Product resolution, procedure

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. 

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... 

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... 

The main general routes for the synthesis of the a-amino acids are illustrated in the following sections (pp. 746-750). Some of the natural amino acids can be isolated from the hydrolsates of suitable proteins examples are provided on p. 750. They are optically active having the l [(S)] configuration. The synthetic products, formed by routes not involving asymmetric syntheses, are of of course racemic, from which the optically active forms may be obtained by the process of resolution. Some resolution procedures are discussed in Section 5.19. 

In a typical resolution procedure, two equivalents of a racemic compound and one equivalent of a chiral host dissolved in an inert solvent (toluene, benzene or hexane) are left to crystallize. The resulting crystalline product is an inclusion compound with a typical host guest ratio of 1 1 or 2 1. The guest compound... 

Although some kinds of optically active compounds can be prepared by an asymmetric synthesis using a chiral catalyst, this method is not applicable for preparation of all kinds of compounds. Furthermore, optical yields of the product are not always very high. On the contrary, optical resolution method by inclusion complexation with a chiral host is applicable to various kinds of guest compounds as described in this chapter. When optically pure product cannot be obtained by one resolution procedure, perfect resolution can be accomplished by repeating the process, although asymmetric synthetic process cannot be repeated. Especially, optical resolutions by inclusion complexation with a chiral host in a water suspension medium and by fractional distillation in the presence of a chiral host are valuable as green and sustainable processes. 

Detection of side products generated by Rubisco is accomplished by various means. XuBP (30) and pyruvate (36) are both conveniently detected spectrophotometrically by coupling to NADH oxidation with appropriate enzymes. Alternatively, our chromatographic procedure (27) gives a complete profile of all RuBP-derived products. Resolution of these compounds is enhanced by inclusion of 10 mM sodium borate, which complexes vic-diols, in elution buffers. Since our initial report of the separation of borohydride-reduced misprotonation products (27), we have observed that borate also effects complete separation of unreduced RuBP and XuBP (37). Thus, the analysis is simplified by circumventing the necessity to deduce the amounts of misprotonation-derived bisphosphate based on ratios of ribitol-, arabinitol-, and xylitol-1,5-bisphosphates. 

The compounds obtained by the resolution procedures can often directly be used as chiral auxiliaries, but sometimes it is necessary to convert them to other products, e.g., planar chiral compounds. Frequent functional group transformations are summarized in Sections 4.3.3 and 4.3.3.2. The link to planar chiral compounds is described in Sections 4.3.3.3 and 4.4.1. 

As resolution procedures are often tedious, and asymmetric synthesis provides chiral products with only limited enantiomeric excess, it seems an obvious strategy to use an enantiomerically pure material from the chiral pool to construct chiral ferrocenes by incorporating these compounds in the final product. As such chiral materials, cheap terpenes (menthone, a- and -pinene, and camphor) were chosen. The reaction of ferrocene with carbonyl compounds under acidic conditions is a very convenient way to obtain directly a-ferrocenylalkyl carbocations. The starting materials were therefore converted to aldehydes or their enol ethers (menthone and camphor are too sterically hindered and do not react with ferrocene). Joint dissolution of the aldehydes and ferrocene in trifluoroacetic acid or in the trichloroacetic acid/ fluorosulfonic acid system gives a-ferrocenylalkyl carbocations, which can either... 

In addition to stereoselective metalation, other methods have been applied for the synthesis of enantiomerically pure planar chiral compounds. Many racemic planar chiral amines and acids can be resolved by both classical and chromatographic techniques (see Sect. 4.3.1.1 for references on resolution procedures). Some enzymes have the remarkable ability to differentiate planar chiral compounds. For example, horse liver alcohol dehydrogenase (HLADH) catalyzes the oxidation of achiral ferrocene-1,2-dimethanol by NAD to (S)-2-hydroxymethyl-ferrocenealdehyde with 86% ee (Fig. 4-2la) and the reduction of ferrocene-1,2-dialdehyde by NADH to (I )-2-hydroxymethyl-ferrocenealdehyde with 94% ee (Fig. 4-2lb) [14]. Fermenting baker s yeast also reduces ferrocene-1,2-dialdehyde to (I )-2-hydroxymethyl-ferro-cenealdehyde [17]. HLADH has been used for a kinetic resolution of 2-methyl-ferrocenemethanol, giving 64% ee in the product, (S)-2-methyl-ferrocenealdehyde... 

Preparation. - Supercritical nitrous oxide has been shown to oxidise phosphines to the related phosphine oxides under mild conditions, allowing a simple isolation of products. Oxidation of precursor phosphines by hydrogen peroxide is the final step in the synthesis of the chiral functionalised phosphine oxides (219) and (220). A novel resolution procedure for the preparation of P-stereogenic phosphine oxides is afforded by the reactions of racemic chiral tertiary phosphines with an optically pure camphorsulfonyl azide, followed by separation of the diastereoisomeric phosphazenes, and acid... 

