The design and development of metal-cluster-based heterogeneous catalysts with high activity, selectivity, and stability under solution-phase reaction conditions will enable their applications as recyclable catalysts in large-scale fine chemicals production. To achieve these required catalytic properties, a heterogeneous catalyst must contain specific catalytically active species in high concentration, and the active species must be stabilized on a solid catalyst support under solution-phase reaction conditions. These requirements pose a great challenge for catalysis research to design metal-cluster-based catalysts for solution-phase catalytic processes. Here, we focus on a silica-supported, polymer-encapsulated Pt catalyst for an electrophilic hydroalkoxylation reaction in toluene, which exhibits superior selectivity and stability against leaching under mild reaction conditions. We unveil the key factors leading to the observed superior catalytic performance by combining X-ray absorption spectroscopy (XAS) and reaction kinetic studies. On the basis of the mechanistic understandings obtained in this work, we also provide useful guidelines for designing metal-cluster-based catalyst for a broader range of reactions in the solution phase.

A sequential rhodium-catalyzed silylcarbocyclization of enynes parlayed with a palladium-catalyzed, silicon-based cross-coupling reaction has been developed for the synthesis of highly substituted cyclopentanes. 1,6-Enynes reacted with benzyldimethylsilane in the presence of rhodium catalysts to afford five-membered rings bearing a (Z)-alkylidenylbenzylsilyl group. A variety of substitution patterns and heteroatom substituents were compatible. The silylcarbocyclization in which an unsaturated ester participated was also achieved. The resulting alkylidenylsilanes underwent palladium-catalyzed cross-coupling using tetra-n-butylammonium fluoride. This cross-coupling reaction displayed a broad substrate scope. A wide variety of substitution patterns, electronic properties, and heteroatoms were compatible. All of the cross-coupling reactions proceeded in high yields under very mild conditions and with complete retention of double bond configuration, resulting in densely functionalized 3-(Z)-benzylidenecyclopentanes and heterocycles.

The total syntheses of marine natural products belonging to the kainoid family, isodomoic acids G and H are described. The strategic connection involves a sequential silylcarbocyclization/siliconbased cross-coupling process. These total syntheses were achieved efficiently via a twelve and a thirteen step, longest-linear sequence, respectively. The key transformations include a diastereoselective rhodium-catalyzed carbonylative silylcarbocyclization reaction of a (L)-vinylglycine-derived 1,6-enyne, a desilylative iodination reaction, as well as an alkenyl-alkenyl silicon-based cross-coupling reaction. The mechanistic insight garnered during the investigation of the iododesilylation reaction enabled stereocontrolled introduction of the iodine with either inversion or retention of double bond configuration. The invertive desilylative iodination leads to the total synthesis of isodomoic acid H, while its congener, isodomoic acid G, was obtained via a retentive iododesilylation.Isodomoic acids G (1) and H (2) were isolated in 1997 by Arakawa from red alga Chondria armata. 1 They belong to the family of kainoid amino acids, that includes kainic acid, domoic acid, and isodomoic acids, a series of structurally related natural products bearing a 3-carboxymethylproline moiety and a side-chain on C(4). These compounds differ in the position and configuration of the double bond at C(4). 2 Kainoid amino acids have long been recognized as neuroexcitatory agents, and their high potency makes them extremely valuable as research tools in neuroscience as well as medicinal chemistry. 3 In fact, in 2000 the shortage of kainic acid threatened to hamper research projects in neurodegenerative diseases and a call for new supplies for isolation or synthesis was issued. 4a Even now, the price of kainic acid remains extremely high and other kainoid derivatives are obtained in only minute quantities from natural sources. 4b In response, many syntheses of kainic acid have been reported, whereas sdenmark@illinois.edu. Supporting Information Available: Full experimental procedures and characterization data for intermediates and synthetic natural product described. This material is available free of charge via the Internet at http://pubs.acs.org. Our interest in developing a new synthetic route to these natural products stems from the desire (1) to showcase the synthetic utility of the sequential silylcarbocyclization/silicon-based crosscoupling technology recently developed in these laboratories and (2) to potentially provide access to various analogues by a modular approach. 6 We describe herein efficient, stereoselective total syntheses of 1 and 2 via a common intermediate. 7 NIH Public AccessAn obvious disconnection of 1 and 2 is the division into the substituted proline core and sidechain fragments at C(1′)-C(2′) (Scheme 1). The construction of the conjugated diene would involve the silicon-based cross-coupling reaction of silanol 3 8 with iodide 4 or 5, both of which would be derived from aldehyde 6 via a stereo-divergent iodode...

Although developed somewhat later, silicon-based cross-coupling has become a viable alternative to the more conventional Suzuki-Miyaura, Stille-Kosugi-Migita, and Negishi cross-coupling reactions because of its broad substrate scope, high stability of silicon-containing reagents, and low toxicity of waste streams. An empowering and yet underappreciated feature unique to silicon-based cross-coupling is the wide range of sequential processes available. In these processes, simple precursors are first converted to complex silicon-containing cross-coupling substrates, and the subsequent silicon-based cross-coupling reaction affords an even more highly functionalized product in a stereoselective fashion. In so doing, structurally simple and inexpensive starting materials are quickly transformed into value-added and densely substituted products. Therefore, sequential processes are often useful in constructing the carbon backbones of natural products. In this review, studies of sequential processes involving silicon-based cross-coupling are discussed. Additionally, the total syntheses that utilize these sequential processes are also presented.

Marine neuroexcitatory compounds isodomoic acids G and H were efficiently synthesized from a common intermediate using a silicon-based cross-coupling reaction. Dividing each target compound into the core fragment and the side-chain fragment enabled the synthesis to be convergent. The trans-2,3-disubstituted pyrrolidine core fragment was accessed through a diastereoselective rhodium-catalyzed carbonylative silylcarbocyclization reaction of a vinylglycine-derived 1,6-enyne. A stereochemically divergent desilylative iodination reaction was developed, converting of the cyclization product to both E-and Z-alkenyl iodides, which would eventually lead to isodomoic acid G and isodomoic acid H, respectively. The late stage alkenylalkenyl silicon-based cross-coupling reaction uniting the core alkenyl iodides and the side-chain alkenylsilanol was achieved under mild conditions. Finally, two mild deprotections afforded the target molecules.