Opioid receptor probes derived from cycloaddition of the hallucinogen natural product salvinorin A

Abstract

As part of our continuing efforts toward more fully understanding the structure-activity relationships of the neoclerodane diterpene salvinorin A, we report the synthesis and biological characterization of unique cycloadducts through [4+2] Diels-Alder cycloaddition. Microwave-assisted methods were developed and successfully employed, aiding in functionalizing the chemically sensitive salvinorin A scaffold. This demonstrates the first reported results for both cycloaddition of the furan ring and functionalization via microwave-assisted methodology of the salvinorin A skeleton. The cycloadducts yielded herein introduce electron-withdrawing substituents and bulky aromatic groups into the C-12 position. Kappa opioid (KOP) receptor space was explored through aromatization of the bent oxanorbornadiene system possessed by the cycloadducts to a planar phenyl ring system. Although dimethyl- and diethylcarboxylate analogues 5 and 6 retain some affinity and selectivity for KOP receptors and are full agonists, their aromatized counterparts 13 and 14 have reduced affinity for KOP receptors. The methods developed herein signify a novel approach toward rapidly probing the structure-activity relationships of furan-containing natural products.

Figure 1

Formation of oxanorbornadiene analogues

Figure 2

Partial numbering of compounds 16a, 16b, and 17a with selected HMBC correlations.

Scheme 1^a

^aReagents and Conditions: (a) Appropriate alkyne, toluene, reflux (b) 2-(Trimethylsilyl)phenyl trifluoromethane sulfonate, CsF, CH₃CN, room temperature

Scheme 2^a

^aReagents and conditions: (a) Br₂, CH₂Cl₂; (b) KOt-Bu, THF, furan or 2-methyl furan; (c) 1, toluene, reflux

Scheme 3^a

^aReagents and conditions: (a) Fe₂(CO)₉, toluene, reflux

Scheme 4^a

^aReagents and conditions: (a) Ethyl 4,4,4-trifluoro-2-butynoate, toluene, reflux; (b) Fe₂(CO)₉, toluene, reflux