Claisen rearrangement of chorismate

The enzyme chorismate mutase was found to accelerate the Claisen rearrangement of chorismic acid.147 For many years, the origin of the acceleration perplexed and intrigued chemists and biochemists. Polar... 

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 Shikimate pathway is responsible for biosynthesis of aromatic amino acids in bacteria, fungi and plants [28], and the absence of this pathway in mammals makes it an interesting target for designing novel antibiotics, fungicides and herbicides. After the production of chorismate the pathway branches and, via specific internal pathways, the chorismate intermediate is converted to the three aromatic amino acids, in addition to a number of other aromatic compounds [29], The enzyme chorismate mutase (CM) is a key enzyme responsible for the Claisen rearrangement of chorismate to prephenate (Scheme 1-1), the first step in the branch that ultimately leads to production of tyrosine and phenylalanine. 

Chorismate mutase catalyzes the Claisen rearrangement of chorismate to prephenate at a rate 106 times greater than that in solution (Fig. 5.5). This enzyme reaction has attracted the attention of computational (bio)chemists, because it is a rare example of an enzyme-catalyzed pericyclic reaction. Several research groups have studied the mechanism of this enzyme by use of QM/MM methods [76-78], It has also been studied with the effective fragment potential (EFP) method [79, 80]. In this method the chemically active part of an enzyme is treated by use of the ab initio QM method and the rest of the system (protein environment) by effective fragment potentials. These potentials account... 

Fig. 12. Pseudodiequatorial reactant (left) and transition structure (right) for the Claisen rearrangement of chorismate...

The Claisen rearrangement has attracted special attention because of the pronounced solvent dependence of the reaction [92] and the biochemically important Claisen rearrangement of chorismate to prephenate in the shikimic add pathway [93] (Fig. 12). Both aspects of the reaction have been studied recently using DFT methods. 

Chorismate mutase catalyses the Claisen rearrangement of chorismate to form prephenate. It is an excellent system for analysing catalysis because the same reaction occurs in solution with the same reaction mechanism no covalent catalysis by the... 

Hur S, TC Bruice (2003a) Comparison of formation of reactive conformers (NACs) for the Claisen rearrangement of chorismate to prephenate in water and in the E-coli mutase The efficiency of the enzyme catalysis. J. Am. Chem. Soc. 125 (19) 5964-5972... 

Before we embark on our journey into the world of six-membered transition states, I would like to speak briefly about one reaction, to illustrate how a transition state is drawn throughout the book. The enzyme-catalyzed transformation of chorsimate (2) to prephenate (3) is a classic example of a [3,3]-sigmatropic Claisen rearrangement6 (Scheme IV). As an old bond is being broken and at the same time a new bond is formed in the transition state, the transition state for the Claisen rearrangement of chorismate to prephenate would look more like transistion state A than like B. Still, for the convenience of following the bond connection event clearly, I prefer to draw the transition state like B. 

Chorismate mutase provides an example of an enzyme where QM/MM calculations have identified an important catalytic principle at work [8], This enzyme catalyses the Claisen rearrangement of chorismate to prephenate. The reaction within the enzyme is not believed to involve chemical catalysis, and this pericylic reaction also occurs readily in solution. Lyne et al. [8] investigated the reaction in chorismate mutase in QM/MM calculations, at the AMI QM level (AMI was found to perform acceptably well for this reaction in comparisons with ab initio results for the reaction in the gas phase [8]). Different sizes of QM system were tested in the QM/MM studies (e.g. including the substrate and no, or up to three, protein side chains), and similar results found in all cases. The reaction was modelled by minimization along an approximate reaction coordinate, defined as the ratio of the forming C-C and breaking C-0 bonds. Values of the reaction coordinate were taken from the AMI intrinsic reaction coordinate for the gas-phase reaction. 

