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.
Highlights
In a recent Communication, we reported the total synthesis of the methyl ester of nominal chagosensine (2aa).[1]
We conjectured that our first-generation synthesis of nominal chagosensine methyl ester 2aa meets this strategic precondition well:[1] we had devised a new entry into the idiosyncratic chloro-1,3-diene unit of the target, after a number of other options had been ruled out.[1,15,16]
The strain imparted onto the macrocycle by the two inscribed 2,5-trans-configured THF rings and the rigid chlorodiene is the likely cause why all our attempts to use alternative cyclization reactions had failed, despite considerable experimentation;[15] this includes ring closing metathesis of olefins or alkynes.[26,27]
Summary
In a recent Communication, we reported the total synthesis of the methyl ester of nominal chagosensine (2aa).[1]. The literature reports an absorption maximum of the natural product of λmax = 230 nm (MeOH),[2] whereas all synthetic samples show λmax ≥ 244 nm (MeOH/H2O or MeCN/ H2O).[78] One might argue that our reference compounds are macrolides in which the 1,3-chlorodiene unit could be twisted out of coplanarity, whereas the issues addressed above cast doubts if the natural product really contains the proposed macrolactone ring Even if it does not, such a bathochromic shift corresponding to an excitation energy difference of at least 0.25 eV is almost certainly too big to be explained by conformational differences; for example, acyclic 7-chloroocta-4,6dienoic acid ester absorbs at λmax = 244 nm (solvent not specified).[79] Curiously, it was this particular compound that had been cited in the isolation paper to support the structure assignment but without mentioning the actual data or discussing the obvious discrepancy.[2] (vii) For compound 2aa, which is nominal chagosensine methyl ester, we obtained high-resolution mass data for [M + Na]+ (m/z = 553.1809) corresponding to m/z =.
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