Synthetic studies of neoclerodane diterpenes from Salvia divinorum: role of the furan in affinity for opioid receptors

Abstract

Further synthetic modification of the furan ring of salvinorin A (1), the major active component of Salvia divinorum, has resulted in novel neoclerodane diterpenes with opioid receptor affinity and activity. A computational study has predicted 1 to be a reproductive toxicant in mammals and is suggestive that use of 1 may be associated with adverse effects. We report in this study that piperidine 21 and thiomorpholine 23 have been identified as selective partial agonists at kappa opioid receptors. This indicates that additional structural modifications of 1 may provide ligands with good selectivity for opioid receptors but with reduced potential for toxicity.

Figure 1

Results from the X-ray analysis on 33b drawn from the experimentally determined coordinates.

Scheme 1

Reagents and conditions: (a) NaIO₄, RuCl₃•3H₂O, CH₃CN/CCl₄/H₂O; (b) Appropriate amine or alcohol, EDCI, HOBt, Et₃N, CH₂Cl₂

Scheme 2

Reagents and conditions: (a) CDMT, NMM, EtSH, CH₂Cl₂, 88%; (b) Pd/C, Et₃SiH, CH₂Cl₂, 82%; (c) 9-(1R, 2R-pseudoephedrinyl)-(10S)-(trimethylsilyl)-9-borabicyclo[3.3.2]decane, allylMgBr, Et₂O; (d) 1. (R)-(+)-α-Methoxy-α-trifluoromethylphenylacetic acid, oxalyl chloride, benzene; 2. DMAP, NEt₃, CH₂Cl₂, 82%; (e) acryloyl chloride, DMAP, Et₃N, CH₂Cl₂, 40%; (f) Grubbs II, CH₂Cl₂, 58%; (g) Appropriate Wittig reagent; (h) 1. EDCI, C₆H₅C(NH₂)=NOH, CH₂Cl₂; 2. Toluene, heat