in otically stable form. Methods for synthesis of optically active phosphines include cathodic reduction or base-catalyzed hydrolysis 3° 31) of optically active phosphonium salts, reduction of optically active phosphine oxides with silane hydrides 32), and kinetic 3 0 or direct 33) resolution. The ready availability of optically pure phosphine oxides of known absolute configuration by the Grignard method (see Sect. 2.1) led to a study 3 ) of a convenient, general, and stereospecific method for their reduction, thus providing a combined methodology for preparation of phosphines of known chirality and of high enantiomeric purity. 

Hydride-transfer reactions suffer from the several shortcomings. First, a conventional optical resolution must usually be performed to obtain an optically active carbinol, which is then converted to the halide when the Grignard method is to be used. The actual reduction is generally not the only reaction pathway hence carbinol by-product is produced. More undesirable, however, is the fact that the asymmetric center of the organometallic reagent is sacrificed when the new chiral center is created. Unless the reaction is stereospecific, which is rarely the case, a net overall decrease in chirality results. 

The reduction process has not been of great synthetic importance, although its potential for asymmetric reductions of ketones has been recognized and investigated." For example, the reduction of isopropyl phenyl ketone to the corresponding alcohol occurs in 82% optical yield with the optically active Grignard reagent 1 ... 

Reduction of ketones with Grignard reagents prepared from certain optically active halides yields optically active secondary alcohols. Mosher and his associates (Burrows et al., 1960 Birtwistle et al., 1964 and references therein) have studied both the qualitative and quantitative aspects of such asymmetric reductions. 

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