Organic Chemistry Portal
Organic Chemistry Highlights

Total Synthesis

Monday, April 5, 2004
Douglass Taber
University of Delaware

Synthesis of the Mesotricyclic Diterpenoids Jatrophatrione and Citlalitrione

Leo Paquette of Ohio State recently reported (J. Am. Chem. Soc. 2003, 125, 1567. DOI: 10.1021/ja021177r) the total synthesis of jatrophatrione 1 and citlalitrione 2. These diterpenes, which share a central highly-subsituted 5-9-5 core, show remarkable tumor-inhibitory activity.

The 5-9-5 skeleton was assembled by the addition of the alkenyl cerate derived from 6 with the ketone 4, to give 7. Oxy-Cope rearrangement then gave the 5-9-5 enolate, which was quenched with methyl iodide to give 8. The ketone 8 underwent spontaneous intramolecular ene cyclization, to give 9.

The transient 5-9-5 ketone 8 has two cis-fused rings. To invert the ring stereochemistry, the alkene 9 was oxidized to the enone 10. After some experimentation, it was found that a CuH preparation would reduce the enone to give predominantly the trans-fused ketone. Monomesylation of the derived diol set the stage for Grob fragmentation to reopen the nine-membered ring, providing, after reduction, the alcohol 12.

At this point, there were two problems in selective alkene functionalization to be addressed. Although all attempts at oxidation of the cyclopentene failed, intramolecular hydrosilylation proceeded smoothly, to give 13. On exposure of the derived cyclic carbonate to , the cyclononene then underwent allylic oxidation, to give 14.

Attempts to functionalize the homoallylic alcohol 15 quickly revealed that this product of an intramolecular aldol condensation was sensitive to base. Fortunately, heating with thiocarbonyldiimidazole effected clean dehydration to give predominantly the desired regioisomer of the diene. Methanolysis followed by oxidation then gave the triketone 1, which on epoxidation with MCPBA gave 2 as the minor component of a 3:1 mixture.

Further Information:

J. Yang, Ph.D. Thesis, Ohio State University, 2003. Link

D. F. Taber, Org. Chem. Highlights 2004, April 5.