Diastereomer kinetic resolution

When a mixture of diastereomers reacts with a chiral or achiral reagent, it involves two competitive reactions. The rate laws are very similar to the one estabhshed for the KR (see Section 2.1). The stereoselectivity factor is the relative rate constants of reaction of the two diastereomers. One of the two diastereomers will be destroyed more slowly than the other and will be recovered with some diastereomeric excess (de jj ) that increases with conversion. Equation 2.6 applies by replacing ee j by de j.  

This section reports some representative examples of KR of two enantiomericaUy pure diastereomers, when these stereomers react with an achiral reagent with different rates. This process generally results in the recovery of a diastereomericaUy enriched substrate and (or) product. 

Diastereomer KR has been applied for the resolution of racemic ketones by diastereoselective hydrolysis of a mixture of stereoisomeric acetals made from condensation with diethyl (-l-)-(R,R)-tartrate [89]. Kinetic studies established the rate constants for hydrolysis of each diastereomer. 

Yamamoto could resolve a number of 2-alkylcyclohexanones through a diastereoselective opening of the chiral dioxolanes made with (-)-(2R,4R)-2,4-pentanediol 146 [90]. As an example, treatment of the diastereomers 147 with 2 equiv of tri-isobutylaluminium (TIBA) (i-BUjAl) afforded the enol ether 148 (34%, 98% de) along with the recovered, diastereomericaUy enriched acetal 147 (62%). Separation 

Husson et id. [91] looked at the diastereoselective saponification of a mixture of two enantiomerically pure diastereomers 149. As preliminary experiments carried out with both diastereomers showed rate differences, the treatment of a mixture of diastereomers under appropriate conditions allowed the preferential saponification 

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D Partially resolved mixture Resolution Crystallization Oural or achiral chromatography Amplification of ee (eg. Horeau duplication) - Separation via diastereomers - Kinetic resolution with or without creation of new chiral units - Asymmetric transformation - Deracemization... 

Clearly, there is a need for techniques which provide access to enantiomerically pure compounds. There are a number of methods by which this goal can be achieved . One can start from naturally occurring enantiomerically pure compounds (the chiral pool). Alternatively, racemic mixtures can be separated via kinetic resolutions or via conversion into diastereomers which can be separated by crystallisation. Finally, enantiomerically pure compounds can be obtained through asymmetric synthesis. One possibility is the use of chiral auxiliaries derived from the chiral pool. The most elegant metliod, however, is enantioselective catalysis. In this method only a catalytic quantity of enantiomerically pure material suffices to convert achiral starting materials into, ideally, enantiomerically pure products. This approach has found application in a large number of organic... 

Since the addition of dialkylzinc reagents to aldehydes can be performed enantioselectively in the presence of a chiral amino alcohol catalyst, such as (-)-(1S,2/ )-Ar,A -dibutylnorephedrine (see Section 1.3.1.7.1.), this reaction is suitable for the kinetic resolution of racemic aldehydes127 and/or the enantioselective synthesis of optically active alcohols with two stereogenic centers starting from racemic aldehydes128 129. Thus, addition of diethylzinc to racemic 2-phenylpropanal in the presence of (-)-(lS,2/ )-Ar,W-dibutylnorephedrine gave a 75 25 mixture of the diastereomeric alcohols syn-4 and anti-4 with 65% ee and 93% ee, respectively, and 60% total yield. In the case of the syn-diastereomer, the (2.S, 3S)-enantiomer predominated, whereas with the twtf-diastereomer, the (2f ,3S)-enantiomer was formed preferentially. 

Figure 10.47 Dynamic kinetic resolution ofThrA generated diastereomers by enantioselective decarboxylation (a).

Conventional kinetic resolution of diastereomer mixtures by retroaldolization for preparation of enantiopure arylserines and for a synthetic intermediate of an antiparkinsonism drug (b). 

