Exploring Natural Diels-Alder Reactions

          Named after German chemists Otto Diels and Kurt Alder, the Diels-Alder reaction is an addition reaction that forms a six-membered ring.  A 1,3 diene reacts with an alkene called a dienophile.  Since these reactions form new carbon-carbon bonds, they can be used to synthesize larger, more complex molecules from smaller ones (2).  From organic lecture to researching the internet, there are several compounds that can undergo a Diels-Alder reaction.  However, the purpose of this blog was to try to find a biological or environmental compound that could undergo this type of reaction and was supported by evidence of such.  When searching the internet, this task was not easy.  Many articles had to be purchased in order to view them, so instead, Campbellsville University's library online database was utilized in order to retrieve the article of interest.

        Even though the options were limited, an article titled "Insight into a natural Diels-Alder reaction from he structure of macrophomate synthase" sparked interest after reading the abstract. This article was published in 2003 but states that evidence on natural Diels-Alder reaction had been collected in the biosynthesis of secondary metabolites.  However; there had been no information on the structural details.  This article focuses on fungal macrophomate synthase (MPS)3 in complex with pyruvate, a natural Diels-Alderase.  Amino acid residues can hydrogen-bond to the substrate 2-pyrone because the active site of the enzyme is large and hydrophobic.  The data suggest "the reaction proceeds via a large-scale structural reorganization of the product (1)." 

        Macrophoma commelinae, a phyopathogenic fungus, transforms 2-pyrone derivatives into macrophomate 1.  Mucopolysaccharidose, MPS, is the only enzyme that will catalyze this transformation with oxalacetate as a substrate.  The mechanism for the whole pathway includes three separate steps.  The first step is a decarboxylation of oxalacetate, then the Diels-Alder reaction takes place with carbon-carbon bond formations, and lastly "decarboxylation with concomitant dehydration."  The three-step mechanism is shown in Figure 1 (1).                                                        

                         Figure 1

         During the second step, the Diels-Alder reaction part, the cycloaddition of the enolate and the 2-pyrone 2 takes place.  The 2-pyrone molecule is most likely placed through two hydrogen bonds between the carbonyl oxygen of 2-pyrone and Arg 101, and the C5-acyl oxygen and Tyr 169.  Stacking Tyr 169 with Phe 149 places it in the proper orientation (1).        

                           Figure 2

        At the time this article was written, three natural Diels-Alderase were known and are shown in Figure 3.  These three examples can be "classified as producers of reactive substrate with an entropy trap for [ 4 + 2 ] cycloaddition (1)".  This type of reaction has an advantage because of "its ability to use a highly reactive substrate that is not stable in reaction medium (1)."

                                                                                                                                                                         Figure 3

        In conclusion, natural Diels-Alder reactions are not significant in number and require brain power to understand when looking at complex molecules, such as this article describes.  This article is eleven years old and little information was known about this type of natural reactions.  New information may be available now, but if not I am sure advancing technology will allow scientists to advance in this field in the future.

A link to the article is found below.

   http://0-eds.b.ebscohost.com.library.acaweb.org/eds/pdfviewer/pdfviewer?sid=63b11ce8-07d6-4cab-a5b9-4d2b257a4ae5%40sessionmgr114&vid=6&hid=106


Works Cited

 1)    Ose, T; Watanabe, K; Mie, Takashi; Honma, M; Watanabe, H; Yao, M; Oikawa, H; Tanaka, I. Insight into a natural Diels-Alder reaction from the structure of macrophomate synthase. Nature. [Online] March 13, 2003, p 185-188. Campbellsville University Academic Index. http://0-eds.b.ebscohost.com.library.acaweb.org/eds/pdfviewer/pdfviewer?sid=63b11ce8-07d6-4cab-a5b9-4d2b257a4ae5%40sessionmgr114&vid=6&hid=106 (accessed Feb 03, 2014)

 2)      Smith, J. Organic Chemistry, 3^rd ed.; McGraw-Hill: New York, 2011.