Collective Total Synthesis of Casbane Diterpenes: One Strategy, Multiple Targets.

Of the more than 100 casbane diterpenes known to date, only the eponymous parent hydrocarbon casbene itself has ever been targeted by chemical synthesis. Outlined herein is a conceptually new approach that brings not a single but a variety of casbane derivatives into reach, especially the more highly oxygenated and arguably more relevant members of this family. The key design elements are a catalyst-controlled intramolecular cyclopropanation with or without subsequent equilibration, chain extension of the resulting stereoisomeric cyclopropane building blocks by chemoselective hydroboration/cross-coupling, and the efficient closure of the strained macrobicyclic framework by ring-closing alkyne metathesis. A hydroxy-directed catalytic trans-hydrostannation allows for late-stage diversity. These virtues are manifested in the concise total syntheses of depressin, yuexiandajisu A, and ent-pekinenin C. The last compound turned out to be identical to euphorhylonal A, the structure of which had clearly been misassigned.

Enantioselective Synthesis of the Cyclopiazonic Acid Family Using Sulfur Ylides.

A convergent, nine-step (LLS), enantioselective synthesis of α-cyclopiazonic acid and related natural products is reported. The route features a) an enantioselective aziridination of an imine with a chiral sulfur ylide; b) a bioinspired (3+2)-cycloaddition of the aziridine onto an alkene; and c) installation of the acetyltetramic acid by an unprecedented tandem carbonylative lactamization/N-O cleavage of a bromoisoxazole.

Enantioselective Total Synthesis of Secalonic Acid E.

The first enantioselective synthesis of a secalonic acid containing a dimeric tetrahydroxanthenone skeleton is described, using a Wacker-type cyclization of a methoxyphenolic compound to form a chiral chroman with a quaternary carbon stereogenic center with >99% ee. Further steps are a Sharpless dihydroxylation and a Dieckmann condensation to give a tetrahydroxanthenone. A late-stage one-pot palladium-catalyzed Suzuki-dimerization reaction leads to the 2,2'-biphenol linkage to complete the enantioselective total synthesis of secalonic acid E in 18 steps with 8% overall yield.