Stereochemistry kinetic resolution

Chiral sulphoxides are the most important group of compounds among a vast number of various types of chiral organosulphur compounds. In the first period of the development of sulphur stereochemistry, optically active sulphoxides were mainly used as model compounds in stereochemical studies2 5 6. At present, chiral sulphoxides play an important role in asymmetric synthesis, especially in an asymmetric C—C bond formation257. Therefore, much effort has been devoted to elaboration of convenient methods for their synthesis. Until now, optically active sulphoxides have been obtained in the following ways optical resolution, asymmetric synthesis, kinetic resolution and stereospecific synthesis. These methods are briefly discussed below. 

Biooxidative deracemization of racemic sec-alcohols to single enantiomers [47,48] is complementary to combined metal-assisted lipase-mediated strategies [49,50]. In general, deracemization can be realized by either an enantioconvergent, a dynamic kinetic resolution, or a stereoinversion process. The latter concept is particularly appealing, as only half of the substrate needs to be converted, as the remaining half already represents the product with correct stereochemistry. 

Stereoinversion Stereoinversion can be achieved either using a chemoenzymatic approach or a purely biocatalytic method. As an example of the former case, deracemization of secondary alcohols via enzymatic hydrolysis of their acetates may be mentioned. Thus, after the first step, kinetic resolution of a racemate, the enantiomeric alcohol resulting from hydrolysis of the fast reacting enantiomer of the substrate is chemically transformed into an activated ester, for example, by mesylation. The mixture of both esters is then subjected to basic hydrolysis. Each hydrolysis proceeds with different stereochemistry - the acetate is hydrolyzed with retention of configuration due to the attack of the hydroxy anion on the carbonyl carbon, and the mesylate - with inversion as a result of the attack of the hydroxy anion on the stereogenic carbon atom. As a result, a single enantiomer of the secondary alcohol is obtained (Scheme 5.12) [8, 50a]. 

Another enantioselective synthesis, shown in Scheme 13.18, involves a early kinetic resolution of the alcohol intermediate in Step B-2 by lipase PS. The stereochemistry at the C(7) methyl group is controlled by the exo selectivity in the conjugate addition (Step D-l). 

For leading references on kinetic resolution, see E. L. Elier, S. H. Wilen, L. M. Mandar, Stereochemistry of organic compounds, (Wiley-Interscience, New York, 1994, pp. 395-415. 

In 2001, Takahashi and his co-workers developed the first asymmetric ruthenium-catalyzed allylic alkylation of allylic carbonates with sodium malonates which gave the corresponding alkylated compounds with an excellent enantioselectivity (Equation (Sy)). Use of planar-chiral cyclopentadienylruthenium complexes 143 with an anchor phosphine moiety is essential to promote this asymmetric allylic alkylation efficiently. The substituents at the 4-position of the cyclopentadienyl ring play a crucial role in controlling the stereochemistry. A kinetic resolution of racemic allylic carbonates has been achieved in the same reaction system (up to 99% ee). ... 

The reaction with N-Boc-pyrrolidine may be taken a step further by inducing a double C-H insertion sequence [27]. This results in the formation of the elaborate C2-symmetric amine 35 as a single diastereomer with control of stereochemistry at four stereogenic centers. The enantiomeric purity of 35 is higher than that obtained for the single C-H insertion products, presumably because kinetic resolution is occurring in the second C-H insertion step. 

Solution-state NMR studies suggest that the catalysts containing l- and D-Pro adopt p-turns and p-hairpins in solution,respectively. Reactions exhibit first-order dependence on catalyst 24, consistent with a monomeric catalyst in the ratedetermining step of the reaction. These catalysts exhibit enantiospecific rate acceleration, in comparison to the reaction rate when NMI is employed as catalyst. An isosteric replacement of an alkene for a backbone amide in a tetrapeptide catalyst (catalysts 32 and 33, Fig. 4) has lent credence to a proposed mechanism of rate acceleration [31). While catalyst 32 exhibits a fcrei=28 with substrate 27, alkene-containing catalyst 33 is not selective in this kinetic resolution and also affords a reduced reaction rate. This suggests that the prolyl amide is kinetically significant in the stereochemistry-determining step of the reaction. 

