Retrosynthetic
analysis
Retrosynthetic analysis is a technique for
solving problems in the planning of
organic syntheses. This is achieved by
transforming a target molecule into
simpler precursor structures without
assumptions regarding starting materials.
Each precursor material is examined using
the same method. This procedure is
repeated until simple or commercially
available structures are reached. E.J.
Corey formalized this concept in his book
The Logic of Chemical Synthesis.[1][2][3]
The power of retrosynthetic analysis
becomes evident in the design of a
synthesis. The goal of retrosynthetic
analysis is structural simplification. Often,
a synthesis will have more than one
possible synthetic route. Retrosynthesis is
well suited for discovering different
synthetic routes and comparing them in a
logical and straightfoward fashion.[4] A
database may be consulted at each stage
of the analysis, to determine whether a
component already exists in the literature.
In that case, no further exploration of that
compound would be required.
Definitions
Disconnection
A retrosynthetic step involving the
breaking of a bond to form two (or
more) synthons.
Retron
A minimal molecular substructure that
enables certain transformations.
Retrosynthetic tree
A directed acyclic graph of several (or
all) possible retrosyntheses of a single
target.
Synthon
An idealized molecular fragment. A
synthon and the corresponding
commercially available synthetic
equivalent are shown below:
Target
The desired final compound.
Transform
The reverse of a synthetic reaction; the
formation of starting materials from a
single product.
Example
An example will allow the concept of
retrosynthetic analysis to be easily
understood.
In planning the synthesis of phenylacetic
acid, two synthons are identified. A
nucleophilic "-COOH" group, and an
electrophilic "PhCH2+" group. Of course,
both synthons do not exist per se;
synthetic equivalents corresponding to the
synthons are reacted to produce the
desired product. In this case, the cyanide
anion is the synthetic equivalent for the
−COOH synthon, while benzyl bromide is
the synthetic equivalent for the benzyl
synthon.
The synthesis of phenylacetic acid
determined by retrosynthetic analysis is
thus:
PhCH2Br + NaCN → PhCH2CN + NaBr
PhCH2CN + 2 H2O → PhCH2COOH +
NH3
In fact, phenylacetic acid has been
synthesized from benzyl cyanide,[5] itself
prepared by the analogous reaction of
benzyl chloride with sodium cyanide.[6]
Strategies
Functional group strategies
Manipulation of functional groups can
lead to significant reductions in molecular
complexity.
Stereochemical strategies
Numerous chemical targets have distinct
stereochemical demands. Stereochemical
transformations (such as the Claisen
rearrangement and Mitsunobu reaction)
can remove or transfer the desired chirality
thus simplifying the target.
Structure-goal strategies
Directing a synthesis toward a desirable
intermediate can greatly narrow the focus
of an analysis. This allows bidirectional
search techniques.
Transform-based strategies
The application of transformations to
retrosynthetic analysis can lead to
powerful reductions in molecular
complexity. Unfortunately, powerful
transform-based retrons are rarely present
in complex molecules, and additional
synthetic steps are often needed to
establish their presence.
Topological strategies
The identification one or more key bond
disconnections may lead to the
identification of key substructures or
difficult to identify rearrangement
transformations in order to identify the key
structures .
Disconnections that preserve ring
structures are encouraged.
Disconnections that create rings larger
than 7 members are discouraged.
See also
Organic synthesis
Total synthesis
References
1. E. J. Corey, X-M. Cheng (1995). The Logic
of Chemical Synthesis. New York: Wiley.
ISBN 0-471-11594-0.
2. E. J. Corey (1988). "Retrosynthetic
Thinking - Essentials and Examples". Chem.
Soc. Rev. 17: 111–133.
doi:10.1039/CS9881700111 .
3. E. J. Corey (1991). "The Logic of
Chemical Synthesis: Multistep Synthesis of
Complex Carbogenic Molecules (Nobel
Lecture)" (Reprint). Angewandte Chemie
International Edition in English. 30 (5): 455–
465. doi:10.1002/anie.199104553 .
4. James Law et.al:"Route Designer: A
Retrosynthetic Analysis Tool Utilizing
Automated Retrosynthetic Rule Generation",
Journal of Chemical Information and
Modelling (ACS JCIM) Publication Date
(Web): February 6, 2009;
doi:10.1021/ci800228y ,
http://pubs.acs.org/doi/abs/10.1021/ci800
228y
5. Wilhelm Wenner (1963).
"Phenylacetamide" . Organic Syntheses.;
Collective Volume, 4, p. 760
6. Roger Adams; A. F. Thal (1941). "Benzyl
Cyanide" . Organic Syntheses.; Collective
Volume, 1, p. 107
External links
Wikiquote has quotations related to:
Retrosynthetic analysis
Centre for Molecular and Biomolecular
Informatics
Presentation on ARChem Route
Designer, ACS, Philadelphia, September
2008 for more info on ARChem see the
SimBioSys pages.
Retrosynthesis planning tool: ICSynth by
InfoChem
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