Discovery, total syntheses and potent anti-inflammatory activity of pyrrolinone-fused benzoazepine alkaloids Asperazepanones A and B from Aspergillus candidus

Abstract

Natural products are well established as an important resource and play an important role in drug discovery. Here, two pyrrolinone-fused benzoazepine alkaloids, (+)-asperazepanones A (1) and B (2) with a 6/7/5 ring system, together with the artifact (−)-asperazepanone A (1), were isolated from the coral-derived Aspergillus candidus fungus. Their structures including absolute configurations were elucidated by extensive spectroscopic methods, single crystal X-ray diffraction, and ECD calculations. Furthermore, total syntheses of (±)-1 and (±)-2 have been achieved starting from the commercially L-aspartic acid diethyl ester hydrochloride and monoethyl malonate in 7 and 8 steps, respectively. The key step in the syntheses was an intramolecular Friedel-Crafts reaction to build the unique tricyclic skeleton. Interestingly, (+)-2 not only showed obviously inhibitory activity against NO production, but also inhibited potent LPS-induced expression of TNF-α and IL-6 at the concentration of 0.1 μM. It thus represents a potentially promising lead for anti-inflammatory drug discovery.

Cytosporones W and X: Two Mutually Converting Epimers from a Mangrove Endophytic Fungus Diaporthe sp. ZJHJYZ-1

“…In the meanwhile, (±)-3 were also isolated by using HPLC with the same chiral-ND column, respectively, at t R = 7.5 and 10.0 min (the gradient was n-hexane/2-propanol v/v, 80:20, flow rate: 1 mL/min), and the structures of (±)-3 were determined by comparing their NMR data to cytosporone D. 9 Similarly, (±)-3 showed the enantiomerization equilibrium appearance with HPLC-DAD analysis. 5 C-1 and C-6′ were two chiral centers of 1 and 2, and C-1 was the unique chiral center of (±)-3. Sharing the similar converting behavior indicated that C-1 was the key to the converting mechanism, and configuration of C-6′ of 1 is the same as 2, because it is unlikely for a chiral carbon's configuration converting on an aliphatic chain in this very situation, which could be further supported by their chemical shifts (δ H -1′ 1.84 in 1 while at δ H -1′ 1.83 in 2).…”

“…To verify hypotheses that is similar to the above plausible mechanism, methylation methods were performed in previously reported articles. , Likewise, methylation reactions of the hydroxyl groups of 1 and 2 with different reagents were applied: (i) sodium hydride and iodomethane, (ii) and (iii) thionyl chloride (SOCl 2 ) in methanol (MeOH) in different addition sequences, and (iv) (trimethylsilyl)­diazomethane (TMS-CHN 2 ). The conditions and the results are listed in Table .…”

“…The plausible mechanism of the epimerization equilibrium between 1 and 2 was proposed (Figure ). − The transferring of electrons caused the opening of lactone ring and sp 2 planarization of C-1. Then the oxygen anion could attack C-1 of the intermediate evenly from both directions of the plane, which finally led to the racemization for the lactone ring.…”

“…Tautomeric and stereoisomerized compounds are common in the field of natural products research, especially for ketone–enol, − enamine–imino, hemiketal–aldol, , and (retro-)­oxa-Micheal addition tautomerism. Convincing hypotheses were proposed to clarify the converting mechanism, and NMR calculation, acid or alkali treatment, chiral-phase high-performance liquid chromatography (HPLC) analysis, and methylation reactions were reported to verify some of those hypotheses. − …”

Marine natural products

“…Total syntheses of both metabolites were achieved by employing an intramolecular Friedel–Crafts reaction and 296 exhibited potent LPS-induced expression of both TNF-α and IL-6. 131 Co-culture of A. candidus and Beauveria felina yielded drimane sesquiterpenes 297 and 298 that were mixtures of stereoisomers. 132 Chevalinulins A 299 and B 300 , alkaloids with an unprecedented spiro[bicyclo[2.2.2]octane-diketopiperazine] skeleton, were isolated from A. chevalieri sourced from deep-sea cold-seep sediment, 133 whilst another deep-sea-derived strain of A. chevalieri yielded indole diketopiperazine alkaloids 301 and 302 .…”