Multistep synthesis

Concepts in multistep synthesis - strategies

for retrosynthetic analysis, synthon and
planning - functional group introduction -
removal and interconversion -
retrosynthetic analysis - disconnections –
synthons -a,d synthons
References
1. Organic Chemistry, Claiden, Greeves, Warren and Wothers
2. F.A.Carey and R.J. Sundberg, Advanced Organic Chemistry, Part A and Part B, 5th edition, Springer, New York (2007).
3. Advanced Organic chemistry, Jerry March
4. William Carruthers and Iain Coldham, Modern Methods of Organic Synthesis, 3rd edition, Cambridge University
Press (2005 reprinted).
5. Principles of organic synthesis, R.O.C.Norman and J.M.Coxon, CRC Press,Special Indian Edition, first Indian Edition
2009
Reactions studied so far( Egs…) provide tools for synthesizing new and complex
molecules.

A strategy for using these tools is essential to successful synthesis of molecules by

multistep synthetic sequences.

The sequence of individual reactions must be planned so that they are mutually
compatible.

Certain functional groups can interfere with prospective reactions, and such
problems must be avoided either by modification of the sequence or by
temporarily masking (protecting) the interfering group.Protective groups are used
to temporarily modify functionality, which is then restored when the protecting
group is removed.

Another approach is to use synthetic equivalent groups in which a particular

functionality is introduced as an alternative structure that can subsequently be
converted to the desired group.

Control of stereochemistry ; C-C & C = C forming reactions

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The chemists who plan to make a molecule (eg ….) can chose any route—any starting
materials and any sequence of reactions. All that matters is the final product—what
we will call the target molecule.

Synthetic planning starts with the product, which is fixed and unchangeable,
and works backwards towards the starting materials. This process is called
retrosynthesis,andthe art of planning the synthesis of a target molecule is
calledretrosynthetic analysis.

The aim of this chapter is to introduce you to the principles of retrosynthetic analysis:

once you have read and understood it you will be well on the way to designing your
own organic syntheses.

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Retrosynthetic analysis: synthesis backwards
 Most of the chemistry 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?’).

 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 logic).

 A scheme with a retrosynthetic arrow means ‘Z could be made

from X plus Y’.

 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.
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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

Disconnections must correspond to known, reliable reactions The

chemists who first made amelfolide chose to make it from an amine and an acyl
chloride because they knew that this reaction, the 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
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reliable reaction in a way that no other possible disconnection of this molecule does.
Now that you’ve seen the principle of retrosynthetic analysis at work, you should be
able to suggest a reasonable disconnection of this compound, which is known as
daminozide.

You probably spotted immediately that 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.

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Now, in fact, there is a problem with this acyl chloride—it would be unstable as it can
cyclize to an anhydride.

But this poses no problem for the synthesis of daminozide—we could just use the
anhydride instead, since the reaction should be just as reliable.

A better retrosynthesis therefore gives the anhydride and indeed this is how
daminozide is made

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In some cases, there are several alternative reagents all corresponding to the same
disconnection.

Paracetamol, for example, is an amide that can be disconnected either to amine + acyl
chloride or to amine + anhydride.

Which reagent is best can often only be determined by experimentation—

commercially, paracetamol is made from para-aminophenol and acetic anhydride
largely because the by-product, acetic acid, is easier to handle than HCl.

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 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+ , called 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.
Synthons
 They are not themselves reagents, though they may are
occasionally turn out to be intermediates along the
reaction pathway.
idealized
reagents
 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.
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Synthesis of the herbicide 2,4-D (2,4-dichlorophenoxyacetic acid).

The most reasonable disconnection of an ether is the C–O bond because we know that
ethers can be made from alkyl halides by substitution with an alkoxide anion.

We don’t at this stage need to decide exactly which alkyl halide or alkoxide to use, so
we just write the synthons.

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Once the retrosynthetic analysis is done, choose the 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.

Then write out a suggested synthesis in full from start to finish

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Choosing a disconnection
The hardest task in designing a retrosynthetic analysis is spotting where to make the
disconnections.

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
The ether 2,4-D should be disconnected 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.

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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, sulfides, and so on,
because these compounds are often made by a substitution reaction.

Chlorbenside is used to kill ticks and mites. Using the above Guideline we can suggest
a disconnection next to the sulfur atom; using the Guideline shown in the previous
page, we know that we must disconnect on the alkyl and not on the aryl side.

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We can now suggest reagents corresponding to the synthons, and propose a synthetic
scheme.

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Ethyl ester of, and precursor to, cetaben, a drug that can be used to lower blood lipid
levels. It is an amine, so we disconnect next to the nitrogen atom.

The alkyl bromide is available but we shall need to make the aromatic amino-ester and
the best disconnection for an ester is the C–O bond between the carbonyl group and
the esterifying group.

