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. 2017 Oct 6;19(19):5414-5417.
doi: 10.1021/acs.orglett.7b02684. Epub 2017 Sep 14.

Modular Approach to pseudo-Neoclerodanes as Designer κ-Opioid Ligands

Alexander M Sherwood  1 , Samuel E Williamson  1 , Rachel S Crowley  1 , Logan M Abbott  1 , Victor W Day  1 , Thomas E Prisinzano  1
Affiliations

Modular Approach to pseudo-Neoclerodanes as Designer κ-Opioid Ligands

Alexander M Sherwood et al. Org Lett. .

Abstract

Informed by previous semisynthetic work on salvinorin A, a modular total synthesis has been developed capable of producing novel compounds targeting the κ-opioid receptor. The strategy has permitted the deliberate simplification and introduction of functionality about the target molecule to provide access to molecular features on salvinorin A otherwise unattainable by semisynthesis. Using this approach, a potent pseudo-neoclerodane κ-opioid receptor ligand (2) has been realized.

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Figures

Figure 1
Figure 1
Salvinorin A (1) and representative semi-synthetic derivatives (3–7) in support of 3-point bind-ing model hypothesis. Values indicate fold-change in activity relative to 1 in the assay readout evaluated.
Figure 2
Figure 2
Disconnect strategy and retrosynthesis to 14-membered bisenone macrolide 8 that is capable of undergoing a diastereoselective transannular cascade reaction to 2.
Scheme 1
Scheme 1
Synthetic route to pseudo-neoclerodane 2 with unambiguous characterization by single crystal X-ray diffraction.
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