Combinatorial and parallel synthesis have become

established tools in drug discovery and drug

development, allowing the use of a defi ned
reaction route to produce a large number of
compounds in a short period of time. Th e full set
of compounds produced in this way is called a
compound library
Reactions are usually carried out on small scale
and the process can be automated or semi-
automated, allowing reactions to be carried out
in several reaction vessels at the same time and
under identical conditions, but using different
reagents for each vessel. Research groups can
rapidly synthesize and screen thousands of
structures in orderto find new lead compounds
In the past, medicinal chemistry involved the identifi
cation of a lead compound having a useful activity
which was then modified to develop a clinically
useful drug. Identification of the molecular target for
the drug, and the mechanism by which it worked,
oft en took many years to establish. Today, most
medicinal chemistry projects start with an identifi
able target, and the emphasis is on discovering a
lead compound that will interact with this target.
Pharmaceutical companies were faced with the
problem of identifying the function of each target
and finding a lead compound to interact with it.
Before the advent of combinatorial chemistry and
parallel synthesis, the need to fi nd a lead
compound was becoming the limiting factor in
the whole process.
Now, with the aid of these techniques, research
groups can rapidly synthesize and screen
thousands of structures in order to find new lead
compounds, identify structure–activity relationships,
and find analogues with good activity and minimal
side effects
The procedures used in combinatorial synthesis
are designed to produce mixtures of different
compounds within each reaction vessel, whereas
those used in parallel synthesis produce a single
product in each vessel. In general, parallel
synthesis is favoured because it is easier to
identify the structures that are synthesized.
However, there is still scope for combinatorial
chemistry in finding lead compounds,
especially as this procedure can generate
significantly more structures in a set period of
time, thus increasing the chances of finding a
lead compound. Both methods generally
involve the use of solid phase techniques.
Solid phase techniques

Solid phase techniques can be used to carry out

reactions where the starting material is linked to a
solid support, such as a resin bead. Several
reactions can then be carried out in sequence on
the attached molecule. Th e final structure is then
detached from the solid support. There are
several advantages to this.
since the starting material, intermediates, and fi nal
product are bound to a solid support, excess
reagents or unbound by-products from each
reaction can be easily removed by washing the
resin;
• large excesses of reagents can be used to drive
the reactions to completion (greater than 99%)
because of the ease with which excess reagent can
be removed;
• intermediates in a reaction sequence are
bound to the bead and do not need to be
purified;
• the polymeric support can be regenerated
and reused if appropriate cleavage conditions
and suitable anchor/ linker groups are chosen
• automation is possible
• Beads can be mixed together such that all the
starting materials are treated withanother
reagent in a single experiment
• Mixing all starting materials together in solution
chemistry is a recipe for disaster, with
polymerizations and side reactions producing a
tarry mess
• Individual beads can be separated at the end of the
experiment to give individual products
The essential requirements for solid phase
synthesis are
• a cross-linked insoluble polymeric support which is
inert to the synthetic conditions (e.g. a resin bead);
• an anchor or linker covalently linked to the resin—
the anchor has a reactive functional group that can
be used to attach a substrate
• a bond linking the substrate to the linker, which
will be stable to the reaction conditions used in
the synthesis;
• a means of cleaving the product or the
intermediates from the linker;
• protecting groups for functional groups not
involved in the synthetic route.
The solid support

The first successful example of solid phase

synthesis was the Merrifield resin peptide synthesis.
Th e resin involved consisted of polystyrene beads
where the styrene is partially cross-linked with 1%
divinylbenzene. The beads are derivatized with a
chloromethyl group (the anchor/ linker) to which
amino acids can be coupled via an ester group
Th is ester group is stable to the reaction
conditions used in peptide synthesis, but can be
cleaved at the end of the synthesis using
vigorous acidic conditions
One disadvantage of polystyrene beads-
hydrophobic
• growing peptide chain is hydrophilic
• peptide chain is not solvated and oft en folds in
on itself to form internal hydrogenbonds
• It hinders access of further amino acids to the
exposed end of the growing chain
• More polar solid phases were developed, such
as Sheppard's polyamide resin

• Tentagel resin is 80% polyethylene glycol

grafted to cross-linked polystyrene
• Regardless of the polymer that is used, the bead
should be capable of swelling insolvent while
remaining stable
Regardless of the polymer that is used, the bead
should be capable of swelling in solvent while
remaining stable. Swelling is important because most
of the reactions involved in solid phase synthesis
take place in the interior of the bead rather than on
the surface. It is wrong to think of resin beads as
being like miniature marbles with an impenetrable
surface.
Each bead is a polymer and swelling involves
unfolding of the polymer chains such that solvent
and reagents can move between the chains into
the heart of the polymer
• Molecular unit covalently attached to the polymer
chain making up the solid support
• It contains a reactive functional group with which
the starting material in the proposed synthesis can
react
• Resulting link must be stable to the reaction
conditions
• Easily cleaved to release the final compound once
the synthesis is complete
• Different linkers are used depending on
• the functional group which will be present on the
starting material;
• the functional group which is desired on the final
product once it is released
Resins having different linkers are given diff erent
names . For example, the Wang resin has a linker
which is suitable for the attachment and release of
carboxylic acids. It can be used in peptide synthesis
by linking an N -protected amino acid to the resin by
means of an ester link.
This ester link remains stable to coupling and de-
protection steps in the peptide synthesis, and can
then be cleaved using trifluoroacetic acid (TFA) to
release the final peptide from the bead
Solution Phase synthesis
• Reaction is carried out in a series of wells such that
each well contains a single product
• Method is a ‘quality rather than quantity’ approach
and is oft en used for focusedlead optimization studies
• Necessary to remove or simplify the bottlenecks
associated with classical organic synthesis
• Include laborious work-ups, extractions, solvent
evaporations, and purifications
Solution phase organic synthesis ( SPOS )
• Considering the synthesis of an amide, which
typically involves the reaction of acarboxylic acid
with an amine in the presence of a coupling reagent
such as dicyclohexylcarbodiimide (DCC)
• Work-up procedure involves washing the
organic solution with aqueous acid in orderto
remove unreacted amine
• Once the aqueous and organic layers have
been separated,
• Organic layer is washed with an aqueous base
in order to remove unreacted acid
• Organic layer is treated with a drying agent
such as magnesium sulphate
• Drying agent is filtered off and then the solvent
is removed to afford the crude amide
• Purification then has to be carried out by
crystallization or chromatography
• One would have to repeat all of these steps and
this would prove both time consuming and
equipment intensive
• Possible to house a mini-parallel synthesis
laboratory in a fume cupboard for each
chemist
Parallel synthesis
With parallel synthesis, that same researcher can
synthesize a dozen or more pure molecules.
Equipment miniaturization for parallel synthesis means
that it is possible to house a mini-parallel synthesis
laboratory in a fume cupboard for each chemist .
Small footprint work stations often enable one to
perform up to 24 reactions followed by 24
simultaneous evaporations on a normal heater
stirrer unit. Multiple parallel or sequential
automated chromatography units can facilitate
purification, and microwave reactors can
dramatically speed up reaction times. In this way,
all 12 amides in our library can be made at the
same time in parallel.
A variety of useful techniques can also be used to
minimize the work-up procedures as described in
the next sections