Abstract:We accomplished the divergent total syntheses of ten pentacyclic cytochalasans (aspergillin PZ, trichodermone, trichoderones, flavipesines, and flavichalasines) from a common precursor aspochalasin D and revised the structures of trichoderone B, spicochalasin A, flavichalasine C, aspergilluchalasin based on structure network analysis of the cytochalasans biosynthetic pathways and DFT calculations. The key steps of the syntheses include transannular alkene/epoxyalkene and carbonyl‐ene cyclizations to establish … Show more
“…According to the above results, pcCYTs 1 and 2 are the nonenzymatic conversion products obtained from simple moCYTs 8 and 7 . This discovery is the opposite of a previous biosynthetic hypothesis, that the formation of polycyclic skeletons in CYTs, from the common macrocycle framework, may need to involve a series of diverse oxidative reactions 3 , 12 . This nonenzymatic polycyclic transformation might be related to the highly reactive features of the γ‐keto‐α,β‐unsaturated moiety in 7 and 8 , which might also be important for linking the macrocycle framework to other chemical functional groups via a Diels-Alder reaction, heterocycloaddition or Michael addition.…”
Section: Resultscontrasting
confidence: 58%
“…1d ), such as the 5/6/6/5/6-fused pentacyclic ring in aspergillin PZ ( 1 ) and its dehydroxylated derivate 2 . Therefore, these fantastic transformation reactions towards moCYT scaffolds represent a good learning example to understand the chemical logic of nature during the construction of complex natural products 3 , and more importantly, to provide an insightful biomimetic strategy for chemists to synthesize this family of compounds 4 – 12 . Fig.…”
Cytochalasans (CYTs), as well as their polycyclic (pcCYTs) and polymerized (meCYTs) derivatives, constitute one of the largest families of fungal polyketide-nonribosomal peptide (PK-NRP) hybrid natural products. However, the mechanism of chemical conversion from mono-CYTs (moCYTs) to both pcCYTs and meCYTs remains unknown. Here, we show the first successful example of the reconstitution of the CYT core backbone as well as the whole pathway in a heterologous host. Importantly, we also describe the berberine bridge enzyme (BBE)-like oxidase AspoA, which uses Glu538 as a general acid biocatalyst to catalyse an unusual protonation-driven double bond isomerization reaction and acts as a switch to alter the native (for moCYTs) and nonenzymatic (for pcCYTs and meCYTs) pathways to synthesize aspochalasin family compounds. Our results present an unprecedented function of BBE-like enzymes and highly suggest that the isolated pcCYTs and meCYTs are most likely artificially derived products.
“…According to the above results, pcCYTs 1 and 2 are the nonenzymatic conversion products obtained from simple moCYTs 8 and 7 . This discovery is the opposite of a previous biosynthetic hypothesis, that the formation of polycyclic skeletons in CYTs, from the common macrocycle framework, may need to involve a series of diverse oxidative reactions 3 , 12 . This nonenzymatic polycyclic transformation might be related to the highly reactive features of the γ‐keto‐α,β‐unsaturated moiety in 7 and 8 , which might also be important for linking the macrocycle framework to other chemical functional groups via a Diels-Alder reaction, heterocycloaddition or Michael addition.…”
Section: Resultscontrasting
confidence: 58%
“…1d ), such as the 5/6/6/5/6-fused pentacyclic ring in aspergillin PZ ( 1 ) and its dehydroxylated derivate 2 . Therefore, these fantastic transformation reactions towards moCYT scaffolds represent a good learning example to understand the chemical logic of nature during the construction of complex natural products 3 , and more importantly, to provide an insightful biomimetic strategy for chemists to synthesize this family of compounds 4 – 12 . Fig.…”
Cytochalasans (CYTs), as well as their polycyclic (pcCYTs) and polymerized (meCYTs) derivatives, constitute one of the largest families of fungal polyketide-nonribosomal peptide (PK-NRP) hybrid natural products. However, the mechanism of chemical conversion from mono-CYTs (moCYTs) to both pcCYTs and meCYTs remains unknown. Here, we show the first successful example of the reconstitution of the CYT core backbone as well as the whole pathway in a heterologous host. Importantly, we also describe the berberine bridge enzyme (BBE)-like oxidase AspoA, which uses Glu538 as a general acid biocatalyst to catalyse an unusual protonation-driven double bond isomerization reaction and acts as a switch to alter the native (for moCYTs) and nonenzymatic (for pcCYTs and meCYTs) pathways to synthesize aspochalasin family compounds. Our results present an unprecedented function of BBE-like enzymes and highly suggest that the isolated pcCYTs and meCYTs are most likely artificially derived products.
