Corey's synthesis of pentacycloanammoxic acid

Fatty acid based derivatives of this target compound are major components of organelles in anammoxic microbes. These microbes use hydrazine and nitrite as intermediates en route to the production of energy. This is extraordinary because hydrazine is a major component of rocket fuel!

Purpose of Synthesis

It is known that the anammoxic microbes contain this acid, however the specific mechanism of this compound is unknown in the cell. Another component to the cloud of mystery that surrounds this compound is how the microbes themselves biosynthesize it. The five cyclobutane rings are all anti to each other, and the biological pathway to this highly strained target needs to be pinned down. Understanding this biological synthesis could lend itself to more general methods of overcoming high thermodynamic barriers. An obvious way to make the pentacyclododecane system would be to adjoin two hexatriene molecules together. However, this would require 19.6 kcal/mol! So, by understanding how the microbes can do this might be instrumental in overcoming all sorts of thermodynamic synthetic obstacles.

The Synthesis

The synthesis starts out using cyclooctatetraene, which is cheap, and very readily available. It is also very easily functionalized. Corey has devised a linear synthesis for the target, and although it successfully produces the acid, there is only about a 1% overall yield. This low overall yield is attributed to the second step of the third reaction sequence, when the ring flip occurs in acetonitrile. There is only a 6% yield in this one step. Dr. Corey's pathway can be seen below:

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Important Steps

In the third reaction sequence, an all anti pentacycle is formed. This is achieved through a photochemical extrusion, where there is a homolytic cleavage of one C–N bond in the excited state, to give a diradical. Once the diradical intermediate is present, the ring flips itself upward, just as a bird flapping a wing. The bon across the ring is then formed through the displacement of the diradical.

In the fifth reaction sequence, there is a ring contraction of the 5-membered ring, an alpha-diazoketone. This is a relatively high yield process, although it is thermodynamically disfavored (higher ring strain in the product). To overcome this, Corey employs a photochemical reaction run at cold temperatures.

Big Picture

The biosynthesis of this compound by microbes must be very complex. In order to overcome thermodynamic obstacles, Corey used a lot of photochemical processes. The microbes, however, are not likely to photosynthesize this molecule; they must make it thermodynamically. The ability for them to overcome this obstacle lends itself to the complexity of the undiscovered biosynthesis.

References

1. Mascitti, Vincent; Corey, E. J. Total Synthesis of (±)-Pentacycloanammoxic Acid. J. Am. Chem. Soc. 2004, 126 (48), 15664–65. DOI: 10.1021/ja044089a.
2. Mascitti, Vincent; Corey, E. J. Enantioselective Synthesis of Pentacycloanammoxic Acid. J. Am. Chem. Soc. 2006, 128 (10), 3118–19. DOI: 10.1021/ja058370g.
3. Sinninghe Damaste, Jaap S.; Strous, Marc; Rijpstra, W. Irene C.; Hopmans, Ellen C.; Greenvasen, Jan A. J.; van Duin, Adri C. T.; van Niftrik, Laura A.; Jetten, Mike S. M. Linearly concatenated cyclobutane lipids form a dense bacterial membrane. Nature 2002, 419, 708–12. DOI: 10.1038/nature01128.