B X A X. In this case the star denotes a chiral center.

Transcription

1 Lecture 13 Chirality III October 29, 2013 We can also access chiral molecules through the use of something called chiral auxiliaries, which basically is a chiral attachment that you add to your molecule temporarily to induce chirality in the area of the molecule you are interested in. Once the key reaction is done, you can remove the attachment while maintaining the new chirality that you formed. One way that people have done this is called the self reproduction of stereocenters. This is something that was developed by a guy named Dieter Seebach in the 1980s. He was trying to solve the following problem: Let s say I have a chiral center with one of the four substituents being a hydrogen atom and I want to alkylate this center. The standard way to do this would be to deprotonate the compound (lose the hydrogen) and then add an alkyl halide to alkylate. However, when you deprotonate the carbon you have a trigonal intermediate which is completely flat and has lost all of its chirality so a simple deprotonation/ alkylation is going to give you a racemic product, since now the alkylating agent has no preference for one side over the other. The problem: R1 A X R1 1 Y * R3 3 * H In this case the star denotes a chiral center. B X So what Seebach did is develop the idea that you could introduce a second temporary chiral center, for example by condensation with an aldehyde (shown below) and then when you deprotonate, you still have a chiral center in the molecule. Alkylation then can occur stereoselectively. Finally, you remove the chiral auxiliary group and end up with the desired chiral product. This is shown schematically below: Y O - R2 H

2 I know this sounds a little convoluted, but in practice it s been used to synthesize quite a few compounds. One example is to synthesize alpha methyl amino acids from the corresponding normal amino acids: We will go through each reaction necessary to do this transformation. Reaction 1: Formation of oxazolidinone: The amino group acts as a nucleophile to attack the pivalaldehyde, and the aldehyde anion then attacks the carbonyl to form the five membered ring. This reaction could lead to the formation of two different diastereomers one where both the isopropyl and the tert butyl are on the same side of the molecule, and one in which they are on opposite sides: It turns out that the cis diastereomer is highly favored for five membered rings. We can make molecular models of these compounds to show how the cis diastereomer allows both substituents to be equatorial, whereas the trans arrangement requires one to be axial. So now you have a five membered ring system (predominantly cis, although you can separate out any trans amount using a regular silica gel column). This ring has two different chiral centers. Reaction 2: Protection of the nitrogen: This is a pretty straightforward reaction. We use the acyl chloride, which is attacked by the nucleophilic amine moiety to kick out the chloride and generate the protected amine. This particular acyl chloride is called Cbz chloride, or carbobenzyloxy chloride. Reaction 3: Deprotonation and methylation:

3 Now when we deprotonate the a carbon and alkylate it with methyl iodide, the methyl group is directed to come from the bottom face of the molecule, because the top face is blocked by the bulky t butyl group. This is the key step, because we have now methylated at the target carbon while maintaining its chirality. A few notes on this step: 1. once you deprotonate, it doesn t matter that the isopropyl group used to be up, because once you form the anion, that is planar and it has no memory of chirality. The reason that the isopropyl group helps us is that it caused the t butyl group to go up as well. 2. in general, people have also used other aldehydes (not just t butyl aldehyde) to form these oxazolidinones, but one advantage to the t butyl is that it is very sterically bulky. the bulkier it is, the stronger the preference for the two substitutents to be on the same side of the molecule. when people have used t butyl aldehyde, they get a 15:1 ratio (roughly of cis to trans diastereomers). if they use benzylaldehyde (which they also have), the ratio is more like 9:1 or 10:1. 3. you really have two potential sites for deprotonation you can deprotonate on the alpha carbon (which is what you want), or you can also deprotonate at the carbon between the oxygen and the nitrogen (which is not what you want). this proton is also kind of acidic because it is between the nitrogen and the oxygen. if you are not careful, you will get deprotonation here as well, but by using a bulky base (KHMDS) and low temperatures, you can control the deprotonation. Reaction 4: Hydrolysis of the oxazolidinone ring:

4 I think the way this works is that the base will deprotonate the hydrogen that is between the nitrogen and oxygen on the oxazolidinone ring, although you are not responsible for the actual mechanism. Reaction 5: Deprotection of the nitrogen group: This is a hydrogenolysis reaction. Again, you are not responsible for the details, but it pays to know that this is how you remove a Cbz group from a nitrogen to form the desired free amino acid product. another interesting note about this is that the side products are toluene (which you can rotovap off) and carbon dioxide (which just comes off the reaction), so it is really very easy to work up. I want to move now to talk about the topic of chiral catalysis, which is a very active research area. We will try to cover some key highlights. Within the topic of chiral catalysis, we are going to focus exclusively on chiral organocatalysis, even though there are a lot of other subtopics in this field. The first step in this discussion is to understand what organocatalysis is. Basically, it is catalysis of a reaction using an organic compound. Historically, people knew that you could use a variety of transition metals to catalyze and/or accelerate reactions, but people generally didn t think about using organic molecules to catalyze organic reactions. I think the prevailing thought was, organic compounds react so they can t be used as catalysts (by definition, things that are unchanging during the course of the reaction). This started to change when people started thinking about enzymatic catalysis. Enzymes catalyze reactions using a number of forces, mostly non covalent interactions. We will not discuss these in detail, but the point is that while certain enzymes use metals for catalysis, large numbers of enzymes use simple interactions between the organic molecules of the enzyme and the organic molecules of the substrate to achieve efficient catalysis. So chemists thought, why can t we utilize the same principles of enzymes to inspire our catalysis design? 1. Secondary amines: The first bio inspired small molecule organic catalyst was L proline, which was used to catalyze an intramolecular aldol reaction with high enantioselectivities: We can draw a mechanism for this aldol reaction which doesn t involve proline at all:

5 For the proline catalyzed reaction, the NH of the proline can form an iminium with the methyl ketone, and that then converts into a chiral enamine. The chiral enamine is your nucleophile for this reaction (sort of an enolate surrogate) and it subsequently attacks the other carbonyl in the C C bond forming event: