Enantioselective α-Boryl Carbene Transformations.

Carbenes, recognized as potent intermediates, enable unique chemical transformations, and organoborons are pivotal in diverse chemical applications. As a hybrid of carbene and the boryl group, α-boryl carbenes are promising intermediates for the construction of organoborons; unfortunately, such carbenes are hard to access and have low structural diversity with their asymmetric transformations largely uncharted. In this research, we utilized boryl cyclopropenes as precursors for the swift synthesis of α-boryl metal carbenes, a powerful category of intermediates for chiral organoboron synthesis. These α-boryl carbenes undergo a series of highly enantioselective transfer reactions, including B-H and Si-H insertion, cyclopropanation, and cyclopropanation/Cope rearrangement, catalyzed by a singular chiral copper complex. This approach opens paths to previously unattainable but easily transformable chiral organoborons, expanding both carbene and organoboron chemistry.

Iron-Catalyzed Allylic C(sp3)-H Silylation: Spin-Crossover-Efficiency-Determined Chemoselectivity.

The nuanced role of spin effects remains a critical gap in designing proficient open-shell catalysts. This study elucidates an iron-catalyzed allylic C(sp3)-H silylation/alkyne hydrosilylation reaction, in which the spin state of the open-shell iron catalyst dictates the reaction kinetics and pathway. Specifically, spin crossover led to alkyne hydrosilylation, whereas spin conservation resulted in a novel allylic C(sp3)-H silylation reaction. This chemoselectivity, governed by the spin-crossover efficiency, reveals an unexpected dimension in spin effects and a first in the realm of transition-metal-catalyzed in situ silylation of allylic C(sp3)-H bonds, which had been previously inhibited by the heightened reactivity of alkenes in hydrosilylation reactions. Furthermore, this spin crossover can either accelerate or hinder the reaction at different stages within a single catalytic reaction, a phenomenon scarcely documented. Moreover, we identify a substrate-assisted C-H activation mechanism, a departure from known ligand-assisted processes, offering a fresh perspective on C-H activation strategies.

Spin effect on redox acceleration and regioselectivity in Fe-catalyzed alkyne hydrosilylation.

Iron catalysts are ideal transition metal catalysts because of the Earths abundant, cheap, biocompatible features of iron salts. Iron catalysts often have unique open-shell structures that easily undergo spin crossover in chemical transformations, a feature rarely found in noble metal catalysts. Unfortunately, little is known currently about how the open-shell structure and spin crossover affect the reactivity and selectivity of iron catalysts, which makes the development of iron catalysts a low efficient trial-and-error program. In this paper, a combination of experiments and theoretical calculations revealed that the iron-catalyzed hydrosilylation of alkynes is typical spin-crossover catalysis. Deep insight into the electronic structures of a set of well-defined open-shell active formal Fe(0) catalysts revealed that the spin-delocalization between the iron center and the 1,10-phenanthroline ligand effectively regulates the iron center's spin and oxidation state to meet the opposite electrostatic requirements of oxidative addition and reductive elimination, respectively, and the spin crossover is essential for this electron transfer process. The triplet transition state was essential for achieving high regioselectivity through tuning the nonbonding interactions. These findings provide an important reference for understanding the effect of catalyst spin state on reaction. It is inspiring for the development of iron catalysts and other Earth-abundant metal catalysts, especially from the point of view of ligand development.

Iron-Catalyzed C(sp3)-C(sp3) Coupling to Construct Quaternary Carbon Centers.

The construction of quaternary carbon centers via C-C coupling protocols remains challenging. The coupling of tertiary C(sp3) with secondary or tertiary C(sp3) counterparts has been hindered by pronounced steric clashes and many side reactions. Herein, we have successfully developed a type of bisphosphine ligand iron complex-catalyzed coupling reactions of tertiary alkyl halides with secondary alkyl zinc reagents and efficiently realized the coupling reaction between tertiary C(sp3) and secondary C(sp3) with high selectivity for the initial instance, which provided an efficient method for the construction of quaternary carbon centers with high steric hindrance. The combination of an iron catalyst and directing group of the substrate makes the great challenging transformation possible.

Asymmetric Synthesis of Cyclopamine, a Hedgehog (Hh) Signaling Pathway Inhibitor.

Cyclopamine is a teratogenic steroidal alkaloid, which inhibits the Hedgehog (Hh) signaling pathway by targeting the Smoothened (Smo) receptor. Suppression of Hh signaling with synthetic small molecules has been pursued as a therapeutic approach for the treatment of cancer. We report herein the asymmetric synthesis of cyclopamine based on a two-stage relay strategy. Stage-I: total synthesis of veratramine through a convergent approach, wherein a crucial photoinduced excited-state Nazarov reaction was applied to construct the basic [6-6-5-6] skeleton of C-nor-D-homo-steroid. Stage-II: conversion of veratramine to cyclopamine was achieved through a sequence of chemo-selective redox manipulations.

