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.