Kinetic resolution procedure

Another approach to the synthesis of chiral non-racemic hydroxyalkyl sulfones used enzyme-catalysed kinetic resolution of racemic substrates. In the first attempt. Porcine pancreas lipase was applied to acylate racemic (3, y and 8-hydroxyalkyl sulfones using trichloroethyl butyrate. Although both enantiomers of the products could be obtained, their enantiomeric excesses were only low to moderate. Recently, we have found that a stereoselective acetylation of racemic p-hydroxyalkyl sulfones can be successfully carried out using several lipases, among which CAL-B and lipase PS (AMANO) proved most efficient. Moreover, application of a dynamic kinetic resolution procedure, in which lipase-promoted kinetic resolution was combined with a concomitant ruthenium-catalysed racem-ization of the substrates, gave the corresponding p-acetoxyalkyl sulfones 8 in yields... 

Interestingly, for the transformation of both the racemic 1-hydroxyalkanephosphonates 41 and 2-hydroxyalkanephosphonates 43 into almost enantiopure acetyl derivatives 42 and 44, respectively, a dynamic kinetic resolution procedure was applied. Pamies and BackvalP used the enzymatic kinetic resolution in combination with a ruthenium-catalysed alcohol racemization and obtained the appropriate O-acetyl derivatives in high yields and with almost full stereoselectivity (Equation 25, Table 5). It should be mentioned that lowering... 

Having explored the scope of this reaction, it was then possible to use an optically active phosphoramidate (232.d), derived from (5)-a-methyl-benzylamine, to perform a kinetic resolution procedure.134,138 Upon reaction of 221 with 0.5 equiv of the phosphoramidate anion 232.d, selective reaction with the 7 -isomer of 221 resulted in an enhancement in the proportion of 5-221 along with the expected ketenimine products (233). The absolute configuration of i -233.d was determined by X-ray crystallography, and thus all other absolute configurations assigned by comparison of CD and HPLC data.39,138... 

Goti, Brandi, and co-workers have investigated this PKR strategy using two quasi-enantiomeric dihydropyrans 21 and 22 as complimentary reagents (Scheme 5) [9], They have shown that under a traditional kinetic resolution procedure the racemic syn-dihydroxypyrroline N-oxide 23 can be partially resolved using a 1,3-dipolar cycloaddition... 

Conventional kinetic resolution procedures often provide an effective route for the preparation of enantiomerically enriched compounds. However, a resolution of two enantiomers will only provide a maximum of 50% yield of the enantiomerically pure material. This limitation can be overcome in a number of ways, including inversion of the stereochemistry of the unwanted enantiomer, racemization and recycling of the unwanted enantiomer or dynamic kinetic resolution. 

Figure 8.2. Origins of selectivity in the Sharpless kinetic resolution procedure.

Applications of asymmetric epoxidation and kinetic resolution procedures The importance of the Sharpless AE and KR procedures is best measured by the speed with which they have become a part of the synthetic chemist s bag of tricks . Although a measure of their utility can be gleaned from examples given in sections... 

Scheme 2.5 gives some specific examples of kinetic resolution procedures. Entries 1 to 3 in Scheme 2.5 are acylation reactions in which esters are formed. Either the... 

As we predicted in last year s Report, the Sharpless chiral epoxidation procedure for allylic alcohols is beginning to make its impact with the synthesis of several important synthetic intermediates and natural products. We highlight here just one application to the synthesis of a key building block (2) for methymycin synthesis. This epoxide was produced in 79% yield and in >95% e.e. (Scheme 4). Owing to the water solubility of (2) modified work-up conditions were also developed and discussed. This enantioselective epoxidation method has been applied to produce a remarkably high kinetic resolution procedure for... 

