Oxazaphospholidines and Derivatives

2-oxazaphospholidines are the N,0 counterparts of the 1,3,2-diazapho-spholidines discussed in the previous section. Not surprisingly, the preparative 

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Table 3.9 lists most of the oxazaphospholidines and derivatives prepared from ephedrine reported to date. 

The latter compound is the amino alcohol analogue of the diamine (S)-2-(anilinomethyl)pyrrolidine (Scheme 3.1, Section 3.2.1). Not surprisingly, pro-linol has also been used to prepare bicyclic P-stereogenic oxazaphospholidines and derivatives thereof. As anticipated, their preparative methods are the same as those described in the preceding sections (Scheme 3.21). 

Other cyclic alcohols apart from prolinol have been used to synthesise bicyclie oxazaphospholidines and derivatives. One important example is (5)-(—)-a,a-diphenylprolinol (51), which is nowadays commercially available (Scheme 3.22). 

Although the stereoselective formation of C-C bonds has been actively pursued in the last two decades, it was not until 1982 that the first stereoselective C — N bond formation was reported20, using the enantiomerically pure 1,3,2-oxazaphospholidine and 1,3,2-oxazaphosphorinane derivatives 1 and 2, respectively, as well as their enantiomers. Derivative 1 is easily accessible from (—)-ephedrine, phosphonis oxychloride and AUV-dimethyl hydroxylamine. A related route leads to 2. 

Table 3.9 Ephedrine-based oxazaphospholidines and some derivatives.

Inch and co-workers reported in 1979 the preparation of P-stereogenic phosphinothioic aeids starting from 1,3,2-oxazaphospholidine sulfides derived from (-)-ephedrine (Scheme 4.48). 

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. 

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... 

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. 

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... 

M-Benzyl-O-methyl-L-serinoate (173) was condensed with phosphoryl trichloride giving cyclic chloridate 174 that reacted with the Tegafur derivative 175 with the formation of almost equal amounts of 2-alkoxy-l,3,2 oxazaphospholidine-2-oxides 176a and 176b (Scheme 49) [80],... 

A rich family of 2-alkoxycarbonyl-l,3,2-oxazaphospholidine-2-oxides 179-181 was prepared from the reaction of camphor derived aminoalcohols 177 and 178 with either methoxycarbonyl phosphonic dichloride or ethyl dichlorophosphite followed by the reaction with methyl bromoacetate. The reaction with aminoalcohol 177a afforded the phosphorus epimers 179 and 180, in ratios from 1/1 to 12/1 depending on the iV-substituent which could be separated easily by column chromatography. The reaction with aminoalcohols 178a-c, however, gave a single epimer 181a-c in each case (Scheme 50) [81]. 

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

A similar reaction of A-toluenesulfonyl derivatives of (.S )-alanine, phenylalanine, and valine (188-190) with PhPCl2 gave 4-methyl, benzyl, and isopropyl derivatives of 2-phenyl-1-p-toluenesulfonyl-l, 3,2-oxazaphospholidin-5-one, 191-193 in high yields (Scheme 53) [84], The ratios of the (2.V,4.V)/(2/f,4.V) diastereomers (which were designated as cis/trans isomers) were 1 1, 2 1, and 10 1 for 191a,b, 192a,b, and... 

R = PhCHMe) have been prepared and distinguished by n.m.r. spectroscopy.31 Attempts to prepare 7V-aryl derivatives of cyclophosphamide by cyclization of the phosphoramides (36) proved unsuccessful.32 Although this type of reaction has proved to be of great value in the preparation of perhydro-l,3,2-oxazaphosphorines and 1,3,2-oxazaphospholidines when NaOEt, NaOH, or NaH are employed as reagent, in this instance the bis(chloroethyl)amide side-chain presents a further possible reaction site. However, steric effects, also considered as an explanation for instances of failure of the reaction (see Organophosphorus Chemistry , Vol. 7, p. Ill) may be operating adversely. 

