Retrosynthetic analysis will only lead to useful results if it is
directed towards some goal. The basic goal is to generate precursors
that correspond to available starting materials. However, this goal
can be used as a guiding principle only when possible starting
materials can be identified from the target structure.
In general, obvious starting points cannot be found when it comes to
complex target structures (and that is where RA is most useful).
The basic goal, then, becomes the generation of precursors that are
easier to synthesize than the original target; such precursors are
likely to be closer to available compounds than the original target.
Stated differently, retrosynthetic analysis is directed towards
molecular simplification. Corey has formulated five main types
of strategies that lead to the desired simplification.
These will be treated briefly, each illustrated by a sample analysis:
- Functional-group based strategies
in the target structure may direct the transform search in several ways:
The reconnective strategy is constrained by strategic rules.
Clearly, it is not practical to attempt every possible reconnection.
- Removal of reactive and masked functionality
- Disconnection based on the location of functional groups
- Reconnection of functional groups to form rings retrosynthetically
- Topological strategies
The disconnection of specific,
so-called `strategic' bonds can lead to major molecular simplification.
There are several types of strategic bonds:
Heuristics (empirical rules) have been devised to select
these types of bonds from any target structure.
It is also possible to identify rings which should
be disassembled early in the retrosynthetic process,
or rings which should be kept intact during these stages.
- Bonds in (poly)cyclic ring systems
- Bonds in (poly)fused ring systems
- Pairs of bonds in ring systems
(disconnection by intramolecular cycloaddition transforms)
- Bonds connecting chains to rings
- Bonds connecting chains to other chains
- Bonds connecting chains to functional groups
- Transform-based strategies
A very useful
guidance for retrosynthetic analysis can be provided by
the application of a
powerfully simplifying transform -- corresponding
to a reaction effecting a considerable increase in complexity.
Very often such an application is suggested
by the presence of (functionalized) rings of specific sizes
in the target molecule.
Some powerfully simplifying transforms are:
- Hetero Diels-Alder
- Robinson annulation
- Birch reduction
- Internal ene reaction
- Structure-goal strategies
The analysis can also be directed
towards a particular (sub)structure. Such a (sub)structure can be a:
An analysis directed towards such a structure-goal does not need to be
purely retrosynthetic. It can even be synthetic, but
probably the most efficient search would be a bidirectional one.
- Starting material
- Chiral building block
- Retron-containing structure
- Stereochemical strategies
Here the focus is on removal of stereocenters under stereocontrol.
Stereocontrol can be achieved through either mechanistic
control or substrate control.
Reconnections that move stereocenters from chains
(where they are difficult to introduce)
into rings (where introduction is usually much easier)
can also be considered stereochemically strategic.
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Page author: Martin Ott
Last update: Wednesday, 1 September 2004