Salvinicins A and B, New Neoclerodane Diterpenes from Salvia divinorum

Abstract

Two new neoclerodane diterpenes, salvinicins A (4) and B (5), were isolated from the dried leaves of Salvia divinorum. The structures of these compounds were elucidated by spectroscopic techniques, including 1 H and 13 C NMR, NOESY, HMQC, and HMBC. The absolute stereochemistry of these compounds was assigned on the basis of single crystal X-ray crystallographic analysis of salvinicin A (4) and a 3,4-dichlorobenzoate derivative of salvinorin B.The genus Salvia is one of the most widespread members of the Lamiaceae (formerly Labiatae) family and is featured prominently in the pharmacopeias of many countries throughout the world. 1 Among these is Salvia divinorum Epling & Játiva, a sage native to Oaxaca, Mexico. An infusion prepared from four or five pairs of fresh or dried leaves is used by the Mazatec Indians to stop diarrhea, relieve headache and rheumatism, and to treat a 'semi-magical' disease known as panzón de barrego or swollen belly. 2 S. divinorum is also used in traditional spiritual practices of the Mazatecs to produce "mystical" or hallucinogenic experiences. 2The active ingredient in S. divinorum is salvinorin A (1a) (Figure 1) Currently, S. divinorum is unregulated in most countries and available throughout the world for purchase over the internet. However, it is listed as a controlled substance in Denmark, Australia, and Italy. Obtaining S. divinorum is easy in countries where it is unregulated, and it represents a cheap, easy solution for those who wish to experiment with drugs and perception altering substances. To date, U.S. laws for controlled substances do not ban the sale of S. divinorum or its active components. This has resulted in various on-line botanical companies advertising and selling S. divinorum as a legal alternative to other regulated plant hallucinogens. Therefore, it is predictable that its misuse will increase.As a hallucinogen, 1a is structurally unique. It bears no similarity to classical hallucinogens, such as LSD (2). Furthermore, it has no similarity to other opioid ligands, such as morphine (3). Given its potential for abuse, as well as, its unique pharmacological properties, we 18-20 and others 21-23 have begun to study the chemistry and pharmacology associated with constituents from S. divinorum.Previous phytochemical investigation of S. divinorum resulted in the identification of several neoclerodane diterpenes present in the leaves, salvinorins A -F and divinatorins A -C. 5,6, 8,24,25 Here, we report the identification of two new neoclerodane diterpenes present in commercially available S. divinorum leaves.Commercially available dried leaves of S. divinorum were extracted with acetone, and the acetone extract was subjected to repeated flash column chromatographies using a variety of solvent mixtures to afford salvinicins A (4) (65 mg) and B (5) (14 mg). Compound 4 gave a pseudomolecular ion peak at m/z 551.2080 ([M+Na] + ) in the HRESIMS suggesting a molecular formula of C 25 H 36 O 12 and an index of unsaturation of 8. Its IR spectrum showed absorption bands f...

Clerodane diterpenes: sources, structures, and biological activities

“…266 Salvinicins A ( 684 ) and B ( 685 ) from the same plant are unique neo -clerodanes with a 3,4-dihydroxy-2,5-dimethoxytetrahydrofuran ring. 273 Their absolute stereochemistry ( neo -series, A/B ring trans , B/C ring trans ) was based on X-ray crystallographic analysis. Interestingly, salvinicin A ( 684 ) exhibited partial κ agonist activity with an EC 50 value of 4.1 ± 0.6 μM ( E max = 80% relative to (-)-U50, 488H), while salvinicin B ( 685 ) exhibited antagonist activity at μ receptors with a K i of >1.9 μM.…”

“…This report provided a new lead in the development of opioid receptor antagonists. 273 Salvidivins A ( 686 ) and B ( 687 ) are a pair of geometrical isomers of the γ-hydroxy-α,β-unsaturated γ-lactone, differing from each other in the linkage position to C-12. It appears that 686 and 687 are important precursors of 684 (a partial agonist of the κ-opioid receptor) and 685 (the first μ-opioid antagonist with a neo -clerodane skeleton).…”

“…166,167,235,263–266,273,451 (The structures of 409–410 , 659, 686, 1240 , and 1241 are specifically shown, the remaining compounds can be found in the Structure Tables in ESI†.) In a modification study of 9 , salvinorin C ( 659 ) had 250-fold lower KOR affinity compared with 9 ( K i = 1022 nM vs .…”

Synthetic studies of neoclerodane diterpenes from Salvia divinorum: Selective modification of the furan ring

“…This was based on the activities of salvinicin A and B, as well as, our goal to reduce the potential for hepatotoxicity seen with furan containing natural products. [16][17][18][19] There are few reported methods for the functionalization of 3-substi- tuted furans. [20][21][22][23] Previously described methods have detailed the photooxidation of the furan moeity under basic conditions to form a c-hydroxybutenolide.…”

Studies Towards the Synthesis of Salvinorin A

“…Salvinorins B 2, [2] C, [9] D-F, [10] and G [11] have also been isolated from leaf extracts, along with salvinicins A and B [12] and divinatorins A, B, and C [13] and D and E [11] in low concentrations. So far there have been no reports of isolated metabolites possessing KOR activity higher than that of 1.…”