1.4.2- Oxazaphospholidines, synthesis

The stereochemistries of the reactions between 0-aryl 0-methyl phosphonochloridothioates and nucleophiles have been studied in relation to the synthesis of 1,3,2-oxazaphospholidines. No displacement of chlorine takes place on treatment of O-methyl 0-4-nitrophenyl phosphonochloridothioate with 2-methoxyethanol, and in the presence of 1-phenylethylamine, it is only the latter which reacts. In addition, when the same phosphonochloridothioate is treated with sodium ethoxide, it is the 4-nitrophenoxy group, rather than chlorine, which is displaced. Both displacements were shown to occur with inversion of configuration at phosphorus. The use of such an acid chloride as a two-step 1cyclophosphorylating1 agent of 2-aminoalcohols to give 1,3,2-oxazaphospholidines (209), is illustrated. ... 

The asymmetric synthesis of 2-aryl(alkyl)-l,3,2-oxazaphospholidines 52 was based on the reaction of achiral organophosphonous diamides 51 with L-ephedrine (42) (Scheme 19) [44], The diastereomeric excess ranges from 0% (R=Ph) to 95%... 

A modification of this procedure allowed the isolation of 1,3,2-oxazaphospholidine 52a as a single diastereomer [41] and its application to asymmetric synthesis of enantiomerically and diastereomerically pure phosphinic acid derivatives 53 and 54 and tertiary phosphine oxides 55 (Scheme 20) [45], A few years later, a similar approach for the synthesis of enantiomerically pure tertiary phosphine oxides 55... 

The first report on the reaction of D-pseudoephedrine 66 with phosphoryl chloride appeared as early as 1962 [49], More recently it was found that this condensation gave 2-chloro-l,3,2-oxazaphospholidine 2-oxides 67 as a single diastereomer which was subsequently esterified with racemic aldehyde cyanohydrins 68 without racemization at the phosphorus atom. The prepared diastereomeric esters 69 were used as substrates for the asymmetric synthesis of optically active cyanohydrins 72, which involves the intermediate formation of the tertiary esters 70, as shown in Scheme 22 [50],... 

Scheme 29 Synthesis of 2-chloro-1,3,2-oxazaphospholidine 2-thiones 101a,b...

Table 1 Synthesis of 2-alkyl(aryl)-2-oxo-1,3,2-oxazaphospholidines (25,45,5/J)-107a-l 13a and (2/t,4S,5fl)-107b-113b...

Scheme 31 Synthesis of 2-alkyl(aryl)-2-oxo-l,3,2-oxazaphospholidines (2S,4S,5K)-107a-113a and (27 , 45, 5f )-107b-l 13b...

Synthesis of 1,3,2 oxazaphospholidines 128a-c derived from (S)-prolinol 127 was based either on the thermal aminoalcoholysis of the latter with prochiral alkyl(aryl) phosphonousdiamides 51a-c or its condensation reaction with /-butylphosphonous dichloride carried out in the presence of triethylamine (Scheme 37) [68], The diastereomeric excesses of the prepared derivatives ranged from 80 to 95%. 

A series of 2-chloro-l,3,2-oxazaphospholidine derivatives 131a-f were prepared by reaction of six enantio-pure alcohols 129a-f with phosphorus trichloride carried out in the presence of an organic base as HC1 scavenger (Scheme 38) [69], The 31P and II-NMR spectra of crude 131a, d, e containing a small amount of the HC1 salt produced during the synthesis of 131, as well as the distilled samples, indicated that the formed chloro derivatives were ca. 1 1 mixtures of the cis and trans isomers. 

Scheme 38 Synthesis of the nucleoside 3 -0-oxazaphospholidine derivatives 132a-f...

Scheme 43 Synthesis of 1,3,2 oxazaphospholidine-2-one 155 a and b and their conversion to the pyridinium salts 156a and 156b...

