Retrosynthetic analysis : Synthesis backward
Chemistry is above all a creative science. Nearly all that you have learned so far in this book has had one underlying aim:
to teach you how to make molecules. This is after all what most chemists do, for whatever reason.
Small amounts of many drugs can be isolated from plants or marine animals; much greater quantities are made by chemists in laboratories.
A limited range of dyes can be extracted from plants; many more vivid and permanent ones are made by chemists in the laboratory.
Synthetic polymers, created by chemists, have replaced more expensive and less durable alternatives like rubber
Most of the improvements in the quality of life over the last 50 to 100 years can be traced to new molecules created by chemists.
But, faced with the challenge of making a new compound, how do chemists go about deciding how to make it?
Synthetic planning starts with the product, which is fixed and unchangeable, and works backwards towards the starting materials. This
process is called retrosynthesis, and the art of planning the synthesis of a target molecule is called RETROSYNTHETIC ANALYSIS
Most of the chemistry you have learned so far has concentrated on reactions. questions like ‘What do you need to
add to X to get Y?’) or on products (questions like ‘What will happen if X and Y react together?’).
X+Y products
Now we’re looking at starting materials (questions like ‘What X and Y do you need to react together to make Z?’)
We’re looking at reactions in reverse, and we have a special symbol for a reverse
reaction called a retrosynthetic arrow (the ‘implies’ arrow from a
retrosynthetic arrow logic).
A scheme with a retrosynthetic arrow
(margin) means
‘Z could be made from X plus Y’
Here’s a very simple first example. This compound is used as an insect repellent. As it’s an ester, we know that it can be made from
alcohol plus acyl chloride, and we can represent this using a retrosynthetic arrow
The aromatic amide amelfolide is a cardiac antiarrhythmic agent. Because we see that it is an amide, we know that it can be made
quite simply from p-nitrobenzoyl chloride and 2,6-dimethylaniline—again, we can represent this using a retrosynthetic arrow.
Mentally breaking a molecule into its component parts like this is known as disconnection, and it’s helpful to indicate the site of the
disconnection with a wiggly line as we have here.
The chemists who first made amelfolide chose to make it from an amine and an acyl chloride because they knew that this reaction,
a standard way of making an amide, had a very good chance of success. They chose to disconnect the C–N bond because this
disconnection corresponds to a reliable reaction in a way that no other possible disconnection of this molecule does.
Disconnections should correspond to known reliable reactions
daminozide is again an amide, so the best disconnection is the C–N bond, which could take us back to acyl chloride and
dimethylhydrazine. This time we’ve written ‘C–N amide’ above the retrosynthetic arrow as a reminder of why we’ve
made the disconnection and we advise you to follow this practice
Synthons: Idealized reagents
Paracetamol, for example, is an amide that can be disconnected either to amine + acyl chloride
or to amine + anhydride
Paracetamol is made from para-aminophenol and acetic anhydride largely because the byproduct, acetic acid, is
easier to handle than HCl.
In a retrosynthetic analysis, we don’t really want to be bothered by this sort of decision, which is best made later, so it’s
useful to have a single way of representing the key attributes of alternative reagents.
We can depict both anhydride and acyl chloride in this scheme as an ‘idealized reagent’—an electrophilic acetyl group
MeCO+ . We call such idealized reagents synthons.
Synthons are fragments of molecules with an associated polarity (represented by a ‘ + ‘ or ‘–’) which
stand for the reagents we are going to use in the forward synthesis. They are not themselves reagents,
although they may occasionally turn out to be intermediates along the reaction pathway.
By disconnecting bonds to synthons rather than to actual reagents we can indicate the polarity of the bond-forming
reaction we are going to use without having to specify details of the reagents
Once the retrosynthetic analysis is done, we can go back and use our knowledge of chemistry to think of reagents
corresponding to these synthons. Here, for example, we should certainly choose the anion of the phenol as the nucleophile
and some functionalized acetic acid molecule with a leaving group in the α position.
We can then write out a suggested synthesis in full from start to finish.
Guidelines for Choosing a disconnection
The hardest task in designing a retrosynthetic analysis is spotting where to make the disconnections. We shall offer some
guidelines to help you, but the best way to learn is through experience and practice. The overall aim of retrosynthetic
analysis is to get back to starting materials that are available from chemical suppliers, and to do this as efficiently as
possible
Guideline 1: Disconnections must correspond to known, reliable reactions
When we disconnected the ether 2,4-D we chose to disconnect next to the oxygen atom because we know about the
synthesis of ethers.
We chose not to disconnect on the aryl side of the oxygen atom because we know of no reliable reaction
corresponding to nucleophilic attack of an alcohol on an unactivated aromatic ring.
Guideline 2 For compounds consisting of two parts joined by a heteroatom, disconnect next to the heteroatom. In all the
retrosynthetic analyses you’ve seen so far there is a heteroatom (N or O) joining the rest of the molecule together, and in
each case we made the disconnection next to that N or O. This guideline works for esters, amides, ethers, amines, acetals,
sulfi des, and so on because these compounds are often made by a substitution reaction.
Guideline 3: Disconnect reactive groups first.
• Retrosynthetic analysis - the process of breaking down a target molecule into readily available starting materials
by means of imaginary breaking of bonds and by the conversion of one functional group into another by efficient
chemical reaction. The readily available starting materials are used for the synthesis of the target molecule.
