Chagosensine: A Riddle Wrapped in a Mystery Inside an Enigma

Abstract

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 Formosalides: Structure Determination by Total Synthesis

“…The required aldehyde 18 was attained in either enantiomeric form starting from 16 by a cobalt‐catalyzed oxidative cyclization which forms the trans ‐disubstituted tetrahydrofuran ring with excellent selectivity (Scheme 3). [45] This exact transformation had already served our previous total synthesis of amphidinolide C and F; [46] it illustrates the chemoselectivity of such oxidative Mukaiyama cyclization reactions in that only the olefinic site of 16 is engaged by the cobalt catalyst, [45, 47] whereas the triple bond remains untouched [13a,b, 46] …”

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

“…9:1). [39] Thes omewhat modest yields of 19 and 20 solely reflect the high volatility of these hydrocarbons.T he enantiomeric compounds are obviously equally well accessible. [40] Fragment 24 to be used twice during the synthesis was readily obtained on treatment of the lithium salt of 3-pentyn-1-ol ( 21)with the cyanocuprate derived from PhMe 2 SiLi and CuCN (Scheme 3).…”

The Tetrahydrofuran Motif in Polyketide Marine Drugs

“…Chagosensine structure is similar to the haterumalide and biselide families, but the conjugated chlorodiene unit is only present in this natural product. Nevertheless, Fürstner and co-workers have shown disagreement with the proposed structure and have carried out different synthetic studies in order to demonstrate their arguments [48,49]. The synthesis of putative chagosensine proposed by Fürstner relied on Mukaiyama cyclizations using Co(II) catalyst to obtain 2,5-trans-tetrahydrofuran derivatives 60 and 61 from the appropriate alkenols 62 and 63 [48].…”

“…The product proved unstable and had to be transformed into the known methyl esther, though huge deviations in the NMR seemed to indicate that the structure was misassigned. More recently, further efforts were made to access eight different diastereomers in order to find the correct structure [49]. Unfortunately, none of the structures synthesized matched the original spectroscopic data.…”