The first electrophilic α-amination reaction of labdane-type diterpene (−)-(5S,9S,10S,13S)-labd-7-en-15-oic acid and (+)-(5S,8R,9R,10S,13R)-8-hydroxylabdan-15-oic acid, isolated from aerial parts of Ageratina jocotepecana is presented. In the presence of dibenzylazodicarboxylate and proline followed by an in situ reduction, the corresponding hydrazino alcohols were obtained. It is demonstrated that the first diterpene moiety had no influence in the diastereoselectivity that is then controlled by the catalyst used, at the opposite to the second diterpene that mainly control the diastereochemistry of the product. Graphical Abstract

(−)-Patagonic acid (1) is a clerodane diterpene isolated from several plants from the Alismataceae, Asteraceae, Euphorbiaceae, Fabaceae, Lamiaceae, Salicaceae, Sapindaceae, and Velloziaceae families, and its biological potential as an inhibitor of butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) and as an anti-inflammatory compound has been described. Furthermore, the enantiomer (+)-1 is also described in Fabaceae and Verbenaceae. A lack of formal studies about the absolute configuration (AC) determination of 1 is emphasized. Thus, the present manuscript describes the AC determination of patagonic acid (1). The chemical correlation of (−)-1 from (−)-hardwickiic acid (2) was achieved by a simplistic oxidative process. The specific rotation value and electronic circular dichroism (ECD) analysis allowed for the AC determination of (−)-1 as (5R,8R,9S,10R)-(−)-patagonic acid. ECD revealed a positive exciton chirality (EC) phenomenon in both (−)-1 and (−)-2, which is directly associated with their configuration and conformational preferences, which were assessed by DFT calculations at the B3LYP/DGDZVP level of theory. Since the NMR data of (+)-1 are fully coincident with those from its enantiomer studied herein, the chirality of (5S,8S,9R,10S)-(+)-patagonic acid could also be determined. These experimental conclusions deeply complement the literature related to clerodane compounds biosynthesized in several families of plants of scientific interest.

Strategic scaffolds in molecules increase the possibility of obtaining derivatives with potential uses in scientific and industrial areas. The regio- and stereoselective reactions can be considered to gain these tactical motifs. Natural diterpenes are key molecules for reaching such aims. Among this class of compounds, neo-clerodanes are highlighted by the presence of a furan moiety in their chemical structure. This work describes a regio- and stereoselective strategy to gain beta-lactone and oxirane derivatives from kerlinic acid (1) when the β,γ-unsaturated carboxylic acid system is oxidized, preserving the furan moiety. Oxidation of 1 yielded salviaolide (2), suggesting regio- and stereoselective means. A reaction mechanism was proposed when oxidation of the acetate (1a), benzoate (1b), and methyl ester (1c) derivatives from 1 were gained. The obtention of the epoxide derivative 3, kernolide (4), and kernolide epoxide (5) also supported the reaction mechanism. X-ray diffraction analysis of 3, Karplus-type analyses, and DFT calculations from hypothetical intermediates revealed conformational preferences that guide the regioselectivity. The stereoselectivity was attributed to the natural origin of 1. All compounds were characterized by their physical and spectroscopical data. These results suggest the feasibility of promoting regioselective oxidation on neo-clerodane compounds, preserving the furan moiety.

Objective: This study aims to convert cativic acid, which was isolated from Ageratina jocotepecana, into cistendiol (5), an analog of cistenolic acid isolated from Cistus symphytifolius. The position of hydroxyl at C-7 in compound 5 could be achieved by applying the Schenck reaction with singlet oxygen (¹O₂) through photooxidation reaction of 6. Additionally, epoxidation reaction of 1, followed by further reduction and acid treatment, can serve as another pathway to obtain compound 5. Methods: Cativic acid was isolated from Ageratina jocotepecana flowers, reduction methodology was realized with THF and LiAlH₄, epoxidation reaction was carried out with mCPBA in CH₂Cl₂ and K₂CO₃, oxidation of alcohol with PCC in CH₂Cl₂ and MgSO₄, photooxidation reaction was realized with blue and white light using singlet oxygen (¹O₂) and photosensitizers such as eosin, methylene blue and Ru(bpy)₃(PF₆)₂ in acetonitrile. Geometry optimizations for transition states were performed using MMFF94 with Monte Carlo protocol, and G_DFT was used B3LYP/DGDZVP level of theory with Gaussian 09. Results: Cistendiol was synthesized by photooxidation reaction of 6 with Ru(bpy)₃(PF₆)₂ and air such oxidant with a ratio of 8:1, while epoxidation of 1 further reduction and acid treatment afforded cistendiol with a ratio of 9:1, the ratio was determined by NMR, additionally the global minimum energy structures G_DFT calculated values supports the results described by NMR ratio. The stereochemistry was also confirmed by NOESY experiment and the comparison is in agreement with literature data. Conclusion: Herein, we described the conversion of cativic acid isolated from Ageratina jocotepecana employing a new photooxidation methodology and classic epoxidation techniques, to produce an analog of cistenolic acid isolated from Cistus symphytifolius. The results, which include Supplemental material, enable comparison of stereochemistry, specifically the 13 S for C-13 of Ageratina jocotepecana with other compounds such as cistenolic or salvic acid, which had been the subject of study by researchers.