Rearrangement to prephenate

The reaction in the shikimic acid pathway is, of course, the [3,3]-sigmatropic shift in which chorismic acid rearranges to prephenic acid on the way to aromatic rings (p. 1403). The simpler reaction given here is one of the family of reactions from Chapter 36 (pp. 944-6) using an allylic alcohol and an enol derivative of a carbonyl compound. In this case we have the enol ether of a ketone. We must combine these to make an allyl vinyl ether for rearrangement. 

PROBLEM 20.45 We saw on page 1063 that chorismate undergoes a [3,3] sigmatropic shift (Claisen rearrangement) to prephenate catalyzed by the enzyme chorismate mutase. This enzyme-catalyzed reaction occurs more than 1 million times faster than the corresponding nonenzymatic reaction. How does the enzyme effect rate enhancement Both enzymatic and nonenzymatic reactions proceed through a chairlike transition state. However, the predominant conformer of chorismate in solution, as determined by H NMR spectroscopy, is the pseudodiequatorial conformer 2, which cannot undergo the reaction. 

One of the metabolic reactions in the biosynthesis of the amino acid phenylalanine occurs by a [3,3] sigmatropic shift in a reaction called a Claisen rearrangement. In this reaction, chorismate, a vinyl ether, rearranges to prephenate. 

In this contribution, we describe work from our group in the development and application of alternatives that allow the explicit inclusion of environment effects while treating the most relevant part of the system with full quantum mechanics. The first methodology, dubbed MD/QM, was used for the study of the electronic spectrum of prephenate dianion in solution [18] and later coupled to the Effective Fragment Potential (EFP) [19] to the study of the Claisen rearrangement reaction from chorismate to prephenate catalyzed by the chorismate mutase (CM) enzyme [20]. 

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... 

Claisen rearrangement chorismic acid to prephenic acid... 

The hydrophobic effects between the apolar gronps involved in the Diels-Alder reaction also occnr when the apolar gronps belong to the same molecules, and thus should also be beneficial to the Claisen rearrangement. The nonenzymatic rearrangement of chorismate to prephenate occurs 100 times faster in water than in methanol (Copley and Knowles, 1987 Grieco et al., 1989). 

Claisen rearrangement plays an important part in the biosynthesis of several natural products. For example, the chorismate ion is rearranged to the prephenate ion by the Claisen rearrangement, which is catalysed by the enzyme chorismate mutase. This prephenate ion is a key intermediate in the shikimic acid pathway for the biosynthesis of phenylalanine, tyrosine and many other biologically important natural products. 

FIGURE 22-19 Biosynthesis of phenylalanine and tyrosine from chorismate in bacteria and plants. Conversion of chorismate to prephenate is a rare biological example of a Claisen rearrangement. 

A thoroughly investigated reaction on the biosynthetic pathway to aromatics is the [3+3]-sigmatropic Claisen rearrangement from chorismic acid to prephenic acid (Figure 18.8). 

Figure 18.8 Claisen rearrangement from chorismate to prephenate catalyzed by antibodies.

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. 

Woodcock HL, M Hodoscek, P Sherwood, YS Lee, HF Schaefer, BR Brooks (2003) Exploring the quantum mechanical/molecular mechanical replica path method a pathway optimization of the chorismate to prephenate Claisen rearrangement catalyzed by chorismate mutase. Theor. Chem. Acc. 109 (3) 140-148... 

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. 

On standing in alkali in the laboratory, prephenic acid rearranges to 4-hydroxyphenyl-lactic acid with specific incorporation of deuterium label as shown. Suggest a mechanism, being careful to draw realistic conformations. 

Under conditions in which all of (-)-chorismate rearranges, only half of the racemic substrate is converted to prephenate by 1F7 (37). The kcat value for ( )-chorismate is the same as that measured for the pure (-)-isomer, but its apparent is twice larger. Because the kcat value determined for the racemate is unchanged relative to the optically pure material, (+)-chorismate can be treated as a competitive inhibitor. From our data, the term O.SKn/Ki must be much less than 1, indicating that binding of the (+)-isomer to the antibody is at least one or two orders of magnitude weaker than that of (-)-chorismate. 

The utilization of evolutionary strategies in the laboratory can be illustrated with proteins that catalyze simple metabolic reactions. One of the simplest such reactions is the conversion of chorismate to prephenate (Fig. 3.3), a [3,3]-sigmatropic rearrangement. This transformation is a key step in the shikimate pathway leading to aromatic amino acids in plants and lower organisms [28, 29]. It is accelerated more than a million-fold by enzymes called chorismate mutases [30],... 

Andrews, P. R. Smith, G. D. Yonng, I. G. Transition-state stabilization and enzymic catalysis. Kinetic and molecular orbital studies of the rearrangement of chorismate to prephenate, Biochemistry 1973,12, 3492-3498. 

Hur, S. Bruice, T. C. lust a near attack conformer for catalysis (chorismate to prephenate rearrangements in water, antibody, enzymes, and their mutants), J. Am. Chem. Soc. 2003,125, 10540-10542. 

---