Faq Total Synthesis

[Dan_Ny]

Hi all,

 

since I have a lot of questions about what is commonly referred to as "Total Synthesis of Natural Products", this Topic is for questions about it that might occur to anybody at any stage of their organic synthesis efforts.

 

My first question would be this:

Why is the first synthetic aproach towards a target molecule always a racemic approach using racemates as starting materials? Is it not possible that the diastereomers, thus formed, will react quite differently giving misleading results and yields?

 

Thanks to everybody in advance for their help, answers and questions.

 

Dan

[mississippichem]

Hi all,

 

since I have a lot of questions about what is commonly referred to as "Total Synthesis of Natural Products", this Topic is for questions about it that might occur to anybody at any stage of their organic synthesis efforts.

 

My first question would be this:

Why is the first synthetic aproach towards a target molecule always a racemic approach using racemates as starting materials? Is it not possible that the diastereomers, thus formed, will react quite differently giving misleading results and yields?

 

Thanks to everybody in advance for their help, answers and questions.

 

Dan

 

I've thought about this before. Great minds think alike .

 

I think the idea is to find a viable synthetic route and to make sure one is feasible before the inevitable complications of enantiomeric catalysts and such are employed.

 

A good organic chemist will be able to forsee these diastereometric complications and adjust synthetic methods accordingly. For example, if we have reaction that we know will produce a "useless" diastereomer, then before the next step we'll just selectively re-crystallize and drive the "bad-diastereomer" out preemptively. The last thing an organic chemist needs is a yield robbing side product.

 

I'm really into inorganic and physical chemistry so even though my answer works, I'm sure Hypervalent_iodine or Horza2002 might give more insightful answers.

Edited March 9, 2011 by mississippichem

[Dan_Ny]

I've thought about this before. Great minds think alike .

 

I think the idea is to find a viable synthetic route and to make sure one is feasible before the inevitable complications of enantiomeric catalysts and such are employed.

 

A good organic chemist will be able to forsee these diastereometric complications and adjust synthetic methods accordingly. For example, if we have reaction that we know will produce a "useless" diastereomer, then before the next step we'll just selectively re-crystallize and drive the "bad-diastereomer" out preemptively. The last thing an organic chemist needs is a yield robbing side product.

 

I'm really into inorganic and physical chemistry so even though my answer works, I'm sure Hypervalent_iodine or Horza2002 might give more insightful answers.

 

Sounds convincing. Especially that part about my mind. It would be quite unfortunate, then, not to be a good organic chemist, right?

 

Well, only the recognition of the undesired diastereomers in question might become a problem. Imagine them to be unseperable by silica... same mass in the LCMS, of course, and those NMR spectra of complex precursors - I need quite a big amount of endurance for those sometimes...

 

But yeah, I agree, the best way to solve that is to think by yourself about what might happen to your molecule in a specific reaction.

Edited March 9, 2011 by Dan_iel

[Horza2002]

Did I hear somebody call me?

 

There are a range of reason as to why the racemate is synthesised first. In some cases, the absolute stereochemistry of the natural product is unknown so you don;t know which enatiomer you want. Another reason is ease and cost of the synthesis. Generally, it is far easier and cheaper to make a racemate than an enantioselective product; especially if you don't even know which enatiopmer you actually want! Nowadays, there are an awful lot of chiral catalysts that allow you to get high enationselectivity in reactions, but they are often pretty expensive. This is also a good way to devise an efficient synthetic route; especially as natural product synthetic routes tend to be very long.

 

When a new natrual product is identified and its structure determined (using MS, MS-MS and NMR), the hardest job is assiging the absolute stereochemisrty of the chiral centres. Using NMR studies (typically NOSEY experiments), the relative stereochemistry between each of the stereocentres is normally the first step. Then to confirm the absolute stereochemistry, each enatiomer is synthesised enationselectivly and then compared to the orginal using chiral HPLC.

[Dan_Ny]

Did I hear somebody call me?

 

There are a range of reason as to why the racemate is synthesised first. In some cases, the absolute stereochemistry of the natural product is unknown so you don;t know which enatiomer you want. Another reason is ease and cost of the synthesis. Generally, it is far easier and cheaper to make a racemate than an enantioselective product; especially if you don't even know which enatiopmer you actually want! Nowadays, there are an awful lot of chiral catalysts that allow you to get high enationselectivity in reactions, but they are often pretty expensive. This is also a good way to devise an efficient synthetic route; especially as natural product synthetic routes tend to be very long.

