David MacMillan

Asymmetric Chemistry and Sugar Synthesis
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Professor David MacMillan
Professor of Chemistry, California Institute of Technology

The chemistry of life relies heavily on special molecules that are ideally suited for their various roles.  Part of this design often involves an asymmetric design that enables their activity.  However, this asymmetry poses a problem for chemists interested in replicating these biologically important molecules.

Joining us today to discuss the synthesis of natural compounds is Prof. David MacMillan.  Prof. MacMillan is a professor of chemistry at the California Institute of Technology, where his interests include new reaction design, enantioselective catalysis, and natural product synthesis.

Prof. David MacMillan (DM) joins Charles Lee (CL) to discuss asymmetric catalysis and the synthesis of carbohydrates from simple starting materials.

CL: Prof. MacMillan, thank you for joining us today.

DM: Thank you for having me.

CL: It’s certainly our pleasure.  It looks like you are doing some very fascinating work in the field of enantioselective catalysis.  I’m curious if you could explain to our audience, what exactly is enantioselective catalysis?

DM: Well, enantioselective catalysis is basically generating single enantiomers using catalysts.  The reason why you need single enantiomers, as you stated in your introduction, is that a lot of times people in chemistry and biology are interested in generating organic molecules, which are molecules that revolve around the atom carbon.  Carbon, as most people who have done chemistry know, exists in a tetrahedral format, which means that it has four different substituents, and can therefore exist as two different mirror images.  It turns out that being able to produce one mirror image over another one has a lot of implications for biology.  Sometimes molecules that exist in one mirror image will provide benefits for therapeutic use, whereas the other mirror image might actually be harmful to biological systems.  As such there is a big pressure in organic synthesis to be able to generate one of these mirror images, which are called single enantiomers, selectively.  And one way that this can actually be done is to develop catalysts that allow the production of one mirror image in preference to the other one.  And, that’s why the name enantioselective, or asymmetric meaning non-symmetrical, catalysis came about.  And, that’s why there’s been a lot of work over the last 30 years towards developing catalysts that allow the production of one enantiomer in preference to the other one.

CL: Are there any good examples of two different enantiomers, where one is beneficial and the other harmful?

DM: Some of the most famous are birth defects that arise due to the Thalidomide drug.  Thalidomide was a drug that exists as three enantiomers.  It turns out that one of the mirror images actually provides the beneficial effects, which remove morning sickness whenever a woman is going through a pregnancy in her first trimester.  However, the other enantiomer leads to the birth defects that has led to this disastrous phenomenon known as Thalidomide children.  So, that’s one example that led to the FDA coming out with very strong guidelines that modern pharmaceuticals have to be registered in their single enantiomer format.

CL: Is most of nature constructed in this way, where specific enantiomers are important?

DM: You do find molecules in nature that exist as both mirror images.  But, for the most part, most molecules in biological systems, such as proteins, DNA, and RNA, are formed around one enantiomeric series of a core molecular structure.  So, really it is just based on one of two mirror images.

CL: Why is the construction of different enantiomers very difficult then?

DM: It’s very difficult because when you carry out a transformation on a molecule and generate a molecule with carbon and four different substituents, that’s called a stereogenic center.  It’s called stereogenic because it can exits in two different formats.  Whenever you carry out this transformation, there is a 50:50 probability that you’ll make one or the other mirror images.  So, to take the same molecule and make it undergo one of the transformations that will form one mirror image is actually very difficult.  It has to be carried out in a transition state, where the energy required to form one mirror image is lower than the energy to form the other.  And, so for the last 30 years or so, organic chemists have been focused on trying to come up with methods to do just that.  It’s an interesting situation because it’s only in the last 10 years that chemists have become very successful at it.

CL: So, what are the strategies that chemists have used to get one form preferred over the other one?

