Catalytic Enantioselective Synthesis of a cis-β-Boronyl Cyclobutylcarboxyester Scaffold and Its Highly Diastereoselective Nickel/Photoredox Dual-Catalyzed Csp3–Csp2 Cross-Coupling to Access Elusive trans-β-Aryl/Heteroaryl Cyclobutylcarboxyesters
datasetposted on 21.12.2020, 20:16 by Kevin Nguyen, Helen A. Clement, Louise Bernier, Jotham W. Coe, William Farrell, Christopher J. Helal, Matthew R. Reese, Neal W. Sach, Jack C. Lee, Dennis G. Hall
Chiral cyclobutanes are components of numerous bioactive natural products, and consequently, they have also gained significant attention in medicinal chemistry. Optically enriched cyclobutylboronates can serve as valuable synthetic intermediates for the synthesis of a broad variety of chiral cyclobutanes through exploiting the versatility of the boronyl functionality. Herein, by using a high-throughput ligand screening approach, an efficient method for the asymmetric conjugate borylation of a cyclobutene 1-carboxyester was optimized, leading to a highly enantioenriched cis-β-boronyl cyclobutylcarboxyester scaffold (99% ee, >20:1 dr). Of the 118 ligands screened, the Naud family of phosphine–oxazoline ligands was found to be the most effective. Computational modeling of the possible preinsertion complexes shows a large preference for the π-bound Cu(I)–alkene complex where the substrate’s large benzhydryl ester occupies a relatively unhindered quadrant of the chiral ligand in a spatially tight environment that is highly specific for the cyclobutenoate substrate and imparts much lower selectivity with larger ring substrates. The cis diastereoselectivity is proposed to arise from a sterically controlled, irreversible protodecupration step. A highly diastereoselective nickel/photoredox dual-catalyzed Csp3–Csp2 cross-coupling of the corresponding trifluoroborate salt with aryl/heteroaryl bromides and cycloalkenyl nonaflates was developed, providing access to a wide diversity of trans-β-aryl/heteroaryl and cycloalkenyl cyclobutylcarboxyesters with an excellent diastereoselectivity and high retention of optical purity (91–99% ee, >20:1 dr). Azaheterocyclic halides, which are notoriously challenging substrates in Pd-catalyzed cross-coupling, are successful with this Ni/photoredox manifold. A stereoconvergent model based on steric factors is proposed for the key carbon–carbon bond forming step, leading to a high diastereoselectivity. Despite the radical nature of the cross-coupling conditions, the flanking carboxyester proved to be a reliable chirality relay group to maintain the stereochemical integrity of the organoboron intermediate. Furthermore, mild oxidation of the carbon–boron bond and extension of the catalytic asymmetric conjugate borylation reaction to a three-component aldol reaction with an aldehyde afford valuable enantioenriched cyclobutane products.
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high-throughput ligand screening ap...ring substratesconjugate borylationsteric factorstrancycloalkenyl cyclobutylcarboxyesterscis diastereoselectivityarylbond118 ligandsCatalytic Enantioselective Synthesiscycloalkenyl nonaflatesCspbenzhydryl esterprotodecupration stepenantioenriched cyclobutane productscross-coupling conditionstrifluoroborate saltcyclobutene 1- carboxyesterstereoconvergent modelcyclobutenoate substrateComputational modelingpreinsertion complexesNaud familythree-component aldol reactionchiral cyclobutanescis -β- Boronyl Cyclobutylcarboxyes...chiral ligandboronyl functionalityPd-catalyzed cross-couplingconjugate borylation reactionstereochemical integrityAzaheterocyclic halides