Merging Ring-Opening 1,2-Metallate Shift with Asymmetric C(sp3)-H Borylation of Aziridines.

Chiral secondary alkyl amines with a vicinal quaternary stereocenter are undoubtedly important and ubiquitous subunits in natural products and pharmaceuticals. However, their asymmetric synthesis remains a formidable challenge. Herein, we merge the ring-opening 1,2-metallate shift with iridium-catalyzed enantioselective C(sp3)-H borylation of aziridines to deliver these frameworks with high enantioselectivities. We also demonstrated the synthetic application by downstream transformations, including the total synthesis of two Amaryllidaceae alkaloids, (-)-crinane and (+)-mesmebrane.

Catalytic Enantioselective Primary C-H Borylation for Acyclic All-Carbon Quaternary Stereocenters.

Creating a perfect catalyst to operate enzyme-like chiral recognition has been a long-sought aim. A challenging example in this context is constructing acyclic all-carbon quaternary stereogenic centers by transition metal-catalyzed enantioselective C-H activation. We now report highly enantioselective iridium-catalyzed primary C-H borylation of α-all-carbon substituted 2,2-dimethyl amides enabled by a tailor-made chiral bidentate boryl ligand (CBL). The success of the current transformation is attributed to the CBL/iridium catalyst, which has a confined chiral pocket. This protocol provides a diverse array of acyclic all-carbon quaternary stereocenters with excellent enantiocontrol and distinct structural features. Computational study reveals that steric hindrance of CBL could regulate the type of dominant orbital interaction between the catalyst and substrate, which is crucial to conferring high chiral induction.

Aryl Chloride-Directed Enantioselective C(sp2)-H Borylation Enabled by Iridium Catalysis.

We herein report the iridium-catalyzed enantioselective C-H borylation of aryl chlorides. A variety of prochiral biaryl compounds could be well-tolerated, affording a vast array of axially chiral biaryls with high enantioselectivities. The current method exhibits a high turnover number (TON) of 7000, which represents the highest in functional-group-directed asymmetric C-H activation. The high TON was attributed to a weak catalyst-substrate interaction that was caused by mismatched chirality between catalyst and substrate. We also demonstrated the synthetic application of the current method by C-B, ortho-C-H, and C-Cl bond functionalization, including programmed Suzuki-Miyaura coupling for the synthesis of axially chiral polyarenes.

Mechanism of Pd/Senphos-Catalyzed trans-Hydroboration of 1,3-Enynes: Experimental and Computational Evidence in Support of the Unusual Outer-Sphere Oxidative Addition Pathway.

The reaction mechanism of the Pd/Senphos-catalyzed trans-hydroboration reaction of 1,3-enynes was investigated using various experimental techniques, including deuterium and double crossover labeling experiments, X-ray crystallographic characterization of model reaction intermediates, and reaction progress kinetic analysis. Our experimental data are in support of an unusual outer-sphere oxidative addition mechanism where the catecholborane serves as a suitable electrophile to activate the Pd0-bound 1,3-enyne substrate to form a Pd-η3-π-allyl species, which has been determined to be the likely resting state of the catalytic cycle. Double crossover labeling of the catecholborane points toward a second role played by the borane as a hydride delivery shuttle. Density functional theory calculations reveal that the rate-limiting transition state of the reaction is the hydride abstraction by the catecholborane shuttle, which is consistent with the experimentally determined rate law: rate = k[enyne]0[borane]1[catalyst]1. The computed activation free energy ΔG‡ = 17.7 kcal/mol and KIE (kH/kD = 1.3) are also in line with experimental observations. Overall, this work experimentally establishes Lewis acids such as catecholborane as viable electrophilic activators to engage in an outer-sphere oxidative addition reaction and points toward this underutilized mechanism as a general approach to activate unsaturated substrates.

Simple Ether-Directed Enantioselective C(sp3 )-H Borylation of Cyclopropanes Enabled by Iridium Catalysis.

Reported here is an efficient and simple ether-directed iridium-catalyzed enantioselective C(sp3 )-H borylation of cyclopropanes. Various functional groups were well-tolerated, affording a vast array of chiral cyclopropanes with high enantioselectivities. We also demonstrated that the turnover numbers of the current reaction could be up to 335.

Synthesis of Chiral Sulfoximines via Iridium-Catalyzed Regio- and Enantioselective C-H Borylation: A Remarkable Sidearm Effect of Ligand.