DM: In terms of catalysis, there have been several different forms.  It typically revolves around the type of catalyst, and the mode of catalytic activation, which simply means the method by which the catalyst will activate the starting material in such a way that you can discriminate between the different enatiomers that are formed.  There has really been three different types of catalysts which have been utilized.  There has been two types of organometallic catalysts using transition metal catalyzed processes such as hydrogenation or insertion chemistry.  Or, you could have another type of organometallic catalysis which is based around Lewis acid catalysis, which is simply a method by which you lower the electron density in a substrate to the point where it can now engage in a reaction with a more electron rich partner.  The third method, which my group has been working on for the past 5 – 6 years, is called organic catalysis.  This uses organic molecules to function as catalysts to interact with starting materials to energetically partition them between the production of one enantiomer in preference to the other one.  It’s an interesting area to be involved with, because if you think about biology, in many cases biology is organic catalysis, which will often involve enzymes that allow the production of one mirror image in preference to the other one.

CL: So, has the design of chemical catalysts taken a cue from biological catalsysis?

DM: It’s an interesting question, and I would answer that by saying ‘no’.  Up until this point, there has not been a lot of work in organic synthesis utilizing the types of catalysis which have been learned from biology or biochemistry and trying to take those catalysis concepts and applying them to organic synthesis.  Now, in the field of bio-inorganic chemistry there’s been a lot of work in trying to understand the methods by which these systems carry out catalysis as a means to develop and design catalysts that could do the same thing in a laboratory setting.  But, in terms of organic synthesis, most of the methods that have been developed have not been based on what you might call the blueprints that came from biology.  Most of them have been de novo catalysis concepts which have been utilized to try and partition between these two single mirror images.

CL: Is it easier to design these organic catalysts then attempt to reconstruct biological catalysis?

DM: I think that has typically been the case, and it makes sense.  Biological systems are very complex for a reason.  They focus on carrying out selective reactions, but they also focus on molecular recognition, so that one specific molecule will undergo one specific reaction from a large milieu of many different types of molecules.  And, in the laboratory setting, you also typically want one molecule to undergo one transformation.  But, it’s much easier to focus on developing catalysts that can carry out chemical reactions on a series of substrates, but doing them one molecule and one reaction flask at a time.  The focus in this case is not to go after one molecule to do one selective transformation, as much as it is to take one class of different molecules and to be able to carry out enantioselective catalysis on one class of molecules, making a more general approach to what you might call enantioselective induction.  This means if you want the capacity to build one enantiomer in preference to the other one, you want to do it on a general class instead of one particular molecule.

CL: So, it’s weighing the generality and the specificity of the two methods.

DM: Absolutely.

CL: Recently, your group published an interesting paper in Science about synthesizing sugars in a two-step synthesis.  Could you tell us about that?

DM: One of the things my group is interested in is a concept that is central to organic synthesis, which is the rapid development of molecular complexity.  How can we generate very complex organic molecules in a very rapid fashion?  And in doing this, how can we focus on molecular structures and architectures that are prevalently used by chemists, biologists, biochemists, but that at the moment there might not be straightforward ways to get their hands on them or utilize them?  In this regard in biological systems, I would argue there are three main bioarchitectures.  You have DNA or RNA, nucleic acid based architectures.  You have amino acid, or protein, based systems.  And, the third major bioarchiteture is carbohydrates.

Carbohydrates are actually the most prevalent form of bioarchitecture found in biological systems, and they also have a widespread role in many biological processes, such as signal tansduction, cognition, as well as the immune response.  The interesting thing is that carbohydrates in their monomer forms, that is the single unit form such as glucose, manose, allose, or galactose, it is very difficult to take those carbohydrates and either selectively functionalize them or couple them to each other.  The reason why it is very difficult is that each carbohydrate has five oxygens, which are basically substiuent groups that are attached to the carbohydrates central framework.  And it’s very difficult to differentiate each of those hydroxyl groups from each other.  For example, if I wanted to couple two carbohydrates, glucose at the anomeric position to galactose at the fourth position, it would be very difficult to do that.  Chemically, you couldn’t actually perform that transformation.

The thing that we were very interested in doing was finding a method that we could come up with, a synthesis or a way to construct these carbohydrates selectively and as a single enantiomer, but at the same time differentiate all of these oxygens which reside on the periphery of the carbohydrate.  The nice thing with this is that it would have to be very rapid.  For example, if you were to take glucose from a bottle and try to chemically differentiate all of those oxygens, it would typically take anywhere from eight to fourteen chemical steps depending upon how you wanted to differentiate all of these oxygens.  We were interested in coming up with a way to differentiate all of those oxygens in a relatively straightforward fashion.

