Phenyl ethers resolution

Several reports regarding the directed evolution of enantioselective epoxide hydrolases (EHs) have appeared [23,57-59]. These enzymes constitute important catalysts in synthetic organic chemistry [4,60]. The first two reported studies concern the Aspergillus niger epoxide hydrolase (ANEH) [57,58]. Initial attempts were made to enhance the enantioselectivity of the AN E H -catalyzed hydrolytic kinetic resolution of glycidyl phenyl ether (rac-19). The WT leads to an Evalue of only 4.6 in favor of (S)-20 (see Scheme 2.4) [58]. 

Carreira et al. reported the kinetic resolution of branched allylic carbonates catalyzed by an iridium complex derived from a chiral [2.2.2]-bicyclooctadiene [48]. Reactions of allylic carbonates with phenol were run to 50% conversion of the carbonate, leaving unreacted allylic carbonate in high enantiomeric excess (Scheme 32). The phenyl ether products were also isolated in mid-to-high enantiomeric excess. 

Hoveyda et al. reported a novel method for synthesizing of chromene 71 by ROM-RCM of cycloalkene 70 bearing the phenyl ether at the 3-position [Eq. (6.48)]." ° The yield is improved when the reaction is carried out under ethylene gas. In the case of cyclopentene 70a (n = 0) or cyclohexene 70b (n = 1), the yield is poor because the starting cycloalkene is in a state of equihbrium with the product and a thermodynamic product should be formed under these reaction conditions. They obtained enantiomeric ally pure cycloheptene derivative (5)-70e using zirconium-catalyzed kinetic resolution of 70e developed by their group, and chromene 71c was synthesized as a chiral form via ROM-RCM using lb [Eq. (6.49)] ... 

The kinetic resolution of racemic 1-phenylethyl Grignard reagent 2a was also observed in the cross-coupling with allylic substrates, such as allyl phenyl ether, in the presence of NiC12[(S, .S )-chiraphos (81)] which gave (/ )-4-phenyl-1 -butene (56) with 58% ee [59] (Scheme 8F.19). 

Phenols are used as the nucleophile in the asymmetric aUylation of 7r-aUylpalladium complexes. Trost and Toste attained asymmetric phenyl ether formation in high enantiomeric excess (ee) using diphosphine ligand derived from chiral 1,2-cyclohexanediamine (equation 10). Dynamic kinetic resolution of the racemic secondary aUylic carbonate is conducted in the presence of tetrabutylammonium chloride, which increases the rate of ft—a—ft isomerization of the jr-allyl palladium intermediate (equation 11). Lautens and coworkers cleaved meio-oxabicyclic alkenes with phenol in the presence of a catalytic amount of a chiral ferrocenyldiphosphine and a rhodium complex (equation 12). ... 

An early example by Reetz and co-workers [79] demonstrated the evaluation of a series of biocatalysts for the hydrolytic kinetic resolution of chiral glycidyl phenyl ethers. Employing a fused-silica reactor, the authors developed an integrated reaction system capable of performing biocatalytic hydrolysis, along with separation and detection of the reaction products. Using the enantioselective hydrolysis of 2-phenoxymethyloxirane (136) to 3-phenoxypropane-l,2-diol (137) as a model reaction (Table 6.14), the authors evaluated the biocatalytic activity of a series of epoxide... 

Scheme 2.2 Biocatalytic resolution of racemic glycidyl phenyl ether using BmEH under modulated conditions.

Figure 2.5 Enzymatic resolution of racemic glycidyl phenyl ether (10 mM) by partially purifled enzyme in Ifis-HCl buffer (pH 7.5). Part A effect of temperature on EH activity with either ( ) Tween-80 (0.5%, w/v) or ( ) DMSO (5%, v/v) (A) represents spontaneous hydrolysis without enzyme. Part B residual EH activity after incubation at the indicated temperatures for 1 h with ( ) 5% (v/v) DMSO or ( ) 0.5% (w/v) Tween-80, or (0) without additives. Part C time-course of epoxide enantiomers (i )-GPE ( , o) and (S)-GPE ( , 0), in the presence of (o, <>) DMSO (5%, w/v) or ( , ) Tween-80 (0.5%, w/v).

Figure 2.6 Biocatalytic resolution of glycidyl phenyl ether (GPE) with resting cells of Bacillus megaterium ECUlOOl in a stirred reactor. Concentrations of the epoxide ( ) and the diol (A), and enantiomeric excesses of the epoxide ( ) and the diol (A) were plotted versus the reaction time. Reaction conditions epoxide, 12 mmol cells, 1.56 g (DCW) isooctane, 20 mL buffer, 50 mM KPB, pH 8.0,100 mL 30 °C, 600 rpm.