Transition metal-catalyzed enantioselective C-H activation of prochiral sulfoximines for non-annulated products remains a formidable challenge. We herein report iridium-catalyzed enantioselective C-H borylation of N-silyl diaryl sulfoximines using a well-designed chiral bidentate boryl ligand with a bulky side arm. This method is capable of accommodating a broad range of substrates under mild reaction conditions, affording a vast array of chiral sulfoximines with high enantioselectivities. We also demonstrated the synthetic utility on a preparative-scale C-H borylation for diverse downstream transformations, including the synthesis of chiral version of bioactive molecules. Computational studies showed that the bulky side arm of the ligand confers high regio- and enantioselectivity through steric effect.

Site- and Stereoselective C(sp3 )-H Borylation of Strained (Hetero)Cycloalkanols Enabled by Iridium Catalysis.

Transition metal-catalyzed site- and stereoselective C-H activation of strained (hetero)cycloalkanes remains a formidable challenge. We herein report a carbamate-directed iridium-catalyzed asymmetric ß-C(sp3 )-H borylation of cyclopropanol derivatives. A variety of densely functionalized cyclopropanols were obtained in good enantioselectivities via desymmetrization and kinetic resolution. In addition, site-selective C(sp3 )-H borylation of methine groups furnished α-borylated (hetero)cycloalkanols in moderate to good yields. The synthetic utility of the method was further shown in a gram-scale synthesis and diverse downstream transformations of borylated products.

Iridium-Catalyzed Enantioselective C(sp3 )-H Borylation of Aminocyclopropanes.

Transition-metal-catalyzed regio- and stereo-controllable C-H functionalization remains a formidable challenge in asymmetric catalysis. Herein, we disclose the first example of iridium-catalyzed C(sp3 )-H borylation of aminocyclopropanes by using simple imides as weakly coordinating directing groups under mild reaction conditions. The reaction proceeded via a six-membered iridacycle, affording a vast range of chiral aminocyclopropyl boronates. The current method features a broad spectrum of functional groups (36 examples) and high enantioselectivities (up to 99 %). We also demonstrated the synthetic utility by a preparative scale C-H borylation, C-B bond transformations, and conversion of the directing group.

Iridium-Catalyzed Regio- and Enantioselective Borylation of Unbiased Methylene C(sp3 )-H Bonds at the Position ß to a Nitrogen Center.

Reported herein is the pyrazole-directed iridium-catalyzed enantioselective borylation of unbiased methylene C-H bonds at the position ß to a nitrogen center. The combination of a chiral bidentate boryl ligand, iridium precursor, and pyrazole directing group was responsible for the high regio- and enantioselectivity observed. The method tolerated a vast array of functional groups to afford the corresponding C(sp3 )-H functionalization products with good to excellent enantioselectivity.

Ligand-free iridium-catalyzed regioselective C-H borylation of indoles.

We herein report a ligand-free Ir-catalyzed C-H borylation of N-acyl protected indoles. This simple protocol could tolerate a variety of functional groups, affording C3 borylated indoles in good yields with excellent regioselectivities. We also demonstrated that the current method is amenable to gram-scale borylation and the C-B bonds could be easily converted to C-C and C-heteroatom bonds.

Iridium-Catalyzed Enantioselective Unbiased Methylene C(sp3 )-H Borylation of Acyclic Amides.

We herein report amide directed enantioselective ß-C(sp3 )-H borylation of unbiased methylene C-H bonds of acyclic amides enabled by iridium catalysis for the first time. The key to the success of this transformation relies on the careful selection of the combination of iridium precursor and chiral bidentate boryl ligands. A variety of functional groups are well-tolerated, affording chiral ß-functionalized amides in good to excellent enantioselectivities. We also demonstrate the application of the current method by stereospecific conversion of C-B bond into other functionalities.

Iridium-Catalyzed Enantioselective α-C(sp3)-H Borylation of Azacycles.

We herein report an iridium-catalyzed enantioselective α-C(sp3)-H borylation of a wide range of azacycles. The combination of an iridium precursor and a chiral bidentate boryl ligand has been shown to effectively differentiate enantiotropic methylene C-H bonds from a single carbon center, affording a variety of synthetically useful azacycles from readily available starting materials with good to excellent enantioselectivities.

Iridium-Catalyzed γ-Selective Hydroboration of γ-Substituted Allylic Amides.

