Total synthesis of the proposed structure of astakolactin

Abstract

SummaryThe first total synthesis of the proposed structure of astakolactin, a sesterterpene metabolite isolated from the marine sponge Cacospongia scalaris, has been achieved, mainly featuring Johnson–Claisen rearrangement, asymmetric Mukaiyama aldol reaction and MNBA-mediated lactonization.

Asymmetric Total Synthesis of (−)-Astakolactin and Confirmation of Its Stereostructure

“…Diol 12 (378 mg, 1.19 mmol) was converted into 13 (656 mg, 99%) as previously described (and in the Supporting Information).…”

“…Consequently, we envisioned the total synthesis of 1 employing a synthetic strategy involving the dehydration condensation of 2-methyl-6-nitrobenzoic anhydride (MNBA) using 4-dimethylaminopyridine for the construction of the eight-membered lactone moeity . Although 1 and its diastereomer have been successfully synthesized by our group, the spectroscopic data of the synthetic products are not identical to those of the natural compound . Particularly, the chemical shifts in the 1 H and 13 C NMR spectra corresponding to the lactone ring moiety of the synthetic compounds were significantly different from those of the natural product.…”

“…The chain precursor 3 would be accessed through an asymmetric Mukaiyama aldol reaction to obtain syn -aldol products. The aldehyde 5 could be formed from farnesol via the route outlined in our synthesis of 1 …”

“…The synthetic route to (21 S ,22 R )- 2 is depicted in Scheme . It proceeded from intermediate 7 , which was prepared as described in our synthesis of structure 1 . After protection of the secondary hydroxy group with a tert -butyldimethylsilyl (TBS) group, reduction of 11 followed by deprotection of the silyl group afforded diol 12 .…”

“…7 Although 1 and its diastereomer have been successfully synthesized by our group, the spectroscopic data of the synthetic products are not identical to those of the natural compound. 8 Particularly, the chemical shifts in the 1 H and 13 C NMR spectra corresponding to the lactone ring moiety of the synthetic compounds were significantly different from those of the natural product. This indicates that the proposed eightmembered lactone moiety is not present in naturally occurring astakolactin.…”