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.

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.

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.

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-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.

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.

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.

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.

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.

Enantioselective Insertion of Alkynyl Carbenes into Si-H Bonds: An Efficient Access to Chiral Propargylsilanes and Allenylsilanes.

Chiral propargylsilanes and chiral allenylsilanes have emerged as versatile building blocks for organic synthesis. However, efficient methods for preparing these organosilicon compounds are lacking. We herein report a highly enantioselective method for synthesis of chiral propargylsilanes and chiral allenylsilanes from readily available alkynyl sulfonylhydrazones. Specifically, chiral spiro phosphate dirhodium complexes were used to catalyze asymmetric insertion of alkynyl carbenes into the Si-H bonds of silanes to afford a variety of chiral propargylsilanes with excellent enantioselectivity. Subsequently, a platinum catalyst was used for stereospecific isomerization of the chiral propargylsilanes to the corresponding chiral allenylsilanes.

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.

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.

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.

Iron-Catalyzed Regiodivergent Alkyne Hydrosilylation.

Although tremendous effort has been devoted to the development of methods for iron catalysis, few of the catalysts reported to date exhibit clear superiority to other metal catalysts, and the mechanisms of most iron catalysis remain unclear. Herein, we report that iron complexes bearing 2,9-diaryl-1,10-phenanthroline ligands exhibit not only unprecedented catalytic activity but also unusual ligand-controlled divergent regioselectivity in hydrosilylation reactions of various alkynes. The hydrosilylation protocol described herein provides a highly efficient method for preparing useful di- and trisubstituted olefins on a relatively large scale under mild conditions, and its use markedly improved the synthetic efficiency of a number of bioactive compounds. Mechanistic studies based on control experiments and density functional theory calculations were performed to understand the catalytic pathway and the observed regioselectivity.

Enantioselective Diarylcarbene Insertion into Si-H Bonds Induced by Electronic Properties of the Carbenes.

Catalytic enantioselection usually depends on differences in steric interactions between prochiral substrates and a chiral catalyst. We have discovered a carbene Si-H insertion in which the enantioselectivity depends primarily on the electronic characteristics of the carbene substrate, and the log(er) values are linearly related to Hammett parameters. A new class of chiral tetraphosphate dirhodium catalysts was developed; it shows excellent activity and enantioselectivity for the insertion of diarylcarbenes into the Si-H bond of silanes. Computational and mechanistic studies show how the electronic differences between the two aryls of the carbene lead to differences in energies of the diastereomeric transition states. This study provides a new strategy for asymmetric catalysis exploiting the electronic properties of the substrates.

Insertion of Alkylidene Carbenes into B-H Bonds.

We have developed a protocol for insertion of alkylidene carbenes into the B-H bonds of amine-borane adducts, enabling, for the first time, the construction of C(sp2)-B bonds by means of carbene-insertion reactions. Various acyclic and cyclic alkenyl borane-amine adducts were prepared from readily accessible starting materials in good to high yields and were subsequently subjected to a diverse array of functional group transformations. The unprecedented spiro B-N heterocycles prepared in this study have potential utility as building blocks for the synthesis of pharmaceuticals. Preliminary mechanistic studies suggest that insertion of the alkylidene carbenes into the B-H bonds of the amine-borane adducts proceeds via a concerted process involving a three-membered-ring transition state.

Highly Enantioselective O-H Bond Insertion Reaction of α-Alkyl- and α-Alkenyl-α-diazoacetates with Water.

Catalytic asymmetric reactions in which water is a substrate are rare. Enantioselective transition-metal-catalyzed insertion of carbenes into the O-H bond of water can be used to incorporate water into the stereogenic center, but the reported chiral catalysts give good results only when α-aryl-α-diazoesters are used as the carbene precursors. Herein we report the first highly enantioselective O-H bond insertion reactions between water and α-alkyl- and α-alkenyl-α-diazoesters as carbene precursors, with catalysis by a combination of achiral dirhodium complexes and chiral phosphoric acids or chiral phosphoramides. Participation of the phosphoric acids or phosphoramides in the carbene transfer reaction markedly suppressed competing side reactions, such as ß-H migration, carbene dimerization, and olefin isomerization, and thus ensured good yields of the desired products. Fine-tuning of the ester moiety facilitated enantiocontrol of the proton transfer reactions of the enol intermediates and resulted in excellent enantioselectivity. This protocol represents an efficient new method for preparation of multifunctionalized chiral α-alkyl and α-alkenyl hydroxyl esters, which readily undergo various transformations and can thus be used for the synthesis of bioactive compounds. Mechanistic studies revealed that the phosphoric acids and phosphoramides promoted highly enantioselective [1,2]- and [1,3]-proton transfer reactions of the enol intermediates. Maximization of molecular orbital overlap in the transition states of the proton transfer reactions was the original driving force to involve the proton shuttle catalysts in this process.

Iron-Catalyzed Dihydrosilylation of Alkynes: Efficient Access to Geminal Bis(silanes).

Geminal bis(silanes) are versatile synthetic building blocks owing to their stability and propensity to undergo a variety of transformations. However, the scarcity of catalytic methods for their synthesis limits their structural diversity and thus their utility for further applications. Herein we report a new method for synthesis of geminal bis(silanes) by means of iron-catalyzed dihydrosilylation of alkynes. Iron catalysts were distinctly superior to the other tested catalysts, which clearly demonstrates that novel reactivity can be found by using iron catalysts. This method features 100% atom economy, regiospecificity, mild reaction conditions, and readily available starting materials. Using this method, we prepared a new type of geminal bis(silane) with secondary silane moieties, the Si-H bonds of which can easily undergo various transformations, facilitating the synthetic applications of these compounds. Preliminary mechanistic studies demonstrated that the reaction proceeds via two iron-catalyzed hydrosilylation reactions, the first generating ß-( E)-vinylsilanes and the second producing geminal bis(silanes).

Highly Enantioselective Nickel-Catalyzed Intramolecular Hydroalkenylation of N- and O-Tethered 1,6-Dienes To Form Six-Membered Heterocycles.

A highly enantioselective nickel-catalyzed intramolecular hydroalkenylation of N- or O-tethered 1,6-dienes was developed by using monodentate chiral spiro phosphoramidite ligands. The reaction provides an efficient and straightforward method for preparing very useful six-membered N- and O-heterocycles with high regioselectivity as well as excellent stereoselectivity from easily accessible starting materials under mild reaction conditions. The chiral spiro nickel catalyst developed in this study represents one of the few catalysts for highly enantioselective cyclization of unconjugated dienes.