Reported here for the first time is the Ir-catalyzed γ-selective hydroboration of γ-substituted allylic amides under mild reaction conditions. A variety of functional groups could be compatible with reaction conditions, affording γ-branched amides in good yields with ≤97% γ-selectivity. We have also demonstrated that the obtained borylated products could be used in a series of C-O, C-F, C-Br, and C-C bond-forming reactions.

Chiral Bidentate Boryl Ligand Enabled Iridium-Catalyzed Enantioselective C(sp3)-H Borylation of Cyclopropanes.

We herein report an Ir-catalyzed enantioselective C(sp3)-H borylation of cyclopropanecarboxamides using a chiral bidentate boryl ligand for the first time. A variety of substrates with α-quaternary carbon centers could be compatible in this reaction to provide ß-borylated products with good to excellent enantioselectivities. We have also demonstrated that the borylated products can be used as versatile precursors engaging in stereospecific transformations of C-B bonds, including the synthesis of a bioactive compound Levomilnacipran.

Iridium-Catalyzed Distal Hydroboration of Aliphatic Internal Alkenes.

The regioselective hydroboration of aliphatic internal alkenes remains a great challenge. Reported herein is an iridium-catalyzed hydroboration of aliphatic internal alkenes, providing distal-borylated products in good to excellent yields with high regioselectivity (up to 99:1). We also demonstrate that the C-B bond of the distal-borylated product can be readily converted into other functional groups. DFT calculations indicate that the reaction proceeds through an unexpected IrIII /IrV cycle.

NHC-Copper-Catalyzed Asymmetric Dearomative Silylation of Indoles.

We report an asymmetric dearomative silylation reaction of 3-acylindoles using a chiral NHC-copper(I) complex as catalyst to afford a range of cyclic α-aminosilanes with high regio- and enantioselectivity. Initial mechanistic studies revealed that the observed high diastereoselectivity was attributed to the facile epimerization of the 3-acyl group. We also demonstrated that the product could be used as a versatile precursor for the synthesis of functionalized indolines in high enantiomeric purity.

Synthesis of cyclic chiral α-amino boronates by copper-catalyzed asymmetric dearomative borylation of indoles.

A copper(i)-catalyzed dearomative borylation of N-alkoxycarbonyl protected indole-3-carboxylates has been developed. The boron addition in this reaction occurred regioselectively at the 2-position of indoles followed by diastereoselective protonation, affording the corresponding stable cyclic chiral α-amino boronates (2-borylindolines) in moderate to good yields with excellent diastereo- and enantioselectivities. The product 2c could be used as a versatile precursor to undergo subsequent stereoselective transformations, delivering highly functionalized 2,3,3-trisubstituted chiral indolines.

Palladium-catalyzed synthesis of fluoreones from bis(2-bromophenyl)methanols.

A palladium-catalyzed synthesis method of fluorenones has been developed. A variety of bis(2-bromophenyl)methanols could undergo the reaction smoothly in the presence of Pd(OAc)2, affording a series of fluorenones in moderate to good yields (two steps). Mechanistic studies reveal that the reaction might be triggered by oxidation of alcohol followed by intramolecular reductive coupling.

Copper-Catalyzed Asymmetric Protoboration of ß-Amidoacrylonitriles and ß-Amidoacrylate Esters: An Efficient Approach to Functionalized Chiral α-Amino Boronate Esters.

A copper-catalyzed asymmetric protoboration of both Z-ß-amidoacrylonitriles and ethyl E-ß-amidoacrylates using bis(pinacolato)diboron has been developed for the first time. The process tolerates a vast array of substrates, delivering a series of stable functionalized chiral α-amino boronate esters in good yields and enantioselectivities under mild reaction conditions. The current method is also applicable for gram-scale synthesis without erosion of enantioselectivity. This work provides an attractive and complementary approach to synthesizing enantioriched chiral α-amino boronate esters.

Transition-metal-free synthesis of 1,1-diboronate esters with a fully substituted benzylic center via diborylation of lithiated carbamates.

A transition-metal-free lithiation-borylation method has been developed to access a variety of 1,1-diboronate esters with a fully substituted benzylic center from readily available secondary benzylic N,N-diisopropyl carbamates. The method is applicable to scale-up synthesis of 1,1-diboron compounds. Furthermore, the current method is also applicable to synthesizing optically active 1,1-silylboronate esters.