The Total Synthesis of () 7-HDHA

Fatty acid () 7-HDHA was recently identified as an endogenous ligand for PPAR/ receptors by one of our collaborators Dr. Henry Krause group. While this discovery is promising in understanding PPARs mechanism of effects and related diseases (Alzheimers disease, cerebral ischemia, retina inflammation, etc.), the study of 7-HDHA in relation to PPARs has been hampered by the high cost and limited supply of 7-HDHA.

The total synthesis of 7-HDHA was attempted using four different strategies, and finally achieved in 11 steps in the longest reaction sequence, starting from commercially available (triisopropylsilyl)acetylene and 2-pentyn-1-ol. The overall yield of this synthesis was 12%. This concise route mainly relies on the one-step generation of three Z-double bonds with the semi-hydrogenation catalyst P2-Nickel, and a late-stage semi-hydrogenation with Zn(Cu/Ag) reagent. The completion of this synthesis will now provide large quantities of 7-HDHA quickly, and thus enable extensive studies of PPAR 7-HDHA interaction.