Total Synthesis, Stereochemical Reassignment, and Biological Evaluation of (−)‐Lyngbyaloside B

Abstract

(-)-Lyngbyaloside B is a 14-membered macrolide glycoside isolated from the marine cyanobacterium Lyngbya sp. as a cytotoxic substance by Moore and co-workers. The first total synthesis of (-)-lyngbyaloside B and the reassignment of its stereostructure is described. The synthesis features an Abiko-Masamune aldol reaction, a vinylogous Mukaiyama aldol reaction, and a macrocyclization involving an acyl ketene intermediate for the construction of the macrocyclic backbone, which contains an acylated tertiary alcohol. The antiproliferative activity of selected compounds against a small panel of human cancer cell lines is also reported.

O-Glycosylation methods in the total synthesis of complex natural glycosides

“…79 Additionally, total synthesis and stereochemical reassignment of (À)-lyngbyaloside B, a structure analogue of aurisides, were recently reported by Fuwa et al, wherein a glycosyl trichloroacetimidate was used as the key glycosylation step. 80 Vicenistatin (23) 81,82 In Kanoh's synthesis, the Mukaiyama protocol (with SnCl 2 -AgClO 4 as the promoter) was found not to be reproducible, therefore, the glycosylation of polyene lactam 25 with 2-deoxy-glycosyl uoride 24 was performed in the presence of TMSOTf; 83 subsequent cleavage of the carbamate under basic conditions delivered vicenistatin (23) and its a-anomer in 10% and 18% yield (for two steps), respectively.…”

Total Synthesis and Structural Reassignment of Lyngbyaloside C Highlighted by Intermolecular Ketene Esterification

“…[4] These efforts culminated in the first total synthesis of lyngbyaloside B by Fuwa et al in 2014, in which the stereochemical configuration of lyngbyaloside B was reassigned. [4f] However, previous synthetic endeavors all focused on the lyngbyalosides which possess the (E,E) diene appendage (lyngbouilloside and lyngbyaloside B). Lyngbyaloside B also contains an additional methyl stereogenic center at C6.…”

“…Yadav et al recently reported a similar strategy towards the synthesis of lyngbyaloside B. [4d] For preparation of the tertiary alcohol, we envisioned the installation of the 1,3- syn diol through utilization of an electrophilic-induced ether transfer methodology recently developed in our labs. [5] The alkene required for the subsequent RCM step provided us with an opportunity to explore a unique ether transfer substrate which contains potentially competing 1,1-disubstituted and terminal alkenes.…”

Synthetic studies to lyngbouilloside: a phosphate tether-mediated synthesis of the macrolactone core

“…In 2014, Fuwa and coworkers 7 completed an elegant total synthesis of (−)-lyngbyaloside B, employing innovative use of an Abiko–Masamune anti- aldol and a vinylogous Mukaiyama to install the requisite stereochemistry in the starting building blocks. In this work, synthetic, spectroscopic and molecular modeling studies provided unequivocal stereochemical reassignment of (−)-lyngbyaloside B having epimeric stereogenic centers at C10/C11 and C13 as shown for the reassigned lyngbyaloside B ( 2b ) (Figure 1) when compared with the original assigned structure of lyngbyaloside B ( 2a ).…”

“…7 Highlights of the synthesis include a phosphate tether-mediated, one-pot, sequential RCM/CM/chemoselective hydrogenation reaction, Roskamp homologation, and a high yielding Boeckman acylketene cyclization. Overall, the synthesis is highly modular and will enable analog synthesis.…”