Isocomene

Isocomene
Ball-and-stick model of the isocomene molecule
Names
IUPAC name
(3aS,5aS,8aR)-1,3a,4,5a-Tetramethyl-1,2,3,3a,5a,6,7,8-octahydrocyclopenta[c]pentalene
Identifiers
3D model (JSmol)
ChemSpider
Properties
C15H24
Molar mass 204.36 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

Isocomene is a naturally occurring sesquiterpene first isolated from the rayless golden rod Isocoma wrightii, from which it derives its name. Its unusual structure consisting of three fused cyclopentane rings was first described by Zalkow et al. in 1977. The first total synthesis of isocomene was published by M.C. Pirrung in 1979.[1] The key steps are a photocatalyzed intramolecular [2 + 2] cycloaddition reaction followed by a rearrangement reaction which forms three contiguous chiral centers.[2] There are several synthesis pathways developed for isocomene, the two most efficient ones are by Weiss and Cook and by M.C. Pirrung with the starting material being enol ether.

Biosynthesis

Isocomene from enol ether copy

The Weiss and Cook synthesis pathways consists of 5 steps starting with the condensation of 2 moles of dimethyl-1,3-acetonedicarboxylate and a α-dicarbonyl compound.[3] This reaction is catalyzed by aqueous methanol and afford a high yield of 80%. The product of this is then undergo decarboxylation in step II to remove the carboxylate functional group and allow the formation of a  cis-bicyclo[3.3.0]octa-3,7-dione. Step II is a multiple synthesis step where the compound from previous step is hydrolyze and decarboxylate through the treatment of series of reagent going from reagents b through e. The resulting product is a diketal and then is hydrolyzed into a monoketal that allow the reaction to go on to the next step. The monoketal undergo Wolff-Kishner reaction with hydrazine in aqueous potassium hydroxide in step III. Wolff-Kishner reaction turn a ketone to aalkane, the carbon oxygen double bond is broken and 2 hydrogen atoms are added to give the compound after step III. Step IV is a cyclization under the catalyst of p-toluenesulfonic acid. The reaction gives a moderate high yield of 88%. The product of this step is a β-diketone system which is then “completely nonenolized” when treated with LDA, THF and Methyl iodide. Alternative reagent for this step is sodium tert-amylate, DME and Methyl iodide.


The first ever developed synthesis path was by M.C Pirrung with enol ether as the beginning material.[1] This synthetic method is said to be the most efficient method and afford the high yield of the desired product and also includes 5 steps. The starting reagent was let react to form a conjugated compound through Stork and Danheiser in step I. In step II, this compound then under go Grignard reaction with 5-bromo-2-methyl-1pentene, an organomagnesium compound that is also known as Grignard reagent. The reaction is catalyzed by aqueous acid and give a very high yield. The compound form is a dienone compound. It is then treat with light with the wavelength of 350 nm to allow the formation of a cycloadduct compound. The product is in a waxy solid form with a melting point ranges from 63 to 68 degree Celsius. The compound then undergo Wittig reaction: methylenetriphenylphosphorane in step IV with Witting reagent to form a new carbon carbon bond from the previously exist carbon oxygen double bond. The reaction produce the hydrocarbon that exist with several different stereochemistry. The yield of this step is also moderate with 77%. The final step is to treat the compound with TsOH - p-toluenesulfonic acid, benzene and catalyze with heat. The product formed is a racemic mixture of isocomene with an extremely high yield of 98%. The final product is collected in solid form and has a melting point of around 60 degree Celsius. This synthesis method is the most effective of all with a high overall percentage yield that is higher than 40%. [4]

Another alternative way of synthesizing isocomene is through the use of rearrangement. The synthesis focused on the rearrangement ability of sesquiterpene compound through intramolecular ketene cycloadditions. This type of synthesis aim to the formation of cyclobutanone, an intermediate that can be used as a material for isocomene synthesis.[5] 

Isocomene WEiss and COok GIF

References

  1. 1 2 Michael C. Pirrung (1979). "Total synthesis of (±)-isocomene". Journal of the American Chemical Society. 101 (23): 7130–7131. doi:10.1021/ja00517a087.
  2. ↑ Nicolaou, K. C.; E. J. Sorensen (1996). Classics in Total Synthesis. Weinheim, Germany: VCH. p. 221. ISBN 3-527-29284-5.
  3. ↑ Dauben, William G.; Walker, Daniel M. (1980). "Formal Total Synthesis of (f)-Isocomene". Journal of Organic Chemistry. 46 (6): 1103–1108. doi:10.1021/jo00319a013 – via ACS Publication.
  4. ↑ Pirrung, Michael C. (1980). "Total Synthesis of (f)-Isocomene and Related Studies". Journal of the American Chemical Society. 103: 82–87. doi:10.1021/ja00391a016 – via ACS Publication.
  5. ↑ Snider, Barry; Beal, Richard B. (1988). "Total Synthesis of Sesquiterpenes via Intramolecular Ketene Cycloadditions: Isocomeneanda-cis-anda-trans-Bergamotenes,an Approach to Seychellene". Journal of Organic Chemistry. 53 (19): 4508–4515. doi:10.1021/jo00254a017 – via ACS Publication.
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