Economies of Synthesis: Determining the Best Route to the Target
There was a time when completing the synthesis of a complex target molecule was a big deal, no matter the yield and waste and the number of steps involved. However, today, 20 years into the twenty first century, the value of a total synthesis totally depends the overall yield and waste management of the process and how short and green the synthesis is. (I am assuming you are at least little bit familiar with total synthesis, at least the concept of it. In case this sounds new to you feel free to quickly get an idea here and check out my earlier post on the blog).
This article in Chemical Society Reviews appeared a decade ago authored by Newhouse, Hoffmann and Baran, and discusses the crucial aspect of 'economy' in natural product synthesis. They argue that improving the three economies of synthesis should be the goal of a synthetic chemist in achieving a practical route to the target molecule.
This is darn exciting because there are not many papers that deal with this kind of topics and we need more of them to appear. Imagine if you are a student and the teacher had given a molecule to do retrosynthesis as homework. Now, I bet different group will come up with various routes that are all chemically viable and uses very different synthetic strategies (unless they conspire together). Now, how do you determine which route is superior to the other. Is it the one that uses fascinating reactions but takes a large number of steps, or is the one where they quickly achieved at the target but used dull and low-yielding transformations or is it say a cascade reaction that cuts the number of steps by half but give only 20% yield ?
One way of judging the superiority will be to look for the route that minimizes the three economies. (Much like a mathematical analysis).
The first of the three is Step Economy. As the name says, it is to do with the total number of steps involved. The lesser the better. Yields always decreases with the number of steps unless you have 100% yield for a steps which is not possible to achieve practically (Even 99% yield is impossible to get). And, to be frank, come on! the lesser number of columns you need to do the better. To emphasize a bit more on how to reduce step economy, I have to talk about the "No Protecting Group Strategy" popularized by Baran.
Protecting groups are very important in multi-step synthesis and helps to avoid chemoselectivity and other problems, but the fact remains that for each orthogonal protecting group you need to add two more steps to the route (protection and deprotection). But Baran argues, that by intelligent planning and choosing correct strategy one can avoid them mostly and therefore reduce step economy drastically. Use of late-stage fictionalizations, chemoselective transformations and cascade steps are some of the systematic ways to avoid protecting groups.
The second class of economy is a very interesting one and reducing it also in turn reduces the step economy automatically. It is called the Redox Economy. Allow me to explain.
Most organic transformations involves oxidations and reductions. But one must try to avoid any non-strategic redox manipulation in a synthesis. Let me give you an example of what I mean. Say you have an ester and you want it to convert to an aldehyde. You can go on and use a reducing agent, say LAH, to reduce it to alcohol and then oxidize it back to aldehyde. This process took 2 steps. But if you had used reagents/conditions that can directly reduce the ester to aldehyde (e.g., DIBAL at -78 °C), you would save on step. Thus by avoiding one unnecessary oxidation step you increase the yield of the overall process. This is what I mean when I say that avoid non-strategic (=unnecessary) redox steps. In an ideal synthesis where there is no unnecessary redox steps the overall oxidation state would either continuously increase or decrease, but never both. To give a beautiful example how managing redox economy improves the synthesis drastically let me give another example.
The synthetic route on the left shows a two electron strategy (ionic pathway) for the overall transformation and a one electron strategy (radical pathway) on the right. Note all the steps marked red on the left are nonstrategic redox manipulations and are avoided on the right by changing the tactic. As you can see now, redox economy also automatically reduces the number of steps and thus is directly connect to step economy.
The last economy on the list is quite famous by now and an essectial principle of green chemistry. that is Atom Economy. First proposed by Trost back in 1991, the concept of atom economy is basically a sort of mass efficiency in synthesis. It states, the more the fraction of total mass of all the reactants gets transferred to the product the better. This can be translated as, a high atom economic reaction incorporates most of the atoms present in all the reactants into the product. Atom economy thus emphasize on the amount of waste being generated (high molecular weight by-products and side-products, solvents etc) and avoidance of use of high molecular weight reagents. Interestingly, the last point connects atom economy to redox economy. Most redox transformations uses a oxidizing or reducing agent that changes only a few atoms of the substrate (add or remove oxygens/hydrogens). For example, the famous Swern Oxidation of alcohols to aldehydes employs reagents of total mass 306 (except the substrate) just to remove two hydrogen from the molecule.
Thus, reducing redox economy also improves the atom economy of the overall synthesis.
