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Retrosynthetic analysis is a technique for solving problems in the planning of
organic syntheses ''Organic Syntheses'' is a peer-reviewed scientific journal that was established in 1921. It publishes detailed and checked procedures for the synthesis of organic compounds. A unique feature of the review process is that all of the data and exp ...
. This is achieved by transforming a target molecule into simpler precursor structures regardless of any potential reactivity/interaction with reagents. Each precursor material is examined using the same method. This procedure is repeated until simple or commercially available structures are reached. These simpler/commercially available compounds can be used to form a synthesis of the target molecule. E.J. Corey formalized this concept in his book ''The Logic of Chemical Synthesis''. The power of retrosynthetic analysis becomes evident in the design of a synthesis. The goal of retrosynthetic analysis is a 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 straightforward fashion. 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. If that compound exists, it can be a jumping point for further steps developed to reach a synthesis.


Definitions

;Disconnection: A retrosynthetic step involving the breaking of a bond to form two (or more)
synthon In retrosynthetic analysis, a synthon is a hypothetical unit within a target molecule that represents a potential starting reagent in the retroactive synthesis of that target molecule. The term was coined in 1967 by E. J. Corey. He noted in 1 ...
s. ;Retron: A minimal molecular substructure that enables certain transformations. ;Retrosynthetic tree: A
directed acyclic graph In mathematics, particularly graph theory, and computer science, a directed acyclic graph (DAG) is a directed graph with no directed cycles. That is, it consists of vertices and edges (also called ''arcs''), with each edge directed from one ...
of several (or all) possible retrosyntheses of a single target. ;Synthon: A fragment of a compound that assists in the formation of a synthesis, derived from that target molecule. 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 Phenylacetic acid (PAA; conjugate base phenylacetate), also known by various synonyms, is an organic compound containing a phenyl functional group and a carboxylic acid functional group. It is a white solid with a strong honey-like odor. Endogen ...
, 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 Cyanide is a naturally occurring, rapidly acting, toxic chemical that can exist in many different forms. In chemistry, a cyanide () is a chemical compound that contains a functional group. This group, known as the cyano group, consists of ...
is the synthetic equivalent for the COOH synthon, while
benzyl bromide Benzyl bromide is an organic compound with the formula . The molecule consists of a benzene ring substituted with a bromomethyl group. It is a colorless liquid with lachrymatory properties. The compound is a reagent for introducing benzyl groups ...
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, itself prepared by the analogous reaction of
benzyl bromide Benzyl bromide is an organic compound with the formula . The molecule consists of a benzene ring substituted with a bromomethyl group. It is a colorless liquid with lachrymatory properties. The compound is a reagent for introducing benzyl groups ...
with
sodium cyanide Sodium cyanide is a poisonous compound with the formula Na C N. It is a white, water-soluble solid. Cyanide has a high affinity for metals, which leads to the high toxicity of this salt. Its main application, in gold mining, also exploits its hi ...
.


Strategies


Functional group strategies

Manipulation of
functional group In organic chemistry, a functional group is a substituent or moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions regardless of the r ...
s 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 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 of 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. *Disconnection involves creativity.


See also

*
Organic synthesis Organic synthesis is a special branch of chemical synthesis and is concerned with the intentional construction of organic compounds. Organic molecules are often more complex than inorganic compounds, and their synthesis has developed into one o ...
* Total synthesis


References


External links


Centre for Molecular and Biomolecular Informatics

Presentation on ARChem Route Designer, ACS, Philadelphia, September 2008
for more info on ARChem see the SimBioSys pages.
Manifold, Software freely available for academic users developed by PostEra

Retrosynthesis planning tool: ICSynth by InfoChem

Spaya, Software freely available proposed by Iktos
{{Branches of chemistry Chemical synthesis Organic chemistry Chemical reaction engineering