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We have now designed a two-step synthesis of our target molecule, and this is how
it was carried out

Guideline 3: Consider alternative disconnections and choose routes that avoid

chemoselectivity problems — often this means disconnecting reactive groups first

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Retrosynthetic analysis of an intermediate in the synthesis of the potential anti-obesity
drug ICI-D7114

With two ethers and an amine functional group, it requires several disconnections totake
it back to simple compounds

Which do we do first?

One way to solve the problem is to write down all the possibilities and see which looks
best. Here there are four reasonable disconnections: one at each of the ether groups (a
and b) or on either side of the amine (c and d).
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Both (a) and (b) pose problems of chemoselectivity as it would be hard to alkylate the
phenol in the presence of the basic nitrogen atom.

Between (c ) and (d ), (c ) appears to be the better choice because the next

disconnection after (d ) will have to be an alkylation of O in the presence of an NH 2
group.

To avoid chemoselectivity problems like this, we want to try and introduce reactive
groups late in the synthesis .

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The next retrosynthetic step for the ICI-D7114 intermediate. Disconnection (c ) gave us
a compound with two ethers that might be disconnected further by disconnection (e )
or (f ).

Disconnection (e ) requires alkylation of a compound that is itself an alkylating agent.

Disconnection (f ) is much more satisfactory, and leads to a compound that is easily
disconnected to 4-hydroxyphenol (para -cresol) and 1,2-dibromethane.

Using Guideline 3, we can say that it’s best to disconnect the bromoethyl group (f )
before the benzyl group because the bromoethyl group is more reactive and more
likely to cause problems of chemoselectivity.

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Functional group interconversion We have to construct
an amine in the
presence of an
acyl chloride!

constructing the
amide in the
presence of the
resulting
NH2group Chemoselectivity problems

The antihypertensive drug ofominecontains an amide and an amine functional group,

and we need to decide which to disconnect first.

However, we shall want to make the acyl chloride from the carboxylic acid, which can
then easily be disconnected to 2-aminobenzoic acid (anthranilic acid) and 4-
chloropyridine.

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The retrosynthetic transformation of an acyl chloride to a carboxylic acid is not really a
disconnection because nothing is being disconnected.

Instead it is a functional group interconversion, or FGI , as written above the

retrosynthetic arrow.

FGIs often aid disconnections because the sort of reactive functional groups (acyl
chlorides, alkyl halides) we want in starting materials are not desirable in compounds
to be disconnected because they pose chemoselectivity problems.

They are also useful if the target molecule contains functional groups that are not
easily disconnected 26
By using an appropriate reagent or series of reagents, almost any functional
group can be converted into any other

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Amine synthesis using functional group interconversions
The synthesis of amines poses a special problem because only in certain cases is the obvious
disconnection successful

The product is usually more reactive than the starting material and there is a
danger that multiple alkylation will take place.

Exception: Cetaben ethyl ester - further alkylation is made unfavourable by the increased
steric hindrance that would result.

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What are the alternatives? There are two main ones, and both involve functional group
interconversion, with the reactive amine being converted to a less reactive derivative before
disconnection.

The first solution is to convert the amine to an amide and then disconnect that. The
reduction of amide to amine is quite reliable, so the FGI is a reasonable one.Eg.

C-N amide

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The second alternative is to convert to an imine, which can be disconnected to amine
plus carbonyl compound. This approach is known as reductive amination

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Ocfentanil is an opioid painkiller that lacks the addictive properties of morphine.

Disconnection of the amide gives a secondary amine that we can convert to an imine
for disconnection to a ketone plus 2-fluoro aniline.

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 The synthesis is straightforward: a reductive amination followed by acylation of the only
remaining NH group. The tertiary amine in the left-hand ring interferes with neither of these
reactions.

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Donor and acceptor synthons
You’ve now met a variety of synthons and it’s useful to be able to classify them as
donor or acceptor synthons. We call a negatively polarized synthon a donor synthon
and give it the symbol ‘d’.

Positively polarized synthons - acceptor synthons and are given the symbol ‘a’.

The first synthon in the diagram below, which corresponds to an aldehyde, we call an
a1 synthon, because it is an acceptor that carries a functional group on the same
carbon as its reactive centre.

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The second is a d2 synthon because it is a donor whose reacting site is in the 2-
position relative to the carbonyl group.

Earlier you met two other types of synthon, corresponding to epoxide and Michael
acceptor, and we can now classify these as a2 and a3 synthons.

This terminology is useful because it reduces synthons to the bare essentials: what
polarity they are and where the polarity is sited.

The actual functional group they carry is, as you now appreciate, less important
because FGI will usually allow us to turn one FG into another
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Introduction/removal of functional groups

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