Synthetic studies of neoclerodane diterpenes from Salvia divinorum: semisynthesis of salvinicins A and B and other chemical transformations of salvinorin A

Abstract

Salvinorin A (1) is a hallucinogenic neoclerodane diterpene isolated from the widely available psychoactive plant Salvia divinorum and is the first example of a non-nitrogenous opioid receptor ligand. At present, there is little information available as to why this compound is selective for kappa opioid receptors. One approach to better understanding the mode of binding of 1 at kappa receptors is to systematically alter the structure of 1 and examine the effects on opioid receptor affinity and activity. Currently, there is a paucity of methods described for the preparation of analogues derived from 1. Here, we report the investigation of several chemical transformations of 1 isolated from S. divinorum. In particular, this work provides a semisynthesis of salvinicins A (2) and B (3) and has identified 10a as the first neoclerodane diterpene with delta opioid antagonist activity.

Figure 1

Representative data from the [³⁵S]GTP-γ-S binding and Calcium 3 dye assays. All the compounds displayed greater potency in the calcium flux assay suggesting greater receptor/effector coupling in the G_α16-hκOR CHO cells. Both 1 and 10a were full agonists in the [³⁵S]GTP-γ-S binding assay and 1, but not 10a, elicited greater calcium stimulation than U69,593 in the calcium flux assay.

Scheme 1

(i) Br₂, MeOH, CH₂CI₂, -30 °C; (ii) KMnO₄, THF/H₂O, -10 °C; (iii) RuCI₃, NalO₄, CCI₄/CH₃CN/H₂O; (iv) NBS, CH₃CN; (v) Br₂, DMF

Scheme 1

(i) Br₂, MeOH, CH₂CI₂, -30 °C; (ii) KMnO₄, THF/H₂O, -10 °C; (iii) RuCI₃, NalO₄, CCI₄/CH₃CN/H₂O; (iv) NBS, CH₃CN; (v) Br₂, DMF

Scheme 2

(i) (lm)₂CS, DMAP, CH₂CI₂; (ii) AIBN, Bu₃SnH, Toluene; (iii) Appropriate acid, (2-Py)PPh₂, DBAD, THF; (iv) CrO₃, Pyridine