The preparation of enantiopure or enriched complexes possessing planar chirality has been accomplished either by resolution of racemic mixtures or by asymmetric syntheses. Reported methods for the resolution of planar chirality include both chemical and kinetic resolution procedures, whilst reported asymmetric syntheses of enantiomerically pure or enriched benchrotrenic complexes include enantioselective ort/io-deprotonations with chiral lithium amide bases, and the transfer of side chain chirality onto the arene ring mediated by diastereoselective orf/io-nucleophilic additions and o/tfeo-metalations. 

Sharpless epoxidations can also be used to separate enantiomers of chiral allylic alcohols by kinetic resolution (V.S. Martin, 1981 K.B. Sharpless, 1983 B). In this procedure the epoxidation of the allylic alcohol is stopped at 50% conversion, and the desired alcohol is either enriched in the epoxide fraction or in the non-reacted allylic alcohol fraction. Examples are given in section 4.8.3. 

The variety of enzyme-catalyzed kinetic resolutions of enantiomers reported ia recent years is enormous. Similar to asymmetric synthesis, enantioselective resolutions are carried out ia either hydrolytic or esterification—transesterification modes. Both modes have advantages and disadvantages. Hydrolytic resolutions that are carried out ia a predominantiy aqueous medium are usually faster and, as a consequence, require smaller quantities of enzymes. On the other hand, esterifications ia organic solvents are experimentally simpler procedures, aHowiag easy product isolation and reuse of the enzyme without immobilization. 

Jacobsen has utilized [(salen)Co]-catalyzed kinetic resolutions of tenninal epoxides to prepare N-nosyl aziridines with high levels of enantioselectivity [72], A range of racemic aryl and aliphatic epoxides are thus converted into aziridines in a four-step process, by sequential treatment with water (0.55 equivalents), Ns-NH-BOC, TFA, Ms20, and carbonate (Scheme 4.49). Despite the apparently lengthy procedure, overall yields of the product aziridines are excellent and only one chromatographic purification is required in the entire sequence. 

A very interesting approach to optically active sulphoxides, based on a kinetic resolution in a Pummerer-type reaction with optically active a-phenylbutyric acid chloride 269 in the presence of /V,A -dimethyIaniline, was reported by Juge and Kagan332 (equation 149). In contrast to the asymmetric reductions discussed above, this procedure afforded the recovered sulphoxides in optical yields up to 70%. Chiral a, /1-unsaturated sulphoxides 270 were prepared via a kinetic resolution elaborated by Marchese and coworkers333. They found that elimination of HX from racemic /i-halogenosulphoxides 271 in the presence of chiral tertiary amines takes place in an asymmetric way leading to both sulphoxides 270 and 271, which are optically active (optical yields up to 20%) with opposite configurations at sulphur (equation 150). 

This type of procedure is referred to as a kinetic resolution since the enantiomers of the racemic substrate exhibit different rates of reaction with the optically active compound, i.e. the diastereomeric transition states that arise from differences in e.g. non-bonded interactions have different free energies. Horeau and Nouaille (1966) estimate that a rate difference corresponding to A AG of the order of 0 2 cal mol at 25°C could in principle be revealed by this method. 

The phosphotriesterase from Pseudomonas diminuta was shown to catalyze the enantioselective hydrolysis of several racemic phosphates (21), the Sp isomer reacting faster than the Rp compound [65,66]. Further improvements using directed evolution were achieved by first carrying out a restricted alanine-scan [67] (i.e. at predetermined amino acid positions alanine was introduced). Whenever an effect on activity/ enantioselectivity was observed, the position was defined as a hot spot. Subsequently, randomization at several hot spots was performed, which led to the identification of several highly (S)- or (R)-selective mutants [66]. A similar procedure was applied to the generation of mutant phosphotriesterases as catalysts in the kinetic resolution of racemic phosphonates [68]. 

