Ephedrine Juge-Stephan method

Ephedrine as Chiral Auxiliary (Juge-Stephan Method). 180... 

Juge developed a powerful method (Juge-Stephan method) [1, 51] for the preparation of / -stereogenic phosphines based on the use of ephedrine as a chiral auxiliary. The key reactants in this methodology are 1,3,2-oxazaphospholidine boranes 78, prepared by a one-pot reaction from bis(diethylamino)phenylphosphine and (—)-ephedrine, followed by protection with BH3. The cyclization of the (—)-ephedrine takes place stereoselectively, with preferential formation of the (/ p)-diastereoisomer in 90% de [52, 53]. The absolute configuration at the phosphorus atom has been determined by chemical correlations and NMR analysis, and proved by X-ray analysis [54]. Oxazaphospholidines react readily with electrophiles or nucleophiles to provide various chiral phosphorus compounds. Enantiomeric antipodes of tertiary phosphines (Sp)-79 and (Rp)-81 were obtained from (-1-)- or (-)-ephedrine, as shown in Scheme 25. The configuration at the E-atom is controlled by the configuration at the Ph-substituted Cj of (-i-)-pseudoephedrine or ( )-ephedrine, respectively. This was confirmed by X-ray crystal-structure analyses of two intermediate compounds in the synthetic route to the chiral triarylborane-phosphine adducts [54]. 

In the original Juge-Stephan method A-B = ephedrine, X = BH3, HY = MeOH/ H2SO4 and M = Li. This method is depicted in Scheme 4.2. 

Aminophosphine phosphinite (AMPP) ligands constitute an important class of non-C2 diphosphorus ligands. Some of them are prepared from ephedrine and therefore the Juge-Stephan method constitutes an ideal procedure for the synthesis of P-stereogenic AMPP ligands (Scheme 4.30). ... 

Before the Juge-Stephan method was established and widely used other similar approaches, also based on the use of ephedrine as a chiral auxiliary, were studied. Although they have been eompletely eclipsed by the modern strategy, they are noteworthy as they give an interesting perspective on how the eurrent method was originally developed. 

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. 

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 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. 

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