Iron-Catalyzed Stereoconvergent 1,4-Hydrosilylation of Conjugated Dienes.

Stereoconvergent transformation of E/Z mixtures of olefins to products with a single steric configuration is of great practical importance but hard to achieve. Herein, we report an iron-catalyzed stereoconvergent 1,4-hydrosilylation reactions of E/Z mixtures of readily available conjugated dienes for the synthesis of Z-allylsilanes with high regioselectivity and exclusive stereoselectivity. Mechanistic studies suggest that the reactions most likely proceed through a two-electron redox mechanism. The stereoselectivity of the reactions is ultimately determined by the crowded reaction cavity of the α-diimine ligand-modified iron catalyst, which forces the conjugated diene to coordinate with the iron center in a cis conformation, which in turn results in generation of an anti-π-allyl iron intermediate. The mechanism of this stereoconvergent transformation differs from previously reported mechanisms of other related reactions involving radicals or metal-hydride species.

Chiral gem-difluoroalkyl reagents: gem-difluoroalkyl propargylic borons and gem-difluoroalkyl α-allenols.

Chiral fluorinated reagents provide new opportunities for the discovery of drugs and functional materials because the introduction of a fluorinated group significantly alters a molecule's physicochemical properties. Chiral gem-difluoroalkyl fragments (R-CF2-C*) are key motifs in many drugs. However, the scarcity of synthetic methods and types of chiral gem-difluoroalkyl reagents limits the applications of these compounds. Herein, we report two types of chiral gem-difluoroalkyl reagents chiral gem-difluoroalkyl propargylic borons and gem-difluoroalkyl α-allenols and their synthesis by means of methods involving rhodium-catalyzed enantioselective B-H bond insertion reactions of carbenes and Lewis acid-promoted allenylation reactions. The mild, operationally simple method features a broad substrate scope and good functional group tolerance. These two types of reagents contain easily transformable boron and alkynyl or allenyl moieties and thus might facilitate rapid modular construction of chiral molecules containing chiral gem-difluoroalkyl fragments and might provide new opportunities for the discovery of chiral gem-difluoroalkyl drugs and other functional molecules.

Catalyst-Oriented Design Based on Elementary Reactions (CODER) for Triarylamine Synthesis.

Recently, the application of computational tools to the rational design of catalysts has received considerable attention, but progress has been limited by the reliance on databases and because mechanistic data have been almost neglected. Herein, we report a new strategy for catalyst design, designated catalyst-oriented design based on elementary reactions (CODER), which fully utilizes mechanistic data, combines the strengths of computational tools and researcher experience. CODER enabled the development of extremely efficient Pd catalysts for C-N coupling, which markedly improved the efficiency of the synthesis of widely used triarylamine optoelectronic materials by enhancing the turnover numbers (up to 340000) to 1-3 orders of magnitude towards literature values.

Wittig/B─H insertion reaction: A unique access to trisubstituted Z-alkenes.

The Wittig reaction, which is one of the most effective methods for synthesizing alkenes from carbonyl compounds, generally gives thermodynamically stable E-alkenes, and synthesis of trisubstituted Z-alkenes from ketones presents notable challenges. Here, we report what we refer to as Wittig/B─H insertion reactions, which innovatively combine a Wittig reaction with carbene insertion into a B─H bond and constitute a promising method for the synthesis of thermodynamically unstable trisubstituted Z-boryl alkenes. Combined with the easy transformations of boryl group, this methodology provides efficient access to a variety of previously unavailable trisubstituted Z-alkenes and thus provides a platform for discovery of pharmaceuticals. The unique Z-selectivity of the reaction is determined by the maximum overlap of the orbitals between the B─H bond of the borane adduct and the alkylidene carbene intermediate in the transition state.

Iron-Catalyzed Alkene Hydroalumination.

Hydroalumination of olefins generally gives thermodynamically controlled anti-Markovnikov addition selectivity in literatures. In this paper, a highly Markovnikov hydroalumination of aromatic terminal alkenes was realized to prepare various new benzylaluminum complexes by using the well-defined 2,9-diaryl-1,10-phenanthroline modified iron complex as the catalyst and commercially available DIBAL-H as the aluminum hydride reagent. This is the first ironcatalyzed alkene hydroalumination, and the regioselectivity observed in this study is different from the related reactions reported in the literatures.

Highly Enantioselective Brønsted Acid Catalyzed Heyns Rearrangement.