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). ... 

The bicyclic 1,3,2-dioxaphosphorinanes have lost their popularity and have been replaced, both for mechanistic studies and for synthetic purposes, by the monocyclic and yet diastereoisomeric 3,4-dimethyl-5-phenyl-l,3,2-oxazaphospholidines . The most widely employed of these compounds have been those derived from (-)-ephedrine and of 4S,5R geometry (79), from (+)-ephedrine, and so of 4R,5S geometry, and from (+)-pseudoephedrine, which are of structure 83 with 4S,5R stereochemistry. Their syntheses with a dichloride RP(Z)Cl2 in the presence of an appropriate HCl acceptor yield mixtures of products, epimeric at phosphorus, and generally separable. A few other compounds have been derived from norephedrine. The stereochemistries of several such compounds have been determined by X-ray crystallography, and reference has just been made to some... 

The oxazaphospholidine-based methodology has been developed to provide syntheses of chiral (chloromethyl)-, (dichloromethyl)-and (trichloromethyl)-phosphonic esters, and those of the corresponding phosphonothioic acids , and also chiral derivatives of (fluo-romethyl)phosphonic acid and (fluoromethyl)phosphonothioic acid ... 

Cullis et al. (1987) have demonstrated that incubation of either diastereomer of the l,3,2-oxazaphospholidine-2-thione [33a] in anhydrous pyridine results in epimerization (ti = 12h at room temperature). This result was repeated with the thio derivatives [33b] (ti = 16h at 31°C) and in the case of [33a] with A, A -dimethylaminopyridine or 7V-methylimidazole in place of pyridine. In the latter experiments, it was postulated that the cyclic intermediates corresponding to [33c] are detected. Furthermore, incubation of either diastereomer of [33a] with tetrabutylammonium fluoride in the THF gives identical epimeric mixtures of product [33d]. 

The synthesis of P-chiral diarylphosphinocarboxylic acids 120 was achieved with excellent enantiopurity starting from the oxazaphospholidine boranes 82. Amido- and amino-diphosphine ligands 121, containing an L-proline backbone, were also derived from 82. The catalytic activities of the ligands 121 were evaluated in the Pd-catalyzed allylic alkylation reaction of 1,3-diphenylpropenyl acetate (Scheme 36) [66]. 

In the last section several oxazaphospholidine oxides, obtained by oxidation of the P(III) precursor with t-BuOOH, have already been described. There is also one report by Juge and co-workers in which they prepare oxazaphospholidine oxides and sulfides by in situ deboronation/oxidation of oxazaphospholidine boranes. This section illustrates some more derivatives, prepared directly from P(V) species and ephedrine. Chronologically, these types of compounds were studied earlier than the corresponding P(III) counterparts. Nowadays oxazaphospholidine boranes, not oxides, are the most important precursors used to prepare enantiopure phosphorus ligands. However, apart from historic interest, ephedrine-derived oxazaphospholidine oxides, sulfides and selenides occupy an important place in the study of phosphorus stereochemistry and conformational analysis. Only a few examples are described here. 

During the 1970s Inch and co-workers ° published a series of detailed papers where they studied many 1,3,2-oxazaphospholidines derived from (—)-ephedrine, prepared from common P(V) precursors (Scheme 3.18). 

The mentioned compounds have been used in systematic studies on the regio-and stereoselectivity of substitution reactions at the phosphorus atom. ° los.iii 112 The same authors also reported a similar study on oxazaphospholidine oxides and sulfides derived from (+)-norephedrine (Figure 3.3). 

In parallel to P(V) diazaphospholidines (see Section 3.2.2), a totally regio-selective [1,3] P-0 to P-C rearrangement was observed upon treatment of P(V) (pseudo)ephedrine-derived oxazaphospholidines with LDA. This was observed first by Welch and co-workers (Scheme 3.19). ... 

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