Although there are other methods of improving the quality of a synthesis (ideality, scalability, robustness) these three economies plays a very important part in increasing the overall quality of the synthesis by reducing steps, avoiding unnecessary transformations and managing the waste. So next time you are doing a retrosynthesis of a complex molecule, don't forget to consider the Trio into your plan. You may just come up with a practical route that can actually be done in lab.
This article in Chemical Society Reviews appeared a decade ago authored by Newhouse, Hoffmann and Baran, and discusses the crucial aspect of 'economy' in natural product synthesis. They argue that improving the three economies of synthesis should be the goal of a synthetic chemist in achieving a practical route to the target molecule.
This is darn exciting because there are not many papers that deal with this kind of topics and we need more of them to appear. Imagine if you are a student and the teacher had given a molecule to do retrosynthesis as homework. Now, I bet different group will come up with various routes that are all chemically viable and uses very different synthetic strategies (unless they conspire together). Now, how do you determine which route is superior to the other. Is it the one that uses fascinating reactions but takes a large number of steps, or is the one where they quickly achieved at the target but used dull and low-yielding transformations or is it say a cascade reaction that cuts the number of steps by half but give only 20% yield ?
One way of judging the superiority will be to look for the route that minimizes the three economies. (Much like a mathematical analysis).
The first of the three is Step Economy. As the name says, it is to do with the total number of steps involved. The lesser the better. Yields always decreases with the number of steps unless you have 100% yield for a steps which is not possible to achieve practically (Even 99% yield is impossible to get). And, to be frank, come on! the lesser number of columns you need to do the better. To emphasize a bit more on how to reduce step economy, I have to talk about the "No Protecting Group Strategy" popularized by Baran.
Protecting groups are very important in multi-step synthesis and helps to avoid chemoselectivity and other problems, but the fact remains that for each orthogonal protecting group you need to add two more steps to the route (protection and deprotection). But Baran argues, that by intelligent planning and choosing correct strategy one can avoid them mostly and therefore reduce step economy drastically. Use of late-stage fictionalizations, chemoselective transformations and cascade steps are some of the systematic ways to avoid protecting groups.
The second class of economy is a very interesting one and reducing it also in turn reduces the step economy automatically. It is called the Redox Economy. Allow me to explain.
Most organic transformations involves oxidations and reductions. But one must try to avoid any non-strategic redox manipulation in a synthesis. Let me give you an example of what I mean. Say you have an ester and you want it to convert to an aldehyde. You can go on and use a reducing agent, say LAH, to reduce it to alcohol and then oxidize it back to aldehyde. This process took 2 steps. But if you had used reagents/conditions that can directly reduce the ester to aldehyde (e.g., DIBAL at -78 °C), you would save on step. Thus by avoiding one unnecessary oxidation step you increase the yield of the overall process. This is what I mean when I say that avoid non-strategic (=unnecessary) redox steps. In an ideal synthesis where there is no unnecessary redox steps the overall oxidation state would either continuously increase or decrease, but never both. To give a beautiful example how managing redox economy improves the synthesis drastically let me give another example.
The synthetic route on the left shows a two electron strategy (ionic pathway) for the overall transformation and a one electron strategy (radical pathway) on the right. Note all the steps marked red on the left are nonstrategic redox manipulations and are avoided on the right by changing the tactic. As you can see now, redox economy also automatically reduces the number of steps and thus is directly connect to step economy.
The last economy on the list is quite famous by now and an essectial principle of green chemistry. that is Atom Economy. First proposed by Trost back in 1991, the concept of atom economy is basically a sort of mass efficiency in synthesis. It states, the more the fraction of total mass of all the reactants gets transferred to the product the better. This can be translated as, a high atom economic reaction incorporates most of the atoms present in all the reactants into the product. Atom economy thus emphasize on the amount of waste being generated (high molecular weight by-products and side-products, solvents etc) and avoidance of use of high molecular weight reagents. Interestingly, the last point connects atom economy to redox economy. Most redox transformations uses a oxidizing or reducing agent that changes only a few atoms of the substrate (add or remove oxygens/hydrogens). For example, the famous Swern Oxidation of alcohols to aldehydes employs reagents of total mass 306 (except the substrate) just to remove two hydrogen from the molecule.
Thus, reducing redox economy also improves the atom economy of the overall synthesis.
Although there are other methods of improving the quality of a synthesis (ideality, scalability, robustness) these three economies plays a very important part in increasing the overall quality of the synthesis by reducing steps, avoiding unnecessary transformations and managing the waste. So next time you are doing a retrosynthesis of a complex molecule, don't forget to consider the Trio into your plan. You may just come up with a practical route that can actually be done in lab.
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