Claisen rearrangements transition state structures

Structure B corresponds to the most stable transition state of the Ireland-Claisen rearrangement of Figure 14.49. In this transition state, the substituent at the allylic stereocenter is in a pseudo-equatorial orientation with respect to the chair-shaped skeleton. This is the same preferred geometry as in the case of the most stable transition state B of the Claisen rearrangement of Figure 14.48. The reason for this preference is as before that is, an allylic substituent that is oriented in this way experiences the smallest possible interaction with the chair skeleton. The obvious similarity of the preferred transition state structures of the Ireland-Claisen rearrangements of Figures 14.49 and 14.48 causes the same trans-selectivity. 

The geometry of the vinyl ethers is one important factor that determines the stereochemical outcome of the rearrangement. The vinyl ether geometry strongly depends on the variant employed. Furthermore, the transition-state structures are paramount to the stereochemistry of Claisen rearrangements. The transition state geometry is controlled by both steric and electronic features of the Claisen system. 

The loss of rotational freedom when the cyclic transition state is formed from the acyclic starting material accounts for the observed negative entropies and volumes of activation. It has been established that the transition state of the closely related Cope rearrangement (see below) resembles the chair conformation of cyclohexane. An analogous transition state structure for the Claisen rearrangement would account for the fact that isomerization of vinyl a-methylallyl ether yields 97% trans 4-hexQm and 3% cw-4-hexenal, since there should be a preference for an equatorial orientation of the methyl group in a cyclohexane chair-like transition state . 

Draw transition state structures that rationalize the stereochemistry of the two Ireland-Claisen rearrangements shown in Eq. 15.45. 

The differences in the rate constant for the water reaction and the catalyzed reactions reside in the mole fraction of substrate present as near attack conformers (NACs).171 These results and knowledge of the importance of transition-state stabilization in other cases support a proposal that enzymes utilize both NAC and transition-state stabilization in the mix required for the most efficient catalysis. Using a combined QM/MM Monte Carlo/free-energy perturbation (MC/FEP) method, 82%, 57%, and 1% of chorismate conformers were found to be NAC structures (NACs) in water, methanol, and the gas phase, respectively.172 The fact that the reaction occurred faster in water than in methanol was attributed to greater stabilization of the TS in water by specific interactions with first-shell solvent molecules. The Claisen rearrangements of chorismate in water and at the active site of E. coli chorismate mutase have been compared.173 It follows that the efficiency of formation of NAC (7.8 kcal/mol) at the active site provides approximately 90% of the kinetic advantage of the enzymatic reaction as compared with the water reaction. 

The Claisen rearrangement is an electrocyclic reaction which converts an allyl vinyl ether into a y,8-unsaturated aldehyde or ketone, via a (3.3) sigmatropic shift. The rate of this reaction can be largely increased in polar solvents. Several works have addressed the study of the reaction mechanism and the electronic structure of the transition state (TS) by examining substituent and solvent effects on the rate of this reaction. 

The conversion of [49] into [50] involves a Claisen rearrangement. Once this was realized it was less surprising that no specific catalytic groups on the enzyme are involved. Support for the Claisen-type mechanism comes from the inhibition shown by the bicyclic dicarboxylate [51], prepared by Bartlett and Johnson (1985) as an analogue of the presumed transition state [52], This same structure [51], coupled through the hydroxyl group to a small protein, was used as a hapten to induce antibodies, one (out of eight) of which mimics the behaviour of chorismate mutase, albeit less efficiently (Table 7). 

Discussing the stereochemical outcome of the Claisen rearrangements, two aspects had to be considered. On the one hand, the relative configuration of the new stereogenic centers was found to be exclusively syn in 201 and 202, pointing out the passing of a chair-like transition state c-a and c-jS, respectively, including a Z-acylammonium enolate structure (complete simple diastereo-selectivity/internal asymmetric induction). 

The mechanism and stereochemistry of the ortho ester Claisen rearrangement are analogous to those of the Cope rearrangement. The reaction is stereospecific with respect to the double bond present in the initial allylic alcohol. In acyclic molecules, the stereochemistry of the product can usually be predicted on the basis of a chairlike transition state.158 When steric effects or ring geometry preclude a chairlike structure, the reaction can proceed through a boatlike transition state.159... 

One potentially interesting aspect of this particular system, and Claisen rearrangements in general, is the close structural resemblance of the transition state to the tetrahydropyran ring. 

Two main mechanistic hypotheses were considered for this reaction type38, a zinca ene 39 reaction and a metallo-Claisen rearrangement (equations 31 and 32). 70 and 71 are drawn as monomers for the sake of simplicity. The former probably exists in oligomeric form (see Section . . ), whereas the transition state of the metallo-Claisen rearrangement may involve two molecules of 7138. Since the simplified structures are perfectly suitable to rationalize the selectivity and reactivity of these reactions, they are used throughout this chapter. 

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