Retrosynthetic analysis

<h2 id="definitions">Definitions</h2>
Disconnection
A retrosynthetic step involving the breaking of a bond to form two (or more) <a href="/facts/Synthon/ILGlTRt1">synthons</a>.
Retron
A minimal molecular substructure that enables certain transformations.
Retrosynthetic tree
A <a href="/facts/Directed_acyclic_graph/k6zq1os9">directed acyclic graph</a> 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.
<h2 id="example">Example</h2>
<p>Shown below is a retrosynthetic analysis of <a href="/facts/Phenylacetic_acid/cjfwIEs2">phenylacetic acid</a>:
</p><p>In planning the synthesis, two synthons are identified. A nucleophilic "-COOH" group, and an electrophilic "PhCH2+" group. Both synthons do not exist as written; synthetic equivalents corresponding to the synthons are reacted to produce the desired product. In this case, the <a href="/facts/Cyanide_anion/t0o8FMKI">cyanide anion</a> is the synthetic equivalent for the −COOH synthon, while <a href="/facts/Benzyl_bromide/o46vSJu3">benzyl bromide</a> is the synthetic equivalent for the benzyl synthon.
</p><p>The synthesis of phenylacetic acid determined by retrosynthetic analysis is thus:
</p>
PhCH2Br + NaCN → PhCH2CN + NaBr
PhCH2CN + 2 H2O → PhCH2COOH + NH3

<p>In fact, phenylacetic acid has been synthesized from <a href="/facts/Benzyl_cyanide/PY6qMHBa">benzyl cyanide</a>,<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> itself prepared by the analogous reaction of <a href="/facts/Benzyl_bromide/o46vSJu3">benzyl bromide</a> with <a href="/facts/Sodium_cyanide/CQfl206o">sodium cyanide</a>.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a>
</p>
<h2 id="strategies">Strategies</h2>
<h3>Functional group strategies</h3>
<p>Manipulation of <a href="/facts/Functional_group/GXkSPsjM">functional groups</a> can lead to significant reductions in molecular complexity.
</p>
<h3>Stereochemical strategies</h3>
<p>Numerous chemical targets have distinct <a href="/facts/Stereochemistry/XkcRVNwd">stereochemical</a> demands. Stereochemical transformations (such as the <a href="/facts/Claisen_rearrangement/GJvfAk6h">Claisen rearrangement</a> and <a href="/facts/Mitsunobu_reaction/kVuwYbRH">Mitsunobu reaction</a>) can remove or transfer the desired chirality thus simplifying the target.
</p>
<h3>Structure-goal strategies</h3>
<p>Directing a synthesis toward a desirable intermediate can greatly narrow the focus of analysis. This allows bidirectional search techniques.
</p>
<h3>Transform-based strategies</h3>
<p>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.
</p>
<h3>Topological strategies</h3>
<p>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.
</p>
<ul><li>Disconnections that preserve ring structures are encouraged.</li>
<li>Disconnections that create rings larger than 7 members are discouraged.</li>
<li>Disconnection involves creativity.</li></ul>
<h2 id="see-also">See also</h2>
<ul><li><a href="/facts/Organic_synthesis/aprl6Iq7">Organic synthesis</a></li>
<li><a href="/facts/Total_synthesis/3GGoqhBm">Total synthesis</a></li></ul>

<h2 id="external-links">External links</h2>

Wikiquote has quotations related to <i>Retrosynthetic analysis</i>.

