Chiral phosphonic acids resolution

Chiral phosphonous acid diester induces the kinetic resolution of racemic a-substituted y-unsaturated carboxylic acids through asymmetric protolac-tonization (Scheme 53) (130L2838). Dinamic kinetic resolution with Candida antartica lipase B and the ruthenium catalyst [RuCl(CO)2(T -C5Ph5)] of several homoallylic alcohols is applied in the key step to the synthesis of enantiomericaUy pure 5,6-dihydro-2ff-pyran-2-ones ( [13CEJ13859]). 

Bohman and Allenmark resolved a series of sulphoxide derivatives of unsaturated malonic acids of the general structure 228. The classical method of resolution via formation of diastereoisomeric salts with cinchonine and quinine has also been used by Kapovits and coworkers " to resolve sulphoxides 229, 230, 231 and 232 which are precursors of chiral sulphuranes. Miko/ajczyk and his coworkers achieved optical resolution of sulphoxide 233 by utilizing the phosphonic acid moiety for salt formation with quinine. The racemic sulphinylacetic acid 234, which has a second centre of chirality on the a-carbon atom, was resolved into pure diastereoisomers by Holmberg. Racemic 2-hydroxy- and 4-hydroxyphenyl alkyl sulphoxides were separated via the diastereoisomeric 2- or 4-(tetra-0-acetyl-D-glucopyranosyloxy)phenyl alkyl sulphoxides 235. The optically active sulphoxides were recovered from the isolated diastereoisomers 235 by deacetylation with base and cleavage of the acetal. Racemic 1,3-dithian-l-oxide 236... 

Some epoxides carry functional groups. The compound (lR,2S)-(-)-(l,2)-cpox-ypropyl phosphonic acid (fosfomycin) is a clinically important drug with wide-spectrum antibiotic activity. It was isolated originally from a fermentation broth of Streptomyces fradiae and prepared mainly by epoxidation of cfs-l-propenylpho-sphonic acid (CPPA) [42] followed by optical resolution of the racemic epoxide with chiral amines. Recently, chiral W (salen) and Mo (salen) complexes have been used in the asymmetric epoxidation of CPPA [43]. 

List and coworkers reported an excellent approach to the enantioselective synthesis of P branched a amino phosphonates, which involved the extension of the dynamic kinetic resolution strategy (Scheme 3.53) [110] that was previously applied to the enantioselective reductive amination of a branched aldehydes by his research group (see Scheme 3.45). The method combines dynamic kinetic resolution with the parallel creation of an additional stereogenic center. They successfully accomplished the direct three component Kabachnik Fields reaction of 1 equiv each of the racemic aldehyde, p anisidine, and di(3 pentyl)phosphite in the presence of newly developed chiral phosphoric acid It. The corresponding p branched a amino phosphonates were obtained in high diastereo and enantioselectivities, especially for the aldehydes bearing a secondary alkyl group at the a position. 

Many of the functionalized phosphonic acids and their derivatives described so far in this and the preceding chapter are capable of resolution into enantiomeric forms, through chirality at the carbon atom which carries the functional group. In the case of functionalized phosphonic acids, diastereoisomeric forms become possible as a result of any additional chirality at phosphorus. In practice, few resolutions have been carried out amongst the many types of functionalized acids considered so far, even for those classes of acids in which there is potential biological interest, e.g. the (hydroxyalkyl)phosphonic acids. Two examples of the latter are (l-hydroxy-3-methylbutyl)phosphonic acid, in the form of its monobenzyl ester, and (a-hydroxybenzyl)phosphonic acid , each of which has been resolved with stereoisomers of ephedrine. Nor have many syntheses been devised in the course of which one stereoisomer is obtained preferentially. 

Another example of this category is the first dynamic kinetic resolution of a racemic a-amino aldehyde [93]. It has been shown that the N-tosyl-protected aldehyde 149 reacts with a near equimolar amount of chiral phosphonate 27e to afford vinylogous amino acid esters (R, )-150 with excellent diastereoselectivity and chemical yield. Similarly, the N-tosyl-protected piperidine 151 was converted into the trisubstituted alkene 152 with good diastereoselectivity and in high chemical yield by reaction with chiral phosphonate 28. In several cases, it has been shown that the selectivity obtained under dynamic conditions exceeds that obtained by a traditional kinetic resolution. The HWE products obtained appear to be attractive precursors for non-proteinogenic amino acids [83] as well as various alkaloids. 

The applications of re-acidic chiral stationary phases include the resolution of a-blockers and /1-blockers, amines, arylacetamine, alkylcarbinols, hydantoins, barbiturates, naphthols, benzodiazapines, carboxylic acids, lactams, lactones, phthaldehydes selenoids, and phosphorus compounds. Hyun et al. [16] achieved a chiral resolution of a homologous series of iV-acyl-x-(l-naphthyl )cthylaminc on AA(3,5-dinitrobenzoyl-(i )-phenylglycine and N-(3,5 - dini tr o ben zoy I)-(,S ) -1 c u c ine CSPs. The authors used hexane-2-propanol (80 20, v/v) as the mobile phase. Similarly, the scope of re-basic CSPs comprises the chiral resolution of / -blockers, amino acids, amines, diamines, amino phosphonates, naphthols, benza-diazapines, carboxylic acids, hydroxy acids, dipeptides, tripeptides, diols,... 

A very large amount of NMR spectroscopic data has been collected during the year under review. The presentation of data in addition to data is now almost routine. NMR spectroscopic studies have now been presented for phosphonocarboxylic acids and their esters,some new phosphinic amides, and for Lawesson s reagent (solid and solution data). A spectroscopic study of the dimer of the nitrile oxide (401) suggested the structure (402). 1-(1-Naphthalenyl)ethylamine and ephedrine are recommended for the NMR spectroscopic determination of the enantiomeric composition of (1-aminoalkyl)-phosphonates, but of quinine and rert-butylphenylphosphinothioic acid, only the former was effective for the chiral resolution of the diethyl esters in the determination of e.e.s of (2-hydroxyalkyl)phosphonates. Conformational analyses, based on NMR spectroscopic data, have been carried out for dialkyl (2-hydroxyalkyl)phosphonates. ... 

An array of 16 enantiomeric pairs of chiral phosphate, phosphonate and phosphinate esters was used to establish the breadth of stereoselective discrimination inherent within the bacterial phosphotriesterase and 15 mutant enzymes. The results demonstrate that the catal5hic properties of the wide-type of phosphotriesterases can be exploited for the kinetic resolution of a wide-range of compounds and that the active site of this enzyme is remarkably amenable to structural perturbations via amino acid substitution. The first use of dialkyl phosphates as stereodirecting... 

---