Clavilactone C

A structural revision of clavilactone D, a potent inhibitor of protein tyrosine kinases, was achieved by total syntheses of two newly proposed structures. The syntheses relied on ring-opening/ring-closing metathesis, which transformed a cyclobutenecarboxylate into a γ-butenolide. The syntheses confirmed that the correct structure of clavilactone D has an amino group at C-3 instead of a hydroxy group at C-2 in the originally proposed structure.

The first total synthesis of (+)-clavilactone B, a potent antifungal agent and novel tyrosine kinase inhibitor, is described. The absolute configuration of clavilactones has been unambiguously established by using Sharpless asymmetric epoxidation to generate the enantiomerically pure substrate. The strategy highlights the use of a powerful and convergent three-component benzyne coupling with a methylallyl Grignard and a chiral epoxy-aldehyde to generate two C-C bonds and install the carbon skeleton of clavilactone. Oxidative lactonization, ten-membered ring construction by ring closing metathesis, and oxidation gave clavilactone B.

Three novel geranylhydroquinone derived meroterpenoids, named clavilactones J and K (1-2) and clavipol C (3), were isolated from the basidiomycete Clitocybe clavipes. Their structures were unambiguously identified by extensive spectroscopic data analysis, and the electronic circular dichroism (ECD) calculation, Gauge-Including Atomic Orbitals (GIAO) NMR calculations and Mo2(OAc)4-induced electronic circular dichroism experiments were used to establish their absolute configurations. Compound 1, with two epoxy groups located at the 10-membered carbocycle, is uncommon in the reported meroterpenoids from C. clavipes. All the obtained compounds (1-3) were tested for their cytotoxic activity against human tumor cell line HGC-27 by using the MTT assay. All the compounds exhibited moderate cytotoxic activities against HGC-27 cell with IC50 values ranging from 33.5 to 56.6 μM.