Despite its widespread application [31,32], the kinetic resolution has two major drawbacks (i) the maximum theoretical yield is 50% owing to the consumption of only one enantiomer, (ii) the separation of the product and the remaining starting material may be laborious. The separation is usually carried out by chromatography, which is inefficient on a large scale, and several alternative methods have been developed (Figure 6.2). For example, when a cyclic anhydride is the acyl donor in an esterification reaction, the water-soluble monoester monoacid is separable by extraction with an aqueous alkaline solution [33,34]. Also, fiuorous phase separation techniques have been combined with enzymatic kinetic resolutions [35]. To overcome the 50% yield limitation, one of the enantiomers may, in some cases, be racemized and resubmitted to the resolution procedure. 

When a reverse procedure was applied, i.e. enzymatic acetylation of racemic 3, formed in situ from the appropriate aldehydes and thiols, the reaction proceeded under the conditions of dynamic kinetic resolution and gave enantiomerically enriched acetates 2 with 65-90% yields and with ees up to 95% (Equation 2). It must be mentioned that the addition of silica proved crucial, as in its absence no racemization of the initially formed substrates 3 occurred and the reaction stopped at the 50% conversion. 

Hydrolytic Kinetic Resolution (HKR) of epichlorohydrin. The HKR reaction was performed by the standard procedure as reported by us earlier (17, 22). After the completion of the HKR reaction, all of the reaction products were removed by evacuation (epoxide was removed at room temperature ( 300 K) and diol was removed at a temperature of 323-329 K). The recovered catalyst was then recycled up to three times in the HKR reaction. For flow experiments, a mixture of racemic epichlorohydrin (600 mmol), water (0.7 eq., 7.56 ml) and chlorobenzene (7.2 ml) in isopropyl alcohol (600 mmol) as the co-solvent was pumped across a 12 cm long stainless steel fixed bed reactor containing SBA-15 Co-OAc salen catalyst (B) bed ( 297 mg) via syringe pump at a flow rate of 35 p,l/min. Approximately 10 cm of the reactor inlet was filled with glass beads and a 2 pm stainless steel frit was installed at the outlet of the reactor. Reaction products were analyzed by gas chromatography using ChiralDex GTA capillary column and an FID detector. 

A patent procedure for formation of compounds 19 from simple tartaric acid derivatives has appeared <06USP047129> and various new routes to chiral dioxolanones include synthesis of dioxolan-2-ones either by transition metal-mediated asymmetric synthesis <06T1864> or enzyme-mediated kinetic resolution <06H(68)1329> and a new synthesis of the chiral dioxolan-4-ones 21 from lactic or mandelic acid involving initial formation of intermediates 20 with trimethyl orthoformate in cyclohexane followed by reaction with pivalaldehyde <06S3915>. 

In the contemporary production of enantiopure compounds this feature is highly appreciated. Currently, kinetic resolution of racemates is the most important method for the industrial production of enantiomerically pure compounds. This procedure is based on chiral catalysts or enzymes, which catalyze conversion of the enantiomers at different rates. The theoretical yield of this type of reaction is only 50%, because the unwanted enantiomer is discarded. This generates a huge waste stream, and is an undesirable situation from both environmental and economic points of view. Efficient racemization catalysts that enable recycling of the undesired enantiomer are, therefore, of great importance. 

Regeneration of the oxidized form of the cofactors, while not within the frame of this chapter, is needed for several biotransformations (e.g., oxidative kinetic resolution of diols). In these procedures, transition-metal complexes have also been applied. For this task, Ru(phend)3 complex and derivatives thereof can be used, either with oxygen or in an electrochemical procedure [49-51]. 

The 4 A Molecular Sieves System. The initial procedure for the Sharpless reaction required a stoichiometric amount of the tartrate Ti complex promoter. In the presence of 4 A molecular sieves, the asymmetric reaction can be achieved with a catalytic amount of titanium tetraisopropoxide and DET (Table 4-2).15 This can be explained by the fact that the molecular sieves may remove the co-existing water in the reaction system and thus avoid catalyst deactivation. Similar results may be observed in kinetic resolution (Table 4-3).15... 

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