A similar synthesis of chiral (o-hydroxyaryl)oxazaphospholidine oxides 166a-b, 167a-b, and 169a-d derived from (5)-prolinol 127 and its diphenyl derivative 163 was achieved from precursors 164a-b, 165a-b, and 168 which were easily available from two different procedures as outlined in Scheme 46 [77], The first pathway gave the two expected diastereomers of 164 and 165 in a ratio... 

Scheme 46 Synthesis of (ohydroxyaryl)oxazaphospholidine oxides 166a-b and 167a-b and (ohydroxyaryl)oxazaphospholidine oxides 169a-d...

Scheme 47 Synthesis of 2-phenyl-1,3,2 oxazaphospholidine-2-oxides 170a and 170b...

Scheme 49 Synthesis of 2-alkoxy-l,3,2 oxazaphospholidine-2-oxides 176a and 176b...

Scheme 51 Synthesis of 2-chloromethyl-l,3.2-oxazaphospholidine-2-oxide 182 and its conver-tion into the cyano derivative 183...

Scheme 53 Synthesis of 2-phenyl-l-/ -toluenesulfonyl-l,3,2-oxazaphospholidin-5-one 191-193 and the cis/cis, cis/trans, and trans/trans diphosphorus heterocycles 196a-c...

Chiral [160, l70, l80]phosphomonoesters and ATPy[l60, l70, lsO] have been synthesized by Knowles and associates, who devised the procedure outlined in Fig. 19 [51-55], The procedure has been used to synthesize phenyl[160, l70, l80]phos-phate and 2-[160,170,180]phospho-D-glycerate as well as the propylene glycol ester shown. The starting cyclic adduct was prepared by reaction of (— )-ephedrine with P17OCl3, giving a separable mixture of 2-chloro-l,3,2-oxazaphospholidin-2-ones whose chemistry had been described [56], The major isomer was converted to (/ p)-l-[160, nO,180]phospho-1,2-propanediol and (Sp)-ATPy[l60, nO, lsO] by the reactions shown. The stereochemistry at each step of the synthesis was well prece-dented in the literature nevertheless, the configurations were verified by independent methods described in the next section. 

The synthesis of various new chiral (o-hydroxyaryl)oxazaphospholidine oxides (139), derived from (S)-proline derivatives, from precursors (140) have been elaborated. This two-step reaction involves an unstable metallated intermediate that undergoes a fast 1,3-rearrangement with the formation of phosphorus-carbon bond. These catalysts have been successfully applied to the catalytic asymmetric borane reduction of numerous prochiral ketones with enantiomeric excess up to 84% ee (Scheme 35). ... 

Brown and co-workers synthesized optically active phosphine oxides from phosphorus trichloride by sequential addition of nucleophiles to chiral oxazaphospholidine [Eq. (24)]. The key step in this synthesis is control of the stereochemistry of the oxazaphospholidine, since the stereochemistry from the other steps is well characterized. The overall result is a greater than 94% e.e. 

Nevertheless, this mechanism cannot fully explain the enantioselectivity encountered. In the same area, Martens et al. have reported the synthesis of numerous oxazaphospholidine borane complexes and their use in the enantiose-... 

Various approaches are currently being made to the asymmetric synthesis of silyl ethers of (oc-hydroxyalkyl)phosphonic acids. One approach consists of the use of chiral 1,3,2-oxazaphospholidines (216 R = Et or Ph, R 3 = Bu Mc2), as a mixture of diastereoisomers, which react smoothly at room temperature with an aldehyde to give the diastereoisomer-ic silyl ethers 217 with retention of configuration at phosphorus ". In a second approach, the reaction between benzaldehyde and (EtO)2POSiMe2Bu was carried out in the presence of the chiral Lewis acids 187 (R = Me or Ph, X = Cl) a higher reaction yield accompanied a lower enantiomeric excess in the product, and vice versa, but the enantiomeric excess was never higher than about 25% ". ... 

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