Racemization phosphine

Macaudiere et al. first reported the enantiomeric separation of racemic phosphine oxides and amides on native cyclodextrin-based CSPs under subcritical conditions [53]. The separations obtained were indicative of inclusion complexation. When the CO,-methanol eluent used in SFC was replaced with hexane-ethanol in LC, reduced selectivity was observed. The authors proposed that the smaller size of the CO, molecule made it less likely than hexane to compete with the analyte for the cyclodextrin cavity. 

Optically stable racemic phosphines have been oxidized with one half equivalents of optically active peracid. The remaining phosphine, oxidized with perbenzoic acid, showed low optical activity, but the phosphine oxides obtained in the asymmetric oxidation were optically inactive. ... 

The reduction of optically active phosphonium salts by lithium aluminum hydride, which probably does involve 70 as an intermediate, affords racemic phosphines, presumably by pseudorotation in 70 before it decomposes 63). 

Suisse and co-workers have studied the asymmetric cyclization/silylformylation of enynes employing catalytic mixtures of a rhodium(i) carbonyl complex and a chiral, non-racemic phosphine ligand. Unfortunately, only modest enantioselectivities were realized.For example, reaction of diethyl allylpropargylmalonate with dimethylphenyl-silane (1.2 equiv.) catalyzed by a 1 1 mixture of Rh(acac)(GO)2 and (i )-BINAP in toluene at 70 °G for 15 h under GO (20 bar) led to 90% conversion to form a 15 1 mixture of cyclization/silylformylation product 67 and cyclization/ hydrosilylation product 68. Aldehyde 67 was formed with 27% ee (Equation (46)). 

The scheme followed more recently by Moriarty et al139 again involved a racemic phosphine (64, in Scheme 7), used to synthesize a racemic phosphorane 65, but the optically active ligand was introduced only at that point, to replace NMe2. As before, two diastereoisomers, 66a and b, were obtained, as proved by the two series of signals in the 31P, lH and 13C NMR spectra, and of the S and J values which were determined for the... 

Temperature is another important parameter that can improve the yield of nucleophilic substitution by suppressing the competitive reactions. Interestingly, low temperature can be used to selectively make mixed alkyl or aryl compounds [Eq. (47) 95]. This can be an effective one-pot synthesis to make a chiral, albeit racemic, phosphine. 

Stereospecific syntheses have been reported for ethyl isopropyl methyl phosphate, O-ethyl 0,S-dimethyl phosphorothioate, and ethyl methyl methyl-phosphonate,"" " and optically active alkyl S-methyl methyl phosphonothioates and dialkyl S-methyl methyl phosphorothioates have been prepared from ephedrine-RPSCU starting materials."" Finally, optically active phosphines can be obtained when a racemic phosphine oxide such as MePr"PhPO or (97) is reduced with a chiral, non-racemic aluminium hydride." "... 

Tertiary phosphines have been partially resolved by complexation with the asymmetric palladium(ii) complex (16), Treatment of this complex with racemic phosphine gave (17), phosphine of low rotation being recovered from the mother liquor. The enantiomeric phosphine can be... 

A racemic phosphine 28 was obtained by consecutive displacement of hydrogen atoms of phenylphosphine (8) with two different aryl iodides 25 and 27. For the coupling of diphenylphosphine with aryl iodides, Pd on carbon is a good catalyst in DMF under microwave dielectric heating in DMF [3]. 

A P-chirogenic phosphine can be synthesized by Pd-catalyzed asymmetric phos-phination. Coupling of the racemic phosphine 28a with iodobenzene afforded the... 

In 1971, an interesting application of the chlorobridged Pd(II) complexes with orthometallated chiral amines was demonstrated by Otsuka and co-workers resolution of racemic chiral phosphincs. The binuclear species reacts with tertiary phosphines or arsines to form two equivalents of mononuclear complexes (Scheme 3). If both the phosphines and the orthometallated palladium complexes were chiral, the mononuclear products could be a mixture of diastereomers. With appropriate combinations of the chiral racemic phosphines and the enantiomerically pure orthometallated palladium species, one of the two enantiomers of the phosphines reacts with the palladium complex selectively to give a specific diastereomer of the mononuclear palladium complexes, leaving the other enantiomer of the phosphine unreacted. 

The synthesis of phosphinate derivatives 32 described by Pompei was performed by coupling of the key macrocyclic acid 30 [35, 39], with racemic phosphinic acid 31 (Scheme 5) [34], This coupling occurred by converting the carboxylic acid of pyroUdine ring with ethyl chloroformate into an anhydride intermediate which was subsequently trapped by the amino function of phosphinic acid derivatives. 

GiUieany et al. [71-76] reported the oxidation of tertiary phosphine 133 with polyhaloalkanes in the presence of chiral proton-donating auxiliary L-menthol (the asymmetric Appel reaction). As a result, chiral phosphine oxides 134 were prepared with good enantiomeric excess. The latter were then treated with LDA and copper chloride to afford the bis-phosphine oxide which is a useful chiral ligand for asymmetric catalysis. The chiral bis-phosphine oxide R,R)-liS was produced in 98% ee and the minor amount of meso-isomer formed was easily removed by recrystallization from benzene, which yielded enantiopure (>99.9% ee) bis-phosphine oxide 135 in an isolated yield of 73% from the racemic phosphine 133 (Scheme 41). 

