[formula: see text] A highly diastereoselective, microwave-induced Claisen rearrangement of an appropriately substituted propargylic enol ether allows the formation of the sterically congested C8-C14 bond of azadirachtin. When combined with a radical-mediated cyclization of the corresponding allene, this sequence offers rapid entry to the framework of azadirachtin.

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We describe in full the first synthesis of the potent insect antifeedant azadirachtin through a highly convergent approach. An O-alkylation reaction is used to unite decalin ketone and propargylic mesylate fragments, after which a Claisen rearrangement constructs the central C8-C14 bond in a stereoselective fashion. The allene which results from this sequence then enables a second critical carbon-carbon bond forming event whereby the [3.2.1] bicyclic system, present in the natural product, is generated via a 5-exo-radical cyclisation process. Finally, using knowledge gained through our early studies into the reactivity of the natural product, a series of carefully designed steps completes the synthesis of this challenging molecule.

Recognizing the value of including complex pyridines in small-molecule screening collections, we developed a previously unexplored [2 + 2 + 2]-cycloaddition of silyl-tethered diynes with nitriles. The tether provides high regioselectivity, while the solvent THF allows catalytic CpCo(CO)2 to be used without exogenous irradiation. One of the resulting bicyclic and monocyclic (desilylated) pyridines was identified as an inhibitor of neuregulin-induced neurite outgrowth (EC50 = 0.30 µM) in a screen that probes a pathway likely to be involved in breast cancers and schizophrenia.

Two Pd-catalyzed reductive transformations of diynes tethered through a silyl ether linkage were developed, where the reaction outcomes were controlled solely by selection of phosphine ligand. We screened Pd precatalysts, ligands, and additives to optimize conditions selective either for reductive cyclization or hydrogenation of this substrate class. Sixteen silyl ether-tethered diynes were prepared and subjected to the best catalyst/ligand combinations for each pathway. Silacyclic dienes and silyl-tethered enyne products of these reactions were elaborated to densely substituted, stereochemically- and appendage-rich, bicyclic and tricyclic small molecules in 1-3 synthetic steps. These studies illustrate how small modifications to a transition-metal catalyst can be used to access a diverse set of small molecules, in a fashion analogous to biosynthetic pathways such as terpene biosynthesis, where minor changes to enzyme structure direct skeletal differentiation.

Environmental issues and recent developments in chemistry and biology have introduced a number of compelling requirements that must be met in the development of practical catalysts. Recyclability is one important attribute. Retrievable catalysts that are recovered inexpensively and without significant waste generation efficiently deliver products of higher purity and lower toxicity. The emerging significance of combinatorial chemistry demands that a catalyst promote reactions efficiently and selectively while being easily adaptable to 96-well and higher density formats; repeated weighing of catalysts or substrates for a library synthesis and subsequent purification of each mixture is costly and time-consuming.Herein we disclose the synthesis and activity of Ru complexes supported by monolithic (smallest dimension 1 mm) samples of porous sol ± gel glass that effectively promote various olefin metathesis reactions. [1] These catalysts can be easily employed in a library synthesis format without multiple weighings, in air and with undistilled commercial reagent-grade solvents. Catalyst recovery is simply carried out with a pair of tweezers; it does not require filtration and generates minimal solvent waste. The catalyst retains its activity after multiple cycles (b 15), affording products that are of high (often analytical) purity without recourse to any purification steps.Recent reports from our laboratories relate to the chemistry of recyclable monomeric metathesis catalysts (1 and 2). [2] A key feature of these systems is the isopropyl styrenyl ether; this bidentate ligand favors efficient metal recovery for entropic reasons, allowing the promotion of olefin metathesis by a release/return mechanism. [2] These Ru complexes can also offer reactivity and chemo-and stereoselectivity profiles [3] which differ from the alternative catalysts 3, [4] 4, [5] and 5. [6] Although 1 and 2 are robust and recyclable, catalyst retrieval generates substantial amounts of silica gel and solvent waste. Based on the release/return mechanism, Ru ± carbenes 1, [7] 3, [8] and 5 [9] were subsequently attached to insoluble cross-linked and monoporous polystyrene polymers as well as to a soluble polyethylene glycol (PEG) resin. However, these supported catalysts typically suffer from one or more of the following shortcomings: 1) There are no reports of catalyst utility in the synthesis of trisubstituted olefins; efficient processes involve only ring-closing metathesis (RCM) reactions with terminal olefin substrates or those that benefit from entropic factors. [7±9a] 2) Diminished [5] E. A. Permyakov, L.

A crossover in the ability of two distinct ruthenium-based metathesis pre-catalysts to effect the synthesis of dialkenylboronic esters in solution and on the solid-phase was observed. Specifically, while the Grubbs 2nd generation pre-catalyst 3 affords a greater degree of conversion to product than the Hoveyda-Grubbs pre-catalyst 2 in a solution-phase enyne-metathesis reaction, this trend is reversed in the solid-phase variant. Systematic investigation showed this trend to be general, regardless of variations in the homoallylic alcohol and alkynylboronic ester components of the reaction, as well as in the type of solid support employed. Experiments to determine a mechanistic hypothesis for this trend highlighted the significance of the ruthenium remaining bound to the substrate after metathetic rearrangement and found the presence of phosphine ligand to be detrimental to the success of the solid-phase reaction. Therefore, these results suggest an expanded role for phosphine-free pre-catalysts, such as 2, in challenging solid-phase metathesis reactions.