Kinetic stereoselectivity

The kinetic stereoselection of this process is rationalized in terms of the formation of Schiff bases with anti configuration. 

From these and many related examples the following generalizations can be made about kinetic stereoselection in aldol additions of lithium enolates. (1) The chair TS model provides a basis for analyzing the stereoselectivity observed in aldol reactions of ketone enolates having one bulky substituent. The preference is Z-enolate syn aldol /(-enolate anti aldol. (2) When the enolate has no bulky substituent, stereoselectivity is low. (3) Z-Enolates are more stereoselective than /(-enolates. Table 2.1 gives some illustrative data. 

The observed aldol stereoselection as a function of both enolate geometry and enolate ligand Rx is summarized in Table 5. It is clear from these results that the increasing steric requirements of the substituent Ri appear to confer greater kinetic stereoselection from the (Z)- as opposed to the ( )-enolate geometry (Scheme 2). 

The steric influence of the enolate substituents Ri and Rj plays a dominant role in the alteration of kinetic stereoselectivity, whereas the aldehyde ligand appears to contribute to a minor extent. Good correlation between enolate geometry and aldol stereochemistry is possible when Rj is sterically demanding and Rj.is sterically subordinate (Rj = methyl or n-alkyl). In this case dominant path A stereoselection is observed. When R2 becomes sterically demanding (R2 = t-Bu) path B stereoselection is observed and becomes dominant. 

In an interesting extension of this work, the Neu5Ac aldolase from E. coli was subjected to directed evolution to expand its catalytic activity for enantiomeric forms of the usual substrates to include A -acetyl-L-mannosamine and L-arabinose with formation of the synthetically important products L-sialic add and L-3-deoxy-L-manno-oct-2-ulosonic add (l-KDO) (163). The evolved Neu5Ac aldolases were characterized by sequence analysis, kinetics, stereoselectivity, and in one case even by an X-ray structure analysis. Again, remote mutations were identified. It is significant... 

The reactive open-chain substrate 29 with the natural D-threo configuration was prepared along a chemoenzymatic route by making use of the common constitutional and stereochemical relationship which substrates of transaldolase share with those of transketolase. Thus, the R-configured 2-hydroxyaldehyde 28 was chain-extended under transketolase catalysis in the presence of 20 as ketol donor to yield the desired aldol. By this approach, several transaldolases could indeed be shown to display different levels of kinetic stereoselectivity. 

This high-kinetic stereoselectivity can be rationalized as shown below. In the two kinds of folded chairlike transition states A and B, steric... 

The stereochemistry outcome of the aldol additions is an issue of paramount importance in the synthesis of iminosugars. Based on mechanistic considerations of the DHAP aldolases [29, 30] it can be assumed that the absolute configuration at C-3 (i.e. the stereocenter arising from DHAP) is independent of the acceptor used in the reaction. Analysis of the stereochemistry at C-4 (i.e. the one generated from the aldehyde) can be used to infer the kinetic stereoselectivity of the aldolases towards each of the N-protected amino aldehydes (Figure 19.4). For the selected... 

The renal clearance of two enantiomers will be different if any of the abovementioned processes exhibit stereoselectivity (12-14). The filtration clearance (GFR fu) wUl reflect differences between enantiomers if a compound is bound stereoselectively to plasma proteins (12-14). The rate of reabsorption or secretion of enantiomers can be different if transport proteins at either the basolateral or brush border membrane exhibit stereoselective kinetics. Stereoselective cellular metabolism is a well described process and is dealt with in depth elsewhere in this book. However, the possibility of stereoselective metabolism occurring within the renal cells cannot be ignored as a potential mechanism responsible for differing renal clearance between two enantiomers. 

Several workers have studied platinum(II) complexes of olefins containing chiral amine or amino-acid ligands. Panunzi(9) observed stereoselectivity in the reaction between cis-(S - a-methylbenzylamine)dichloroplatinum (II) and trans-2-butene with the major diastereomer formed to the extent of 70% of total complex. More recently (10), it has been shown that the replacement of coordinated trans-2-butene by free olefin in (S-prolinato) dichloroplatinum (II) complexes takes place more easily with retention than with inversion. Addition of a large excess of trans-2-butene to solutions of the corresponding ethylene complexes produced first an increase and then a gradual decrease in their circular dichroism. The kinetic stereoselectivity in this reaction (that is, the differing reaction rates of the two prochiral faces of trans-but-2-ene) was 3 1, but at equilibrium the ratio of major and minor diastereomers was 64 36 in the cis-isomer and 59 41 in the trans-isomer. 

The kinetic stereoselectivity of the aldol is a function of the enolate stereochemistry and its structure. One often reads the over-generalization that (Z)-enolates gives syn aldols and (E)-enolates give anti al-dols. However, the situation is much more complex than this in addition to enolate geometry, several variables are involved. The following generalizations may be made at this time (refer to equation 37 for definition of R , R- and R ). 

Because of conflicting reports or inadequate controls, the question of kinetic or thermodynamic control of stereochemistry for reported Reformatsky reactions often has no satisfactory answer. Jacques and co-workers have concluded that Reformatsky reactions of benzaldehyde in refluxing benzene can be completed with kinetic stereoselection. The relatively high syn.anti ratios they observed, at least with small R groups (equation 36 and Table 4), are not those expected for equilibrated zinc chelates. 

The optimum approach to kinetic stereoselection in the Reformatsky reaction would appear to be the use of two-stage procedures, which allows the zinc aldolates to be formed at the lowest possible temperature. Gaudemar-Bardone and Gaudemar prepared a variety of zinc ester enolates in dimethoxymethane at 40 C which were then reacted at lower temperatures with benzaldehyde or with acetophenone (equation 38). Selected data from their study are shown in Table 5. If these data are the result of total kinetic control, as concluded by the authors, it is clear that the reactions exhibit only a modest kinetic stereoselectivity. 

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