Retrosynthetic analysis

Retrosynthetically or retrosynthetic analysis is a technique when scheduling a chemical synthesis of complex organic molecules. Here, the molecule is notionally split into simpler building blocks, known synthesis examples of their link. In this way one arrives gradually commercially available or known in the literature blocks. This leads to a schema, which is branched like a tree downwards. EJ Corey has introduced this formalism and was honored course of this work in 1990 with the Nobel Prize for Chemistry. The thickness of the retrosynthesis shows up when a new synthesis route should be designed. The goal is to simplify the structure required and on. Several possible routes which make up the synthesis tree as a whole resulting in the rule. The task of the chemist, it is now select the ideal path, but this has to be the Shortest not always.

Definitions

For these formal sections Corey has developed a simple block model, which can provide the retro synthetic scheme even with a computer program ( LHASA ) using a reaction database. To this end, several possible reaction steps were abstracted and formulated in the following definitions.

  • Disconnections: A retro synthetic step which means the breaking of one or more bonds to several synthons
  • Retron: The starting molecule at the lower end of the retrosynthetic tree
  • Retrosynthetic tree: retrosynthesis tree
  • Synthon: See separate article Synthon
  • Target: The target molecule
  • Transform: The reverse step as during the actual synthesis operation, which may also be steps that enable a functional group involved (functional group transformation )

Example

In the simple example of phenylacetic acid, the concept of retro synthesis can be illustrated:

In planning the synthesis of two synthons can be detected. The one synthon is the carboxy group -COOH as a nucleophilic synthon. As a complementary electrophilic synthon can see the PhCH2 group, ie the benzylic recognize. Both synthons are not stable as a connection. These synthetic equivalents now be sought. One equivalent of the -COOH is the cyanide anion and the other for the benzylic bromide, benzyl bromide were. Is indicative of a synthetic equivalent that it reflects the properties of the electronic synthon, so should have its reactivity, and that the molecule obtained by chemical linkage of the synthons later by manipulation of the functional group (here, the nitrile group ) in the target, that is phenylacetic acid can be converted. The conversion would be, in this example by acidic or basic hydrolysis possible:

Alternatively, the retrosynthetic analysis for the preparation of phenylacetic acid could also be two other Syntons result, the PhCH2 - group and COOH . These two synthons are not stable as a connection. Therefore synthetic equivalents now be sought. One equivalent for PhCH2 - group benzylmagnesium ( PhCH2MgBr ) with the negatively polarized benzylic carbon atom, the synthetic equivalent of COOH carbon dioxide, CO2:

By linking these two synthons PhCH2CO2MgBr would result, its hydrolysis then provides the target molecule of phenylacetic acid.

Strategies

  • Functional - group strategy changes the functional group results in a reduction of the complexity of the molecule.
  • Stereochemical strategy: Many targets are stereochemically complex molecules. Stereochemical transformations can be transferred, or modified by stereospecific reactions. Examples include the Diels -Alder reaction, the Claisen rearrangement, or the Mitsunobu reaction. Consequently, the target will be stereochemically simplified.
  • Structure - goal strategy: This strategy bidirectional approaches the target molecule from both sides, ie from the retro synthetic as well as of the synthetic side to a common intermediate. This strategy allows the selection or finding a suitable synthetic route simplify.
  • Transformation Strategy: The transformations can reduce the complexity of a molecule significantly. Unfortunately, good Retrone are rare and this may mean that you have to allow additional synthesis steps that enable retron this.
  • Topological Strategy: The finding of one or more strategic cuts can lead to a key intermediate in which a rearrangement transformation of the framework easily can be seen. This is usually considered that ring structures are formed preferentially and that ring sizes with more than seven atoms are no longer preferred.

LHASA

The development of LHASA ( Logic and Heuristic Applied to Synthesis Analysis) is currently operated by three working groups. LHASA calculated synthesis trees exclusively on retro -synthetic basis. It currently has a database of 2,000 transformations. Are assessed on the transformations developed by Corey synthesis strategies.

  • Intermediate step - Transform ( ' subgoal transform '): LHASA limited only to the conversion of functional groups.
  • Strategic Transform ( 'Goal Transform '): tries to LHASA as the destination of each retrosynthetic step retron a strategic Transforms. This leads to a simplification of the synthesis of the target and usually represents a fraction of one or more bonds.
  • Tactical Combination ( ' Tactical Combination '): There is a fixed order of strategic transformations or intermediate step transformations are to simplify the synthetic target.
  • Far-reaching Transform ( ' Long-range Trans- form '): With this strategy, LHASA attempts to provide complex transformations apply which should lead to a maximum simplification of Syntheseintermediates.
Diels–Alder reaction Digital Object Identifier Total synthesis
679676
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