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   practical seven: more problems

Practical Seven: More Problems

(1) Account for the selectivity of a rearrangement

This diol undergoes a pinacol rearrangement when treated with a Lewis acid (Et2O.BF3). The pinacol rearrangement could form a mixture of two different ketones, but it the experiment shows that only one is formed. In this practical you will use molecular mechanics to analyse this reaction, and to rationalise the observed selectivity.

(a) Assume that the reaction is thermodynamically controlled. In this case, the ratio of the products will be controlled by the relative energies of the products. Calculate the relative energies of the products using MacroModel, and the MM2 force field. You could use a Monte-Carlo search to ensure you have a global minimum energy in each case, but it may be quicker to do the search by hand as the ketones are not very flexible.

(b) When you have found the energies of the low energy conformations of the two ketones, calculate the corresponding Boltzmann factors. The relative proportions of the two ketones will be given by the ratio of their Boltzmann factors. Is the experiment consistent with the premise that the reaction is thermodynamically controlled?

(c) Assume that the reaction is kinetically controlled. We must estimate the size of the energy barrier that must be overcome to form the products. In order to do this, note that the carbonium ion formed by removal of one of the hydroxyl groups will be similar in structure to the transition state of the reaction. Calculate the relative energies of the two carbonium ions. What ratio of products is expected now?

(d) Are your results consistent with the experiment?

(2) Design a reagent for a stereoselective aldol reaction

MacroModel's version of the MM2 force field (MM2*) contains parameters that allow it to investigate the structures of the transition state of the boron- mediated aldol reaction. The parameters are only applicable to the reactions of ethyl ketones.

To set up the transition state, draw the following structure in MacroModel. Two of the bonds are 'zero-order.' To draw these, make single bonds, click once on delete, then click once in the centre of each bond. The bonds will go green, to signify zero-order. The boron atom is a user-defined atom type. First draw this atom as a carbon atom, then click on '*' which is just below 'Lp' in the list of atom types. You will be asked for an atom label, and you must type 'B3' (the capital letter is essential). Click on the carbon atom It should go pale green, and be labelled 'B.'

Once you have set up this transition state, you can minimise it, using the MM2* force field. When you start a minimisation, MacroModel will suggest that the lone pairs do not match the force field, and ask to alter them. Usually you would ask MacroModel to alter the lone pairs for you, but in this case, click 'No.'

The energies you obtain for these structures should correspond to the energies of the transition states of the aldol reaction. If you calculate the energies of diastereomeric transition states, you should get a measure of the selectivity of the reaction.

Use this tool to design a selective ligand. Ideally, you would do a full conformational search on each, but if you choose fairly rigid structures, you may be able to get an idea of the global minimum by adjusting the torsion angles by hand (use the Rot T button). The diisopinocampheyl ligand has often been used as a chiral auxiliary in this reaction. Can you design something better?

(3) Design a ligand for ristocetin

Ristocetin is an antibiotic which inhibits bacterial cell wall growth. Like penicillin, it exploits the unusual D-ala-D-ala peptide sequence which is present in cell wall formation. Penicillin mimics this unusual structure, but ristocetin binds to its, thus inhibiting the growth of cell walls. The files /usr/local/examples/rist.dat and /usr/local/examples/ristDD.dat contain the structures of aglyco-ristocetin and acetyl-D-alanine-D-alanine complexed to aglycoristocetin. A thorough study of the binding interactions would require long molecular dynamics simulations, but a qualitative picture emerges from simple minimisations. Use the AMBER force field, and solvent models to investigate the structures.

Experimentally, acetyl-D-alanine-D-alanine binds more strongly than any of its diastereoisomers, or the analogues in which one or both alanines is replaced by glycine. Is this what you would expect from the model? Experiments in vacuo show a much reduced selectivity. Can you rationalise this? Might other peptidic or non-peptidic molecules bind as well or better than acetyl-D-alanine-D-alanine? It will not be possible to get quantitative answers to these questions in the time available, but it may be possible to get a qualitative picture of the likely interactions.

(4) Investigate Enzyme Structure

The structures of several enzymes are in the /usr/local/examples/enzymes. These are an aldolase, carboxypeptidase A bound to an inhibitor, lysozyme bound to a trisaccharide (the natural substrate is a tetrasaccharide), an RNase, and triosephosphate isomerase.

MacroModel can read each of these structures, and manipulate them. They are too big to minimise directly, but you can use the SUBED submode to select the area around the active site for minimisation, or for molecular dynamics. What other molecules might inhibit these enzymes?

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