Figure 1 In a QM/MM calculation, a small region is treated by a quantum mechanical (QM) electronic structure method, and the surroundings treated by simpler, empirical, molecular mechanics. In treating an enzyme-catalysed reaction, the QM region includes the reactive groups, with the bulk of the protein and solvent environment included by molecular mechanics. Here, the approximate transition state for the Claisen rearrangement of chorismate to prephenate (catalysed by the enzyme chorismate mutase) is shown. This was calculated at the RHF(6-31G(d)-CHARMM QM-MM level. The QM region here (the substrate only) is shown by thick tubes, with some important active site residues (treated by MM) also shown. The whole model was based on a 25 A sphere around the active site, and contained 4211 protein atoms, 24 atoms of the substrate and 947 water molecules (including 144 water molecules observed by X-ray crystallography), a total of 7076 atoms. The results showed specific transition state stabilization by the enzyme. Comparison with the same reaction in solution showed that transition state stabilization is important in catalysis by chorismate mutase78.

The Claisen rearrangement of chorismate to prephenate, catalyzed by chorismate mutase, is illustrated below. It... 

The enzyme chorismate mutase258-259 catalyzes the Claisen rearrangement of chorismate to prephenate in the shikimic acid pathway2f n,2fil. 

Claisen rearrangement of chorismic acid 1 to prephenic acid 2 (Scheme 1), which is catalyzed by the enzyme chorismate mutase, can be considered as the key step in the biosynthesis of aromatic compounds, that is the so-called shikimic acid pathway. The chair-like transition state geometry 3 was proved by double isotope-labeling experiments [2]. However, in the laboratory this particular reaction can be accelerated not only by enzymes but also by catalytic antibodies [3]. For the generation of such antibodies haptenes such as 4 were used, that is, molecules whose structure is very similar to the transition state of the particular reaction and which are tightly bound by the antibody. 

Chorismate mutase (CM) catalyzes the Claisen rearrangement of chorismate to prephenate in the shikimic acid pathway used in the biosynthesis of aromatic amino acids. It represents a reference enzyme to explore the fundamentals of catalysis and has been the subject of extensive experimental and computational research. These have shown both that catalysis proceeds without covalent binding of the substrate to the enzyme, and that the uncatalyzed reaction in water proceeds by the same mechanism. This makes CM a particularly convenient target for QM/MM studies. 

Later, various aspects of the catalytic actions of specifically formed adsorbents as catalysts were discussed by Jencks, who theorized that antibodies prepared in the presence of stable analogues that mimic transition states may be able to catalyze the corresponding reactions. Recently Lemer and Mosbach used transition states analogues to imprint the formation of antibodies that were able to function as catalysts for reactions from which the transition-state analogues were prepared. Confirmation of these concepts was obtained fi om studies of the Claisen rearrangement of (-)-chorismate to form prephenate... 

Knowles and coworkers [13, 14] demonstrated that the transition state (1 in Scheme 1.2) for the Claisen rearrangement of chorismate has their atoms in the [3,3]-pericycUc region arranged in a chair-like configuration. The pseudodiaxial CHAIR conformer (2 in Scheme 1.2) is the substrate conformation that can reach this chair-like transihon state directly. The bond breaking and making process... 

This suggests that care must be excised in choosing proper computational methods for the study of the Claisen rearrangement of chorismate. 

The first reported use of water in promoting Claisen rearrangements was in 1970. The first example of the use of pure water for Claisen rearrangement of chorismic acid is given (Scheme 14). ... 

Scheme 17. Enzyme-catalyzed Claisen rearrangement of chorismate and a glycal structural analog [32]...

Figure 2 Examples of structures ftom MC simulations of reactions in solution. Only key solvent molecules from the first solvation shell are illustrated, (a) Transition structure (TS) for the Claisen rearrangement of chorismate in water, (b) TS for the epoxidation of cw-2-butene by dimethyldioxirane in methanol, (c) TS for the Mislow-Evans rearrangement of allyl p-tolyl sulfoxide in methanol, (d) Solvation of a pentamethylcyclohexyl cation in THF...

The Claisen rearrangement of chorismate shows yet again how apparently esoteric organic reactions find their way into the biological world. 

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