Herein we report the first method for highly enantioselective Brønsted acid catalyzed Heyns rearrangements. These reactions, catalyzed by a chiral spiro phosphoric acid, afforded synthetically valuable chiral α-aryl-α-aminoketones which cannot be obtained by means of previously reported Heyns rearrangement methods. This method features low catalyst loadings, high yields and high enantioselectivities, making these reactions highly practical. We used the method to efficiently synthesize various chiral amines, including some biologically active molecules. We experimentally proved that these acid-catalyzed Heyns rearrangements proceeded via a proton-transfer process involving an enol intermediate and the stereocontrol was realized during the proton-transfer step.

Iron-catalysed hydroalumination of internal alkynes.

Although research on iron-catalysed reactions has recently achieved significant progress, the activity and selectivity of iron catalysts are generally inferior to those of noble-metal catalysts. The development of new iron-catalysed reactions, especially those in which iron catalysts exhibit superior activity or selectivity to other catalysts, is the key to promote iron catalysis. Herein, we report the first protocol for iron-catalysed hydroalumination of internal alkynes. Specifically, in the presence of iron catalysts bearing 2,9-diaryl-1,10-phenanthroline ligands, internal alkynes were stereo- and regioselectively hydroaluminated with the commercially available reagent diisobutylaluminum hydride. Compared with other metal-catalysed alkyne hydroalumination reactions reported in the literature, the iron-catalysed protocol has the following advantages: unusual amino-group-directed regioselectivity, a wide substrate scope, good functional group tolerance, high selectivity, and mild reaction conditions. The alkenylaluminum products prepared in this way could undergo a diverse array of transformations, and were used for the synthesis of bioactive compounds. The current study expands the scope of iron catalysis, provides a new efficient access to alkenylaluminum, discloses the origin of the superiority of iron catalysts, and thus may inspire further studies in related fields.

Highly Regioselective Cobalt-Catalyzed Hydroboration of Internal Alkynes.

Herein, we report the development of new Co complexes that have cyclopropane-based diphosphine ligands and can catalyze highly chemo-, regio-, and stereoselective hydroboration reactions of unsymmetrical internal alkynes. These reactions exhibited unusual regioselectivity: specifically, reactions of aryl alkyl internal alkynes showed excellent cis-ß-addition selectivity, and reactions of dialkyl internal alkynes gave excellent cis-α-addition selectivity. Highly regioselective hydroboration of unsymmetrical dialkyl internal alkynes cannot be achieved by other known methods. The reactions described herein are highly synthetically useful, particularly for the stereoselective synthesis of trisubstituted alkenylborates and alkenes. Mechanistic studies indicate that a CoI -H species is a plausible active catalyst and the rigid structure of the cyclopropane skeleton of the ligands and the crowded reaction pocket were responsible for the unprecedented regioselectivity.

Highly Regio-, Stereo-, and Enantioselective Copper-Catalyzed B-H Bond Insertion of α-Silylcarbenes: Efficient Access to Chiral Allylic gem-Silylboranes.

Herein, we report the development of a method for highly regio-, stereo-, and enantioselective B-H bond insertion reactions of α-silylcarbenes generated from 1-silylcyclopropenes in the presence of a chiral copper(I)/bisoxazoline catalyst for the construction of chiral γ,γ-disubstituted allylic gem-silylboranes, which cannot be prepared by any other known methods. This reaction is the first highly enantioselective carbene insertion reaction of α-silylcarbenes ever to be reported. The method shows general applicability for various 3,3-disubstituted silylcyclopropenes and exclusively affords E-products. The novel chiral γ,γ-disubstituted allylic gem-silylborane products are versatile allylic bimetallic reagents with high stability and have great synthetic potential, especially for the construction of complex molecules with continuous chiral centers.

Phenanthroline-imine ligands for iron-catalyzed alkene hydrosilylation.

Iron-catalyzed organic reactions have been attracting increasing research interest but still have serious limitations on activity, selectivity, functional group tolerance, and stability relative to those of precious metal catalysts. Progress in this area will require two key developments: new ligands that can impart new reactivity to iron catalysts and elucidation of the mechanisms of iron catalysis. Herein, we report the development of novel 2-imino-9-aryl-1,10-phenanthrolinyl iron complexes that catalyze both anti-Markovnikov hydrosilylation of terminal alkenes and 1,2-anti-Markovnikov hydrosilylation of various conjugated dienes. Specifically, we achieved the first examples of highly 1,2-anti-Markovnikov hydrosilylation reactions of aryl-substituted 1,3-dienes and 1,1-dialkyl 1,3-dienes with these newly developed iron catalysts. Mechanistic studies suggest that the reactions may involve an Fe(0)-Fe(ii) catalytic cycle and that the extremely crowded environment around the iron center hinders chelating coordination between the diene and the iron atom, thus driving migration of the hydride from the silane to the less-hindered, terminal end of the conjugated diene and ultimately leading to the observed 1,2-anti-Markovnikov selectivity. Our findings, which have expanded the types of iron catalysts available for hydrosilylation reactions and deepened our understanding of the mechanism of iron catalysis, may inspire the development of new iron catalysts and iron-catalyzed reactions.

