Enrichment, preferential resolution

EinaHy, kinetic resolution of racemic olefins and aHenes can be achieved by hydroboration. The reaction of an olefin or aHene racemate with a deficient amount of an asymmetric hydroborating agent results in the preferential conversion of the more reactive enantiomer into the organoborane. The remaining unreacted substrate is enriched in the less reactive enantiomer. Optical purities in the range of 1—65% have been reported (471). 

Two types of sulfoximinocarboxylates (analogous to sulfinylcarboxylates 16), namely 5 -aryl-5 -methoxycarbonylmethyl-A(-methyl sulfoximine 36 and -methyl-5 -phenyl-A(-ethoxycarbonyl sulfoximine 37, were subjected to hydrolysis in the presence of PLE in a phosphate buffer. As a result of a kinetic resolution, both the enantiomerically enriched recovered substrates and the products of hydrolysis and subsequent decarboxylation 38 and 39, respectively, were obtained with moderate to good ees (Equations 20 and 21). Interestingly, in each case the enantiomers of the substrates, having opposite spatial arrangement of the analogous substituents, were preferentially hydrolysed. This was explained in terms of the Jones PLE active site model. ... 

Tamura R, Takahashi H, Fujimoto D, Ushio T (2007) Mechanism and Scope of Preferential Enrichment, a Symmetry-Breaking Enantiomeric Resolution Phenomenon. 269 53-82 Tanaka H, see Matile S (2007) 277 219-250... 

The basic method uses the kinetic resolution of racemic 2-phenylbutanoic acid (1, present in excess). Alcohols of configurational type 2 react preferentially with (S)-2-phenylbutanoyl groups to give 3, hence the residual anhydride is relatively deficient with respect to this form. On hydrolysis the residual anhydride yields 2-phenylbutanoic acid enriched in the (- )-(R)-form 4. Thus, if the 2-phenylbutanoic acid isolated is levorotatory, the secondary alcohol has the absolute configuration depicted in 2. The method has authoritatively been reviewed234. 

Enantiomer-differentiating co-polymerization of terminal epoxides is achieved by chiral chromium and cobalt complexes. Jacobsen etal. reported the co-polymerization of 1-hexene oxide with GO2 by using complex 35a. The reaction proceeds with kinetic resolution at 90% conversion, the unreacted epoxide is found to be enriched in the (i )-enantiomer of 90% ee. Detailed information about the resultant polymer, however, is not described. As discussed in the previous section, chiral cobalt-salen complex 34c co-polymerizes PO and GO2 (Table 3). When 34c with /r<3 / j--(li ,2i )-diaminocyclohexane backbone is applied to the co-polymerization, (A)-PO is consumed preferentially over (i )-enantiomer with a of 2.8 to give optically active PPG (Equation (8)). In a similar manner, a binary catalyst system, 34d/Bu4NGl, preferentially consumes (A)-PO over R)-PO with = 2.8-3.5. ... 

PREFERENTIAL ENRICHMENT A DYNAMIC ENANTIOMERIC RESOLUTION PHENOMENON CAUSED BY POLYMORPHIC TRANSITION DURING CRYSTALLIZATION... 

Figure 4. Enantiomeric resolution of a racemic mixed crystal using Preferential Enrichment a case of an enrichment of the R enantiomer in solution after the first recrystallization of the racemic sample. Actually, the probability for either the R or the S enantiomer to be enriched in solution after recrystallization of an exactly racemic sample was 50% (see ref 9a).

Preferential Enrichment is a secondary phenomenon caused by a polymorphic transition occurring during crystallization from a highly supersaturated solution. This unique dynamic enantiomeric resolution phenomenon has proved to be observable for a fairly ordered racemic mixed crystal showing a polymorphism a solvent-assisted solid-to-sohd type of polymorphic transition from the kinetically-formed metastable crystalline phase comprising homochiral R and S chains into the thermodynamically stable crystalline phase consisting of a heterochiral 2D sheet structure during crystallization is responsible for this phenomenon. That is, it is essential that homochiral R and S ID chain structures are stable in solution while a heterochiral 2D sheet structure is stable in the crystal. 

Apart from the significance as a novel enantiomeric resolution phenomenon, the investigation on the mechanism of Preferential Enrichment has also shed light on the hitherto unknown mechanism of a polymorphic transition occurring during crystallization from a supersaturated solution. A combination of several techniques employed here would also be useful to elucidate the unknown mechanism of another type of polymorphic transition... 

If racemic sec alcohols (e.g., butan-2-ol, 52) undergo partial acylation with an acid anhydride in the presence of an optically active amine, an enantiomer differentiation occurs in the example shown, the (S)-alcohol reacts preferentially forming but-2-yl acetate, 53, which is levorotatory, and leaving behind unchanged alcohol which has been optically enriched [68]. This is a process under kinetic control. For further examples of kinetic resolutions, see [69]. 

A second example of the use of directed molecular evolution for natural product synthesis is the use of lipases by Reetz and colleagues. This work is based on the kinetic hydrolytic resolution of racemic mixtures, in which one enantiomer is preferentially hydrolyzed and the chiral product is thus enriched. Utilizing both random mutagenesis and directed techniques such as CAST,64 they have improved the stereoselectivity of a lipase from Pseudomonas aeruginosa (PAL) on a number of occasions with different substrates. One of the first examples utilized the model substrate 2-methyldecanoic acid /xnitrophenyl ester, for which the wild-type enzyme has an enantioselectivity of E= 1.1. As a consequence of five mutations accumulated through random mutagenesis, followed by saturation mutagenesis, the enantioselectivity was increased to 25.8.123 More... 

Origins of Optical Activity in Nature (Ed. D. C. Walker), Elsevier, New York, 1979 resolution of racemates by crystallization succeeds by Tamura s Preferential Enrichment in the mother liquor T. Ushio, R. Tamura, H. Taka-hashi, N. Azuma, K. Yamamoto, Angew. Chem. 1996, 108, 2544-2546 Angew. Chem. Int. Ed. Engl. 1996, 35, 2372-2374 R. Tamura, T. Ushio, H. Takahashi, K. Nakamura,... 

A resolution process, close to the classical resolutions by formation and separation of diastereoisomers, is the following (Scheme 1.15) a chiral reagent creates a new asymmetric centre in each of the enantiomers of a racemic mixture. This case has been analysed [151, 152]. If the reagent is able to give preferentially on both enantiomers the same absolute configuration at the new asymmetric centre (e.g. a sulfinyl moiety), it is then possible to separate the two major diastereoisomers (58) and (59), each being enantiomerically enriched. This process may be combined to provide a kinetic resolution in a partial conversion where the reagent is also able to react at different rates with the two enantiomers [151]. 

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