Total Synthesis of Putative 11-epi-Lyngbouilloside Aglycon

Abstract

We report here the total synthesis of 11-epi-lyngbouilloside aglycon. Our strategy features a Boeckman-type esterification followed by a RCM to form the 14-membered ring macrolactone and a late-stage side chain introduction via a Wittig olefination. Overall, the final product was obtained in 20 steps and 2% overall yield starting from commercially available 3-methyl-but-3-enol. Most importantly, the strategy employed is versatile enough to eventually allow us to complete the synthesis of the natural product and irrevocably confirm its structure.

A Biocatalytic Route to Highly Enantioenriched β‐Hydroxydioxinones

“…Rawal demonstrated that glyoxolate electrophiles could benefit similarly to the aforementioned chelation system using TADDOL hydrogen‐bond donors to allow for high selectivity . Notably, in their recent total synthesis of lyngbouilloside, Cossy disclosed that using vinylogous Mukaiyama conditions did not provide their desired β‐hydroxydioxinone adduct in a stereoselective manner, requiring them to use preparative supercritical fluid chromatography to separate the enantiomers . These examples, combined with previous methods that are only practically selective for sp 2 ‐type substrates highlight situations where there is limited enantio‐ and diastereocontrol, force the need for step‐uneconomical processes .…”

Synthesis of the C1−C16 Polyol‐Containing Macrolactone of 13‐Desmethyl Lyngbouilloside, an Unnatural Analog of the Originally Assigned Structure of (−)‐Lyngbouilloside

“…It is worthy to note, efforts by Hoye and coworkers in 2008 who reported a dual macrolactonization/pyran–hemiketal formation event using acylketenes with applications to the synthesis of (−)‐callipeltoside A and a lyngbyaloside B model systems [16] . In their synthesis of 1 a , Cossy proposed the aforementioned revised structure of lyngbouilloside with stereochemical reassignment of the C11 stereogenic center as the C11‐epimer, and thus a potential C10/C11 syn relationship that the authors would later revisit in a 2016 report, vide infra [17] …”

“…In 2016, Cossy and coworkers, [17] reported an elegant total synthetic effort to the putative 11‐epi‐lyngbouilloside aglycon featuring a Boeckman esterification, RCM strategy to form the 14‐membered ring macrolactone, Wittig olefination for late‐stage sidechain introduction, and a glycosylation for installation of rhamnose. In this work, the authors provided careful and detailed analysis of the spectroscopic data (see detailed 13 C table) of their synthetic product with the original data reported for lyngbouilloside, and noted that discrepancies still remained.…”