The first example of the use of enzyme and metal combinations to provide a dynamic resolution procedure was reported by Allen and Williams in 1996[18. In this case, a palladium (II) catalyst was employed that was able to racemize the allylic acetate substrate, but did not erode the enantioselectivity of the product allylic alcohol (Fig. 9-11). For example, a cyclic acetate was shown to undergo a simple kinetic resolution, affording enantiomerically enriched starting material and product at approximately 50 % conversion. However, performing the reaction in the presence of a palladium (II) catalyst facilitated a dynamic resolution by continuously racemiz-ing the starting material as the reaction progressed. 

The pure salt (14 g) obtained in the resolution procedure is dissolved in 75 mL of H,0 and 25 in L of 2 N NaOH are added to the solution. The mixture is extracted twice with 50-mL portions of CH.CI, to recover the ephedrine. Then, the aqueous layer is acidified with 4.6 mL of cone HC1 and the mixture concentrated at 60 C under reduced pressure. The residue is dissolved in 70 mL of CH -Oil and cooled to — IO C. 13 mL of SOC1, is added to the solution and the mixture refluxed for 4h. After cooling and concentration, the residue is diluted with NaHCO, solution. The mixture is extracted three times with 60-mL portions of CHXI, and the extracts are combined, dried, and concentrated to give the product yield 6.3 g (94%). (2S, 5S)- 1-Benz l-2,5-bis( hydroxymethyl)pyrrolidine3 6 ... 

Ordinarily, the rate-determining step during phase conversion is the formation of nuclei of the new phase. If suitable nuclei cannot be formed at the conditions of study, then the phase transformation is effectively suspended until the nuclei either form spontaneously or are added by the experimenter. 8ynthetic chemists have long used seed crystals of their desired phase to obtain a sufficient crop of that material and to suppress the formation of unwanted by-products. This procedure is especially important during the resolution of enantiomers and diastereomers by direct crystallization. 

Carbon-phosphorus bonds may also be formed. Chemists at Merck developed a synthesis of either enantiomer of the valuable ligand BINAP 133 from the more easily resolved BINOL 2.612, using a triflate-phosphine coupling reaction (Scheme 2.183). They reasoned that nickel catalysis would be more effective as this metal is harder than palladium and, therefore, less susceptible to catalyst poisoning by the product. BINAP 133 could be obtained with no loss of chirality. They also reported a resolution procedure for BINOL 2.612.224... 

Optically active barbiturates important in pharmacy, are obtained by classical synthesis and resolution procedures [14]. A new approach to the synthesis of optically active barbiturates is enantioselective catalysis with Pd complexes. An example is shown in Scheme 10 on the right side. The synthesis of the enantiomers of a N-methyl barbiturate containing a quaternary asymmetric carbon atom is achieved by allylation of the corresponding precursor with allyl acetate. Pd/triphenylphosphine complexes are efficient catalysts for this reaction which give a racemic mixture of the product. The reaction proceeds via a jt-allyl complex of Pd as an intermediate (Scheme 10, left side). This 7t-allyl complex is attacked by the nucleophile, the anion of N-... 

Resolution may be considered the classical method of obtaining enantiomerically pure products. The procedure relies on the fact that diastereomers, unlike enantiomers, have different physical properties. If the racemic compound which is to be resolved is derivatised by reaction with a naturally occurring enantiomerically pure compound, then the resulting diastereomeric compounds may be separated, most commonly by crystallisation but also by chromatography, and then separately treated to liberate the two enantiomers. If we represent 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... 

A mixture of methyl ethyl ketone and ( —)-2-methylbutan-l-ol added dropwise to a hot suspension of ( + )-Al-tris-(2-methylbutoxide) in ( — )-2-methylbutan-l-ol, and the product removed by distillation after 3 hrs. reflux ( + )-methyl-ethylcarbinol. Y 94.6%. - Laborious resolution procedures can be eliminated by this simple method, which gives high yields and excellent optical purity. F. e. s. S. Yamashita, J. Organometal. Ghem. 11, 377 (1968). 

Among chiral dialkylboranes, diisopinocampheylborane (8) is the most important and best-studied asymmetric hydroborating agent. It is obtained in both enantiomeric forms from naturally occurring a-pinene. Several procedures for its synthesis have been developed (151—153). The most convenient one, providing product of essentially 100% ee, involves the hydroboration of a-pinene with borane—dimethyl sulfide in tetrahydrofuran (154). Other chiral dialkylboranes derived from terpenes, eg, 2- and 3-carene (155), limonene (156), and longifolene (157,158), can also be prepared by controlled hydroboration. A more tedious approach to chiral dialkylboranes is based on the resolution of racemates. /n j -2,5-Dimethylborolane, which shows excellent enantioselectivity in the hydroboration of all principal classes of prochiral alkenes except 1,1-disubstituted terminal double bonds, has been... 

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. 

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