Enantiomeric enrichments

Enzymatic alcoholysis of 3-chloro-2-chloroacetoxy, 3-azido-2-chloroacetoxy and l-chloro-2-chloroacetoxypropyl phosphonates (285), (286) and (287) catalysed by immobilized mucor miehei lipase (IM) and Candida antarectica lipase B was a particularly effective method for the formation of the corresponding highly enriched enantiomerically chloroacetoxyphosphonates (288), (289) and (290). Kinetic resolution by specially selected reaction sequences led to phosphocarnitine (291), phosphogabob (292) and phosphomycin (293) respectively (Scheme 73). ... 

Finally, we discovered that L-(+)-tartaric acid was suitable for preparing the final salt and optically npgrading the enriched (5)-TH[3C. This will have the advantage to eliminate the issue associated with the optical purification of an enriched enantiomeric mixtnre ((5)-TH[3C.HCl or (S)-THpC.citrate) (solnbility phase diagram with two entectics) if the minimnm required optical purity is not achieved. 

At the recrystallization of racemate forming (the most common) enantiomeric mixtures the enriched enantiomeric mixture usually can be recovered from the mother liquor after filtration of the crystalline fraction having near to racemic composition. However, the composition of the crystalline material can be changed when the initial enantiomeric purity is higher then the eutectic composition. A certain example is the recrystallisation of the enantiomeric mixtures of tofizopam (TOF) from ethyl acetate. Almost racemic composition crystallized from small or medium pure enantiomeric mixtures. However the sole enantiomer crystallized from the solution when the initial compwsition was higher than the eutectic one (eeo>85%).3i... 

Further work on the preparation of chiral a-amino-acids reported in the past year (see also the section on asymmetric hydrogenation) includes an extension of the utility of anions derived from lactim ethers (228) in the synthesis of such compounds by condensations with aldehydes and ketones chiral inductions are somewhat lower than in the alkylations of (228) reported previously (4, 320). Enzyme-mediated hydrolysis of 5(4H)-oxazolones by chymotrypsin or subtilisin gives a-acylamino-acids with good enantiomeric enrichments, especially if the substrate carries bulky substituents. Schiff s bases of a-amino-esters can be enriched enantiomerically to an extent of up to 70% by sequential deprotonation with a chiral lithium amide and protonation with an optically pure tartaric acid. ... 

Further, peak overlap results in nonlinear detector response vs concentration. Therefore, some other detection method must be used in conjunction with either of these types of detection. Nevertheless, as can be seen from Figure Ilf, chiroptical detection can be advantageous if there is considerable overlap of the two peaks. In this case, chiroptical detection may reveal that the lea ding and tailing edges of the peak are enantiomerically enriched which may not be apparent from the chromatogram obtained with nonchiroptical detection (Fig. He). 

In a novel approach, enantiomerically enriched (R)-pantolactone (9) is obtained in a enzymatic two-step process starting from racemic pantolactone. 

Preparation of enantiomerically enriched materials by use of chiral catalysts is also based on differences in transition-state energies. While the reactant is part of a complex or intermediate containing a chiral catalyst, it is in a chiral environment. The intermediates and complexes containing each enantiomeric reactant and a homochiral catalyst are diastereomeric and differ in energy. This energy difference can then control selection between the stereoisomeric products of the reaction. If the reaction creates a new stereogenic center in the reactant molecule, there can be a preference for formation of one enantiomer over the other. 

Whereas the barrier for pyramidal inversion is low for second-row elements, the heavier elements have much higher barriers to inversion. The preferred bonding angle at trivalent phosphorus and sulfur is about 100°, and thus a greater distortion is required to reach a planar transition state. Typical barriers for trisubstituted phosphines are BOSS kcal/mol, whereas for sulfoxides the barriers are about 35-45 kcal/mol. Many phosphines and sulfoxides have been isolated in enantiomerically enriched form, and they undergo racemization by pyramidal inversion only at high temperature. ... 

As was the case for kinetic resolution of enantiomers, enzymes typically exhibit a high degree of selectivity toward enantiotopic reaction sites. Selective reactions of enaiitiotopic groups provide enantiomerically enriched products. Thus, the treatment of an achiral material containing two enantiotopic functional groups is a means of obtaining enantiomerically enriched material. Most successful examples reported to date have involved hydrolysis. Several examples are outlined in Scheme 2.11. 

Chiral chemical reagents can react with prochiral centers in achiral substances to give partially or completely enantiomerically pure product. An example of such processes is the preparation of enantiomerically enriched sulfoxides from achiral sulfides with the use of chiral oxidant. The reagent must preferential react with one of the two prochiral faces of the sulfide, that is, the enantiotopic electron pairs. 

The acetolyses of both ero-2-norbomyl brosylate and e do-2-norbomyl brosylate produce exclusively exo-2-norbomyl acetate. The exo-brosylate is more reactive than the endo isomer by a factor of 350. Furthermore, enantiomerically enriched exo-brosylate gave completely racemic ero-acetate, and the endo-brosylate gave acetate that was at least 93% racemic. 

The application of the AE reaction to kinetic resolution of racemic allylic alcohols has been extensively used for the preparation of enantiomerically enriched alcohols and allyl epoxides. Allylic alcohol 48 was obtained via kinetic resolution of the racemic secondary alcohol and utilized in the synthesis of rhozoxin D. Epoxy alcohol 49 was obtained via kinetic resolution of the enantioenriched secondary allylic alcohol (93% ee). The product epoxy alcohol was a key intermediate in the synthesis of (-)-mitralactonine. Allylic alcohol 50 was prepared via kinetic resolution of the secondary alcohol and the product utilized in the synthesis of (+)-manoalide. The mono-tosylated 3-butene-1,2-diol is a useful C4 building block and was obtained in 45% yield and in 95% ee via kinetic resolution of the racemic starting material. 

