Absolute configuration mechanism

In view of the absolute configuration and their optical yields (88-96 %), it follows that the precursor of the (S)-4 should be 2a, which are formed highly diastereoselectively. It is likely that the predominant formation of 2a conforms to the mechanism of the bromolactonization, the S-trans transition state (ref. 3). 

Although the absolute configurations of the products are opposite to that of antiinflammatory active compounds, and the substrate specificity is rather restricted as to the steric bulkiness around the reaction center, the enzyme system of A. bronchisepticus was proved to have a unique reactivity. Thus, detailed studies on the isolated enzyme were expected to elucidate some new interesting mechanism of the new type of decarboxylation. Thus, the enzyme was purified. (The enzyme is now registered as EC 4.1.1.76.) The molecular mass was about 24kDa. The enzyme was named as arylmalonate decarboxylase (AMDase), as the rate of the decarboxylation of phenylmalonic acid was faster than that of the a-methyl derivative. ... 

If the proton-donating ability of the amino acid at 188 is weaker, then the enantioselectivity of the reaction will be reversed compared to that of native enzyme. As shown in Table 3, the absolute configuration of the products by this mutant is opposite to those of the products obtained by the native enzyme and the ee of the products dramatically increased to 94 and 96%, respectively. This inversion of the enantioselectivity of the reaction supports the reaction mechanism that the Cys 188 of the native enzyme is working as the proton donor to the intermediate enolate form of the product. ... 

On the basis of i.r. spectroscopic investigations the authors concluded that in compounds of the latter type the carbonyls are cis to one another, in agreement with the proposed reaction mechanism. However it could not be shown unambiguously whether the absolute configuration is cis,cis or cis,trans. 

On the other hand, optically active telluroxides have not been isolated until recently, although it has been surmised that they are key intermediates in asymmetric synthesis.3,4 In 1997, optically active telluroxides 3, stabilized by bulky substituents toward racemization, were isolated for the first time by liquid chromatography on optically active columns.13,14 The stereochemistry was determined by comparing their chiroptical properties with those of chiral selenoxides with known absolute configurations. The stability of the chiral telluroxides toward racemization was found to be lower than that of the corresponding selenoxides, and the racemization mechanism that involved formation of the achiral hydrate by reaction of water was also clarified. Telluroxides 4 and 5, which were thermodynamically stabilized by nitrogen-tellurium interactions, were also optically resolved and their absolute configurations and stability were studied (Scheme 2).12,14... 

On the other hand, telluronium imides 13 were isolated for the first time in 2002 by optical resolution of their racemic samples on an optically active column by medium-pressure column chromatography.27 The relationship between the absolute configurations and the chiroptical properties was clarified on the basis of their specific rotations and circular dichroism spectra. The racemization mechanism of the optically active telluronium imides, which involved the formation of corresponding telluroxides by hydrolysis of the telluronium imides, was proposed (Scheme 6). 

Optically active sulfonium and selenonium salts are well known and the stereochemistry of the isomers has been studied.1 3 Optically active cyclic diaryl(alkoxy)-sulfonium salts 14, 15, and 16, stabilized by intramolecular sulfur-oxygen interaction, were synthesized in 2000 by reacting optically active spirosulfuranes with trimethyloxonium tetrafluoroborate.29 The absolute configurations were assigned on the basis of the reaction mechanism. The sulfonium salts were hydrolyzed in KHC03aq. to yield optically active sulfoxides in over 86% ee (Scheme 7). 

Recent experimental and theoretical studies on crystal growth, especially in the presence of tailor-made inhibitors, provide a link between macroscopic and microscopic chirality. We shall discuss these principles in some detail for chiral molecules. Furthermore, we shall examine whether it is indeed feasible today to establish the absolute configuration of a chiral crystal from an analysis of solvent-surface interactions. Since these analyses are based on understanding the interactions between a growing crystal and inhibitors present in solution, we shall first illustrate the general mechanism of this effect in various chiral and nonchiral systems. 

Having established the basic mechanism of interaction between tailor-made additives and crystal surfaces, we return now to the original problem of direct assignment of the absolute configuration of a chiral molecule. We shall first examine how to establish by such means the orientation of a chiral molecule in a chiral crystal. 

This anisotropic distribution of the occluded additive provides a second independent method of confirming the absolute configuration assigned by means of the morphological changes, once the mechanism of adsorption is known. This principle will be met again in the growth of centrosymmetric crystals. 

In this study, an important piece of information was gleaned regarding the mechanism of the reaction from the assignment of the absolute sign of the polar axis. Of course, in transformations of this type, if the reaction mechanisms are well established, one may proceed in a reverse manner and assign the absolute polarity of the crystal (and therefore the absolute configuration of the chiral molecules) by determining the preferential direction of the attack. 

In many studies of asymmetric reductions no attempts were made to rationalize either the extent or the sense of the observed asymmetric induction, that is, the absolute configuration of the predominant enantiomer. It is believed that it is premature in certain cases to attempt to construct a model of the transition state of the key reaction step, given the present state of knowledge about the mechanism of these reduction processes. The complexity of many of the reducing systems developed is shown by the fact that the enantiomeric excess or even the sense of asymmetric induction may depend not only on the nature of the reducing agent and substrate, but also on temperature, solvent, concentration, stoichiometry of the reaction, and in some cases the age of the reagent. 

The significance, reversibility, and mechanisms of nonenzymatic lactone hydration may be aptly illustrated with pilocarpine, an extensively investigated drug whose stability in aqueous solution is of great pharmaceutical relevance. Pilocarpine (7.76, Fig. 7.13), whose absolute configuration is... 

The X-ray structure of the Cut complex 21 of phosphoramidite 14 provides additional insight into a possible mechanism for stereocontrol (Fig. 7.3). The formation of the L2CuEt-enone complex involves substitution of the iodide in 21 for the alkyl moiety and of one of the ligands for the -coordinated enone. Coordination of RZnX results in the bimetallic intermediate 19 (Fig. 7.3). The absolute configuration of the two phosphoramidite ligands and the pseudo-C2-symmetric arrangement dictate the formation of (S)-3-ethyl-cyclohexanone. 

Obviously with the indan-l,2-diol substrates there is no symmetrical meso intermediate which makes interpretation of the mechanism more difficult. In both the cyclohexan-l,2-diol and the indan-l,2-diol series the trans diols react faster and cis diols (both enantiomers for indandiol) are seen as intermediates. The (IS,2R) cis indandiol 29 is faster reacting and on incubation of the racemate only a very small trace of the R,R)-trans 28 isomer is observed. 2-Hydroxyin-dan-1 -one 30, an observed intermediate in these biotransformations, undergoes kinetic resolution when incubated as a racemic substrate. The faster reacting enantiomer is reduced to the faster reacting cis (lS,2i )-indan-l,2-diol 29 which is subsequently transformed into both trans diols and ultimately the (S,S)-iso-mer. Current work is focussing on determining the absolute configuration of the intermediate a-hydroxyketone 30. 

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