Centre for Molecular and Biomolecular Informatics Radboud University Nijmegen

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

Functional groups in the target structure may direct the transform search in several ways:

• Removal of reactive and masked functionality
• Disconnection based on the location of functional groups
• Reconnection of functional groups to form rings retrosynthetically

The reconnective strategy is constrained by strategic rules. Clearly, it is not practical to attempt every possible reconnection.

Topological strategies

The disconnection of specific, so-called `strategic' bonds can lead to major molecular simplification. There are several types of strategic bonds:

• 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

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.

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:

• Diels-Alder
• Hetero Diels-Alder
• Robinson annulation
• Birch reduction
• Internal ene reaction
• Halolactonization

Structure-goal strategies

The analysis can also be directed towards a particular (sub)structure. Such a (sub)structure can be a:

• Starting material
• Chiral building block
• Retron-containing structure

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.

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.

Other topics:

• Analysis of Complex Synthetic Problems
• Terminology
• Retrosynthetic Strategies
• Goals and Subgoals
• Computer-Assisted Retrosynthetic Analysis

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