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. 2019 Sep 20;21(18):7394-7399.
doi: 10.1021/acs.orglett.9b02713. Epub 2019 Sep 9.

Pharmacophore-Directed Retrosynthesis Applied to Rameswaralide: Synthesis and Bioactivity of Sinularia Natural Product Tricyclic Cores

Nathanyal J Truax  1 , Safiat Ayinde  2 , Khoi Van  1 , Jun O Liu  2 , Daniel Romo  1
Affiliations

Pharmacophore-Directed Retrosynthesis Applied to Rameswaralide: Synthesis and Bioactivity of Sinularia Natural Product Tricyclic Cores

Nathanyal J Truax et al. Org Lett. .

Abstract

A pharmacophore-directed retrosynthesis strategy applied to rameswaralide provided simplified precursors bearing the common 5,5,6 (red) and 5,5,7 (blue) skeleton present in several cembranoid and norcembranoids from Sinularia soft corals. Key steps include a Diels-Alder lactonization organocascade delivering the common 5,5,6 core and a subsequent ring expansion affording a 5,5,7 core serviceable for the synthesis of rameswaralide. Initial structure-activity relationships of intermediates en route to the natural product have revealed interesting differential and selective cytotoxicity.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
Structurally related, polycyclic, Sinularia diterpenoid natural products.
Scheme 1.
Scheme 1.
Pharmacophore Directed Retrosynthetic (PDR) approach toward rameswaralide
Scheme 2.
Scheme 2.
Synthesis of diene 9 and the 5,5,6 tricyclic cores 8 and 15 via the Diels-Alder Lactonization (DAL) organocascade.
Scheme 3.
Scheme 3.
Alkene transposition of enol ether 8 and a complex-induced, proximity effect driven cyclopropanation.
Scheme 4.
Scheme 4.
Attempted ring expansion of cyclopropane 20.
Scheme 5.
Scheme 5.
Synthesis of bromocyclopropane 24 and ring-expansions to functionalized 5,5,7 tricyclic ring systems.
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References

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