The detection and quantification of polychlorinated dibenzo-p-dioxins, and in particular the 2,3,7,8-tetrachlorinated dibenzo-p-dioxin (2,3,7,8-TCDD), is a major application for double-focusing magnetic-sector mass spectrometers. Despite extensive clean-up procedures, samples still contain compounds such as polychlorinated biphenyls and benzyl phenyl ethers, which have the same nominal masses as the compounds of interest. The sample is spiked with a known amount of the isotope labelled form of 2,3,7,8-TCDD, introduced via gas chromatography and recorded by high-resolution mass spectrometry. The measurement is quantified by comparison of the native dioxin response to that from the C-labelled form, and verified by confirmation of the ratio of the major isotopes of both the native and the C-labelled dioxins. At 10 000 resolving power (10% valley definition) the detection level for 2,3,7,8-TCDD is about 1 femtogram, or 3 attomole (Figure 6). 

It is well known that spontaneous resolution of a racemate may occur upon crystallization if a chiral molecule crystallizes as a conglomerate. With regard to sulphoxides, this phenomenon was observed for the first time in the case of methyl p-tolyl sulphoxide269. The optical rotation of a partially resolved sulphoxide (via /J-cyclodextrin inclusion complexes) was found to increase from [a]589 = + 11.5° (e.e. 8.1%) to [a]589 = +100.8 (e.e. 71.5%) after four fractional crystallizations from light petroleum ether. Later on, few optically active ketosulphoxides of low optical purity were converted into the pure enantiomers by fractional crystallization from ethyl ether-hexane270. This resolution by crystallization was also successful for racemic benzyl p-tolyl sulphoxide and t-butyl phenyl sulphoxide271. 

In another study that appeared prior to the advent of CASTing, the traditional combination of epPCR and DNA shuffling was used to enhance the enantioselectivity of the hydrolytic kinetic resolution of p-nitro phenyl glycidyl ether and other epoxides catalyzed by the EH from Agrobacterium radiobacter [59]. Several mutants were obtained with up to 13-fold improved enantioselectivity. The amino acid exchanges took place around the active site. 

When a mixture of methyl phenyl sulfide (69a) (1 g, 8.1 mmol), 30% H2O2 (1.84 g, 16.2 mmol), and water (10 ml) was stirred at room temperature for 24 h, rac-lOa was produced (Scheme 11). To the water suspension medium of rac-70a was added 10c (2 g, 4 mmol), and the mixture was stirred for 15 h to give a 1 1 inclusion complex of 10c with (+)-70a. Heating the filtered complex in vacuo gave (+)-70a of 57% ee (0.45 g, 82% yield). From the filtrate left after separation of the inclusion complex, (-)-70a of 54% ee (0.4 g, 73% yield) was obtained by extraction with ether. By the same procedure, optically active 70b-d were also prepared (Table 11). In the case of (+)-70b and (-)-70c,the efficiency of the enantiomeric resolution was very high. 

A practical resolution of 3-phenyl-2H-azirine-2-methanol 15 at a very low temperature (-40 °C) was reported by Sakai et al64 to enhance the enantioselectivity in immobilized lipase-catalyzed resolution of 15 using vinyl butanoate as acyl donor in ether as organic solvent. The method was found to be effective in enhancing the enantioselectivity E and affords the primary alcohol (S)-15 with 99% ee and the ester (A)-16 with 91% ee. 

Asymmetric hydroboration.1 Hydroboration of 1-phenyl-1-cyclopentene with IpcBH2 (100% ee) results in a dialkylborane (1) containing the traws-2-phenylcyclopentyl group of 100% ee. However, hydroboration of prochiral trisubstituted alkenes usually results in alkylisopinocampheylboranes of 50-85% ee. Most of these products are solids, and selective crystallization (usually from ether) can give the optically pure dialkyboranes. In some cases resolution can be achieved by allowing the impure borane to age for several... 

Bis (benzoylacetonato) diphenyltin (IV) is a white solid, which is soluble in benzene and toluene and only slightly soluble in petroleum ether. The infrared spectrum (KBr disk) has peaks centered at 1570,1550,1520, and 1374 cm.. The ultraviolet absorption spectrum (benzene) has a band centered at 308 mpi (e = 4.42 X 10 ). Attempts to effect resolution of optical isomers by a chromatographic technique (n-lactose) were unsuccessful, and it has been suggested that the phenyl groups are in trans positions. ... 

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