Total Synthesis and Complete Stereostructure of a Marine Macrolide Glycoside, (−)‐Lyngbyaloside B

Abstract

We have described in detail the total synthesis of both the proposed and correct structures of (-)-lyngbyaloside B, which facilitated the elucidation of the complete stereostructure of this natural product. Our study began with the total synthesis of 13-demethyllyngbyaloside B, in which an esterification/ring-closing metathesis (RCM) strategy was successfully used for the efficient construction of the macrocycle. We also established reliable methods for the introduction of the conjugated diene side chain and the l-rhamnose residue onto the macrocyclic framework. However, the esterification/RCM strategy proved ineffective for the parent natural product because of the difficulties in acylating the sterically encumbered C-13 tertiary alcohol; macrolactionization of a seco-acid was also extensively investigated under various conditions without success. We finally completed the total synthesis of the proposed structure of (-)-lyngbyaloside B by means of a macrolactonization that involves an acyl ketene as the reactive species. However, the NMR spectroscopic data of our synthetic material did not match those of the authentic material, which indicated that the proposed structure must be re-examined. Inspection of the NMR spectroscopic data of the natural product and molecular mechanics calculations led us to postulate that the configuration of the C-10, C-11, and C-13 stereogenic centers had been incorrectly assigned in the proposed structure. Finally, our revised structure of (-)-lyngbyaloside B was unambiguously verified through total synthesis.

Total Synthesis of Putative 11-epi-Lyngbouilloside Aglycon

“…Unfortunately, after careful analysis of the spectroscopic data of our final product with the ones reported for lyngbouilloside, some discrepancies still remained. This observation combined with the recent syntheses of lyngbyaloside B and C by Fuwa (Fuwa et al, 2016) and Taylor (Chang et al, 2015), suggest not only a stereochemical reassignment for C11, but also for C10 and C13. Nonetheless, our strategy featuring a ring-closing metathesis (RCM) to form the 14-membered ring macrolactone, a late stage side chain introduction via a Wittig olefination and a glycosylation to introduce the rhamnose should allow to complete the synthesis of lyngbouilloside and irrevocably confirm its structure.…”

A Review Study on Macrolides Isolated from Cyanobacteria

“…Lyngbyaloside B ( 13 ), isolated from marine cyanobacterium Lyngbya sp., which was collected from Palaua, shows weak cytotoxicity against KB cells and LoVo cells with IC 50 values of 4.3 and 15 µM, respectively [13]. The total synthesis of lyngbyaloside B ( 13 ) has been reported by Fuwa et al [33]. Three analogs of lyngbyaloside ( 12 ), including 2- epi -lyngbyaloside ( 14 ), 18 E -lyngbyaloside C ( 15 ) and 18 Z -lyngbyaloside C ( 16 ), were isolated from the marine cyanobacterium Lyngbya bouillonii , collected from Apra Harbor, Guam.…”

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

“…The nature of the sugar, was assigned by correlations in the 1 H‐ 1 H COSY and HMBC spectral data and comparison with the sugar unit present in auriside A ( 3 a ). In concurrent total synthetic work on lyngbyaloside B, Fuwa in 2016 would reassign C10, C11 and C13 and shed light on a potential similar issue within lyngbouilloside, vide infra [11] …”

“…In 2015 [22] and 2016, [11] Fuwa and coworkers reported an elegant total synthesis of (−)‐lyngbyaloside B ( 2 b ), where they employed an innovative use of an Abiko–Masamune anti‐ aldol and a vinylogous Mukaiyama to install the requisite stereochemistry in the starting building blocks and used the Boeckman acyl ketene method for macrocyclization (Figure 4). Fuwa and coworkers made stereochemical reassignment of (−)‐lyngbyaloside B having epimeric stereogenic centers at C10/C11 and C13 as shown for the reassigned lyngbyaloside B ( 2 c ) (Figure 1) when compared with the original assigned structure of lyngbyaloside B ( 2 b ).…”