Total Synthesis of the Diglycosidic Tetramic Acid Ancorinoside A

Abstract

Ancorinoside A, a metabolite of a sponge Ancorina sp., was prepared in 18 steps as the first derivative of this class of glycosylated 3-acyltetramic acids. It features a β-d-glucopyranosyl-(1→4)-β-d-galacturonic acid linked to a d-aspartic acid derived tetramic acid via a 3-docosanoyl spacer. The diglycoside was built up by connecting the protected monosaccharides d-galactose and d-glucose via a thioglycoside glycosylation. Attachment of the spacer by a subsequent Schmidt glycosylation of this diglycoside, TEMPO oxidation to the uronic acid, functionalisation of the spacer terminus with an N-(β-ketoacyl)aspartate, and a final Dieckmann cyclisation were the key steps leading to ancorinoside A. This approach should also allow access to ancorinoside D.

Marine natural products

“…486 The number of rst total syntheses of sponge metabolites is similar in 2017 (51) to that reported in 2016 (53). Compounds that have been synthesised include ancorinoside A, 487 diacarnoxide C, 488 and plakinidone C. 406 The structures of gracilioether I and mucosin have been disproven by synthesis but no alternatives have been proposed. 489,490 Jaspisin, isojaspisin and (Z)narain have been synthesised, 491 as have smenothiazoles A 406,492 and B.…”

Chemistry and Biology of Bioactive Glycolipids of Marine Origin

“…A total synthesis of ancorinoside A ( 238 ) was achieved in 1.6% yield in 18 steps by Schobert et al [ 108 ], as described in Scheme 20 . The key steps were the Schmidt glycosylation for the introduction of the lipidic spacer, a TEMPO oxidation to the uronic acid, functionalisation of the spacer terminus, and final Dieckmann cyclisation for the construction of the tetramic residue.…”

A Synthetic Route to the MT1-MMP Inhibitor Ancorinoside D

“…and which was synthesised, as the first member of the ancori-noside family, by our group in 2017. 4 To evaluate the flexibility and applicability of our synthetic approach, and for a detailed investigation of the structure dependency of the MT1-MMP inhibition effect, we now wanted to also prepare tetramic acid 1.…”

“…As in our synthesis of ancorinoside A (2), 4 we used the protected disaccharide trichloroacetimidate donor 8 and a monosilylated derivative of an appropriate α,ω-diol, in this case the TBS-ether 9 of undecane -1,11-diol (14), to build up the left half of the 3-acyl sidechain of ancorinoside D (1) (Scheme 1). After protection group modification and oxidation of the disaccharide to the uronic acid, the undecyl appendage was deprotected and oxidised to the corresponding aldehyde 6.…”

“…Such a β-ketothio- The required N-methyl-D-aspartate was prepared as described in our synthesis of ancorinoside A (2). 4 Due to the alkene in the spacer of 1, we used the methyl ester 5 rather than the benzyl ester.…”