The preparation and reactivity of a range of novel paramagnetic chromium(II) complexes supported by a carbazole-based PNP pincer ligand is reported. Deprotonation of the ligand precursors R(PNP)H (1 R ) and subsequent reaction with chromium(II) chloride led to the formation of square-planar chlorido complexes R(PNP)CrCl (2 R ). Further reaction with various alkylating agents resulted in the isolation of chromium alkyl complexes R(PNP)CrR′ (3 R -R′) which were then hydrogenated to yield two rare examples of paramagnetic chromium(II) hydrides 4 i Pr and 4 t Bu . Both compounds were characterized by X-ray diffraction and paramagnetic NMR spectroscopy supported by a comprehensive DFT-supported assignment of the resonances. While the di(tert-butyl)phosphino PNP substituted complex 4 t Bu was found to exhibit a monomeric square-planar molecular structure, its isopropyl-substituted analog 4 i Pr forms a dimer, also indicated by a strong antiferromagnetic coupling of the chromium centers. The pronounced reactivity of these compounds toward CX double bonds was demonstrated by reaction with benzophenone, N,N′-dicyclohexylcarbodiimide, and carbon dioxide, which gave the corresponding insertion products. The alkoxido complex 5 i Pr , the amidinato complex 6 i Pr , and the formato compound 7 t Bu were also characterized by X-ray diffraction.
We report asymmetric bioinspired total syntheses of the fungal metabolites emeriones A-C via stereoselective oxidations of two bicyclo[4.2.0]octadiene diastereomers. The central bicyclic scaffolds are prepared in an 8π/6π electrocyclization cascade of a stereodefined pentaene, which contains the fully assembled side chains of the emeriones. The anti-aldol side chain is made using a Paterson-aldol addition, and the epoxide of the dioxabicyclo[3.1.0]hexane side chain via ring-closure onto an oxidized acetal. Our work has enabled the structural revision of emerione C, and resulted in the synthesis of a "missing" family member, which we call emerione D. DFT calculations identified two methyl groups that govern torquoselectivity in the 8π/6π cascade.Natural products derived from polyenes that undergo cyclization/isomerization cascades initiated by an 8π electrocyclization have intrigued chemists for decades. [1] The emeriones (Figure 1), one such family of natural products that were isolated from the fungus E. nidulans, [2] display oxidized bicyclo[4.2.0]octadiene cores (red) flanked by a seven carbon aldol fragment (blue) and a propenyl-substituted dioxabicyclo[3.1.0]hexane system (black). The two side chains (blue and black) of emerione A (1) and B (2) share the same absolute configurations, while the bicyclo-[4.2.0]octadieneoxide central scaffolds are enantiomeric with respect to each other. Emerione C has a bridging endoperoxide on the central core, and its proposed structure has a stereochemical configuration similar to emerione B.Related substances like shimalactone A (3) [1p] and ocellapyrone B (4) [1m, n] have been synthesized, but the emeriones are arguably the most complex examples of such natural products, each containing twelve stereocenters, eight of which are contiguous, and two quaternary. Moreover, the dioxabicyclo[3.1.0]hexane system, also found in natural products like verrucosidin (5), [3] is a considerable synthetic challenge alongside the oxidized bicyclo[4.2.0]octadiene scaffolds. Emerione A inhibits NO production in lipopolysaccharide-induced RAW264.7 cells [2] as well as NDM-1 [4] at low micromolar concentrations, but the emeriones appear not to have been tested in other assays. Motivated both by their striking structures and potentially undiscovered bioactivities, we chose to target the emeriones for synthesis. We describe herein the successful completion of the syntheses, the structural revision of emerione C, and the synthesis of the originally proposed structure of emerione C, which we name emerione D.
We report scalable syntheses of two potent and selective kallikrein related peptidase 6 (KLK6) inhibitors, as well as X-ray crystal structures of both inhibitors as protein-ligand complexes.
We report an asymmetric bioinspired total synthesis of the fungal metabolites emeriones A–C via stereoselective late-stage epoxidation or endoperoxidation of two bicyclo[4.2.0]octadiene diastereomers. The central bicyclic scaffold is synthesized in an 8pi/6pi electrocyclization cascade of a stereodefined (E,E,Z,Z,E)-pentaene, which contains the fully assembled and unprotected side chains of the natural products. The pentaene is constructed convergently through Stille cross-coupling of two similarly complex polyenes. The anti-aldol side chain of the emeriones is made using a Paterson-aldol approach, and the epoxide of the dioxobicyclo[3.1.0] side chain is synthesized via an unusual ring-closure onto an oxidized para-methoxyphenyl acetal. Our total synthesis has enabled the revision of the structure of emerione C and the synthesis of a “missing” family member, which we hereby call emerione D.
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