P III Oxazaphospholidines

He found that direct cyclisation with dichlorides (method A) in the presence of triethylamine was possible with R = t-Bu but not for R = Me or Ph. For the latter groups, )w(dimethylamino)phosphines proved to be more adequate starting materials (method B). 

Oxazaphospholidines 23 were obtained in 60-82% yields and with diastereo-selectivities in the 85-95% range. No X-ray data was reported, so the absolute configuration at the phosphorus atom of the major diastereomer (irons, that corresponds to R for alkyl or aryl groups) was determined by careful analysis of the and C- P coupling constants. Other groups managed to prepare 

23 with R = Ph using PhPCl2 and iV-methylmorpholine or diisopropyl-ethylamine, ° suggesting that the base can play a critical role in the success of 

Reaction of ephedrine with PCI3 furnishes 26 (entry 1) with different degrees of stereoselectivity depending on the exact conditions, as determined by P NMR. These determinations can be inaccurate, as they depend on many factors such as the resolution of the P NMR spectra, the temperature and the presence or absence of impurities that may favour interchange between the epi-mers. Synthon 26 has been used to prepare other compounds by nucleophilic substitution of the chlorine atom (entries 12, 23, 24, 29-31 and 33). These reactions proceed with predominant retention of configuration, but that depends on the exact structure of the oxazaphospholidine, the temperature and 

In spite of the mentioned stereochemical complexities, in all cases the major diastereomer has the substituent at the P atom and the Ph and Me groups of the ephedrine backbone in trans disposition. This has been confirmed by X-ray crystallography and can be easily rationalised in terms of thermodynamic preference. The result in entry 27 by Hansen and co-workers, who used pseudoephedrine, sheds more light on this issue. They demonstrated that the phenyl groups at the P atom and in the ephedrine have a trans relationship and concluded that the absolute configuration of the P atom is controlled by the carbon atom bearing the phenyl group in the ephedrine or pseudoephedrine. 

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