The Juge-Stephan Method

The first step is the nucleophilic ring opening of 7 with organolithiums at low temperature to produce aminophosphine boranes 8. This step occurs regiose-lectively (P-0 bond cleavage) and diastereoselectively (retention of configuration). The selective cleavage of the P-N bond is then performed in methanol with the presence of one equivalent of sulfuric acid. The products are 

The retention of configuration at the P atom has been confirmed by X-ray analysis of some aminophosphines 8 prepared from alkyl- and aryllithiums. This stereochemistry can be rationalised by a mechanism implying a kinetically 

Many aminophosphines 8 have been prepared in the last 20 years. Most of these are listed in Table 4.1. 

The low diastereoselectivity of these reactions has been attributed to the second nucleophilic attack due to increased steric shielding since it is known that the first attack occurs with a de higher than 96%.  

It was found that the reactions afford complex mixtures, which contain phospholanes 18 along with the non P-stereogenic diaminophosphine 19. These 

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Although methylphosphinite boranes are usually used as electrophilic precursors to phosphine boranes (see Section 4.3.3.1), they can also be deprotected by amines, affording the corresponding optically pure methylphosphinites. The deprotection reaction is very enantioselective, with retention of configuration at the P centre. Only a few free phosphinites have been prepared with the Juge-Stephan method these are listed in Figure 4.1. 

Table 4.4 gives a clear overview of the type of phosphine boranes that can be prepared with the Juge Stephan method. The method seems particularly well suited for the synthesis of phosphines containing at least one aryl group in extremely high enantioselectivities. These include a few dialkylarylphosphine boranes (entries 2-4 and 7), triarylphosphine boranes (entries 17, 18 and 35)... 

One of the most interesting features of the Juge-Stephan method is that it allows the synthesis of both enantiomers of phosphine boranes (Scheme 4.18). 

Scheme 4.18 Different ways to obtain both enantiomers of phosphine boranes via the Juge-Stephan method. Usually = Ph.

Scheme 4.20 First ferrocenylphosphines prepared by the Juge-Stephan method.

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). ... 

Gouverneur and co-workers used several phosphine boranes and phosphinite boranes bearing alkenyl groups prepared by the Juge-Stephan method in metathesis reactions (see Chapter 6, Section 6.2.6), but they were prepared as racemates intentionally. 

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 oxide version of the Juge-Stephan method was reported the same year as the borane version by Brown and co-workers. Unsurprisingly, the first compound to be prepared was the oxide of PAMP, usually known as PAMPO (Scheme 4.49). 

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. 

This chapter describes the preparation of the compounds depicted in Schemes 5.2 and 5.3 by the enantioselective deprotonation protocol. It has become an extremely important procedure to prepare some interesting families of ligands including many electron-rich bulky diphosphines, thus complementing the Juge Stephan method. 

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