1.3.2- Oxazaphospholidines configuration

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. ... 

A-trityl-(l/ ,2S)-norephedrine (58), the corresponding allyl phosphonates 62a,b were obtained via the Arbusov rearrangement of 2-ethoxy-1,3,2-oxazaphospholidine 60. The absolute configuration of the major diastereomer, 62a was determined by X-ray as (2S1,45,51 ).The reaction of the major diastereomer of allyl phosphonates 61a and 62a with DBU afforded the corresponding vinylphosphonates 63a,b (Scheme 21) [48], Nucleophilic addition to these resulted in induction of chirality at the [1-position of the stereogenic phosphorus atom in the initially produced diastereomeric phosphonates 64 or 65 (Scheme 21) [48],... 

The basic hydrolysis of acyclic phosphoramidates occurs with a mixture of C-0 and P-0 bond cleavage (l, 2) however similar treatment of l,3>2-oxazaphospholidines can result in substantial P-N cleavage ( 1, 3). 1,3,2-Oxazaphospholidines derived from (-)-ephedrine react with solutions of alkoxides in alcohol to give only the products of P-N cleavage and with inversion of configuration at phosphorus. Scheme I ( +, 5). ... 

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. 

Treatment of 1,3,2-oxazaphospholidine 2-sulfide 176, bearing two amino residues at phosphorus, with oxaziridine 80 gave 1,3,2-oxazaphospholidine 2-oxide 177 in 92% yield <1997JOC6401>. It was interesting to note that the desulfurization occurred with complete stereoselectivity (>98% de) and with inversion of the configuration at the phosphoms, whereas use of w-chloroperbenzoic acid (MCPBA) resulted in retention of configuration affording 178 (Scheme 6). 

When bis(2-anilinoethyl) phenylphosphonite [PhP(OCH2CH2NHPh)2] (from 2,3-diphenyl-1,3,2-oxazaphospholidine with 2-anilinoethanol) was heated at 200° for Ihour it gave 1,4-diphenylpiperazine (1660). The reaction of p-substituted A -sulfinylanilines (130) with styrene oxide in the presence of tetraethylammonium bromide produced the corresponding 1,2,4,5- (131) and 1,2,4,6-tetraarylpiperazines, whose configurations have been established on the basis of the n.m.r. spectral studies (1661). Heating of A7-sulfinylaniline (130, R = H) with ethylene carbonate (132) and lithium bromide at 140° for 6 hours gave 50% 1,4-diphenylpiperazine (1662). 

An X ray examination of the product from the interaction of (2B,4fi,5S)-(-)-3,4-dimethyl-2-phenyl-1,3,2-oxazaphospholidine 2-oxide with an aryl Grignard reagent has demonstrated that ring opening occurs with retention of configuration at phosphorus in accord with Inch s work, but at variance with that of Koizumi, and also in stereochemical opposition to that displayed by acyclic analogues (Mislow). Acid catalyzed alcoholysis of the acyclic phosphinic amide... 

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% ". ... 

Reactions between the 1,3,2-oxazaphospholidines 613 (X = O) and alkoxide ions are even more remarkable in that ring opening occurs with preferential P—N rather than P—O bond cleavage, and with inversion of configuration at phosphorus, cf. 613 618 . The... 

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]. 

Oxazaphospholidine boranes 82 react regio- and stereoselectively with alkyl lithiums or aryl lithiums in THE at —78°C, with formation of acyclic phosphinite boranes 83. Various substituents R =n-alkyl, c-alkyl, aryl, or ferrocenyl were introduced into aminophosphine boranes 82 in high yield (93-97%) and with high diastereoselectivity dr >98 2). The reaction proceeded with retention of configuration at phosphorus. RecrystaUization of aminophosphine boranes 83 in propanol gave the diastereoisomerically pure products [53]. Acid methanolysis of aminophosphine boranes 83 led to the formation of phosphinite boranes 84 with inversion of configuration on the E-center to yield the compotmds 84 in high... 

The overall retention of configuration was rationalized by a reaction sequence involving attack of ferrocenyllithium (FcLi) on the electrophilic phosphorus followed by pseudo-rotation and termination by chloride elimination [64]. Ortho-lithiation of oxazaphospholidine oxide 113 was carried out with diastereoselectivity... 

The opening of oxazaphospholidine rings (/ p)-122 with tert-butyllithium occurred diastereoselectively with retention of absolute configuration on the phosphorus atom, affording the borane complex of aminophosphine (Rp)-124 [67, 68]. The reaction possibly proceeds via formation of chiral o X -phosphenium cation 126, which was obtained from (Sc)-chlorophosphine 125 and then isolated as borane complex 127 (Scheme 38). 

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... 

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... 

Alcohol 61 is easily prepared from a chemical found in industrial waste and was used to prepare the tricyclic oxazaphospholidine borane 62 in 64% combined yield. The X-ray structure revealed that in this case the phosphorus atom had S absolute configuration. In the same paper they described the preparation of 64 in 40% yield and in optically pure form, starting from the azetidinic alcohol 63. The same authors prepared the phosphine oxide version of 62 via oxidation of the P(III) precursor and by direct reaction of 61 with PhP(0)Cl2/NEt3. 

Methylmagnesium iodide reacted with 122 (X = O) with P-0 bond fission, to afford 123 in quantitative yield. Acidic methanolysis of this compound then produced (/ p)-124 in 92% ee. That implies that the first step occurred with inversion of configuration at the phosphorus atom, in contrast with oxazaphospholidine oxides derived from ephedrine. Similar inversion was observed for X = S and for other Grignard reagents. This example emphasises once more the difficulties of drawing general conclusions about the stereochemical outcome of the substitutions at the phosphorus atom. 

As the NMR spectra of the phospholidine-thiones 2a and 2b do not permit to assign the configuration of the phosphorous chiral center,we have tried to grow crystals suitable for X-ray diffraction. We were successful only for a homologue of 2a with a shorter chain the crystal structure of the major (2-butanoxy-4-phenyl)1,3f2-oxazaphospholidine-2-thione (2a, R = Ci Hg), shows the relative S, R configurations on positions 2 and 4.° As the acid cleavage is expected to proceed with... 

---