Chiral Recognition. The use of chiral hosts to form diastereomeric inclusion compounds was mentioned above. But in some cases it is possible for a host to form an inclusion compound with one enantiomer of a racemic guest, but not the other. This is caUed chiral recognition. One enantiomer fits into the chiral host cavity, the other does not. More often, both diastereomers are formed, but one forms more rapidly than the other, so that if the guest is removed it is already partially resolved (this is a form of kinetic resolution, see category 6). An example is use of the chiral crown ether (53) partially to resolve the racemic amine salt (54). " When an aqueous solution of 54 was... 

Stopping the reaction before completion. This method is very similar to the asymmetric syntheses discussed on page 132. A method has been developed to evaluate the enantiomeric ratio of kinetic resolution using only the extent of substrate conversion. An important application of this method is the resolution of racemic alkenes by treatment with optically active diisopinocampheylborane, since alkenes do not easily lend themselves to conversion to diastereomers if no other functional groups are present. Another example is the resolution of allylic alcohols such as (56 with one... 

Besides discovering this method of resolution, Pasteur also discovered the method of conversion to diastereomers and separation by fractional crystallization and the method of biochemical separation (and, by extension, kinetic resolution). 

The dynamic kinetic resolution (DKR) of a-sulfur-substituted ketones such as 31 and 33 was investigated. When the MOM protected mercaptol ketone 31 was treated with the BINOL-LiAlH4 complex, a moderate diastereoselectivity of 5 1 favoring the desired anti isomer was observed. The major diastereomer had 70%... 

Furthermore, the same methodology was used for an approach towards enantiopure PGFla (2-46) through a catalytic kinetic resolution of racemic 2-43 using (S)-ALB (2-37) (Scheme 2.10) [14]. Reaction of 2-35, 2-36 and 2-43 in the presence of 2-37 led to 2-44 as a 12 1 mixture of diastereomers in 75 % yield (based on malonate 2-36). The transformation proceeds with excellent enantioselectivity thus, the enone 2-45 obtained from 2-44 shows an ee-value of 97 %. 

Kinetic resolution is achieved when racemic enynes are subjected to Zhang s Alder-ene conditions (Scheme 19).66 A single diastereomer of trans-94 (>99% ee) is accessible through the exposure of racemic enyne 93 to the Rh(i) catalyst in the presence of optically pure BINAP ligand. 

Kinetic Resolution Selectively to Afford Diastereomers and Enantiomers I 691... 

Kinetic Resolution to Selectively Afford Diastereomers and Enantiomers... 

In the kinetic resolution, the yield of desired optically active product cannot exceed 50% based on the racemic substrate, even if the chiral-discriminating ability of the chiral catalyst is extremely high. In order to obtain one diastereomer selectively, the conversion must be suppressed to less than 50%, while in order to obtain one enantiomer of the starting material selectively, a higher than 50% conversion is required. If the stereogenic center is labile in the racemic substrate, one can convert the substrate completely to gain almost 100% yield of the diastereomer formation by utilizing dynamic stereomutation. 

There are two possible approaches for the preparation of optically active products by chemical transformation of optically inactive starting materials kinetic resolution and asymmetric synthesis [44,87], For both types of reactions there is one principle in order to make an optically active compound we need another optically active compound. A kinetic resolution depends on the fact that two enantiomers of a racemate react at different rates with a chiral reagent or catalyst. Accordingly, an asymmetric synthesis involves the creation of an asymmetric center that occurs by chiral discrimination of equivalent groups in an achiral starting material. This can be done either by enan-tioselective (which involves the reaction of a prochiral molecule with a chiral substance) or diastereoselective (which involves the preferential formation of a single diastereomer by the creation of a new asymmetric center in a chiral molecule) synthesis. 

Figure 2b shows the other extreme, whereby the rate of epimerization is fast relative to the rate of substitution. In this case, Curtin-Hammett kinetics apply, and the product ratio is determined by AAG. In the specific case of organolithium enantiomers that are rendered diastereomeric by virtue of an external chiral ligand, such a process may be termed a dynamic kinetic resolution. Both of these processes are also known by the more general term asymmetric transformation One should be careful to restrict the term resolution to a separation (either physical or dynamic) of enantiomers. An asymmetric transformation may also afford dynamic separation of equilibrating diastereomers, but such a process is not a resolution. "... 

