A General Approach to Stereospecific Cross-Coupling Reactions of Nitrogen-Containing Stereocenters

Abstract

A novel strategy employing cyclohexyl spectator ligands in Stille cross-coupling reactions has been developed as a general solution to the long-standing challenge of conducting stereospecific cross-coupling reactions at nitrogen-containing stereocenters. This method enables direct access to enantioenriched products that are difficult (or impossible) to obtain via alternative preparative methods. Selective and predictable transfer of a single secondary alkyl unit can be achieved under reaction conditions that exploit subtle electronic differences between activated and unactivated alkyl units. Through this approach, enantioenriched α-stannylated nitrogen-containing stereocenters undergo Pd-catalyzed arylation and acylation reactions with exceptionally high stereofidelity in all instances investigated. We demonstrate this process by using α-stannylated pyrrolidine, azetidine, and open-chain (benzylic and non-benzylic) nucleophiles in stereospecific reactions. This process will facilitate rapid and reliable access to enantioenriched compounds possessing nitrogen-substituted stereocenters, which constitute ubiquitous structural motifs in biologically active compounds emerging from the drug-discovery process.

Pd‐Catalyzed Cross‐Coupling of Alkylzirconocenes and Aryl Chlorides

“…Alkylboron reagents provide a useful alternative but are either sensitive to air or not easy to prepare, while readily accessible alkylboronic esters do not readily undergo transmetalation. Methods using alkyltin or alkylgermanium reagents have been developed by Biscoe [ 7 ] and Xiao, [ 8 ] respectively, providing additional choices for organometallics applied in cross‐coupling reactions with broad substrate scope and good functional group tolerance. However, these reagents are either toxic or non‐trivial to prepare.…”

Highly Diastereoselective Synthesis of 2‐Arylpyrrolidine Derivatives via the Crystallization‐induced Diastereomer Transformation

“…The second approach includes methods based on the functionalization of a pyrrolidine ring ( B ). The Pd‐catalyzed cross‐coupling of aryl bromides with α‐stannylated pyrrolidine leading to 2‐arylpyrrolidines in good to high yields and more than 95% ee is the typical example [8] . Notably, this approach provides more diverse range of substituted pyrrolidines compared to the first one.…”

Regio- and Diastereoselective Synthesis of 2-Arylazetidines: Quantum Chemical Explanation of Baldwin’s Rules for the Ring-Formation Reactions of Oxiranes

“…Only a few approaches have been developed for the synthesis of 2-phenylazetidines. N-Protected 2-arylazetidines can be synthesized by stereospecific crosscoupling reactions, 52 by selective intermolecular sp 3 -C−H amination, 53 or by [2+2] photocycloaddition. 1 A few efficient synthetic methods of diversely substituted N-aryl-2-cyanoazetidines have also been published, based on an anionic ringclosure reaction, which requires the presence of an electronwithdrawing group (EWG) in the starting material.…”