What is Total Synthesis? The Basics Explained

This post explains the question: What is total synthesis? If you read this, you might be forced to study organic chemistry 🙁 or are already interested in total synthesis. In any case, this brief commentary will explain the concept very simply. For advanced content, check out this page or my videos.

Imagine you’re a pastry chef and have stumbled across a picture of the most delicious-looking cake – but you lack the recipe. How can you re-create the culinary masterpiece? It will take some planning (which ingredients do I need?), experimentation (what baking temperature, for how long?), practical skills (how do I pipe the frosting?)

… and luck! As we will see, some chemists had to push the ambiguity to the limit – sometimes testing a thousand reactions for one step, or realizing the shape of their glassware influenced their product!

Cake: Complex molecules

Chemists and the world are interested in complex molecules – a chemist’s cake – with intriguing properties – the cake’s flavours. For instance, natural products produced by other organisms can have biochemical activities that make them candidates for potential medicines.

What is total synthesis? Simply said, it is the complete chemical assembly of complex targets from simpler starting materials – like baking a cake!

Let’s take lissodendoric acid A as an example. This marine natural product isolated from sponges contains several connected rings and functional groups (in blue: amines, double bonds, carboxylic acid). This unique molecular setup gives the molecule anti-Parkinson’s disease activity in certain model experiments.
Once chemists are sufficiently convinced of such a target‘s utility – or sometimes simply its molecular beauty – they need to figure out how to synthesize it. Note: In some cases, large-scale isolation from natural sources or biotechnological production might be feasible.

Recipe: Retrosynthetic analysis

Much like chefs writing recipes, chemists design a plan en route to their masterpiece. This roadmap details the individual steps of reactions needed to transform simple starting materials into the desired molecular delicacy.

This plan is defined in a backward sense and thus called retrosynthetic analysis. This means that the first retrosynthetic “disconnection” corresponds to the final step of the forward/ laboratory synthesis.

Why backwards? Imagine you need to replicate a cake based on an image. Your first thought will be “How do I finish off the top and add the glazing?” (i.e., last ‘forward’ step). Later, you might think “How do I assemble the various layers of the cake?” (i.e., building the cake’s complexity).

You would not directly jump into thinking “For this cake, I need exactly 10 cups of flour and 8 eggs”. This would be a premature move! You haven’t even thought about how many cake layers you need, what their consistency and thickness should be…

How a retrosynthetic analysis looks like in practice. The target natural product (+)-Heilonine (1) is believed to be a constituent in the important Chinese herbal drug “Bei-mu”, which has traditionally been used as a sedative, antitussive, and expectorant.
Source: JACS 2021, 143, 40, 16394 | CC-by-4.0

It’s the same in total synthesis! We first work backwards through plausible, theoretical retrosynthetic disconnections. With this, we arrive at suggested starting materials for our laboratory endeavours in real life.

Experimentation: How To Learn Chemistry

Just like baking, chemistry is highly experimental. How can you tell if baking your cake layers at 170 °C, 180 °C, 190 °C or 200 °C will work best?

1) The first source is intuition to narrow your option space. For instance, baking the layers at 100 °C will either not work or take way too long. Baking them at 300 °C will lead to a bit too much crunch 😉 ! You don’t have to try 300 °C as the outcome is already certain.

Just like a freezing flame, thinking about the deprotonation of ketones with cyanide does not make sense. Once you have studied enough theory and reviewed practice, it becomes second nature!

As an example, we know that certain deprotonation reactions will simply not work if our base is not “strong”/basic enough. This is why pKa values are important!
Chemists acquire their “common sense” by studying the fundamentals of chemical concepts, reactions and synthesis. Additional intuition is gathered by reading about and performing experiments. With time, chemists get a sense of what will likely work vs. what will not.

2) The second source is existing external research. Let’s assume other chefs reported 180 °C to work well for cakes with similar albeit different ingredients. This means starting at 180 °C is a good idea.

Let’s assume a specific Diels-Alder reaction was reported to require elevated temperature (e.g., reflux in toluene). If we want to perform a very similar reaction, we can assume that we don’t need to test cold temperatures like – 78° C.
By reviewing scientific publications and patents, chemists can derive starting points for their experimentation.

3) The third source are your own experiments. If you want to bake a cake no one has ever baked before, you will need to gather completely novel data points.

Let’s pick up the example of (+)-Heilonine again. As reported by the authors, use of standard conditions (data source #2, if you will) was not fruitful. Instead, thorough investigations were need to identify adequate reaction conditions for this unique educt. Such optimization efforts also draw on intuition and inventiveness.

Is Chemistry Random?

Chemistry is only predictable to a certain (low) degree. Finding successful reaction conditions during organic synthesis can be challenging or straight-up impossible!

Roughly 1000 experiments were conducted changing every conceivable variable from the base used to deprotonate, the solvent employed, additives, and the electrophile. Emerging from this exhaustive study was the remarkable finding that the addition of LaCl3·2LiCl to the extended sodium enolate of 3, followed by quenching with freshly prepared formaldehyde gas led to the desired adduct 11 in 84% yield as a 2:1 diastereomeric mixture favoring 11 (3 g scale).

From: 11-Step Total Synthesis of (−)-Maoecrystal V | JACS 2016, 138, 30, 9425

Finding gold nuggets can sometimes be very tedious and serendipitous.
Equally random are findings like the following:

Reproduced from Chem. Sci., 2022,13, 6181 with permission from the Royal Society of Chemistry.

What you are seeing is a reaction that only works in old borosilicate reaction flasks. This can happen in cases where the glass surface of a flask is actually where the reaction occurs.

Similar to such “vessel effects”, the source of chemicals (i.e., the supplier/ vendor) can in rare cases also make or break reactions. This can be driven by trace metal impurities which catalyse or also poison certain reactions. These impurities can vary across suppliers due to different syntheses/ purifications of these chemicals.
Imagine if you could only bake your most beloved cake with a certain brand of milk!

Aside from driving chemists crazy, such unexpected effects exemplify the experimental nature of chemistry. Navigating this uncertainty while using strategic planning, creativity and practical skills – this makes total synthesis an art!





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