The allylic alcohol binds to the remaining axial coordination site, where stereochemical and stcrcoelectronic effects dictate the conformation shown in Figure 6A.9 [6]. The structural model of catalyst, oxidant, and substrate shown in Figure 6A.9 illustrates a detailed version of the formalized rule presented in Figure 6A. 1. Ideally, all observed stereochemistry of epoxy alcohol and kinetic resolution products can be rationalized according to the compatibility of their binding with the stereochemistry and stereoelectronic requirements imposed by this site [6]. A... 

Carbon-Oxygen and Carbon-Sulfur Bonds. A report of modest enantioselectivity up to 48% ee in the 0-alkylation of racemic secondary alcohols (a kinetic resolution) in the presence of a chiral non-racemic non-functionalized quat, (S)-Et3NCH2CH(Me)Et Br, could not be repeated [80]. Such catalysts would not be capable of making the multipoint interaction between catalyst and reactants in the transition state, which are thought to govern the stereochemistry of these types of reactions. Other O-alkylations are noted [lie]. 

Such conventional kinetic resolution reported above often provide an effective route to access to the enantiomerically pure/enriched compounds. However, the limitation of such process is that the resolution of two enantiomers will provide a maximum 50% yield of the enantiomerically pure materials. Such limitation can be overcome in several ways. Among these ways are the use of meso compounds or prochiral substrates,33 inversion of the stereochemistry (stereoinversion) of the unwanted enantiomer (the remaining unreacted substrate),34 racemization and recycling of the unwanted enantiomer and dynamic kinetic resolution (DKR).21... 

The aldol reaction catalyzed by Ab33F12 is outlined in Scheme 5.65. Regardless of the stereochemistry at C(2) of the aldehyde substrate shown (Scheme 5.65), its antibody catalyzed reaction with acetone resulted in a diastereoselective addition of acetone to the S/ -facc of the aldehyde. The products were formed with similar yields, and thus kinetic resolution was observed. However, the degree of facial stereochemical control of the reaction is surprising, since no stereochemical information was built into the hapten. For the... 

This nitrilase dynamic kinetic resolution (DKR) methodology depends on the availability of highly enantioselective biocatalysts that generate a minimum amount of amide. This latter issue may seem trivial and has long been disregarded somewhat, but reports of modest amounts of amide co-products date back to the early days of nitrilase enzymology. Only recently has the subject come under more intense scrutiny [3-5] and has a relationship with the stereochemistry of the nitrile been demonstrated [3, 5]. Hence, we set out to investigate the enantiomer and chemical selectivity of nitrilases in the hydrolysis of a representative set of cyanohydrins. 

The transketolase (TK EC 2.2.1.1) catalyzes the reversible transfer of a hydroxy-acetyl fragment from a ketose to an aldehyde [42]. A notable feature for applications in asymmetric synthesis is that it only accepts the o-enantiomer of 2-hydroxyaldehydes with effective kinetic resolution [117, 118] and adds the nucleophile stereospecifically to the re-face of the acceptor. In effect, this allows to control the stereochemistry of two adjacent stereogenic centers in the generation of (3S,4R)-configurated ketoses by starting from racemic aldehydes thus this provides products stereochemically equivalent to those obtained by FruA catalysis. The natural donor component can be replaced by hydroxy-pyruvate from which the reactive intermediate is formed by a spontaneous decarboxylation, which for preparative purposes renders the overall addition to aldehydic substrates essentially irreversible [42]. 

Chiral catalyst 171 was used to effect kinetic resolution of the racemic lactide in the polymerization of the racemic lactide [216]. At low conversion high enantiomeric enrichment in the polymer was observed (Scheme 6.169). The stereochemistry of the catalyst overrides the tendency for syndiotactic placements that are typically favored by chain-end control. At higher conversions, the ee in the polymer decreases. 

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