The marine macrolide chagosensine is supposedly distinguished by a (Z,Z)-configured 1,3-chlorodiene contained within a highly strained 16-membered lactone ring, which also incorporates two trans-2,5-disubstituted tetrahydrofuran (THF) rings; this array is unique. After our initial synthesis campaign had shown that the originally proposed structure is incorrect, the published data set was critically revisited to identify potential mis-assignments. The “northern” THF ring and the anti-configured diol in the “southern” sector both seemed to be sites of concern, thus making it plausible that a panel of eight diastereomeric chagosensine-like compounds would allow the puzzle to be solved. To meet the challenge, the preparation of the required building blocks was optimized, and a convergent strategy for their assembly was developed. A key role was played by the cobalt-catalyzed oxidative cyclization of alken-5-ol derivatives (“Mukaiyama cyclization”), which is shown to be exquisitely chemoselective for terminal alkenes, leaving even terminal alkynes (and other sites of unsaturation) untouched. Likewise, a palladium-catalyzed alkyne alkoxycarbonylation reaction with formation of an α-methylene-γ-lactone proved instrumental, which had not found application in natural product synthesis before. Further enabling steps were a nickel-catalyzed “Tamaru-type” homocrotylation, stereodivergent aldehyde homologations, radical hydroindation, and palladium-catalyzed alkyne-1,2-bis-stannation. The different building blocks were assembled in a serial fashion to give the idiosyncratic chlorodienes by an unprecedented site-selective Stille coupling followed by copper-mediated tin/chlorine exchange. The macrolactones were closed under forcing Yamaguchi conditions, and the resulting products were elaborated into the targeted compound library. Yet, only one of the eight diastereomers turned out to be stable in the solvent mixture that had been used to analyze the natural product; all other isomers were prone to ring opening and/or ring expansion. In addition to this stability issue, our self-consistent data set suggests that chagosensine has almost certainly little to do with the structure originally proposed by the isolation team.

The marine macrolide chagosensine is the only natural product known to date that embodies a Z,Z-configured chloro-1,3-diene unit. This distinguishing substructure was prepared by a sequence of palladium-catalyzed 1,2-distannation of an alkyne precursor, regioselective Stille cross-coupling at the terminus of the resulting bisstannyl alkene with an elaborated alkenyl iodide, followed by chloro-destannation of the remaining internal site. The preparation of the required substrates centered on cobalt-catalyzed oxidative cyclization reactions of hydroxylated olefin precursors, which allowed the 2,5-trans-disubstituted tetrahydrofuran rings, embedded into each building block, to be formed with excellent selectivity. The highly strained macrolactone could ultimately be closed under forcing Yamaguchi conditions. Comparison of the spectral data of the synthetic sample with those of authentic chagosensine methyl ester confirmed that the structure of this intriguing compound has been mis-assigned by the isolation team.

Propargyl alcohols are privileged substrates for stereochemically unorthodox trans‐hydrostannation reactions catalyzed by [Cp*RuCl]4 (Cp*=pentamethylcyclopentadienyl), because an incipient hydrogen bond between the ‐OH group and the polarized [Ru‐Cl] unit assists substrate binding. For this very reason, it is also possible to subject diyne derivatives carrying one ‐OH group to site‐selective stannylation, even if the acetylene units are conjugated and hence, electronically coupled. An unusual temperature dependence was observed in that heating tends to improve site‐selectivity, whereas per‐stannylation is favored when the reaction is carried out in the cold. This counterintuitive trend can be rationalized based on spectroscopic data; additional support comes from the isolation of the unusual bimetallic complex 11. The bridging fulvene and enynyl ligands in 11 are thought to reflect an interligand redox isomerization process likely triggered by synchronous activation of the 1,3‐diyne substrate by two metal centers. The preparative relevance of site‐selective trans‐hydrostannation is illustrated by the total synthesis of two members of the typhonoside series of glycolipids, which are endowed with neuroprotective properties. Moreover, the preparation of a fluoroalkene sphingosine analogue shows that the tin residue also serves as a versatile handle for late‐stage modification of a bioactive target compound.

An efficient enantioselective synthesis of the ABC tricyclic core of the anticancer drug Taxol is reported. The key step of this synthesis is a cascade metathesis reaction, which leads in one operation to the required tricycle if appropriate fine-tuning of the dienyne precursor is performed.

Tricyclic isotaxane and taxane derivatives have been synthesized by a very efficient cascade ring‐closing dienyne metathesis (RCDEYM) reaction, which formed the A and B rings in one operation. When the alkyne is present at C13 (with no neighboring gem‐dimethyl group), the RCEDYM reaction leads to 14,15‐isotaxanes 16 a,b and 18 b with the gem‐dimethyl group on the A ring. If the alkyne is at the C11 position (and thus flanked by a gem‐dimethyl group), RCEDYM reaction only proceeds in the presence of a trisubstituted olefin at C13, which disfavors the competing diene ring‐closing metathesis reaction, to give the tricyclic core of Taxol 44.