Distal Ionic Substrate–Catalyst Interactions Enable Long-Range Stereocontrol: Access to Remote Quaternary Stereocenters through a Desymmetrizing Suzuki–Miyaura Reaction

Abstract

Spatial distancing of a substrate’s reactive group and nonreactive catalyst-binding group from its pro-stereogenic element presents substantial hurdles in asymmetric catalysis. In this context, we report a desymmetrizing Suzuki–Miyaura reaction that establishes chirality at a remote quaternary carbon. The anionic, chiral catalyst exerts stereocontrol through electrostatic steering of substrates, even as the substrate’s reactive group and charged catalyst-binding group become increasingly distanced. This study demonstrates that precise long-range stereocontrol is achievable by engaging ionic substrate–ligand interactions at a distal position.

An Enantioselective Suzuki–Miyaura Coupling To Form Axially Chiral Biphenols

“…17a , 20 In our previous work on site-selective cross-coupling of related Brønsted acidic substrates we proposed that ligand–substrate electrostatic interactions were key, 16 and in a recent report Zhu and co-workers successfully accomplished a related desymmetrizing Suzuki–Miyaura coupling using a novel chiral phosphonate ligand inspired by that approach. 21 Use of enantiopure sSPhos in the desymmetrizing Suzuki–Miyaura coupling of 8 resulted in high enantioselectivity in the product 9 . This demonstrates its proficiency in the formation of two fundamentally different chirality classes, axial chirality in the synthesis of atropisomers such as 3 and point chirality in the desymmetrization of substrates such as 8 .…”

“…Having applied enantiopure sSPhos to the generation of axial chirality, we were keen to test its ability to introduce point chirality and evaluated it in the desymmetrization of N -triflated benzhydrylamine 8 , in which oxidative addition would now be enantiodetermining and occurs at a position remote from the new stereocenter (Scheme D). Such long-range stereoinduction is a challenge, and one in which catalysts that exploit attractive noncovalent interactions have demonstrated particular advantages. , In our previous work on site-selective cross-coupling of related Brønsted acidic substrates we proposed that ligand–substrate electrostatic interactions were key, and in a recent report Zhu and co-workers successfully accomplished a related desymmetrizing Suzuki–Miyaura coupling using a novel chiral phosphonate ligand inspired by that approach . Use of enantiopure sSPhos in the desymmetrizing Suzuki–Miyaura coupling of 8 resulted in high enantioselectivity in the product 9 .…”

Tethered photocatalyst-directed palladium-catalysed C–H allenylation of N-aryl tetrahydroisoquinolines

“…We have recently achieved stereocontrol by a bifunctional Pd catalyst built on a dialkylbiphenyl phosphine scaffold. 20 Following this principle, the preorganisation of a photocatalyst and Pd complex through a covalent linkage could orient the transient radical intermediate towards a specific site of the allenyl/ propargyl Pd-SPhos intermediate (Scheme 1C).…”

“…Both electron-donating and electron-withdrawing substituted phenyl groups are well tolerated (12)(13)(14)(15)(16)(17). The transformation also provides access to allene products containing a naphthyl group (18) and a range of heteroaromatic rings including benzothiophene (19), furan (20), and thiophene (21). However, the reaction did not convert the substrate bearing a pyridyl group, possibly due to the deleterious effect by the coordination of pyridine to the Pd centre.…”

Meta Selective C–H Borylation Directed by Secondary Silicon Oxygen Interaction

“…This has a profound impact in modern synthetic organic chemistry, ranging from laboratory methods to industrial deployment. 12,13 However, the key underlying principles for the success of the metal catalysis lies on the two important factors, such as: (i) design and synthesis of new generation ligand framework that can produce highly reactive catalyst system 14,15 and (ii) substrates' structure modifications 16 by which site selectivity could be controlled by the steric crowding 17,18,19,20,21 or various weak interactions 22,23,24,25 of the aromatic compounds among several similar type of C-H bonds via the ligandsubstrate pre-organization 26,27 . In recent times, many elegant approaches 28 have been developed for the functionalization of proximal 15,29,30,31 and remote C-H bonds 1,3,32,33,34,35,36,37,38 of arenes by the design of either new ligand frameworks with an extended architectures featuring a weak coordinating functional groups 39 or templates 40 as well as transient mediators 41 or transient directing groups 42 attached with the substrates.…”