Enantioselective desymmetrization of achiral or meso compounds with formation of enantiomerically enriched products, among them heterocycles 99JCS(P1)1765. 

The 1,2-cyclohexanediamine-derived sulfonamide is not unique in its ability to afford enantiomerically enriched cyclopropanes. The efforts at improving the original protocol led not only to higher selectivity, but to a deeper understanding of the nature of the catalytic process. 

It is interesting that the use of excess ligand DBFOX/Ph led to a decreased en-antioselectivity for the endo cycloadduct, especially when the enantiomeric purity of the ligand was low. This phenomenon is closely related with the chirality enrichment mechanism operating in the solution. 

Apart from tertiary amines, the reaction may be catalyzed by phosphines, e.g. tri- -butylphosphine or by diethylaluminium iodide." When a chiral catalyst, such as quinuclidin-3-ol 8 is used in enantiomerically enriched form, an asymmetric Baylis-Hillman reaction is possible. In the reaction of ethyl vinyl ketone with an aromatic aldehyde in the presence of one enantiomer of a chiral 3-(hydroxybenzyl)-pyrrolizidine as base, the coupling product has been obtained in enantiomeric excess of up to 70%, e.g. 11 from 9 - -10 ... 

With this epoxidation procedure it is possible to convert the achiral starting material—i.e. the allylic alcohol—with the aim of a chiral reagent, into a chiral, non-racemic product in many cases an enantiomerically highly-enriched product is obtained. The desired enantiomer of the product epoxy alcohol can be obtained by using either the (-1-)- or (-)- enantiomer of diethyl tartrate as chiral auxiliary ... 

On that basis, crystallization is often used in combination with other enantiose-lective techniques, such as enantioselective synthesis, enzymatic kinetic resolution or simulated moving bed (SMB) chromatography [10, 11]. In general, when referring to crystallization techniques, the aim is to obtain an enantiomeric enrichment in the crystallized solid. However, the possibility of producing an enrichment in the mother liquors [12, 13], even if this is not a general phenomenon [14], must be taken into account. 

In another example of enantioselective distillation, it was the enantiomeric mixture to resolve itself which contributed to create a chiral environment. Thus, non-racemic mixtures of a-phenylethylamine were enantiomerically enriched by submitting to distillation different salts of this amine with achiral acids [199]. 

Although very efficient, the broad application of the direct preparation is restricted due to the limited number of pure starting enantiomers. The design of a multistep process that includes asymmetric synthesis is cumbersome and the development costs may be quite high. This approach is likely best suited for the multi-ton scale production of commodity enantiomers such as the drugs ibuprofen, naproxen, atenolol, and albuterol. However, even the best asymmetric syntheses do not lead to products in an enantiomerically pure state (100 % enantiomeric excess). Typically, the product is enriched to a certain degree with one enantiomer. Therefore, an additional purification step may be needed to achieve the required enantiopurity. 

Discrimination between the enantiomers of a racemic mixture is a complex task in analytical sciences. Because enantiomers differ only in their structural orientation, and not in their physico-chemical properties, separation can only be achieved within an environment which is unichiral. Unichiral means that a counterpart of the race-mate to be separated consists of a pure enantiomeric form, or shows at least enrichment in one isomeric form. Discrimination or separation can be performed by a wide variety of adsorption techniques, e.g. chromatography in different modes and electrophoresis. As explained above, the enantioseparation of a racemate requires a non-racemic counterpart, and this can be presented in three different ways ... 

Following Uskokovic s seminal quinine synthesis [40], Jacobsen has very recently reported the first catalytic asymmetric synthesis of quinine and quinidine. The stereospecific construction of the bicyclic framework, introducing the relative and absolute stereochemistry at the Cg- and expositions, was achieved by way of the enantiomerically enriched trans epoxide 87, prepared from olefin 86 by SAD (AD-mix (3) and subsequent one-pot cyclization of the corresponding diol [2b], The key intramolecular SN2 reaction between the Ni- and the Cg-positions was accomplished by removal of the benzyl carbamate with Et2AlCl/thioanisole and subsequent thermal cyclization to give the desired quinudidine skeleton (Scheme 8.22) [41],... 

The addition of an achiral organometallic reagent (R M) to a chiral carbonyl compound 1 (see Section 1.3.1.1.) leads to a mixture of diastercomers 2 (syn/anti) which can be either racemic, or enantiomerically enriched or pure, depending on whether the substrates are race-mates or pure enantiomers. This section incorporates only those reactions starting from optically pure a-amino aldehydes, however, optical purity of the starting material has not been demonstrated in all cases. 

As well as the addition of achiral organometallic reagents to chiral aldehydes (see also Sections 1.3.2. and 1.3.3.), the addition of chiral organometallic reagents to carbonyl compounds is a well-known and intensively studied process which may lead to enantiomerically and/or diastereomerically enriched products. Chiral organometallic reagents can be classified into three groups ... 

A convenient route to highly enantiomerically enriched a-alkoxy tributylslannanes 17 involves the enanlioselective reduction of acyl stannanes 16 with chiral reducing agents10. Thus reaction of acyl stannanes with lithium aluminum hydride, chirally modified by (S)-l,l -bi-naphthalene-2,2 -diol, followed by protection of the hydroxy group, lead to the desired a-alkoxy stannanes 17 in optical purities as high as 98 % ee. 

When using enantiomerically enriched aldehydes, precautions should be taken in order to avoid their racemization prior to addition. It is recommended not to use reagents of high... 

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