The mechanism of covalent inhibition of LAR phosphatase by illudalic acid.

Leukocyte antigen-related (LAR) phosphatase is a receptor-type protein tyrosine phosphatase involved in cellular signaling and associated with human disease including cancer and metabolic disorders. Selective inhibition of LAR phosphatase activity by well characterized and well validated small molecules would provide key insights into the roles of LAR phosphatase in health and disease, but identifying selective inhibitors of LAR phosphatase activity has been challenging. Recently, we described potent and selective inhibition of LAR phosphatase activity by the fungal natural product illudalic acid.

Derivatives of the Fungal Natural Product Illudalic Acid Inhibit the Activity of Protein Histidine Phosphatase PHPT1.

PHPT1 is a protein histidine phosphatase that has been implicated in several disease pathways, but the chemical tools necessary to study the biological roles of this enzyme and investigate its utility as a therapeutic target have yet to be developed. To this end, the discovery of PHPT1 inhibitors is an area of significant interest. Here, we report an investigation of illudalic acid and illudalic acid analog-based inhibition of PHPT1 activity.

Synthesis of Coprinol and Several Alcyopterosin Sesquiterpenes by Regioselective [2 + 2 + 2] Alkyne Cyclotrimerization.

Alkyne [2 + 2 + 2] cyclotrimerization is a strategically attractive but tactically challenging approach to the synthesis of highly substituted benzene rings. Here, a bimolecular regioselective cyclotrimerization is applied to the total synthesis of the natural product coprinol and several related alcyopterosins from the illudalane family of sesquiterpenes. The synthesis of coprinol from dimedone was completed in six steps and a 57% overall yield.

Synthesis of 4,4-Dimethyl-1,6-heptadiyne and Other Neopentylene-Tethered (NPT) 1,6-Diynes.

Two divergent and complementary methodologies for preparing neopentylene-tethered (NPT) 1,6-diynes are described. These NPT 1,6-diynes are valuable π-systems for reaction discovery and building blocks for target-oriented synthesis. Ring-opening fragmentation of dimedone (and alkylation) produces alkyne-tethered β-keto esters .