 

When a new natrual product is identified and its structure determined (using MS, MS-MS and NMR), the hardest job is assiging the absolute stereochemisrty of the chiral centres. Using NMR studies (typically NOSEY experiments), the relative stereochemistry between each of the stereocentres is normally the first step. Then to confirm the absolute stereochemistry, each enatiomer is synthesised enationselectivly and then compared to the orginal using chiral HPLC.

 

Hm. Is there no way to elucidate the absolute configuration of a natural product? Once the NOESY gives you the relative configuration of the stereocenters, the assignement of one absolute stereocenter in your molecule should be sufficient to elucidate it's overall stereochemistry (I hope I got that right). Why not simply modify your target with a chiral reagent, take the NMR of that and assign a stereocenter - knowing the enantiomer you want now, you can take stereoselctive reactions to build up your molecule instead of going through the racemic route. Without the trouble of carrying through several diastereomers, you prepare only one...

But when it comes to chiral catalysts or auxiliaries, I totally agree that generally you first want to quick (i. e. quick, cheap + racemic) check the feasability of the route and after that go for the enantioselective variant.

 

And what about chiral NMR sovents? Do they exist? Can they be any help in regard to which enantiomer of a nat pdt is at hand?

Edited March 10, 2011 by Dan_Ny

[Horza2002]

Yes, but it is extremely difficult to idenitfy one of those stereogenic centres. Especially when natural product are sooo complicted. The natural product that I am working on is relatively simple and only posses one stereogenic centre. It wasn't until the total synthesis of it was acheived did we know which entantiomer is actually was.

 

What you say is totally correct...once you know one steregogenic centre, then you can assign the others. But remember the NOSEY will only help you if the stereogenic centres are close through space....if they are not, then you won't even be able to get the relative stereochemistry. Altering any of the stereocentres configuration won't help you because you still don't know what the absolute stereochemistry is.

 

Chiral NMR solvents do exist yes. See the reference below:

 

Application of chiral bidentate NMR solvents for assignment of the absolute configuration of alcohols: scope and limitations

Yoshihisa Kobayashia, Nobuyuki Hayashia and Yoshito Kishi, Tetrahedron Letters, 44, 2003

 

However, the NMR spectra of a lot of natural product is just soooooo busy with signals, you siply can't see what is going on. I have never used chiral NMR solvents before mainly because they are far from foolproof and often the nessary interactions are to hard to see. To get the best results though, a high field spectrometer (600MHz or above) would be needed.

[mississippichem]

Another problem with natural products, is that sometimes you are never really sure you have just one compound. Sometimes a mixture can cleverly disguise itself as a pure compound with very similar solubility or strange mass-spec fragmentation patterns.

[Dan_Ny]

Another problem with natural products, is that sometimes you are never really sure you have just one compound. Sometimes a mixture can cleverly disguise itself as a pure compound with very similar solubility or strange mass-spec fragmentation patterns.

 

In that case, I would make a TLC

[hypervalent_iodine]

Honestly. I go away to do science for a week, and people start topics that I can answer, but that have already been answered. (I'm looking at you, Horza).

 

I literally just presented a lecture on this subject 2 days ago.

 

Dan, you mentioned chiral solvents. They are expensive and useless and deuterated NMR solvents would be even more expensive. As Horza said, the use of chiral NMR solvents isn't particularly useful for the large and complex molecules we like to try and make. In terms of their use as an asymmetric synthetic promoter, they are probably one of the most daft agents out there. It costs more money to obtain something that is enantiomerically pure than not, as I mentioned. Solvents being used in large quantities compared to the rest of the components of your reaction makes the whole concept ridiculously unfeasible. In my research for the lecture I presented on Wednesday, I was in fact only able to come up with one paper that used a chiral solvent in their reaction. The thing I found really laughable was that it didn't even work on its own. To give an ee of above 80%, the reaction needed a catalytic amount of enantiomerically pure proline.

