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. 

The cleavage of the P-N bond of 8 in the original Juge-Stephan method is performed by acidic methanolysis (Scheme 4.9). 

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. 

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. 

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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