Closing the Back Door on the Evil Twin Enantioselective Catalysis of b Blockers

by Alice Lurain

Many of the medicines on the market today are chemical compounds that can exist in two different structural forms that are mirror images of each other. Most consumers are unaware that when they take a drug that contains a mixture of these two structural mirror images, called enantiomers, each one can have a different effect on the human body. In Dr. Joseph Bruno's lab at Wesleyan University, Alice Lurain, Pat DeSimone, and Melissa Mushrush are currently working to develop an enantioselective synthesis (a method for making the compound that would produce only one of these mirror image forms) for a class of cardiovascular drugs called b -blockers.

The impetus for this project came from a 1992 ruling by the Food and Drug Administration that was intended to encourage the discovery of syntheses, ways of making a compound, that would produce only one of the mirror images. Since the two enantiomers of a particular compound have identical chemical and physical properties under almost all conditions, they cannot be separated by any normal chemical processes. Therefore, drugs that are synthesized in a laboratory generally result in an equal mixture of the two mirror images and are sold in this form. The human body, however, is always enantiospecific, meaning that it "knows" the difference between the two mirror images of any given compound. The body always produces and uses compounds as single enantiomers (as a single one of the mirror images).

An understanding of this specificity in the human body led to the FDA's ruling in 1992. Since the body utilizes only one enantiomer, patients who receive drugs that are an equal mixture of both mirror images are actually using only half of the drug that is administered. Therefore, drugs given as single enantiomers may have increased activity and require fewer or smaller doses. In addition, the "wrong" enantiomer may be inactive or have negative side effects on the patient. One such case is that of the drug Thalidomide, a sedative that, when administered to pregnant women, was shown to cause birth defects. Although it remains controversial, some studies have attributed these birth defects to the "wrong" enantiomer.

Dr. Bruno's lab is developing an enantioselective synthesis of Alprenolol and other structurally similar b-blockers using chiral early transition metal complexes as catalysts. These cardiovascular drugs are used to treat hypertension and ventricular arrhythmias and are currently available only as a mixture of both enantiomers.

Figure 1. The reaction of interest that leads to the production of an Alprenolol precursor.

After the figure 1 reaction is complete, C undergoes another step to arrive at the final product, the cardiovascular drug Alprenolol. That additional step, however, does not have an effect on the formation of structural mirror images in the final product and, therefore, has not been studied.

If the reaction of interest is allowed to proceed without the special catalyst, the result is

A + B -- C¹ + C²

where C¹ and C² are enantiomers. (Remember that C¹ and C² cannot be distinguished by normal chemical procedures. ) The goal of this project, then, is to eliminate C² from the product so that only the single enantiomer C¹ is made during the reaction. This is the role of the catalyst.

The center of the catalyst and the site at which the reaction takes place is a transition metal, a metal from the middle of the periodic table such as niobium, titanium, or lanthanum. Attached to the metal in three places are one or two big, "floppy" molecules made up of amino acids. These "floppy' molecules surround the metal, or "hug" it, so that only specific surfaces of the metal are exposed.

Figure 2. A metal center is "hugged" by amino acids to form the enantioselective catalyst.

When this specially designed catalyst is added to the reaction described above, compound A becomes attached to the metal center of the catalyst. Compound B wants to come in and "attack" compound A in order for the reaction to proceed, but because of the big, floppy molecules "hugging" the metal center, compound B can gain only limited access to compound A. That is, only specific sides of A are vulnerable to attack by B. If the catalyst is designed correctly, B will only be able to attack A in such a way that C¹ is formed and not C².

One could think of the catalyst as a room in which the reaction between compound A and compound B occurs. A enters the room first and waits for B to come in. If there are several doors leading into the room, then B might come in through any one of them and attack A from any side. If, however, the catalyst is designed so that all but one of the doors leading into the room are closed off by a big, floppy molecule standing guard, then B has only one means of entering and can attack A from only one side.

Figure 3. The catalyst is designed so that amino acids shut the back door and force compound B to come in through the front to attack compund A. This produces an enantioselective synthesis.

If B comes in through door #1, then the reaction produces C¹. If B comes in through door #2, then the reaction produces C². By placing a big, floppy molecule in front of door#2 to stand guard and close it off, B comes in only through door #1 and the reaction produces only C¹. The catalyst has made the reaction enantioselective.

To determine the level of success that the catalyst had in "closing the back door," the product C is run through a special instrument that can separate the enantiomers (C¹ and C²). A printout shows two peaks that represent the two enantiomers. The relative areas of the two peaks tell the investigator the relative amounts of each enantiomer in the product. For example, the printout would show that the product contained 70% C¹ and 30% C² or 90% C¹ and 10% C². The goal, of course, is to achieve 100% C¹ and 0% C². In this case, the printout would show only one peak.

So far, our best results have been in the range of 70% C¹ to 30% C^2,. These results have been achieved by using niobium as the metal center in the catalyst with naphthaldehyde, tryptophan, and phenylalanine attached. We are continuing to explore different combinations of metal centers and amino acids to improve the selectivity of the reaction. In addition, we are experimenting with the conditions of the reaction, such as temperature, time, and acidity, to discover the effects that these may have on the degree of selectivity. In the future, we hope to come up with a completely enantioselective catalytic synthesis that will be applicable, not only to our specific class of target molecules (b-blockers), but to related compounds as well.

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