Unravelling Photochemical Relationships Among Natural Products from Aplysia dactylomela

Abstract

Aplydactone (1) is a brominated ladderane sesquiterpenoid that was isolated from the sea hare Aplysia dactylomela together with the chamigranes dactylone (2) and 10-epi-dactylone (3). Given the habitat of A. dactylomela, it seems likely that 1 is formed from 2 through a photochemical [2 + 2] cycloaddition. Here, we disclose a concise synthesis of 1, 2, and 3 that was guided by excited state theory and relied on several highly stereoselective transformations. Our experiments and calculations confirm the photochemical origin of 1 and explain why it is formed as the sole isomer. Irradiation of 3 with long wavelength UV light resulted in a [2 + 2] cycloaddition that proceeded with opposite regioselectivity. On the basis of this finding, it seems likely that the resulting regioisomer, termed “8-epi-isoaplydactone”, could also be found in A. dactylomela.

Halogenated Metabolites from the Diet of Aplysia dactylomela Rang

“…It recorded a 50% inhibition at 45.4 and 92.4 µmol/L for both the cell lines respectively [58]. Aplydactone (60) was isolated from specimens of Nosy Hara, off the coast of Madagascar [59]. It possesses a highly strained, tetracyclic skeleton with three quaternary stereocenters, which are all embedded in the ladderane substructure [60].…”

“…Aplydactone (60) was isolated from specimens of Nosy Hara, off the coast of Madagascar [59]. It possesses a highly strained, tetracyclic skeleton with three quaternary stereocenters, which are all embedded in the ladderane substructure [60]. It is assumed that dactylone (85) is converted to aplydactone (60) via photochemical addition due to the intense solar irradiation the sea hare is exposed to.…”

“…It is assumed that dactylone (85) is converted to aplydactone (60) via photochemical addition due to the intense solar irradiation the sea hare is exposed to. Laboratory biosynthesis, however, revealed the need for a "biomimetic" light source at 350 nm for 24 h for the reproduction of aplydactone (60). Irradiation of 10-epi-dactylone (61) under the same condition produces 8-epi-isoaplydactone (62) rather than 8-epi-aplydactone (63), which was initially obtained via non-biomimetic synthesis [60].…”

“…Laboratory biosynthesis, however, revealed the need for a "biomimetic" light source at 350 nm for 24 h for the reproduction of aplydactone (60). Irradiation of 10-epi-dactylone (61) under the same condition produces 8-epi-isoaplydactone (62) rather than 8-epi-aplydactone (63), which was initially obtained via non-biomimetic synthesis [60]. Matsuura et al (2017) also reported the metabolites 10-bromo-β-chamigren-2-ol (64) and 10-bromo-β-chamigren-2,3-ol (65).…”

Total Synthesis of Aplydactone by a Conformationally Controlled C−H Functionalization

“…Later Tr auner et al also independently reported their interesting findings in photochemical relationships among brominated sesquiterpenes from Aplysia dactylomela. [7] Herein we report aconcise synthesis of 1 and it is greatly facilitated by an unusual late-stage,r emote C À H functionalization. [8] Theu nprecedented structure of aplydactone inspired us to pursue as trategically unique pathway.A so utlined in Figure 1b,weenvisioned that the brominated carbon stereocenter (C8) of 1 could arise from as tereoselective hydrogenation of the vinyl bromide function (C8 À C9) of the advanced precursor 3.T he bridged cyclohexanone ring in 3 (highlighted with bold lines) could be forged by an intramolecular carbenoid CÀHinsertion [9] from the a-diazoketone 4 which bears a[2]-ladderane scaffold (6/4/4 tricyclic system).…”