So, the method we came up with was taking three two-carbon units, called alpha-oxygenated aldehydes, and asking ourselves the question if we could carry out two chemical reactions which would build the whole carbohydrate framework and at the same time differentiate all of those oxygens, in just a two chemical step process.  And, in fact, that’s the thing that we have been able to accomplish.

CL: That’s very impressive.  So, has the inability to discriminate between these oxygens limited the synthesis or carbohydrate molecules?

DM: Yes.  You can look at people in glycobiology or other biological areas, where they might be interested in generating tetra-saccharides with specific linkages between all of the different carbohydrates linked at different positions.  And, you may have specific substituents, such as sulfate esters, around a variety of oxygen positions to try and test for a number of biological processes.  But, at the moment, it may take many chemical steps to build those types of tetra-saccharides.  However, if you could put those carbohydrates together in just two chemical steps and have them be completely differentially protected on each carbohydrate so that you could couple them all together very rapidly.  In theory you could build these tetra-saccharides in 6 or 7 chemical steps, instead of the 40 or 50 chemical steps that are involved at the moment in terms of the production of all the monomers and then the production of the tetra-saccharide from all of those monomers.  So, it’s very important to be able to develop rapid methods where you can get your hands on these carbohydrates with all of the oxygens differentially protected.  This was one of the things that we were trying to accomplish.

But, the second thing that we were trying to accomplish with the production of carbohydrates from two carbon units, is that you are no longer restricted to having just oxygens around the periphery.  Now, you could start to think could you introduce other atomic systems into different positions.  We call that atomic mutation.  For example, in the fourth position of a carbohydrate, you may decide that you no longer want an oxygen there, maybe you want a sulfur.  To be able to take a natural carbohydrate and derivatize it in such a way that you would differentiate all of those oxygens and then convert the number four position into a sulfur would basically be impossible at this moment in time using other chemical methods.  The means by which you could displace that oxygen with a sulfur is not straightforward.  Well, by the fact that we were actually building these carbohydrates using two carbon units, this allows us to bring in those substituents from the very outset on the two carbon units.  And as such, we can actually build carbohydrates that would contain sulfur at the number four position in only two chemical steps.

The reason why it is important to be able to get our hands on these unnatural carbohydrates is for medicinal chemists.  Medicinal chemists are the people who really do all of the chemistry involved in developing pharmaceuticals.  And, one of the things that they have to do is take biologically active molecules and be able to fine-tune them by taking little components of those pharmaceutical agents, for example converting an oxygen to a sulfur, that’s called a structure-activity relationship.  And this capacity to build unnatural carbohydrates in two steps allows you to do just that.  It allows you to completely pinpoint the atom that you want to change to try and understand what effect that would have in a biological system.

CL: So, rather than derivatizing a natural molecule, you can build it up using components.

DM: Exactly.  It’s a bit like saying, instead of taking a molecule that exists in nature and basically bashing away at it over 14 to 18 chemical steps to convert it into something else.  Wouldn’t it be better if we could actually build it de novo in just two chemical steps by focusing upon the development of two new chemical reactions that would allow you to put it together instead of having to take the naturally occurring material and trying to convert it into something that it is not?  I always tell people that it’s a bit like taking a washing machine and asking yourself can you convert it into a lawnmower?  It’s not a great way of doing things.  It’s usually much easier to build the lawnmower de novo, than trying to convert something that was designed with a completely different framework.

CL: We are running a little out of time, but I’m curious if any medicinal chemists have expressed an interest in using this method?

DM: That’s a great question.  Very interestingly, since this paper was published in Science, we’ve really had a lot of different phone calls from biotech companies and major pharmaceutical companies who are interested in actually utilizing this technology.  There’s one company that right now is actually using this in medicinal chemistry processes, but I can’t actually disclose.  But, you can basically understand that this is a method to generate and carry out structure-activity relationships on carbohydrates that wasn’t possible before, but is now possible in just two chemical steps.  I think from that it’s easy to appreciate how rapidly people will start to adopt the technology.

CL: Right.  Well, it is very fascinating, and certainly a great advance, but we are out of time and I just want to thank you very much for joining us to discuss all of your fascinating research.

DM: Thank you very much.

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