Synthesis and Analysis of Isocarbacyclin Analogs

Isocarbacyclin, an analog of prostacyclin, has been found to be a potent neuroprotective agent. In particular, this compound has been studied in cells and animal models for neural protection from stroke. My group has designed a step-economical synthesis of isocarbacyclin that is conducive to the facile synthesis of analogs where the diversity of the compounds is installed at the final step of the synthesis. This allows for the largest amount of analogs to be synthesized in the fewest number of steps. Using three transition metal catalyzed reactions for the final three steps of the synthesis, a dienyl ester (available in only 4 steps) is converted to the isocarbacyclin analogs. Specifically, a palladium(0) catalyst enables a decarboxylation with concomitant allylic rearrangement, a rhodium(I) catalyst enables a diene-ene [2+2+1] cycloaddition to take place, and a ruthenium(II) catalyst diversifies the structure through a cross-metathesis reaction with various alkene side-chains. These compounds are being explored as neuroprotective compounds and the palladium-catalyzed step is being explored for the synthesis of other compounds that benefit from the dienylation reaction. Funding for this project has been provided by the North Carolina Biotechnology Center in the form of a Biotechnology Research Grant (2014-BRG-1205).

Representative Publications:

“Step-Economical Synthesis of Clinprost and Analogues Utilizing a Novel Decarboxylation Reaction”
Ghina’a I. Abu-Deiab and Mitchell P. Croatt
In Strategies and Tactics in Organic Synthesis Harmata, M. Ed.; Academic Press, 2017, Vol. 12, pp 95-117;

“Sequential Pd(0)-, Rh(I)-, and Ru(II)-catalyzed Reactions in a Nine-step Synthesis of Clinprost”
Emma E. Nagy, I. F. Dempsey Hyatt, Kristen E. Gettys, Shawn T. Yeazell, Stephen K. Frempong Jr., and Mitchell P. Croatt
Organic Letters 201315, 586-589.