Assembly of the Entire Carbon Backbone of a Stereoisomer of the Antitumor Marine Natural Product Hemicalide

Abstract

A strategy for the assembly of the entire carbon backbone of a stereoisomer of the antitumor marine natural product hemicalide has been investigated. The devised convergent approach relies on Horner–Wadsworth–Emmons and Julia–Kocienski olefination reactions for the construction of the C6=C7 and C34=C35 double bonds, respectively, an aldol reaction to create the C27−C28 bond, and a Suzuki–Miyaura cross‐coupling as the endgame to form the C15−C16 bond.

Stereocontrolled Synthesis as an Enabling Tool for the Configurational Assignment of Marine Polyketide Natural Products

“…This result demonstrates that NMR spectroscopic analyses of well‐designed synthetic truncates can discern between diastereomers possessing distally related stereoclusters that may otherwise be difficult to achieve via inferential means. Finally, it is worth noting that the combined Ardisson/Cossy/Meyer teams have recently prepared the partially deprotected full‐carbon skeleton of a diastereomer of hemicalide, bearing the incorrect 13,18‐ anti relationship, which resulted in a poor NMR spectroscopic correlation relative to the C27–C32 region of the natural product . In addition to the conclusions presented above, this gives credence to the idea that a wholly synthesis‐based configurational elucidation of hemicalide is indeed possible.…”

The Structure of Hemicalide from the Marine Sponge Hemimycale sp

“…It was chosen to substitute C‐27 with a OMe (of undetermined configuration) to bear more resemblance to hemicalide. These compounds were compared with hemicalide and with the 13,18 anti ‐derivative 28 previously described [2] . The best fit was obtained for the 13,18 syn derivative 26 (Figure 14).…”

“…[1] When it became clear that very little material could be obtained from the natural source, synthetic programmes were launched culminating in 2019 in the preparation of one of the two million plus possible isomers of the molecule. [2] The initial discovery happened in the course of a screening programme aimed at finding compounds able to block cell mitosis and concerned an extract of the marine sponge Hemimycale sp. originating from the Torres islands (Vanuatu).…”

“…As soon as a reasonable planar structure was obtained and based on the uniqueness of the biological data, a patent application was filed and a patent granted in 2012, in the USA, Europe and Japan [1] . When it became clear that very little material could be obtained from the natural source, synthetic programmes were launched culminating in 2019 in the preparation of one of the two million plus possible isomers of the molecule [2] …”

Deep‐Sea Discovery and Detective Work: Towards Solving the Hemicalide Structural Enigma through Computational NMR Analysis and Stereocontrolled Synthesis

“…This synthetic venture represented the first time the polyacetate region was targeted, even though the four stereocentres appeared to be randomly assigned. [28] While large global Table 3. Determination of the 42,45-anti configuration in hemicalide.…”