Clerodane diterpenes: sources, structures, and biological activities

Abstract

The clerodane diterpenoids are a widespread class of secondary metabolites and have been found in several hundreds of plant species from various families and in organisms from other taxonomic groups. These substances have attracted interest in recent years due to their notable biological activities, particularly insect antifeedant properties. In addition, the major active clerodanes of Salvia divinorum can be used as novel opioid receptor probes, allowing greater insight into opioid receptor-mediated phenomena, as well as opening additional areas for chemical investigation. This article provides extensive coverage of naturally occurring clerodane diterpenes discovered from 1990 until 2015, and follows up on the 1992 review by Merritt and Ley in this same journal. The distribution, chemotaxonomic significance, chemical structures, and biological activities of clerodane diterpenes are summarized. In the cases where sufficient information is available, structure activity relationship (SAR) correlations and mode of action of active clerodanes have been presented.

Diterpene Synthase‐Catalyzed Biosynthesis of Distinct Clerodane Stereoisomers

“…Relative cis ‐ or trans ‐ configurations for the C‐8 and C‐9 methyl groups of CLPP are defined by the first C‐9 to C‐8 hydride migration, and the final C‐4 to C‐5 methyl migration determines the relative cis ‐ or trans ‐ arrangement for the CLPP decalin bridgehead at C‐5 and C‐10 (Scheme S1) –. In addition, the absolute neo ‐ or ent‐neo ‐stereochemistry is dependent on the configuration of the labda‐13 E ‐en‐8‐yl + diphosphate intermediate (Scheme S1) …”

“…Plant clerodane diterpenoids form a diverse group of natural products that have attracted increasing attention for their potential therapeutic applications . Examples include columbin which has anti‐inflammatory and anticancer efficacy, HDK20 (6‐α‐hydroxy‐cleroda‐3,13‐dien‐15,16‐olide) for treating infectious sleeping sickness, and salvinorin A, which has entered phase 1 clinical trials for its possible application in the treatment of drug addictions and neuropsychiatric disorders (https://clinicaltrials.gov/ IDs: NCT03418714, NCT00996411) . Although elaborate multistep chemical synthesis routes have been devised for clerodane products such as salvinorin A, reliable and scalable platforms for producing these compounds remain limited in many, if not most, cases.…”

“…The intermediary carbocation is most commonly terminated by deprotonation or nucleophilic addition at C‐8 to afford different copalyl diphosphate (CPP) derivatives . Alternatively, conversion of the carbocation through a series of alternating 1,2‐migrations of hydride and methyl groups prior to deprotonation yields the clerodienyl diphosphate (CLPP) scaffold (Scheme and Scheme S1 in the Supporting Information) …”

“…When derived from GGPP, clerodanes contain four contiguous stereocenters at C‐5, C‐8, C‐9 and C‐10 that can feature neo ‐ or ent‐neo ‐ absolute configurations of the four relative diastereomers trans‐cis ‐ (TC), trans‐trans ‐ (TT), cis‐trans ‐ (CT) and cis‐cis ‐ (CC) CLPP (Scheme ) . Relative cis ‐ or trans ‐ configurations for the C‐8 and C‐9 methyl groups of CLPP are defined by the first C‐9 to C‐8 hydride migration, and the final C‐4 to C‐5 methyl migration determines the relative cis ‐ or trans ‐ arrangement for the CLPP decalin bridgehead at C‐5 and C‐10 (Scheme S1) –. In addition, the absolute neo ‐ or ent‐neo ‐stereochemistry is dependent on the configuration of the labda‐13 E ‐en‐8‐yl + diphosphate intermediate (Scheme S1) …”

Semisynthesis and Kappa-Opioid Receptor Activity of Derivatives of Columbin, a Furanolactone Diterpene

“…1–3 The genera Tinospora and Jateorhiza belong to the Menispermaceae family and are found most widely in Asia and Africa. Characteristic components of these genera are neoclerodane diterpenoids, 4,5 representative of an important chemical class with a variety of demonstrated biological activities including cytotoxic, analgesic, and antimicrobial activities.…”