 

There is another reason why we use racemates. Horza eluded to the fact that we often do not know which stereoisomer we want. Depending on what your product is designed to do, this may mean that we don't know which stereoisomer confers bioactivity or 'gives the best result' (most natural products we synthesis are studied because of their medicinal properties - it's how we gratuitous chemists get money to do science). Even if we did have an inclination as to which stereoisomer we wanted, we have to be able to present a full activity profile of the compound we are making - and that includes all possible stereoisomers. If we can't do that, it doesn't bode particularly well for in the case where we want to push it through the rigour of the drug design and development process.

 

If you wanted to synthesise a single enantiomer of something, then there are many ways you might choose so as to achieve this. For most practical purposes, asymmetric synthesis will necessitate the use of some enantiomerically pure, chiral component. These may be:

 

- chiral solvents

As I said, these are mostly useless due the cost and need for a high excess of solvent - having said that, chiral solvating agents are a reasonably good alternative, though not often used.

 

- chiral reagents

Many of these fall into the latter category of catalysts. The only true reagent under this category is a LiAlH₄ ester of darvon alcohol to mediate a enantioselevtive reduction. Nice concept, but it doesn't really work terribly well.

 

- chiral adjuvants/auxiliaries

Historically useful, though mostly superseded by recent developments in chiral catalysts - however they remain the only viable route for a number of synthetic transformations. It's based on a similar concept to kinetic resolution - add a temporary chiral moiety to a prochiral compound. The diastereomeric relationship invoked by this conjugation leads to transition states/intermediates/end products of differing energies and will thus favour the formation of one isomer over the other. It of course relies on the group being orthogonal and easily put on/taken off and that upon its removal, stereogenicity is retained. Recyclability is also nice.

 

- chiral catalysts

 

These are the method of choice, where possible. They are cheap by virtue of the fact that they are used in small amounts and are regenerated. An example of this is in Sharpless' epoxidation and dihydroxylation reactions.

 

The assignment of absolute stereochemistry is achieved only through X-ray crystallography (NMR, etc. cannot do this). The problem of this is that it needs, well, crystals. This isn't always possible. Before the development of X-ray crystallography, the determination of stereochemistry was all relative. You should look at the work of Fischer for a better idea of this. What he did was a combination of sheer brilliance and pot-luck. He was able to assign the relative configurations of 3, 4, 5 and 6 membered sugars starting from glycerol through a series of chemical transformations and observations. By a process of sheer luck, he also assigned their absolute configurations, as was found some time after in one of the first published demonstrations of the use of X-rays in this manner.

 

A lot of the time, indeed most of the time, we tend to operate with relative designations. This is okay, provided we use reactions with predictable and well-tested models. Often, the correlations made on asymmetric protocol are speculative and empirical (you should take a look at Horeau's method for determining stereochemistry of secondary alcohols - you can't get much more empirical), with no definitive mechanism. The problem then comes with the ever-present 'exception to the rule', though you can usually discern this via NMR, given that you know the absolute configuration of the rest of your product.

 

To your last post: Certainly, this would be your first port of call. TLC is by no means a fantastic analytical tool (good, but not fantastic). It's helpful if you want a rough guesstimate as to the progress of your reaction or the location of various compounds following column chromatography. Where it falls down though is in the case that a compound you want and some by-product has a similar RF. In combination with what mississippi was saying, this can be a real nightmare. NMR will generally tell you that something is up, particularly if the concentration of one is greater than another (your integrations will look crazy).

 

Anyway, I feel that I am rambling and should probably stop.

[Horza2002]

Hyper, maybe you should go away more often; we could get some good topics started Love you loads really!!

 

As Hypervalent said, the best way to get the absolute stereochemistry is to get an X-Ray crystal structure so then you can actually see which centre you have. The problem is that not all compounds can be crystallised. The stuff I work on for example is not possible to get a crystal; that is why the stereochemistry was determined by comparing an authentic sample with two enantioselective synthetic analoguse using chiral HPLC.

[mississippichem]

To your last post: Certainly, this would be your first port of call. TLC is by no means a fantastic analytical tool (good, but not fantastic). It's helpful if you want a rough guesstimate as to the progress of your reaction or the location of various compounds following column chromatography. Where it falls down though is in the case that a compound you want and some by-product has a similar RF. In combination with what mississippi was saying, this can be a real nightmare. NMR will generally tell you that something is up, particularly if the concentration of one is greater than another (your integrations will look crazy).

