The field of alkene metathesis has seen a lot of development recently, but one advancement in particular deserves special note. A group of chemists from Boston have announced a new catalyst which is chiral.
Chirality is a property that some organic molecules possess, and is best understood by looking at your hands. The left hand looks quite similar to the right hand, with many of the same features and properties. However, there is no way to take your left hand and flip it or orient it in any direction which makes it look exactly like the right hand. The fingers are pointing in the wrong direction. The left hand is a mirror image of the right hand. if you look at your left hand in a mirror, it looks just like your right hand, and vice versa. Chemists would say that your hands are chiral, and this common every-day example can be used to understand molecules that possess chirality. Many important biological molecules such as pharmaceuticals possess both a left-handed and a right-handed version. The carbon atoms at the center of the organic molecules have a tetrahedral, three dimensional shape, just like some of the bone structures in your hand. Therefore many molecules exist which have both a “left-handed” form and a “right-handed” form. They’re not the same molecule, just like your left hand isn’t your right hand. They may have many of the same properties, but chiral molecules differ from their partner in terms of how they interact with the body.
This is because the body controls its chemical reactions through the use of enzymes, which are large molecules with a precise molecular shape; only molecules which match that exact, precise shape can interact with the enzymes. A left handed molecule may fit perfectly, but its right handed partner won’t fit at all, just like your left hand can’t wear your right hands glove. As a result many drug syntheses are complicated by the fact that chemists not only have to make the correct compound, they have to make sure that compound is the correct left or right handed form. This adds a significant level of difficulty to the reaction as the majority of chemistry transformations don’t discriminate between the two products and produce a 50:50 mixture of both of them. It’s then up to the unlucky researcher to try and separate this mixture, which is often impossible. Therefore a lot of research is pouring into new catalysts and synthetic methods which preferentially result in one form or the other, and avoid equally balanced mixtures. Progress has been slow and painful, and so it’s worth taking note of new developments in the area as they represent a lot of hard work.
One such result was recently published by Boston chemists in the journal Nature. They have developed a new catalyst which can produce stereochemically pure products from alkene metathesis reactions. If the stereochemistry (arrangement of atoms) in the product is the desired left or right handed form, it makes it much easier to use the compound in consumer applications. In the case of this latest research, the chemists used their new catalyst to make quebrachamine, which is a medically active molecule found in trace amounts in some types of plant. Making naturally occurring molecules from “scratch”, using only simple and commonly available starting materials, is much easier than trying to process tons of plant material and extract the tiny amount of naturally occurring material.
The new catalyst is based on molybdenum metal, which is a design element I’m familiar with, having designed several new molybdenum metathesis catalysts myself. The innovation behind this new molecular design lies in the use of flexible monodentate ligands. Ligands are organic molecules which attach themselves to the metal atom to give stability and to guide the reaction pathway. Most molybdenum ligands traditionally have been rigid “bidendate” ligands, which take up two binding spots around the metal. These new ligands are flexible and monodendate, taking up only one binding spot. This allows this new catalyst complex to accommodate highly-strained intermediates which, in the case of the prior bidendate design, would not be stable as the ligands would push against the intermediate and force it away from the metal.
Of equal importance is the fact that the molybdenum itself exists solely in a stereochemically pure form. When the starting material attaches itself to the metal catalyst and begins to undergo the chemical reaction, this stereochemical information is passed to the starting material and results in a product that is not a 50:50 mixture of both compounds but rather a single compound with a single type of “handedness”. This technology makes it now possible to synthesize pharmaceuticals via metathesis that are chiral and which are much more powerful on a per molecule basis than their mixed cousins. This work should help to stimulate other chemists who are working in the area of catalysis, as perhaps the strategy of using flexible mono ligands can be put to use in other fields of chemistry as well.
The source of this article can be found at: http://www.nature.com/nature/journal/v456/n7224/full/nature07594.html
