Synthon

For Dutch pharmaceutical company, see Synthon (company).

In retrosynthetic analysis, a synthon is a destructural unit within a molecule which is related to a possible synthetic operation. The term was coined in 1968 by E.J. Corey.[1] He noted in 1988 that the "word synthon has now come to be used to mean synthetic building block rather than retrosynthetic fragmentation structures".[2] It was noted in 1998 [3] that the phrase did not feature very prominently in Corey's 1981 book, The Logic of Chemical Synthesis,[4] as it was not included in the index.

Example

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 reactant. 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

Alternative use in Synthetic Oligonucleotides

This term is also used in the field of gene synthesis—for example "40-base synthetic oligonucleotides are built into 500- to 800-bp synthons".[5]

Carbanionic synthons

Comparison between retrosynthetic analysis and the chemical synthesis for an ester alkylation

In 1968, E. J. Corey introduced the concept of a synthon in retrosynthetic analysis.[6] Planning the steps of a complex molecule synthesis requires recognizing key synthons and identifying how they can be assembled into a desired product.[7] In many retrosynthetic bond disconnections, the bond is broken heterolytically instead of homolytically, generating a carbocationtic and a carbanionic synthon. Most polar-mechanism reactions, whether they are nucleophilic displacements, 1,2-carbonyl additions, Michael reactions, or other processes, involve the fusion of a nucleophilic fragment and an electrophilic fragment.

There are a wide variety of carbanionic synthons available to the organic chemist for the construction of complex molecules. These include enolates, organometallics, acetylides, malonates, and carbanions generated in situ after addition to olefins. An example of a carbanionic synthon for an ester enolate is shown in fig. 1. A carbon-carbon bond alpha to a carbonyl can usually be disconnected to an enolate equivalent and a carbon electrophile. In this case, the enolate is generated by direct deprotonation of the substrate with lithium diisopropyl amide (LDA) base. The electrophile is methyl iodide.

Since synthons are idealized structures, it is often difficult to find equivalent chemical compounds in the real world. Many carbanion synthons, as drawn, present stability issues that render the molecule’s existence in reality impossible. For example, an acyl anions are not stable species, but the acyl anion synthon can be used to represent reagents such as lithiated dithianes, which are nucleophilic and often used in umpolung chemistry[8]

References

  1. ↑ E.J. Corey (1967). "General methods for the construction of complex molecules" (PDF). Pure and Applied Chemistry. 14: 30–37.
  2. ↑ E. J. Corey (1988). "Robert Robinson Lecture. Retrosynthetic thinking—essentials and examples". Chem. Soc. Rev. 17: 111–133. doi:10.1039/CS9881700111.
  3. ↑ W.A. Smit, A.F. Buchkov, R.Cople (1998). Organic Synthesis, the science behind the art. Royal Society of Chemistry. ISBN 0-85404-544-9.
  4. ↑ Elias James Corey; Xue-Min Cheng (1995). The logic of chemical synthesis. Wiley-Interscience. ISBN 0-471-11594-0.
  5. ↑ Sarah J. Kodumal; Kedar G. Patel; Ralph Reid; Hugo G. Menzella; Mark Welch & Daniel V. Santi (November 2, 2004). "Total synthesis of long DNA sequences: Synthesis of a contiguous 32-kb polyketide synthase gene cluster". PNAS. 101 (44): 15573–15578. Bibcode:2004PNAS..10115573K. doi:10.1073/pnas.0406911101.
  6. ↑ Corey, E. J. Pure App. Chem. 1967. 14, 30–37.
  7. ↑ Corey, E. J. Chem. Soc. Rev. 1988, 17, 111-133
  8. ↑ Smith, A. B. III: Adams C. M. Acc Chem. Res. 2004. 37, 365-377
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