Design, synthesis, and biological evaluation of air-stable nafuredin-γ analogs as complex I inhibitors

Reactivity of 2-Nitropyrrole Systems: Development of Improved Synthetic Approaches to Nitropyrrole Natural Products

“…With iodide 22 in hand, the key alkylation of sulfone 21 was next investigated. Despite abundant literature precedent, however, and the examination of a wide range of additional conditions, it did not prove possible to achieve the desired alkylation to effect the union of 21 and 22 . Decomposition of the starting material was observed in most cases, likely due to the sensitive nature of the 2-nitropyrrole motif in 22 .…”

Development of a new air-stable structure-simplified nafuredin-γ analog as a potent and selective nematode complex I inhibitor

“…8 tert-Butyldimethylsilyl protection, deacetylation by methanolysis and sharpless asymmetric epoxidation of a known allyl acetate 9 9 gave chiral epoxyalcohol 10, which was subjected to Appel reaction 10 to afford iodide 11. Introduction of the side chain moiety was achieved by coupling the epoxyiodide 11 with the corresponding known sulfones 12-14.…”

“…The reaction was stirred for 30 min at room temperature, quenched with H 2 O and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried over anhydrous Na 2 9, 135.1, 134.9, 131.4, 124.4, 124.2, 124.1, 123.2, 63.2, 62.9, 60.8, 39.7, 35.1, 28.9, 28.5, 26.8, 26.6, 25.9, 25.7, 25.6, 24.9, 18.3, 17.7, 16.6, 16.0, − 5.3 (R,4E,8E,12E)-5,9,13,17-Tetramethyl-1-((S)-2-methyltetrahydrofuran-2-yl)octadeca -4,8,12,16-tetraen-1-ol (6) To a solution of 17 (9.0 mg, 0.0174 mmol) in THF (1.7 ml) at room temperature was added tetrabutylammonium fluoride (1.0 M in THF, 35 μl, 8,135.0,134.9,131.3,124.4,124.2,124.1,124.0,85.8,76.1,67.9,39.8,39.7,31.9,30.6,26.7,26.6,26.3,25.7,25.1,23.1,17.7,16.1,16.0,15.9;HRMS (FAB, tert-Butyldimethyl(3-((2R,3R)-2-methyl-3-((3E,7E) -4,8,12-trimethyltrideca-3,7,11-trien-1-yl)oxiran-2-yl)propoxy)silane (19) To a solution of 18 (1.25 g, 3.60 mmol) in THF (20 ml) at − 78°C were added hexamethylphosphoramide (3.1 ml, 18.0 mmol) and n-BuLi (1.64 M in n-hexane, 4.4 ml, 7.20 mmol). After stirring for 1 h at − 78°C, a solution of 11 (1.60 mg, 4.30 mmol) in THF (10 ml) was added dropwise to the above mixture.…”

“…Thus, we found that a new nafuredin-γ analog 3 obtained by a concise synthesis approach showed moderate complex I inhibitory activity while having high air stability ( Figure 2). 8 To improve the nematode complex I inhibitory activity of air-stable nafuredin-γ analogs, additional structure-activity relationship studies were carried out over 3. Thus, the length of the isoprene unit as a side chain was changed originating new targets 4-6.…”

Synthesis of Chiral γ,γ-Disubstituted γ-Butenolides via Direct Vinylogous Aldol Reaction of Substituted Furanone Derivatives with Aldehydes

“…This is the first report of a successful direct asymmetric vinylogous aldol reaction of aldehydes with γ-substituted β,γ-butenolides. This methodology will lead to the development of more efficient syntheses for bioactive compounds such as nafuredin-γ . Application of the squaramide–sulfonamide organocatalysts to syntheses of bioactive compounds is currently in progress in our laboratory and will be reported in due course.…”