<ul><li><a href="https://chemical.ai">ChemAIRS, AI-driven retrosynthesis tools by Chemical.AI</a></li>
<li><a href="http://cheminf.cmbi.ru.nl/cheminf/ira/">Centre for Molecular and Biomolecular Informatics</a></li>
<li><a href="https://www.slideshare.net/AntonyWilliams/a-new-automated-retrosynthetic-search-engine-archem-presentation">Presentation on ARChem Route Designer, ACS, Philadelphia, September 2008</a> for more info on ARChem see the <a href="/facts/SimBioSys/fAYQDFzQ">SimBioSys</a> pages.</li>
<li><a href="https://postera.ai/manifold">Manifold, Software freely available for academic users developed by PostEra</a></li>
<li><a href="http://infochem.de/products/software/icsynth.shtml">Retrosynthesis planning tool: ICSynth by InfoChem</a></li>
<li><a href="https://iktos.ai/spaya/">Spaya, Software freely available proposed by Iktos</a></li></ul>

<h2 id="references">References</h2>

<ol>
<li id="fn:1"><p>Robinson, R. (1917). "LXIII. A Synthesis of Tropinone". Journal of the Chemical Society, Transactions. 111: 762–768. doi:10.1039/CT9171100762. <a href="https://zenodo.org/record/1429739" target="_blank">https://zenodo.org/record/1429739</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li>
<li id="fn:2"><p>Ugi, Ivar; Bauer, Johannes; Bley, Klemens; Dengler, Alf; Dietz, Andreas; Fontain, Eric; Gruber, Bernhard; Herges, Rainer; Knauer, Michael; Reitsam, Klaus; Stein, Natalie (1993). "Computer-Assisted Solution of Chemical Problems—The Historical Development and the Present State of the Art of a New Discipline of Chemistry". Angewandte Chemie International Edition in English. 32 (2): 201–227. doi:10.1002/anie.199302011. <a href="https://doi.org/10.1002/anie.199302011" target="_blank">https://doi.org/10.1002/anie.199302011</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li>
<li id="fn:3"><p>Vléduts, G.É. (1963). "Concerning one system of classification and codification of organic reactions". Information Storage and Retrieval. 1 (2–3): 117–146. doi:10.1016/0020-0271(63)90013-5. <a href="https://www.sciencedirect.com/science/article/abs/pii/0020027163900135" target="_blank">https://www.sciencedirect.com/science/article/abs/pii/0020027163900135</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li>
<li id="fn:4"><p>Corey, E. J. (1967). "General methods for the construction of complex molecules". Pure and Applied Chemistry. 14: 19–38. doi:10.1351/pac196714010019. <a href="https://doi.org/10.1351/pac196714010019" target="_blank">https://doi.org/10.1351/pac196714010019</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li>
<li id="fn:5"><p>E. J. Corey, X-M. Cheng (1995). The Logic of Chemical Synthesis. New York: Wiley. ISBN 978-0-471-11594-6. <a href="978-0-471-11594-6" target="_blank">978-0-471-11594-6</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li>
<li id="fn:6"><p>E. J. Corey (1988). "Retrosynthetic Thinking – Essentials and Examples". Chem. Soc. Rev. 17: 111–133. doi:10.1039/CS9881700111. <a href="/wiki/E._J._Corey" target="_blank">/wiki/E._J._Corey</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li>
<li id="fn:7"><p>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. <a href="/wiki/E._J._Corey" target="_blank">/wiki/E._J._Corey</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li>
<li id="fn:8"><p>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/ci800228y <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:8" class="footnote-back-ref">↩</a></p></li>
<li id="fn:9"><p>Wilhelm Wenner (1963). "Phenylacetamide". Organic Syntheses; Collected Volumes, vol. 4, p. 760. <a href="http://www.orgsyn.org/demo.aspx?prep=cv4p0760" target="_blank">http://www.orgsyn.org/demo.aspx?prep=cv4p0760</a> <a href="#fnref:9" class="footnote-back-ref">↩</a></p></li>
<li id="fn:10"><p>Roger Adams; A. F. Thal (1941). "Benzyl Cyanide". Organic Syntheses{{cite journal}}:  CS1 maint: multiple names: authors list (link); Collected Volumes, vol. 1, p. 107. <a href="http://www.orgsyn.org/demo.aspx?prep=cv1p0107" target="_blank">http://www.orgsyn.org/demo.aspx?prep=cv1p0107</a> <a href="#fnref:10" class="footnote-back-ref">↩</a></p></li>
</ol>

Retrosynthetic analysis open-in-new

Retrosynthetic analysis