Ovatodiolides: Scalable Protection‐Free Syntheses, Configuration Determination, and Biological Evaluation against Hepatic Cancer Stem Cells

Abstract

Ac oncise,s calable,s ix-step (longest linear sequence) synthetic route to ovatodiolide scaffolds was developed for the first time.T his protecting-group-free route features tandem ring-opening metathesis/ring-closing metathesis reactions to install the macrocycle-fused butenolide ring and at andem allylboration/lactonization to build the amethylene-g-lactone.Our syntheses have enabled the determination of the hitherto unknown stereochemical configurations of this family of natural products.P reliminary tests of structure-activity relationships were conducted with four natural ovatodiolides and three analogues.F urther assays indicated that the synthetic natural product isoovatodiolide can significantly decrease the population of hepatic cancer stem cells and reduce the tumorsphere-forming capability of HepG2 cells.

Optimization of Two Steps in Scale-Up Synthesis of Nannocystin A

“…By employing the chiral BINOL reagents, this reaction can proceed in an enantio-selective manner with high e.e. value evidenced by our recent synthetic work of ovatodiolide [ 27 ]. Besides, the external addition of BINOL can save the installation and removal of auxiliaries on reactants compared to Evans auxiliary methodology, and BINOL can be recovered after the reaction is completed.…”

Rapid Construction of the Scaffold of Quorumolide A Enabled by a Tandem ROM/RCM Strategy and a Tandem Oxidative Cyclization Strategy

“…Developed by Grubbs and co-workers, 8 this cascade reaction has subsequently served as a powerful tool for the construction of fused butenolide rings, 9 of the humulanolides 10 and our synthesis of the ovatodiolide scaffold. 11 Intermediate 6 could be assembled through esterification and nucleophilic addition. A Mukaiyama-type aldol reaction between compounds 8 and 9 can be employed to connect C5 and C6 in a diastereoselective manner.…”

“…The synthesis started with the easily prepared silyl enol ether 8, which instantly underwent an asymmetric Mukaiyama-type aldol reaction with aldehyde 9 to deliver alcohol 7 in 72% yield with high stereoselectivity. 11 This reaction can be conducted on a 25-g scale. Further treatment of compound 7 with N,Odimethylhydroxylamine hydrochloride and trimethyl aluminum gave Weinreb amide 10 in 60% yield.…”

“…Then, the freshly prepared Grignard reagent 11 attacked the Weinreb amide 10 to provide ketone 12 in 86% yield. Compound 12 was then treated with cyclobut-1-enecarboxylic anhydride 11,12 and converted into 6 in 70% yield (Scheme 2).…”

“…With the intermediate 6 in hand, we attempted the key ROM/RCM cascade reaction to build the butenolide ring and close the 14-membered macroring in a single operation. The optimal condition of this transformation we identified in our previous work 11 is the addition of 10% equivalents of Hoveyda−Grubbs' second generation catalyst to the 1.5 mM of intermediate 6 in refluxing toluene. To our delight, the reaction under these optimal conditions went smoothly, and the desired product 14 was obtained as the main isolated product in 50% yield (E:Z > 10:1).…”