Transition Claisen rearrangements

A highly successful route to stereoisomers of substituted 3-cyclohexene-l-carboxylates runs via Ireland-Claisen rearrangements of silyl enolates of oj-vinyl lactones. The rearrangement proceeds stereospeaifically through the only possible boat-like transition state, in which the connecting carbon atoms come close enough (S. Danishefsky, 1980 see also section 4.8.3, M. Nakatsuka, 1990). 

The transition state for the first step of the Claisen rearrangement bears much m common with the transition state for the Diels-Alder cycloaddition Both involve a con certed six electron reorganization... 

The stereochemical features of the Claisen rearrangement are very similar to those described for the Cope rearrangement, and reliable stereochemical predictions can be made on the basis of the preference for a chairlike transition state. The major product has the -configuration at the newly formed double bond because of the preference for placing the larger substituent in the pseudoequatorial position in the transition state. ... 

Would you describe the transition state for the Claisen rearrangement as early (like reactants), late (like products) or in between Given the overall thermodynamics of reaction, do you conclude that the Hammond Postulate applies Explain. 

The stereochemical outcome of the reaction is determined by the geometry of the transition state for the Claisen rearrangement a chairlike conformation is preferred,and it proceeds strictly by an intramolecular pathway. It is therefore possible to predict the stereochemical course of the reaction, and thus the configuration of the stereogenic centers to be generated. This potential can be used for the planning of stereoselective syntheses e.g the synthesis of natural products. 

Like the Diels-Alder reaction discussed in Sections 14.4 and 14.5, the Claisen rearrangement reaction takes place through a pericyclic mechanism in which a concerted reorganization of bonding electrons occurs through a six-membered, cyclic transition state. The 6-allyl-2,4-cyclohexadienone intermediate then isomerizes to o-allylpbenol (Figure 18.1). 

Because of the nature of the transition state in the pericyclic mechanism, optically active substrates with a chiral carbon at C-3 or C-4 transfer the chirality to the product, making this an enantioselective synthesis (see p. 1451 for an example in the mechanistically similar Claisen rearrangement). ... 

The ester 7-1 gives alternative stereoisomers when subjected to Claisen rearrangement as the lithium enolate or as the silyl ketene acetal. Analyze the respective transition structures and develop a rationale to explain these results. 

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. 

This reaction also is concerted and proceeds via a six-membered transition state, but here the species (59), corresponding to the ene-one intermediate (53a) in the aromatic Claisen rearrangement, is in fact the end-product. This is so because there is in (59) no energetic driving force, comparable to re-aromatisation in (53a— 52a), to promote its enolisation. 

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. 

Originally very few types of such rearrangements were known e.g., Copes rearrangement, Claisen rearrangement and some 1, 5 hydrogen shift in some dienes, but now many others have been discovered. The common feature of such reactions is that they are concerted, uncatalysed and involve a bond migration through a cyclic transition state. 

The Claisen rearrangement goes through a transition state in the chair conformation. This is the supported by the fact that trans, trans-crotyl propenyl ether gave more than 97% of the threo aldehyde showing a preference for the chair form while reaction in the boat gave mainly erythro aldehyde. 

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). 

Only limited precedent exists for the stereoselective enolization and subsequent condensation of a-heteroatom-substituted esters 48a and 48b (eq. [29]). Ireland has examined the enolization process for a-amino ester derivatives where the Claisen rearrangement (chair-preferred transition states) was employed to ascertain enolate geometry (Scheme 10) (43). These results imply that 48a [X = N(CH2Ph)2 ] exhibits only modest selectivity for ( )-enoIate formation under the... 

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