Other Heterobifunctional Chiral Auxiliaries

This route is often cited in the literature along with the Juge-Stephan method as an example of a procedure to prepare P-stereogenic phosphines via enan-tioselective synthesis. In spite of that, it has unfortunately not been applied to prepare other ligands, so its potential remains unknown. The commercial availability of ephedrine but not of the thio alcohol required to prepare 136 is a likely explanation of the lack of development of this method. 

The regio- and stereochemistry of the reactions was explained by addition elimination mechanisms involving pentacoordinated intermediates. 

The comparison between this section and a previous one (Section 4.3) about the Juge-Stephan method shows that ephedrine has totally overshadowed other auxiliaries in the preparation of P-stereogenic ligands. However, the Juge-Stephan method has its limitations and therefore the study of other bifunctional auxiliaries is a rather unexplored area, which awaits further development. 

Despite its versatility, the ephedrine methodology clearly suffers from some limitations. Exceedingly bulky phosphines (bearing mesityl or 9-anthryl groups for example) can only be prepared in low yields if at all. This is because the method is based on nucleophilic substitutions at the phosphorus atom, which become progressively more difficult with increased steric shielding. Another limitation is that all the phosphines prepared bear at least one aryl group (almost exclusively phenyl) and are therefore very basic, trialkylphosphines are not accessible via the ephedrine method. This limitation has been partially overcome by another complementary and extremely important method the enantioselective deprotonation of dimethylphosphine derivatives described in detail in the next chapter. 

Darcel, J. Uziel and S. Juge, in Phosphorus Ligands in Asymmetric Catalysis Synthesis and Applications, A. Borner, (ed.), Wiley-VCH, Weinheim, 2008, p. 1211. 

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Many other heterobifunctional chiral auxiliaries have also been employed to alford P-stereogenic heterocycles. Some of them are discussed here. 

The Juge-Stephan method and its variations reveal that ephedrine is an extraordinary chiral auxiliary in P-stereogenic chemistry, highlighted by the simplicity of its structure. In spite of this, there are no reasons to assume that other chiral amino alcohols or, more generally, other heterobifunctional chiral auxiliaries can not be equally good or even outperform ephedrine. In the literature, there are a few early reports on synthetic sequences resembling the Juge-Stephan method but with other auxiliaries, which are briefly described here. 

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