Synthon

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In retrosynthetic analysis, a synthon is a destructural[clarification needed] unit within a molecule which is related to a possible synthetic operation. The term was coined in 1967 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[edit]

Retrosynthetic analysis of phenylacetic acid

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
Synthesis of phenylacetic acid english.svg

Alternative use in Synthetic Oligonucleotides[edit]

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[edit]

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

In 1967, E. J. Corey introduced the concept of a synthon in retrosynthetic analysis.[1] Planning the steps of a complex molecule synthesis requires recognizing key synthons and identifying how they can be assembled into a desired product.[6] 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.[7]

Carbocationic synthons[edit]

Fig. 1: Strategic disconnection en route to the hops ether
Fig 2: The Pictet-Spengler disconnection.

Many retrosynthetic disconnections important for organic synthesis planning use carbocationic synthons. Carbon-carbon bonds, for example, exist ubiquitously in organic molecules, and are usually disconnected during a retrosynthetic analysis to yield carbocationic and carbanionic synthons. Carbon-heteroatom bonds, such as those found in alkyl halides, alcohols, and amides, can also be traced backwards retrosynthetically to polar C-X bond disconnections yielding a carbocation on carbon. Oxonium and acylium ions are carbocationic synthons for carbonyl compounds such as ketones, aldehydes and carboxylic acid derivatives. An oxonium-type synthon was used in a disconnection en route to the hops ether,[8] a key component of beer (see fig.1). In the forward direction, the researchers used an intramolecular aldol reaction catalyzed by titanium tetrachloride to form the tetrahydrofuran ring of hops ether.

Another common disconnection that features carbocationic synthons is the Pictet-Spengler reaction. The mechanism of the reaction involves C-C pi-bond attack onto an iminium ion, usually formed in situ from the condensation of an amine and an aldehyde. The Pictet-Spengler reaction has been used extensively for the synthesis of numerous indole and isoquinoline alkaloids.[9]

Carbanion alkylation is a common strategy used to create carbon-carbon bonds. The alkylating agent is usually an alkyl halide or an equivalent compound with a good leaving group on carbon. Allyl halides are particularly attractive for Sn2-type reactions due to the increased reactivity added by the allyl system. Celestolide (4-acetyl-6-t-butyl-1,1-dimethylindane, a component of musk perfume) can be synthesized using a benzyl anion alkylation with 3-chloro-2-methyl-1-propene as an intermediate step.[10] The synthesis is fairly straightforward, and has been adapted for teaching purposes in an undergraduate laboratory.

References[edit]

  1. ^ a b E.J. Corey (1967). "General methods for the construction of complex molecules" (PDF). Pure and Applied Chemistry. 14: 30–37. doi:10.1351/pac196714010019. 
  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. PMC 524854Freely accessible. PMID 15496466. doi:10.1073/pnas.0406911101. 
  6. ^ Corey E (1988). "Robert Robinson Lecture. Retrosynthetic thinking?essentials and examples". J. Chem. Soc. Rev. 17: 111–133. doi:10.1039/cs9881700111. 
  7. ^ Smith, Amos B.; Adams, Christopher M. (June 2004). "Evolution of Dithiane-Based Strategies for the Construction of Architecturally Complex Natural Products". Accounts of Chemical Research. 37 (6): 365–377. doi:10.1021/ar030245r. 
  8. ^ Linderman, Russell J.; Godfrey, Alex. (August 1988). "Novel synthesis of tetrahydrofurans via a synthetic equivalent to a carbonyl ylide". Journal of the American Chemical Society. 110 (18): 6249–6251. doi:10.1021/ja00226a052. 
  9. ^ Whaley, W. M.; Govindachari, T. R. (1951). "The Pictet-Spengler Synthesis of Tetrahydroisoquinolines and Related Compounds". In Adams, R. Organic Reactions. VI. New York: John Wiley and Sons. p. 151. doi:10.1002/0471264180.or006.03. 
  10. ^ Kagabu, Shinzo; Kojima, Yuka (May 1992). "A synthesis of indane musk Celestolide". Journal of Chemical Education. 69 (5): 420. Bibcode:1992JChEd..69..420K. doi:10.1021/ed069p420.