It has been demonstrated by Pancrazi, Ardisson and coworkers that an efficient kinetic resolution takes place when an excess (2 equivalents) of the racemic titanated alkenyl carbamate rac-334a (R = Me) is allowed to react with the enantiopure )-hydroxyaldehyde 341 or alternatively the corresponding y-lactol 340, since the mismatched pair contributes to a lower extent to the product ratio (equation 91) . Under best conditions, the ratio of the enantiomerically pure diastereomers 3,4-anti-4,5-syn (342) and 3,4-anti-4,5-anti (343) is close to 14 1. Surprisingly, approximately 9% of the iyw,iyw-diastereomer 344 resulted when the starting (ii)-crotyl carbamate was contaminated by the (Z)-isomer. The reasons which apply here are unknown. Extra base has to be used in order to neutrafize the free hydroxy group. The pure awft, awfi-product 345 was obtained with 85% yield from the reaction of the (W-oxy-substituted titanate rac-334b and lactol 340. 345 is an intermediate in the asymmetric synthesis of tylosine . ... 

This problem was solved by Adam and coworkers in 1994-1998. They presented a high-yielding and diastereoselective method for the preparation of epoxydiols starting from enantiomerically pure allyhc alcohols 39 (Scheme 69). Photooxygenation of the latter produces unsaturated a-hydroxyhydroperoxides 146 via Schenck ene reaction. In this reaction the (Z)-allylic alcohols afford the (5, 5 )-hydroperoxy alcohols 146 as the main diastereomer in a high threo selectivity (dr >92 8) as racemic mixmre. The ( )-allylic alcohols react totally unselectively threolerythro 1/1). Subsequent enzymatic kinetic resolution of rac-146 threolerythro mixture) with horseradish peroxidase (HRP) led to optically active hydroperoxy alcohols S,S) and (//,5 )-146 ee >99%) and the... 

In recent work, Chmielewski and co-workers (174) reported the highly stereoselective reaction of ene-lactones with chiral pyrrolidine nitrone (141) to afford tricyclic adducts (Scheme 1.31). A 1 1 mixture of ene-lactone 142 and nitrone 141 provided adduct 143 with an uncharacterized isomer (97 3) (91%) whUe homo-chiral D-glycero (138) gave the adduct 144 as a single diastereomer (88%). A 2 1 mixture of racemic 138 and nitrone 141 afforded a 91 1 mixture of the two possible adducts, representing an effective kinetic resolution of the racemic lactone. 

There must be no kinetic resolution in the reaction which transforms the mixture of enantiomers into diastereomers. The reaction must therefore proceed to completion. 

No resolvable separation of the signals of the diastereomers formed from reaction of the amino acid with (5)-2-bromopropionyl chloride or Mosher s acid chloride are observed. However, with common amino acids, the latter reagent can be successfully used under similar Schotten -Baumann conditions for the detection of differences in 19F spectra57. The a-alkylated amino acids are particularly challenging. However, by proper choice of solvent and signal, sufficient peak separation can be obtained. No measurable amount of kinetic resolution occurs during acylation of the acids. 

Alternative synthetic approaches include enantioselective addition of the organometallic reagent to quinoline in the first step of the synthesis [16], the resolution of the racemic amines resulting from simple protonation of anions 1 (Scheme 2.1.5.1, Method C) by diastereomeric salts formation [17] or by enzymatic kinetic resolution [18], and the iridium-catalyzed enantioselective hydrogenation of 2-substituted quinolines [19]. All these methodologies would avoid the need for diastereomer separation later on, and give direct access to enantio-enriched QUINAPHOS derivatives bearing achiral or tropoisomeric diols. Current work in our laboratories is directed to the evaluation of these methods. 

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