Variations of the Juge-Stephan Method

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. 

Reaction of optically pure 104 with organolithiums to form 105 occurs with preponderant P-0 bond cleavage and retention of configuration (de 90%), exactly like in the modern Juge-Stephan method, but at that time those observations were unexpected. The retention of configuration in the ring opening of 104 was explained by the sequence formation of a pentacoordinated intermediate-pseudorotation-apical elimination. Acidolysis of 105 produced the desired phosphinothioic acids 106 in ee values better than 90%. This step is also directly comparable to the acidic methanolysis in the modern method. 

There are a few reports following this methodology to prepare P-stereogenic phosphine oxides and some were reduced to the free phosphines with silanes.  

Ring opening of 116 with t-BuLi and subsequent acidolysis with / -toluene-sulfonic acid (PTSA) afforded the secondary phosphine oxide 117 in 40% overall yield but with an interesting 85% ee. This reaction is noteworthy because the reader will probably remember that the acidolysis (either with Me0H/H2S04 or with dry HCl) of t-Bu substituted aminophosphine boranes does not occur (see Section 4.3.2). 

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