Structural Determination of (−)-SCH 64874 and Hirsutellomycin by Semisynthesis

Abstract

The structure of a C-symmetric epidithiodiketopiperazine alkaloid, SCH 64874, was determined by semisynthesis. The relative stereochemistry of the β-hydroxy carboxylic acid chain having three chiral centers was determined by comparison of the NMR data of the four possible diastereomeric β-hydroxy carboxylic acid fragments with those of SCH 64874. Condensation of the (-)-deacetylaranotin core with two enantiomeric β-hydroxy carboxylic acids revealed the relative stereochemistry of SCH 64874. The relative stereochemistry of the β-keto carboxylic acid chain of the analogous alkaloid hirsutellomycin was determined in a stepwise manner. The C4'-C6' syn relationships were predicted by comparing the NMR data of the corresponding ester fragments with that of hirsutellomycin. The relative stereochemistry of the whole molecule, including the epimerizable C2' stereocenter, was determined by introduction of four possible side chains into the bisdethiodi(methylthio)deacetylaranotin core. We found that the stereochemistry of C2' converged with that of the thermodynamically stable form influenced by the core structure.

Muyocopronones A and B: azaphilones from the endophytic fungus Muyocopron laterale

“…During their investigation into the structural determination of (−)-SCH 64874, Tokuyama et al reported the synthesis and NMR characterization of the four possible diastereomers of the β-hydroxycarboxylic acid side chain [20]. Based on the obtained NMR data, the relative structure of the side chain of 1 was determined to adopt the (2′R*,3′R*,4′S*) configuration, as determined by the chemical shifts and the coupling constants between H-2′/H-3′ (J = 8.2 Hz) and H-3′/H-4′ (J = 3.2 Hz).…”

“…Azaphilones containing 6-membered rings constitute less than 10% of the hundreds of azaphilones isolated to date [ 5 ], and to the best of our knowledge, only eight compounds with a 2,4-dimethyl-3-hydroxyhexanoate moiety have been previously reported. More specifically, three thiodiketopiperazines, namely SCH 64874, 64875, and 64877, were isolated from the fermentation broth of an unidentified fungus [ 20 , 26 ], while three azaphilone-related polyketides, namely dothideomycetones A, B, and dothideomycetide A, were isolated from the CR17 fungal strain of the Dothideomycetes class (GeneBank accession number JQ867364) [ 27 ]. Furthermore, two sesquiterpenoids produced by Pithomyces chartarum (Dothideomycetes) were reported as intercellular adhesion molecule-1 (ICAM1) expression inhibitors in a patent literature [ 28 ].…”

Total Synthesis of Oxepin and Dihydrooxepin Containing Natural Products

“…7 Danshen is a traditional Chinese drug used for the treatment of coronary artery disease and is known to possess antiviral, antioxidant, and antitumor activities. The reported total synthesis began with aldehyde 20, which was converted into bromide 21 via bromination and tosyl- In 1991, Castedo reported the synthesis of norsecosarcocapnine (29), which also gave access to secosarcocapnine (30) via an intramolecular Ullmann coupling (Scheme 5). 8 Subsequent Cope elimination of the piperidine motif gave Scheme 3 Ring-closing metathesis for the construction of the oxepin motif in janoxepin (19) by Taylor…”

“…In 1991, Castedo reported the synthesis of norsecosarcocapnine (29), which also gave access to secosarcocapnine (30) via an intramolecular Ullmann coupling (Scheme 5). 8 Subsequent Cope elimination of the piperidine motif gave Scheme 3 Ring-closing metathesis for the construction of the oxepin motif in janoxepin (19) by Taylor…”

“…the desired oxepin structure. Reduction of the hydroxylamine moiety with zinc and sulfuric acid gave norsecosarcocapnine (29), which was then methylated with either methyl iodide followed by treatment with sodium ethanolate or by reductive amination using formaldehyde and sodium borohydride to give secosarcocapnine (30).…”