Preferential Oxidative Addition in Palladium(0)-Catalyzed Suzuki Cross-Coupling Reactions of Dihaloarenes with Arylboronic Acids

The study of Pd(0)-/t-Bu3P system as a powerful catalyst for the cross-coupling of n,m-dihaloarenes with 1 equiv of arylboronic acids is described. Our work demonstrated that the fate of the regenerated Pd(0) catalyst can be controlled when the appropriate ligand is employed. The results described here may lead to the development of new, efficient processes to conjugate polymers with controlled length which are potentially useful in molecular electronics

Pd(OAc)₂-Catalyzed Domino Reactions of 1-Chloro-2-haloarenes and 2-Haloaryl Tosylates with Hindered Grignard Reagents via Palladium-Associated Arynes

The palladium-associated aryne generation strategy and Pd(OAc)2-catalyzed annulative Domino reactions of 1-chloro-2-halobenzenes and 2-haloaryl tosylates with hindered Grignard reagents via palladium-associated arynes are described. The palladium-associated aryne generation strategy described here not only allows the high yield, one-step access to potentially useful substituted fluorenes from readily available 1-chloro-2-halobenzenes and 2-haloaryl tosylates, but may also lead to the development of other tandem reactions based on these readily available ortho leaving group bearing haloarene

Two Palladium-Catalyzed Domino Reactions from One Set of Substrates/Reagents: Efficient Synthesis of Substituted Indenes and <i>cis</i>-Stilbenoid Hydrocarbons from the Same Internal Alkynes and Hindered Grignard Reagents

Two types of domino reactions from the same internal alkynes and hindered Grignard reagents based on carbopalladation, Pd-catalyzed cross-coupling reaction, and a C−H activation strategy are described. The realization of these domino reactions relied on the control of the use of the ligand and the reaction temperature. Our study provides efficient access to useful polysubstituted indenes and cis-substituted stilbenes and may offer a new means of development of tandem/domino reactions in a more efficient way

Catalytic Enantioselective Cr-Mediated Propargylation: Application to Halichondrin Synthesis

A catalytic enantioselective propargylation in the presence of 10 mol % of Cr catalyst prepared from Cr(III) bromide and (R)-sulfonamide E furnishes homopropargyl alcohol 8 in 78% yield with 90% ee. Coupled with the workup based on Amano-lipase, this method provides a practical synthesis of optically pure 8 on a multigram scale. With maintenance of its optical purity, 8 has been converted to 1b, the C14−C19 building block of halichondrins and E7389, in two steps

Catalytic Enantioselective Cr-Mediated Propargylation: Application to Halichondrin Synthesis

A catalytic enantioselective propargylation in the presence of 10 mol % of Cr catalyst prepared from Cr(III) bromide and (R)-sulfonamide E furnishes homopropargyl alcohol 8 in 78% yield with 90% ee. Coupled with the workup based on Amano-lipase, this method provides a practical synthesis of optically pure 8 on a multigram scale. With maintenance of its optical purity, 8 has been converted to 1b, the C14−C19 building block of halichondrins and E7389, in two steps

Anionic Four-Electron Donor-Based Palladacycles as Catalysts for Addition Reactions of Arylboronic Acids with α,β-Unsaturated Ketones, Aldehydes, and α-Ketoesters

Anionic four-electron donor-based palladacycle-catalyzed 1,4-additions of arylboronic acids with α,β-unsaturated ketones and 1,2-additions of arylboronic acids with aldehydes and α-ketoesters are described. Our study demonstrated that palladacycles were highly efficient, practical catalysts for these addition reactions. The work described here not only opened a new paradigm for the application of palladacycles, but may also pave the road for other metalacycles as practically useful catalysts for such addition reactions including asymmetric ones

New Syntheses of E7389 C14−C35 and Halichondrin C14−C38 Building Blocks: Double-Inversion Approach

With sequential use of catalytic asymmetric Cr-mediated coupling reactions, E7389 C14−C35 and halichondrin C14−C38 building blocks have been stereoselectively synthesized. The C19−C20 bond is first formed via the catalytic asymmetric Ni/Cr-mediated coupling, i.e., 8 + 9 → 10 (90%; dr = 22:1), in which vinyl iodide 8 is used as the limiting substrate. The C23−C24 bond is then formed via the catalytic asymmetric Co/Cr-mediated coupling, i.e., 13 + 14 → 4 (82%; dr = 22:1), in which the alkyl−iodide bond in 14 is selectively activated over the vinyl−iodide bond. The catalytic asymmetric Ni/Cr-mediated reaction is employed to couple C14−C26 segment 19 with E7389 C27−C35 segment 20 (91%; dr = >55:1). In this synthesis, the C23−O bond is stereoselectively constructed via a double-inversion process, i.e., 21 → 22, to furnish E7389 C14−C35 building block 22 in 84% yield. The same synthetic sequence has been employed to synthesize halichondrin C14−C38 building block 18b, i.e., 16a + 19 → 18b

Toolbox Approach to the Search for Effective Ligands for Catalytic Asymmetric Cr-Mediated Coupling Reactions

Chromium catalysts derived from chiral sulfonamides represented by A effect the couplings of aldehydes with vinyl, allyl, or alkyl halides. With three distinct sites for structural modification, A affords access to a structurally diverse pool of chiral sulfonamides. The Cr catalysts derived from these sulfonamides exhibit a broad range of catalyst−substrate matching profiles. A strategy is presented to search for a satisfactory chiral sulfonamide for a given substrate. In order to demonstrate the generality and effectiveness of this approach, five diverse C−C bond-forming cases have been selected from the halichondrin synthesis. For each of the cases, two ligands have been deliberately searched for, to induce the formation of (R)- and (S)-alcohols, respectively, at the arbitrarily chosen efficiency level of “≥80% yield with ≥20:1 stereoselectivity in the presence of ≤20 mol % of a Cr catalyst”. For 9 out of the 10 cases studied, a satisfactory catalyst has been found within this pool of sulfonamides. Even for the remaining case, a Cr catalyst inducing stereoselectivity up to 8:1 has been identified

New Syntheses of E7389 C14−C35 and Halichondrin C14−C38 Building Blocks: Reductive Cyclization and Oxy-Michael Cyclization Approaches

Cr-mediated coupling reactions are usually achieved with a slight excess of a given nucleophile. To develop a cost-effective use of this process, two different approaches have been studied. The first approach depends on two consecutive catalytic asymmetric Cr-mediated couplings, with use of coupling partners purposely being of unbalanced molecular size and complexity. The second approach rests on the success in identifying the nucleophile, which allows us to achieve the coupling satisfactorily with a 1:1 molar ratio of the coupling partners. The C23−O bond is stereospecifically constructed via reductive cyclization of the oxonium ion, or oxy-Michael cyclization. Both syntheses have a high overall efficiency: E7389 C14−C35 and halichondrin C14−C38 building blocks have been synthesized from the corresponding C27−C35 and C27−C38 aldehydes, respectively, in high overall yields with an excellent stereoselectivity. Because of operational simplicity, the synthesis outlined herein appears to be well suited for scaling