Abstract
Mechanistic studies on Cu-catalyzed asymmetric additions of alkylzirconocene nucleophiles to racemic allylic halide electrophiles were conducted using a combination of isotopic labeling, NMR spectroscopy, kinetic modeling, structure-activity relationships, and new reaction development. Kinetic and dynamic NMR spectroscopic studies provided insight into the oligomeric Cu-ligand complexes, which evolve during the course of the reaction to become faster and more highly enantioselective. The Cu-counterions play a role in both selecting different pathways and in racemizing the starting material via formation of an allyl iodide intermediate. We quantify the rate of Cu-catalyzed allyl iodide isomerization and identify a series of conditions under which the formation and racemization of the allyl iodide occurs. We developed reaction conditions where racemic allylic phosphates are suitable substrates using new phosphoramidite ligand D. D also allows highly enantioselective addition to racemic seven-membered-ring allyl chlorides for the first time. 1H and 2H NMR spectroscopy experiments on reactions using allylic phosphates showed the importance of allyl chloride intermediates, which form either by the action of TMSCl or from an adventitious chloride source. Overall these studies support a mechanism where complex oligomeric catalysts both racemize the starting material and select one enantiomer for a highly enantioselective reaction. It is anticipated that this work will enable extension of copper-catalyzed asymmetric reactions and provide understanding on how to develop dynamic kinetic asymmetric transformations more broadly.
Highlights
Copper is highly valued in synthetic organic chemistry, and a great number of asymmetric Cu-catalyzed methods have recently been developed.[1−4] the mechanisms and structures of organocopper species involved in asymmetric addition reactions are poorly understood[5,6] despite extensive studies on nonstereoselective processes.[6]In the past decades, asymmetric allylic alkylation (AAA) reactions have emerged as powerful tools[7−12] that may accommodate both achiral and chiral substrates
Enantioselective Cu-catalyzed AAA to prochiral materials can be readily achieved by an array of nucleophiles, ligands, and leaving groups.[1,2,10,12−18] While numerous mechanistic overviews have been outlined, detailed analyses of asymmetric Cucatalyzed pathways are scarce and rely on analogy with work on stoichiometric nonenantioselective methods
To our knowledge, spectroscopic demonstration of transmetalation has only been observed in the addition of Grignard reagents to precatalytic Cu−ferrocenyl dimers,[26] addition of diorganozinc nucleophiles to Cu−phosphoramidite ligand complexes,[27] and for organolithium reagents used in Cucatalyzed AAAs.[28]
Summary
Copper is highly valued in synthetic organic chemistry, and a great number of asymmetric Cu-catalyzed methods have recently been developed.[1−4] the mechanisms and structures of organocopper species involved in asymmetric addition reactions are poorly understood[5,6] despite extensive studies on nonstereoselective processes.[6]In the past decades, asymmetric allylic alkylation (AAA) reactions have emerged as powerful tools[7−12] that may accommodate both achiral and chiral substrates. CuCl-A catalyzed reactions (which normally give 49% ee, Figure 2a, entry 3) carried out in the presence of 10 mol % TMSI gave 4 in 76% ee, while a reaction with 10 mol % TBAI gave 4 in 52% ee, supporting the idea that allyl halide isomerization (Table 2, entries 7 vs 8) is crucial to obtaining high enantioselectivity in these reactions.
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