Iron-Catalyzed Vinylzincation of Terminal Alkynes.

Organozinc reagents are among the most commonly used organometallic reagents in modern synthetic chemistry, and multifunctionalized organozinc reagents can be synthesized from structurally simple, readily available ones by means of alkyne carbozincation. However, this method suffers from poor tolerance for terminal alkynes, and transformation of the newly introduced organic groups is difficult, which limits its applications. Herein, we report a method for vinylzincation of terminal alkynes catalyzed by newly developed iron catalysts bearing 1,10-phenanthroline-imine ligands. This method provides efficient access to novel organozinc reagents with a diverse array of structures and functional groups from readily available vinylzinc reagents and terminal alkynes. The method features excellent functional group tolerance (tolerated functional groups include amino, amide, cyano, ester, hydroxyl, sulfonyl, acetal, phosphono, pyridyl), a good substrate scope (suitable terminal alkynes include aryl, alkenyl, and alkyl acetylenes bearing various functional groups), and high chemoselectivity, regioselectivity, and stereoselectivity. The method could significantly improve the synthetic efficiency of various important bioactive molecules, including vitamin A. Mechanistic studies indicate that the new iron-1,10-phenanthroline-imine catalysts developed in this study have an extremely crowded reaction pocket, which promotes efficient transfer of the vinyl group to the alkynes, disfavors substitution reactions between the zinc reagent and the terminal C-H bond of the alkynes, and prevents the further reactions of the products. Our findings show that iron catalysts can be superior to other metal catalysts in terms of activity, chemoselectivity, regioselectivity, and stereoselectivity when suitable ligands are used.

Dirhodium-Catalyzed Enantioselective B-H Bond Insertion of gem-Diaryl Carbenes: Efficient Access to gem-Diarylmethine Boranes.

The scarcity of reliable methods for synthesizing chiral gem-diarylmethine borons limits their applications. Herein, we report a method for highly enantioselective dirhodium-catalyzed B-H bond insertion reactions with diaryl diazomethanes as carbene precursors. These reactions afforded chiral gem-diarylmethine borane compounds in high yield (up to 99 % yield), high activity (turnover numbers up to 14 300), high enantioselectivity (up to 99 % ee) and showed unprecedented broad functional group tolerance. The borane compounds synthesized by this method could be efficiently transformed into diaryl methanol, diaryl methyl amine, and triaryl methane derivatives with good stereospecificity. Mechanistic studies suggested that the borane adduct coordinated to the rhodium catalyst and thus interfered with decomposition of the diazomethane, and that insertion of a rhodium carbene (generated from the diaryl diazomethane) into the B-H bond was most likely the rate-determining step.

Chiral Dirhodium Tetraphosphate-Catalyzed Enantioselective Si-H Bond Insertion of α-Aryldiazoacetates.

A highly enantioselective Si-H bond insertion reaction of α-aryldiazoacetates catalyzed by chiral spiro dirhodium tetraphosphate was developed. Various chiral α-silyl esters were prepared with high yield (up to 92%) and excellent enantioselectivity (up to >99% ee) through this protocol. It is noteworthy that the 2-substituted aryl diazoacetates, which are challenging substrates for other chiral dirhodium catalysts, also exhibited good results in this reaction. This work represents one of the few successful applications of chiral dirhodium phosphates in asymmetric catalysis.

Nickel-Catalyzed Desymmetrizing Cyclization of 1,6-Dienes to Construct Quaternary Stereocenters.

A highly enantioselective and diastereoselective nickel-catalyzed desymmetrizing cyclization of 1,6-dienes was developed by using chiral spiro phosphoramidite ligands. The reaction provides a new atom- and step-economical approach to chiral spiro lactones and analogues bearing a quaternary stereocenter.

Enantioselective Silicon-Directed Nazarov Cyclization.

The Nazarov electrocyclization reaction is a convenient, widely used method for construction of cyclopentenones. In the past few decades, catalytic asymmetric versions of the reaction have been extensively studied, but the strategies used to control the position of the double bond limit the substituent pattern of the products and thus the synthetic applications of the reaction. Herein, we report highly enantioselective silicon-directed Nazarov reactions which were cooperatively catalyzed by a Lewis acid and a chiral Brønsted acid. The chiral cyclopentenones we synthesized using this method generally cannot be obtained by means of other catalytic enantioselective reactions, including previously reported methods for enantioselective Nazarov cyclization. The silicon group in the dienone substrate stabilized the ß-carbocation of the intermediate, thereby determining the position of the double bond in the product. Mechanistic studies suggested that the combination of Lewis and Brønsted acids synergistically activated the dienone substrate and that the enantioselectivity of the reaction originated from a chiral Brønsted acid promoted proton transfer reaction of the enol intermediate.