 

Anyway, I feel that I am rambling and should probably stop.

 

Nice rant hypervalent...but it was a good rant , at least worthy of a rep point.

 

About the TLC, I'll add that I once saw a reaction where hand held UV-TLC showed only one component but GC showed 4! Given, one of our GCs has a very long tube so our resolution is quite high.

 

I think the future for O-chem in this respect are in the hyphenated techniques. GC-MS, HPLC-NMR and even the glorious MS-C13-NMR-H1-NMR (when you get near the machine, you need to bow down and worship or it will smite you with it's 400,000 Gauss magnetic field). It may seem trivial, but being to run two types of NMR on the same sample [using proton suppression for the 13C of course] followed by an immediate mass spec is unmatched.

[Dan_Ny]

Thank you for your comprehensive remarks, hypervalent_iodine. There definitely is still a lot to discuss about, but (since this is a totaly synth faq) later, because I came over a recently isolated amazing molecule (with also interesting anti-cancer properties).

 

[K. J. Chavez, X. Feng,J. A. Flanders E. Rodriguez, F. C. Schroeder, J. Nat. Pdt. ASAP 2011 (just look into the asaps), dx.doi.org/10.1021/np100891y]

 

What do you think about this analysis?

 

 

I'm not sure about enantioselective addition of LiC2H to an aldehyde like this. As far as I know there are enantioselective protocols for the synthesis of propargyl alcohols. And, of course, the diastereoselectivity of the Diels-Alder could be an issue. And acetylene is a gas, might be difficult to handle.

Edited March 11, 2011 by Dan_Ny

[Dan_Ny]

Dan, you mentioned chiral solvents. They are expensive and useless and deuterated NMR solvents would be even more expensive. As Horza said, the use of chiral NMR solvents isn't particularly useful for the large and complex molecules we like to try and make. In terms of their use as an asymmetric synthetic promoter, they are probably one of the most daft agents out there. It costs more money to obtain something that is enantiomerically pure than not, as I mentioned. Solvents being used in large quantities compared to the rest of the components of your reaction makes the whole concept ridiculously unfeasible. In my research for the lecture I presented on Wednesday, I was in fact only able to come up with one paper that used a chiral solvent in their reaction. The thing I found really laughable was that it didn't even work on its own. To give an ee of above 80%, the reaction needed a catalytic amount of enantiomerically pure proline.

 

 

Yeah, I imagine that chiral solvents, which must be damn expensive (and, like you said, useless), must be even more expensive (and even more, like you said, useless) when deuterated. A shame, the idea using the solvent as the chiral environment neccessary to distinguish or generate stereocenters itself sounds interesting.

 

There is another reason why we use racemates. Horza eluded to the fact that we often do not know which stereoisomer we want. Depending on what your product is designed to do, this may mean that we don't know which stereoisomer confers bioactivity or 'gives the best result' (most natural products we synthesis are studied because of their medicinal properties - it's how we gratuitous chemists get money to do science). Even if we did have an inclination as to which stereoisomer we wanted, we have to be able to present a full activity profile of the compound we are making - and that includes all possible stereoisomers. If we can't do that, it doesn't bode particularly well for in the case where we want to push it through the rigour of the drug design and development process.

 

 

-- Sounds also pretty damn convincing

 

If you wanted to synthesise a single enantiomer of something, then there are many ways you might choose so as to achieve this. For most practical purposes, asymmetric synthesis will necessitate the use of some enantiomerically pure, chiral component. These may be:

 

- chiral solvents

As I said, these are mostly useless due the cost and need for a high excess of solvent - having said that, chiral solvating agents are a reasonably good alternative, though not often used.

 

- chiral reagents

Many of these fall into the latter category of catalysts. The only true reagent under this category is a LiAlH₄ ester of darvon alcohol to mediate a enantioselevtive reduction. Nice concept, but it doesn't really work terribly well.