“…HF was used as apromoter, desired product 25 was obtained as the major product in 80 % yield and hydroxylation product 26 was also obtained in 35 % Scheme 3. Total syntheses of proposed trichoderone B, proposed flavichalasine C, flavichalasines A, and D. [35] Angewandte Chemie Forschungsartikel 16102 www.angewandte.de yield when extra water was added under the same conditions. Fort he synthesis of trichoderone A( 3)f rom 25,as eries of transformations are needed:1 )stereoselective allylic oxidation to form atertiary alcohol;2)amide oxidation to form an in situ imine;3)intramolecular imine addition of the tertiary alcohol.…”
Section: Total Syntheses Of Flavipesines Aa Nd Bmentioning
confidence: 99%
“…Total syntheses of trichoderone Aand trichodermone. [35] Angewandte Chemie Forschungsartikel (88 %y ield). By using ap hotooxygenation of 2, 3-dihydrofurans followed by ferrous ion-catalyzed gem-dehydration procedure developed by Tu ng and Wu, [28] dihydrofuran 29 was successfully converted to trichodermone ( 5)i n8 1%.T he spectra and physical properties of trichoderone A( 3)a nd trichodermone ( 5)w ere identical to those reported for their naturally occurring counterparts,r espectively.N otably,t he biosynthetic pathway for trichoderone A (3)has not yet been proposed due to its unique tetrahydrofuran ring formation.…”
Section: Total Syntheses Of Flavipesines Aa Nd Bmentioning
confidence: 99%
“…Revision of the structures of of trichoderone B, flavichalasine C, spicochalasin Aa nd aspergilluchalasin. [35] Angewandte Chemie Forschungsartikel 16104 www.angewandte.de putative structures,a sw ell as to distinguish diastereomers. Elaborate analyses of the reported NMR data of trichoderone Ba nd flavichalasine C, in combination with subsequent DFT calculations of NMR chemical shifts and coupling constants revealed their most possible structures to be 31 and 32,respectively (see Part III in Supporting Information).…”
Section: Total Syntheses Of Flavipesines Aa Nd Bmentioning
We accomplished the divergent total syntheses of ten pentacyclic cytochalasans (aspergillin PZ, trichodermone, trichoderones, flavipesines, and flavichalasines) from a common precursor aspochalasin D and revised the structures of trichoderone B, spicochalasin A, flavichalasine C, aspergilluchalasin based on structure network analysis of the cytochalasans biosynthetic pathways and DFT calculations. The key steps of the syntheses include transannular alkene/epoxyalkene and carbonyl‐ene cyclizations to establish the C/D ring of pentacyclic aspochalasans. Our bioinspired approach to these pentacyclic cytochalasans validate the proposed biosynthetic speculation from a chemical view and provide a platform for the synthesis of more than 400 valuable cytochalasans bearing different macrocycles and amino‐acid residues.
Comprehensive Summary
Five novel heterodimers of cytochalasan and ergosterol, ergochaeglobosins A—E, were isolated from an endophytic fungus Chaetomium globosum P2‐2‐2. Ergochaeglobosin A (1) possesses an unprecedented 5/6/13/6/5/6/6/6 fused octacyclic ring system, and ergochaeglobosins B (2) and C (3) form a unique 5/6/13/6/6/6/6/5 fused octacyclic ring system, whereas ergochaeglobosins D (4) and F (5) are the first cytochalasan heterodimers formed via a N‐1′/C‐3′′ single bond. Their structures with absolute configurations were established by extensive spectroscopic analyses, single‐crystal X‐ray diffraction, and ECD calculations. The plausible biogenetic pathway of 1—5 was postulated. Compound 1 exhibited inhibitory effects against ConA‐induced T cells and LPS‐induced B cells proliferation with IC50 values of 19.2 and 14.1 μmol/L, respectively. Co‐treatment of 3 (20 μmol/L) with TRAIL (150 ng/mL) could significantly decrease the cell viability of A549 by 24.9% comparing with monotherapy of 3 (20 μmol/L).
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