For the last few year the catalytic asymmetric synthesis of tertiary phosphines has attracted the attention of many chemists. Interesting results were published in many articles and reviews [109-115]. Catalyzed by transition metals, asymmetric phosphination of secondary, racemic phosphines with aryl halides or triflates to prepare a tertiary P-stereogenic phosphines with control of the stereochemistry at the phosphorus atom is shown in Scheme 62. 

Rajendran KV, Gilheany DG (2012) Identificatiem of a key intermeeliate in the asymmetric Appel process one pot stereoselective synthesis of F-stereogemic phosphines and phosphine boranes fiom racemic phosphine oxides. J Chem Soc Chem Commun 48 10040-10042... 

Phosphonium derivatives may be made directly by reacting ethylene dibromide with an appropriate phosphine. Either cis or trans isomers may be obtained, depending upon whether the starting material is a meso or a racemic phosphine (6.840, 6.841). 

NaBH4 and the intermediate free phosphine. Unfortunately, starting from optically pure phosphine oxides yielded only racemic phosphine boranes. Finally, Corey and co-workers ° prepared optically pure phosphine boranes by in situ desulfurisation-complexation (method C), with retention of configuration. 

All the resolutions mentioned above involved non-covalent interactions. There are a few cases of classical resolutions involving covalent binding of the chiral auxiliary to the racemic phosphine and cleavage after the separation of diastereomers. 

A special variant of resolution is called oxidative resolution, because it yields optically pure phosphine oxides from racemic phosphines. To this end, Keay and co-workers" used the Staudinger reaction between racemic phosphines and an optically pure azide (Scheme 2.3). 

The azide 9 was obtained from (+)-CSA" and reacted with several racemic phosphines affording phosphinimines 10 in very good yields. They could be separated by conventional methods and each diastereomer was easily hydrolysed under acidic conditions giving the phosphine oxides 11 in excellent yields and with clean inversion of configuration at the phosphorus atom." ... 

Figure 2.2 Cyclometallated Pd(II) dimers used to resolve racemic phosphines. Only one enantiomer of the chiral amine and only the cis isomer for each complex are represented. Usually, R = R = Me.

Almost at the same time, Imamoto, Johnson and Sato developed a related route starting from a secondary racemic phosphine oxide for the preparation of methylphenylphosphine oxides with encumbered groups (Scheme 2.14). 

These desymmetrisations by CM are challenging because selectivity has to be controlled at several levels. There are many alkenes in the reaction mixture that can undergo undesired self-metathesis reactions. In addition, double metathesis yielding achiral products has to be minimised. Finally, there is the issue of EjZ selectivity. Despite these hurdles, several examples of F-stereogenic (but racemic) phosphine oxides 115 were obtained from prochiral phenyl divinylpho-sphine oxide (114) in 47 6% yield. A three-fold excess of 114 was used to minimise double metathesis. In all but one case none of the E isomer of 115 is formed. The vinyl group in 115 was further functionalised by CM with styrene. 

As early as 1973, Zemer and Dudman reported the kinetic resolution of a P-stereogenic phosphate triester (butylmethyl(p-nitrophenyl)phosphate) by hydrolysis with beef and horse serums, albeit with very low efficiency. The first efficient resolutions of phosphorus stereocentres with enzymes were independently reported in 1994 by two groups. Serreqi and Kazlauskas studied the enantioselective hydrolysis of pendant acetate groups in chiral racemic phosphines and phosphine oxides mediated by several commercially available lipases and esterases, under kinetic resolution conditions i.e. the reaction was stopped at 50% conversion). In general, enantioselectivities were low to moderate, but for one substrate promising results were obtained (Scheme 6.54). 

DyKAT of racemic phosphine to generate a tertiary P-chirogenic phosphine. 

A successful resolution of some alkylaryl-substituted phosphinates 27 and phosphine oxides 28 by crystalline inclusion complexation with optically active form of host 26 has also been achieved The results of these experimmts with various guests are summarized in Table 8. The simplicity of the method used is illustrated by referring to the main stages of the reaction between 26 and the phosphoric ester 27a. Treatmait of the racemic phosphinate 27a with (—)-26 in benzene led to the formation of a 1 1 complex of (+)-27a with (—)-2tf. Two subsequent recrystallizations of the complex fi om benzene i ve a pure compound. Column chromatography of the resulting complex on silica gel gave optically pure (+)-phosphinate 27a. A similar treatment with (+)-26 of the filtrate left after the above described separation of the complex gave finally the optically pure (—)-27a isomer. 

Use of Ru(porp-D2)(0)2 eontaining a chiral picket-fence type porphyrin (H2(porp-D2), see Fig. 10, Section 3.3) in CH2CI2 or CHCis under N2 at 25°C can stoichiometrically oxidize the racemic phosphine P(Me)(Ph)CH2Ph to chiral phosphine oxide with 41% This reaction effects a kinetic... 

P-chiral phosphines, which are potential ligands for transition metal-catalyzed reactions, were synthesized through hpase-catalyzed optical resolution of the corresponding racemic phosphine oxide compounds (Fig. 10.29). For example, lipase from C. rugosa (CRL) was used for the enantioselective hydrolysis of acetoxynaphthyl phosphine oxide (Fig. 10.29(a)). The P-enantiomer was hydrolyzed selectively, leaving the (S)-acetoxy compound, which was further subjected to chemical hydrolysis. Both enantiomeric phosphine oxides were obtained in >95% after recrystallization. Methylation followed by reduction with triethyl amine/trichlorosilane, with inversion of configuration, yielded the desired chiral phosphine. 

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