 

- chiral adjuvants/auxiliaries

Historically useful, though mostly superseded by recent developments in chiral catalysts - however they remain the only viable route for a number of synthetic transformations. It's based on a similar concept to kinetic resolution - add a temporary chiral moiety to a prochiral compound. The diastereomeric relationship invoked by this conjugation leads to transition states/intermediates/end products of differing energies and will thus favour the formation of one isomer over the other. It of course relies on the group being orthogonal and easily put on/taken off and that upon its removal, stereogenicity is retained. Recyclability is also nice.

 

- chiral catalysts

 

These are the method of choice, where possible. They are cheap by virtue of the fact that they are used in small amounts and are regenerated. An example of this is in Sharpless' epoxidation and dihydroxylation reactions.

 

 

Here I take the liberty to extend the "chiral adjuvant/auxiliaries" you mentioned by the substrate itself (once we have that enantiopure). Before the 1980s, the leading paradigm (if I may quote the "classics of total synthesis") of organic synthesis was substrate-controlled stereoselectivity. Woodward himself, for example, in the synthesis of Reserpine, uses substrate-controlled diastereostereoselectivity (caused by preferred conformers of 6-membered rings in the substrate) in truly ingenious ways to stereoselevtive build up complex carbon frameworks "out of nothing". We should never forget, that organic chemistry entered a world of "luxus and decadence" when people like sharpless invented their epoxidations and dihydroxilations to easily override that substrate-generated stereocontrol with their catalysts. So to say.

 

The assignment of absolute stereochemistry is achieved only through X-ray crystallography (NMR, etc. cannot do this). The problem of this is that it needs, well, crystals. This isn't always possible. Before the development of X-ray crystallography, the determination of stereochemistry was all relative. You should look at the work of Fischer for a better idea of this. What he did was a combination of sheer brilliance and pot-luck. He was able to assign the relative configurations of 3, 4, 5 and 6 membered sugars starting from glycerol through a series of chemical transformations and observations. By a process of sheer luck, he also assigned their absolute configurations, as was found some time after in one of the first published demonstrations of the use of X-rays in this manner.

 

A lot of the time, indeed most of the time, we tend to operate with relative designations. This is okay, provided we use reactions with predictable and well-tested models. Often, the correlations made on asymmetric protocol are speculative and empirical (you should take a look at Horeau's method for determining stereochemistry of secondary alcohols - you can't get much more empirical), with no definitive mechanism. The problem then comes with the ever-present 'exception to the rule', though you can usually discern this via NMR, given that you know the absolute configuration of the rest of your product.

 

 

I have been reading a bit in this review, http://pubs.acs.org/....1021/cr000665j, about Mosher's acid, houreau's and helmchen's method for the evaluation of the absolute configuration of alcohols and amines. Interesting stuff. But it doesn't beat Xray, it seems. If you can get crystals, that is.

 

To your last post: Certainly, this would be your first port of call. TLC is by no means a fantastic analytical tool (good, but not fantastic). It's helpful if you want a rough guesstimate as to the progress of your reaction or the location of various compounds following column chromatography. Where it falls down though is in the case that a compound you want and some by-product has a similar RF. In combination with what mississippi was saying, this can be a real nightmare. NMR will generally tell you that something is up, particularly if the concentration of one is greater than another (your integrations will look crazy).

 

Hm. When you only see one spot on your TLC and have two or more compounds at hand, there are still some things to try. Changing the eluent (Acetone rather than Ethyl Acetate, DCM, Ethanol, stuff like that) sometimes also (to a certain extent) can change the RF of one compound relative to the other and seperate the compounds (interestingly). And you also could try different column materials like Alox instead of silica. But it's tough, yeah. And mostly easier to change reaction conditions to avoid the side product in question.

 

Anyway, I feel that I am rambling and should probably stop.

 

never stop when your having fun...

 

I think the future for O-chem in this respect are in the hyphenated techniques. GC-MS, HPLC-NMR and even the glorious MS-C13-NMR-H1-NMR (when you get near the machine, you need to bow down and worship or it will smite you with it's 400,000 Gauss magnetic field). It may seem trivial, but being to run two types of NMR on the same sample [using proton suppression for the 13C of course] followed by an immediate mass spec is unmatched.

 

I am still waiting for the LC/MS or GC/MS with integrated UV trace, IR spectrometer AND multidimensional, time resolved, in-system NMR spectrometer.

Edited March 12, 2011 by Dan_Ny