1,3-Dienes are common scaffolds in biologically active natural products as well as building blocks for chemical synthesis. Developing efficient methods for the synthesis of diverse 1,3-dienes from simple starting materials is therefore highly desirable. Herein, we report a Pd(II)-catalyzed sequential dehydrogenation reaction of free aliphatic acids via β-methylene C–H activation, which enables one-step synthesis of diverse E,E-1,3-dienes. Free aliphatic acids of varying complexities, including the antiasthmatic drug seratrodast, were found to be compatible with the reported protocol. Considering the high lability of 1,3-dienes and lack of protecting strategies, dehydrogenation of aliphatic acids to reveal 1,3-dienes at the late stage of synthesis offers an appealing strategy for the synthesis of complex molecules containing such motifs.
The synthesis and structural reassignment of laurefurenynes C–F has been achieved, with the new structures fitting with a proposed biosynthesis. Also reported is the synthesis of ent-laurencin and ent-deacetyllaurencin via a retrobiomimetic approach.
Pd(II)-catalyzed nondirected C-H functionalization of heteroarenes is a significant challenge for the following reasons: poor reactivity of electron-deficient heterocycles and the unproductive coordination of Lewis basic nitrogen atoms. Existing methodologies using palladium catalysis often employ a large excess of heterocycle substrates to overcome these hurdles. Despite recent advances in nondirected functionalization of arenes that allow them to be used as limiting reagents, the reaction conditions are incompatible with electron-deficient heteroarenes. Herein we report a dual-ligand catalyst that enables Pd(II)-catalyzed nondirected C-H olefination of heteroarenes without using a large excess of substrate. In general, the use of 1-2 equiv of substrates was sufficient to obtain synthetically useful yields. The reactivity was rationalized by the synergy between two types of ligands: a bidentate pyridine-pyridone ligand promotes C-H cleavage; the monodentate heterocycle substrate acts as a second ligand to form a cationic Pd(II) complex that has high affinity for arenes. The proposed dual-ligand cooperation is supported by a combination of X-ray, kinetics, and control experiments.
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
Acetylcholine and S -adenosylmethionine exemplify the tetraalkylammonium (R 4 N + ) and trialkylsulfonium (R 3 S + ) ions used by Nature. The corresponding trialkyloxonium ions (R 3 O + ), however, do not play a central role in biology most likely due to their hydrolytic instability compared with their ammonium and sulfonium counterparts. Indeed, Meerwein’s salts [(CH 3 ) 3 O + BF 4 – and (CH 3 CH 2 ) 3 O + BF 4 – ], the simplest of the trialkyloxonium ions, are among the most powerful alkylating agents known, and they too are unstable to water. Only recently have water stable trialkyloxonium ions been reported which contain an oxatriquinane skeleton. Interestingly, despite the inherent hydrolytic instability of the vast majority of trialkyloxonium ions, they have been postulated as key intermediates in the biosynthesis of a number of complex natural products from Laurencia species. The existence of these complex trialkyloxonium ions has been implied from the structural and stereochemical diversity of these natural products and is supported by elegant biomimetic total syntheses, yet no direct evidence for their existence has been forthcoming. Herein, we report the synthesis and full characterisation of one family of these biosynthetically relevant trialkyloxonium ions - the most structurally and stereochemically complex oxonium ions characterised to date. Additionally, the elucidation of their in vitro reactivity profile has resulted in the synthesis of more than ten complex halogenated natural products. This work substantiates the existence of complex trialkyloxonium ions as key reactive intermediates in the biosynthesis of numerous halogenated natural products from L. spp. – expanding Nature’s rich inventory of onium ions.
Acetylcholine and S -adenosylmethionine exemplify the tetraalkylammonium (R 4 N + ) and trialkylsulfonium (R 3 S + ) ions used by Nature. The corresponding trialkyloxonium ions (R 3 O + ), however, do not play a central role in biology most likely due to their hydrolytic instability compared with their ammonium and sulfonium counterparts. Indeed, Meerwein’s salts [(CH 3 ) 3 O + BF 4 – and (CH 3 CH 2 ) 3 O + BF 4 – ], the simplest of the trialkyloxonium ions, are among the most powerful alkylating agents known, and they too are unstable to water. Only recently have water stable trialkyloxonium ions been reported which contain an oxatriquinane skeleton. Interestingly, despite the inherent hydrolytic instability of the vast majority of trialkyloxonium ions, they have been postulated as key intermediates in the biosynthesis of a number of complex natural products from Laurencia species. The existence of these complex trialkyloxonium ions has been implied from the structural and stereochemical diversity of these natural products and is supported by elegant biomimetic total syntheses, yet no direct evidence for their existence has been forthcoming. Herein, we report the synthesis and full characterisation of one family of these biosynthetically relevant trialkyloxonium ions - the most structurally and stereochemically complex oxonium ions characterised to date. Additionally, the elucidation of their in vitro reactivity profile has resulted in the synthesis of more than ten complex halogenated natural products. This work substantiates the existence of complex trialkyloxonium ions as key reactive intermediates in the biosynthesis of numerous halogenated natural products from L. spp. – expanding Nature’s rich inventory of onium ions.
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