Organic Chemistry Portal
Organic Chemistry Highlights

Monday, December 24, 2012
Douglass F. Taber
University of Delaware

Diels-Alder Cycloaddition: Fawcettimine (Williams), Apiosporic Acid (Helmchen), Marginatone (Abad-Somovilla), Okilactomycin (Hoye), Vinigrol (Barriault), Plakotenin (Bihlmeier/Klopper)

Highly substituted dienes and dienophiles are often reluctant participants in intermolecular Diels-Alder cycloaddition. Nevertheless, Robert M. Williams of Colorado State University, in the course of a synthesis of Fawcettimine (4), was able (J. Org. Chem. 2012, 77, 4801. DOI: 10.1021/jo3006045) to prepare 3 by combining the enone 1 with the diene 2.

Günter Helmchen of the Universität Heidelberg set (J. Org. Chem. 2012, 77, 4491. DOI: 10.1021/jo300519g) the single stereogenic center of 5 by Ir-catalyzed allylic alkylation. The Lewis acid that promoted the cycloaddition also conveniently removed the trityl protecting group, leading to 6, that was saponified to Apiosporic Acid (7).

Antonio Abad-Somovilla of the Universidad de Valencia prepared (J. Org. Chem. 2012, 77, 5664. DOI: 10.1021/jo3008034) the triene 8 in enantiomerically pure form from carvone. Despite the additional substitution on the diene, cycloaddition proceeded smoothly to give 9, which was carried on to Marginatone (10).

One could envision that Okilactomycin (13) could be formed by an intramolecular Diels-Alder cycloaddition. Thomas R. Hoye of the University of Minnesota observed (Org. Lett. 2012, 14, 828. DOI: 10.1021/ol203355g) that the tetraene tetronic acid corresponding to 11 was inert, but that the methyl ether 11 cyclized smoothly to 12. Demethylation then gave the natural product 13.

The complex polycyclic structure of Vinigrol (16) challenged organic synthesis chemists for many years, until a route was established by Phil Baran of Scripps/La Jolla (The Baran Synthesis of Vinigrol 2010, September 6). Louis Barriault cyclized (Angew. Chem. Int. Ed. 2012, 51, 2111. DOI: 10.1002/anie.201108779) 14 to 15 en route to a late intermediate in the Baran synthesis.

It had been hypothesized that the natural product Plakotenin (19) was formed naturally from a tetraene corresponding to 17. The tetraene 17 was prepared, and the cyclization was successful, "confirming" both the structure of the natural product and the biosynthetic hypothesis. Angela Bihlmeier and Wim Klopper of the Karlsruhe Institute of Technology calculated (J. Am. Chem. Soc. 2012, 134, 2154. DOI: 10.1021/ja2087097) the relative energies of the four competing transition states for the cyclization, leading to a correction of the structure of 18, and so of the natural product 19.

D. F. Taber, Org. Chem. Highlights 2012, December 24.